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Sample records for selective hippocampal damage

  1. Under what conditions is recognition spared relative to recall after selective hippocampal damage in humans?

    Science.gov (United States)

    Holdstock, J S; Mayes, A R; Roberts, N; Cezayirli, E; Isaac, C L; O'Reilly, R C; Norman, K A

    2002-01-01

    The claim that recognition memory is spared relative to recall after focal hippocampal damage has been disputed in the literature. We examined this claim by investigating object and object-location recall and recognition memory in a patient, YR, who has adult-onset selective hippocampal damage. Our aim was to identify the conditions under which recognition was spared relative to recall in this patient. She showed unimpaired forced-choice object recognition but clearly impaired recall, even when her control subjects found the object recognition task to be numerically harder than the object recall task. However, on two other recognition tests, YR's performance was not relatively spared. First, she was clearly impaired at an equivalently difficult yes/no object recognition task, but only when targets and foils were very similar. Second, YR was clearly impaired at forced-choice recognition of object-location associations. This impairment was also unrelated to difficulty because this task was no more difficult than the forced-choice object recognition task for control subjects. The clear impairment of yes/no, but not of forced-choice, object recognition after focal hippocampal damage, when targets and foils are very similar, is predicted by the neural network-based Complementary Learning Systems model of recognition. This model postulates that recognition is mediated by hippocampally dependent recollection and cortically dependent familiarity; thus hippocampal damage should not impair item familiarity. The model postulates that familiarity is ineffective when very similar targets and foils are shown one at a time and subjects have to identify which items are old (yes/no recognition). In contrast, familiarity is effective in discriminating which of similar targets and foils, seen together, is old (forced-choice recognition). Independent evidence from the remember/know procedure also indicates that YR's familiarity is normal. The Complementary Learning Systems model can

  2. Mind-Wandering in People with Hippocampal Damage.

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    McCormick, Cornelia; Rosenthal, Clive R; Miller, Thomas D; Maguire, Eleanor A

    2018-03-14

    Subjective inner experiences, such as mind-wandering, represent the fundaments of human cognition. Although the precise function of mind-wandering is still debated, it is increasingly acknowledged to have influence across cognition on processes such as future planning, creative thinking, and problem-solving and even on depressive rumination and other mental health disorders. Recently, there has been important progress in characterizing mind-wandering and identifying the associated neural networks. Two prominent features of mind-wandering are mental time travel and visuospatial imagery, which are often linked with the hippocampus. People with selective bilateral hippocampal damage cannot vividly recall events from their past, envision their future, or imagine fictitious scenes. This raises the question of whether the hippocampus plays a causal role in mind-wandering and, if so, in what way. Leveraging a unique opportunity to shadow people (all males) with bilateral hippocampal damage for several days, we examined, for the first time, what they thought about spontaneously, without direct task demands. We found that they engaged in as much mind-wandering as control participants. However, whereas controls thought about the past, present, and future, imagining vivid visual scenes, hippocampal damage resulted in thoughts primarily about the present comprising verbally mediated semantic knowledge. These findings expose the hippocampus as a key pillar in the neural architecture of mind-wandering and also reveal its impact beyond episodic memory, placing it at the heart of our mental life. SIGNIFICANCE STATEMENT Humans tend to mind-wander ∼30-50% of their waking time. Two prominent features of this pervasive form of thought are mental time travel and visuospatial imagery, which are often associated with the hippocampus. To examine whether the hippocampus plays a causal role in mind-wandering, we examined the frequency and phenomenology of mind-wandering in patients with

  3. Hippocampal Damage Increases Deontological Responses during Moral Decision Making.

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    McCormick, Cornelia; Rosenthal, Clive R; Miller, Thomas D; Maguire, Eleanor A

    2016-11-30

    Complex moral decision making is associated with the ventromedial prefrontal cortex (vmPFC) in humans, and damage to this region significantly increases the frequency of utilitarian judgments. Since the vmPFC has strong anatomical and functional links with the hippocampus, here we asked how patients with selective bilateral hippocampal damage would derive moral decisions on a classic moral dilemmas paradigm. We found that the patients approved of the utilitarian options significantly less often than control participants, favoring instead deontological responses-rejecting actions that harm even one person. Thus, patients with hippocampal damage have a strikingly opposite approach to moral decision making than vmPFC-lesioned patients. Skin-conductance data collected during the task showed increased emotional arousal in the hippocampal-damaged patients and they stated that their moral decisions were based on emotional instinct. By contrast, control participants made moral decisions based on the integration of an adverse emotional response to harming others, visualization of the consequences of one's action, and the rational re-evaluation of future benefits. This integration may be disturbed in patients with either hippocampal or vmPFC damage. Hippocampal lesions decreased the ability to visualize a scenario and its future consequences, which seemed to render the adverse emotional response overwhelmingly dominant. In patients with vmPFC damage, visualization might also be reduced alongside an inability to detect the adverse emotional response, leaving only the utilitarian option open. Overall, these results provide insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions. The ventromedial prefrontal cortex (vmPFC) is closely associated with the ability to make complex moral judgements. When this area is damaged, patients become more utilitarian (the ends justify the means) and have

  4. Relation between hippocampal damage and cerebral cortical function in Alzheimer's disease

    International Nuclear Information System (INIS)

    Hanyu, Haruo; Asano, Tetsuichi; Kogure, Daiji; Sakurai, Hirofumi; Iwamoto, Toshihiko; Takasaki, Masaru

    2000-01-01

    We investigated the relation between hippocampal damage and cerebral cortical dysfunction in Alzheimer's disease (AD) using MRI and SPECT. Nineteen patients with AD and 10 control subjects were studied. Hippocampal damage (including hippocampal formation, entorhinal cortex, and parahippocampal white matter) was assessed to evaluate the severity of atrophy and the magnetization transfer ratio (MTR) and cerebral cortical dysfunction was evaluated by quantitative cerebral blood flow (CBF) measurements using SPECT with 99mTc-ECD. Compared with controls, patients with AD had significantly more atrophy of the medial temporal lobe and a decrease in MTRs of the hippocampus and parahippocampus. There were significant correlations between the severity of hippocampal damage and regional CBF in temporoparietal lobes. Mini-Mental State Examination scores significantly correlated with the severity of hippocampal damage and regional CBFs in temporoparietal lobes. These results suggest that the functional effect of hippocampal damage occurs in temporoparietal lobes in AD, probably due to neuronal disconnections between hippocampal areas (including the entorhinal cortex) and temporoparietal lobes. (author)

  5. Hippocampal damage equally impairs memory for single items and memory for conjunctions.

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    Stark, Craig E L; Squire, Larry R

    2003-01-01

    In a prior study of continuous recognition performance, data were reported in support of the hypothesis that the hippocampus is not needed to remember the individual components of a stimulus but is important for remembering associations between its components (Kroll et al. 1996. J Mem Lang 35:176-196). Patients with left hippocampal damage were able to endorse recently encountered words and to reject novel words, as well as disyllabic words in which one of the syllables had been previously encountered. However, they failed to reject words in which both syllables had been encountered independently in different words. We present data from five experiments designed to examine this finding in more detail. In each experiment, five patients with bilateral hippocampal damage and eight controls were tested using the same protocol as Kroll et al. (1996). On each trial, a two-component stimulus was presented. Stimuli could be entirely novel, novel with one previously encountered (repeated) component, novel but with both components repeated, or a true repetition. The first experiment was a direct replication using the same disyllabic words as Kroll et al. (1996). The second experiment used pseudo-words, constructed of two monosyllabic words (e.g., jambark). The third experiment used the same pairs of monosyllabic words, but presented separately on the screen to encourage participants to treat each component independently. The fourth experiment used pairs of objects, and the fifth experiment used face-house pairs. In all five experiments, patients with hippocampal damage exhibited impaired recognition memory. The impairment extended across all trial types with no evidence that hippocampal damage selectively (or disproportionately) impaired the associative or conjunctive component of memory. We discuss our findings in the light of the work by Kroll et al. (1996) and other recent neuropsychological, electrophysiological, and neuroimaging studies of hippocampal function and

  6. Spontaneous perseverative turning in rats with radiation-induced hippocampal damage

    International Nuclear Information System (INIS)

    Mickley, G.A.; Ferguson, J.L.; Nemeth, T.J.; Mulvihill, M.A.; Alderks, C.E.

    1989-01-01

    This study found a new behavioral correlate of lesions specific to the dentate granule cell layer of the hippocampus: spontaneous perseverative turning. Irradiation of a portion of the neonatal rat cerebral hemispheres produced hypoplasia of the granule cell layer of the hippocampal dentate gyrus while sparing the rest of the brain. Radiation-induced damage to the hippocampal formation caused rats placed in bowls to spontaneously turn in long, slow bouts without reversals. Irradiated subjects also exhibited other behaviors characteristic of hippocampal damage (e.g., perseveration in spontaneous exploration of the arms of a T-maze, retarded acquisition of a passive avoidance task, and increased horizontal locomotion). These data extend previously reported behavioral correlates of fascia dentata lesions and suggest the usefulness of a bout analysis of spontaneous bowl turning as a measure of nondiscrete-trial spontaneous alternation and a sensitive additional indicator of radiation-induced hippocampal damage

  7. Preliminary evidence of hippocampal damage in chronic users of ecstasy.

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    den Hollander, Bjørnar; Schouw, Marieke; Groot, Paul; Huisman, Henk; Caan, Matthan; Barkhof, Frederik; Reneman, Liesbeth

    2012-01-01

    Various studies have shown that ecstasy (3,4-methylenedioxymethamphetamine) users display significant memory impairments, whereas their performance on other cognitive tests is generally normal. The hippocampus plays an essential role in short-term memory. There are, however, no structural human data on the effects of ecstasy on the hippocampus. The objective of this study was to investigate whether the hippocampal volume of chronic ecstasy users is reduced when compared with healthy polydrug-using controls, as an indicator of hippocampal damage. The hippocampus was manually outlined in volumetric MRI scans in 10 male ecstasy users (mean age 25.4 years) and seven healthy age- and gender-matched control subjects (21.3 years). Other than the use of ecstasy, there were no statistically significant differences between both groups in exposure to other drugs of abuse and alcohol. The ecstasy users were on average drug-free for more than 2 months and had used on average 281 tablets over the past six and a half years. The hippocampal volume in the ecstasy using group was on average 10.5% smaller than the hippocampal volume in the control group (p=0.032). These data provide preliminary evidence that ecstasy users may be prone to incurring hippocampal damage, in line with previous reports of acute hippocampal sclerosis and subsequent atrophy in chronic users of this drug.

  8. Damage of hippocampal neurons in rats with chronic alcoholism

    OpenAIRE

    Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

    2014-01-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons i...

  9. Damage of hippocampal neurons in rats with chronic alcoholism.

    Science.gov (United States)

    Du, Ailin; Jiang, Hongbo; Xu, Lei; An, Na; Liu, Hui; Li, Yinsheng; Zhang, Ruiling

    2014-09-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin.

  10. Induction of the Wnt antagonist Dickkopf-1 is involved in stress-induced hippocampal damage.

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    Francesco Matrisciano

    Full Text Available The identification of mechanisms that mediate stress-induced hippocampal damage may shed new light into the pathophysiology of depressive disorders and provide new targets for therapeutic intervention. We focused on the secreted glycoprotein Dickkopf-1 (Dkk-1, an inhibitor of the canonical Wnt pathway, involved in neurodegeneration. Mice exposed to mild restraint stress showed increased hippocampal levels of Dkk-1 and reduced expression of β-catenin, an intracellular protein positively regulated by the canonical Wnt signalling pathway. In adrenalectomized mice, Dkk-1 was induced by corticosterone injection, but not by exposure to stress. Corticosterone also induced Dkk-1 in mouse organotypic hippocampal cultures and primary cultures of hippocampal neurons and, at least in the latter model, the action of corticosterone was reversed by the type-2 glucocorticoid receptor antagonist mifepristone. To examine whether induction of Dkk-1 was causally related to stress-induced hippocampal damage, we used doubleridge mice, which are characterized by a defective induction of Dkk-1. As compared to control mice, doubleridge mice showed a paradoxical increase in basal hippocampal Dkk-1 levels, but no Dkk-1 induction in response to stress. In contrast, stress reduced Dkk-1 levels in doubleridge mice. In control mice, chronic stress induced a reduction in hippocampal volume associated with neuronal loss and dendritic atrophy in the CA1 region, and a reduced neurogenesis in the dentate gyrus. Doubleridge mice were resistant to the detrimental effect of chronic stress and, instead, responded to stress with increases in dendritic arborisation and neurogenesis. Thus, the outcome of chronic stress was tightly related to changes in Dkk-1 expression in the hippocampus. These data indicate that induction of Dkk-1 is causally related to stress-induced hippocampal damage and provide the first evidence that Dkk-1 expression is regulated by corticosteroids in the central

  11. Exercise preconditioning exhibits neuroprotective effects on hippocampal CA1 neuronal damage after cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Nabi Shamsaei; Mehdi Khaksari; Sohaila Erfani; Hamid Rajabi; Nahid Aboutaleb

    2015-01-01

    Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral isch-emic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction th rough occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic ex-ercise signiifcantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration.

  12. Stress, depression and hippocampal damage

    Indian Academy of Sciences (India)

    Amongst the prime targets of stress in the brain is the hippocampus, which has high receptor ... effects on different hippocampal subfields (McEwen 1999). ... disorders, and decreases in hippocampal volume have been observed in patients of ...

  13. Reorganization of associative memory in humans with long-standing hippocampal damage.

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    Braun, Mischa; Finke, Carsten; Ostendorf, Florian; Lehmann, Thomas-Nicolas; Hoffmann, Karl-Titus; Ploner, Christoph J

    2008-10-01

    Conflicting theories have been advanced to explain why hippocampal lesions affect distinct memory domains and spare others. Recent findings in monkeys suggest that lesion-induced plasticity may contribute to the seeming preservation of some of these domains. We tested this hypothesis by investigating visuo-spatial associative memory in two patient groups with similar surgical lesions to the right medial temporal lobe, but different preoperative disease courses (benign brain tumours, mean: 1.8 +/- 0.6 years, n = 5, age: 28.2 +/- 4.0 years; hippocampal sclerosis, mean: 16.8 +/- 1.9 years, n = 9, age: 38.9 +/- 4.1 years). Compared to controls (n = 14), tumour patients showed a significant delay-dependent deficit in memory of colour-location associations. No such deficit was observed in hippocampal sclerosis patients, which appeared to benefit from a compensatory mechanism that was inefficient in tumour patients. These results indicate that long-standing hippocampal damage can yield significant functional reorganization of the neural substrate underlying memory in the human brain. We suppose that this process accounts for some of the discrepancies between results from previous lesion studies of the human medial temporal lobe.

  14. Hippocampal damage and memory impairment in congenital cyanotic heart disease.

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    Muñoz-López, Mónica; Hoskote, Aparna; Chadwick, Martin J; Dzieciol, Anna M; Gadian, David G; Chong, Kling; Banks, Tina; de Haan, Michelle; Baldeweg, Torsten; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2017-04-01

    Neonatal hypoxia can lead to hippocampal atrophy, which can lead, in turn, to memory impairment. To test the generalizability of this causal sequence, we examined a cohort of 41 children aged 8-16, who, having received the arterial switch operation to correct for transposition of the great arteries, had sustained significant neonatal cyanosis but were otherwise neurodevelopmentally normal. As predicted, the cohort had significant bilateral reduction of hippocampal volumes relative to the volumes of 64 normal controls. They also had significant, yet selective, impairment of episodic memory as measured by standard tests of memory, despite relatively normal levels of intelligence, academic attainment, and verbal fluency. Across the cohort, degree of memory impairment was correlated with degree of hippocampal atrophy suggesting that even as early as neonatal life no other structure can fully compensate for hippocampal injury and its special role in serving episodic long term memory. © 2017 Wiley Periodicals, Inc. © 2017 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

  15. Spectroscopic evidence of hippocampal abnormalities in neocortical epilepsy

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    Mueller, S. G.; Laxer, K. D.; Cashdollar, N.; Lopez, R. C.; Weiner, M. W.

    2009-01-01

    Lesional neocortical epilepsy (NE) can be associated with hippocampal sclerosis or hippocampal spectroscopic abnormalities without atrophy (dual pathology). In this study, magnetic resonance spectroscopic imaging (MRSI) was used to determine the frequency of hippocampal damage/dysfunction in NE with and without structural lesion. Sixteen patients with NE [seven temporal NE (NE-T), nine extratemporal (NE-ET)] and 16 controls were studied with a 2D MRSI sequence (Repetition time/echo time (TR/TE) = 1800/135 ms) covering both hippocampi. Seven NE patients had MR visible lesions (NE-Les), nine had normal MRI (NE-no). In each hippocampus, 12 voxels were uniformly selected. In controls, mean (± SD) NAA/(Cr + Cho) values for each voxel were calculated and voxels with NAA/(Cr + Cho) ≤ (mean in controls – 2SD in controls) were defined as ‘pathological’ in patients. Eight of 16 NE patients had at least two ‘pathological’ voxel (mean 2.5, range 2–5) in one hippocampus. Four were NE-Les and four NE-no. Three (43%) NE-T patients, had evidence for hippocampal damage/dysfunction and five (56%) had NE-ET. The ipsilateral hippocampus was affected in six of eight NE patients. Evidence for unilateral hippocampal damage/dysfunction was demonstrated in 50% of the NE patients. The type of NE, i.e. NE-Les or NE-no, NE-T or NE-ET, had no influence on the occurrence of hippocampal damage/dysfunction. PMID:16618342

  16. Comparing and Contrasting the Cognitive Effects of Hippocampal and Ventromedial Prefrontal Cortex Damage: A Review of Human Lesion Studies.

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    McCormick, Cornelia; Ciaramelli, Elisa; De Luca, Flavia; Maguire, Eleanor A

    2018-03-15

    The hippocampus and ventromedial prefrontal cortex (vmPFC) are closely connected brain regions whose functions are still debated. In order to offer a fresh perspective on understanding the contributions of these two brain regions to cognition, in this review we considered cognitive tasks that usually elicit deficits in hippocampal-damaged patients (e.g., autobiographical memory retrieval), and examined the performance of vmPFC-lesioned patients on these tasks. We then took cognitive tasks where performance is typically compromised following vmPFC damage (e.g., decision making), and looked at how these are affected by hippocampal lesions. Three salient motifs emerged. First, there are surprising gaps in our knowledge about how hippocampal and vmPFC patients perform on tasks typically associated with the other group. Second, while hippocampal or vmPFC damage seems to adversely affect performance on so-called hippocampal tasks, the performance of hippocampal and vmPFC patients clearly diverges on classic vmPFC tasks. Third, although performance appears analogous on hippocampal tasks, on closer inspection, there are significant disparities between hippocampal and vmPFC patients. Based on these findings, we suggest a tentative hierarchical model to explain the functions of the hippocampus and vmPFC. We propose that the vmPFC initiates the construction of mental scenes by coordinating the curation of relevant elements from neocortical areas, which are then funneled into the hippocampus to build a scene. The vmPFC then engages in iterative re-initiation via feedback loops with neocortex and hippocampus to facilitate the flow and integration of the multiple scenes that comprise the coherent unfolding of an extended mental event. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. BDNF Regains Function in Hippocampal Long-Term Potentiation Deficits Caused by Diencephalic Damage

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    Vedder, Lindsey C.; Savage, Lisa M.

    2017-01-01

    Thiamine deficiency (TD), commonly associated with chronic alcoholism, leads to diencephalic damage, hippocampal dysfunction, and spatial learning and memory deficits. We show a decrease in the magnitude of long-term potentiation (LTP) and paired-pulse facilitation (PPF) at CA3-CA1 synapses, independent of sex, following diencephalic damage…

  18. Agmatine protects against cell damage induced by NMDA and glutamate in cultured hippocampal neurons

    Science.gov (United States)

    Wang, Wei-Ping; Iyo, Abiye H.; Miguel-Hidalgo, Javier; Regunathan, Soundar; Zhu, Meng-Yang

    2010-01-01

    Agmatine is a polyamine and has been considered as a novel neurotransmitter or neuromodulator in the central nervous system. In the present study, the neuroprotective effect of agmatine against cell damage caused by N-methyl-d-aspartate (NMDA) and glutamate was investigated in cultured rat hippocampal neurons. Lactate dehydrogenase (LDH) activity assay, β-tubulin III immunocytochemical staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end-labeling (TUNEL) assay were conducted to detect cell damage. Exposure of 12-day neuronal cultures of rat hippocampus to NMDA or glutamate for 1 h caused a concentration-dependent neurotoxicity, as indicated by the significant increase in released LDH activities. Addition of 100 µM agmatine into media ablated the neurotoxicity induced by NMDA or glutamate, an effect also produced by the specific NMDA receptor antagonist dizocilpine hydrogen maleate (MK801). Arcaine, an analog of agmatine with similar structure as agmatine, fully prevented the NMDA- or glutamate-induced neuronal damage. Spermine and putrescine, the endogenous polyamine and metabolic products of agmatine without the guanidine moiety of agmatine, failed to show this effect, indicating a structural relevance for this neuroprotection. Immunocytochemical staining and TUNEL assay confirmed the findings in the LDH measurement. That is, agmatine and MK801 markedly attenuated NMDA-induced neuronal death and significantly reduced TUNEL-positive cell numbers induced by exposure of cultured hippocampal neurons to NMDA. Taken together, these results demonstrate that agmatine can protect cultured hippocampal neurons from NMDA- or glutamate-induced excitotoxicity, through a possible blockade of the NMDA receptor channels or a potential anti-apoptotic property. PMID:16546145

  19. Evidence for regional hippocampal damage in patients with schizophrenia

    International Nuclear Information System (INIS)

    Singh, Sadhana; Khushu, Subash; Kumar, Pawan; Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N.

    2018-01-01

    Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ( 1 H MRS) procedures. 1 H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

  20. Evidence for regional hippocampal damage in patients with schizophrenia

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Sadhana; Khushu, Subash; Kumar, Pawan [DRDO, NMR Research Centre, Institute of Nuclear Medicine and Allied Sciences (INMAS), Delhi (India); Goyal, Satnam; Bhatia, Triptish; Deshpande, Smita N. [RML Hospital, Post Graduate Institute of Medical Education and Research (PGIMER), New Delhi (India)

    2018-02-15

    Schizophrenia patients show cognitive and mood impairments, including memory loss and depression, suggesting damage in the brain regions. The hippocampus is a brain structure that is significantly involved in memory and mood function and shows impairment in schizophrenia. In the present study, we examined the regional hippocampal changes in schizophrenia patients using voxel-based morphometry (VBM), Freesurfer, and proton magnetic resonance spectroscopy ({sup 1}H MRS) procedures. {sup 1}H MRS and high-resolution T1-weighted magnetic resonance imaging were collected in both healthy control subjects (N = 28) and schizophrenia patients (N = 28) using 3-Tesla whole body MRI system. Regional hippocampal volume was analyzed using VBM and Freesufer procedures. The relative ratios of the neurometabolites were calculated using linear combination model (LCModel). Compared to controls, schizophrenia patients showed significantly decreased gray matter volume in the hippocampus. Schizophrenia patients also showed significantly reduced glutamate (Glu) and myo-inositol (mI) ratios in the hippocampus. Additionally, significant positive correlation between gray matter volume and Glu/tCr was also observed in the hippocampus in schizophrenia. Our findings provide an evidence for a possible association between structural deficits and metabolic alterations in schizophrenia patients. (orig.)

  1. Methods to induce primary and secondary traumatic damage in organotypic hippocampal slice cultures.

    Science.gov (United States)

    Adamchik, Y; Frantseva, M V; Weisspapir, M; Carlen, P L; Perez Velazquez, J L

    2000-04-01

    Organotypic brain slice cultures have been used in a variety of studies on neurodegenerative processes [K.M. Abdel-Hamid, M. Tymianski, Mechanisms and effects of intracellular calcium buffering on neuronal survival in organotypic hippocampal cultures exposed to anoxia/aglycemia or to excitotoxins, J. Neurosci. 17, 1997, pp. 3538-3553; D.W. Newell, A. Barth, V. Papermaster, A.T. Malouf, Glutamate and non-glutamate receptor mediated toxicity caused by oxygen and glucose deprivation in organotypic hippocampal cultures, J. Neurosci. 15, 1995, pp. 7702-7711; J.L. Perez Velazquez, M.V. Frantseva, P.L. Carlen, In vitro ischemia promotes glutamate mediated free radical generation and intracellular calcium accumulation in pyramidal neurons of cultured hippocampal slices, J. Neurosci. 23, 1997, pp. 9085-9094; L. Stoppini, L.A. Buchs, D. Muller, A simple method for organotypic cultures of nervous tissue, J. Neurosci. Methods 37, 1991, pp. 173-182; R.C. Tasker, J.T. Coyle, J.J. Vornov, The regional vulnerability to hypoglycemia induced neurotoxicity in organotypic hippocampal culture: protection by early tetrodotoxin or delayed MK 801, J. Neurosci. 12, 1992, pp. 4298-4308.]. We describe two methods to induce traumatic cell damage in hippocampal organotypic cultures. Primary trauma injury was achieved by rolling a stainless steel cylinder (0.9 g) on the organotypic slices. Secondary injury was followed after dropping a weight (0.137 g) on a localised area of the organotypic slice, from a height of 2 mm. The time course and extent of cell death were determined by measuring the fluorescence of the viability indicator propidium iodide (PI) at several time points after the injury. The initial localised impact damage spread 24 and 67 h after injury, cell death being 25% and 54%, respectively, when slices were kept at 37 degrees C. To validate these methods as models to assess neuroprotective strategies, similar insults were applied to slices at relatively low temperatures (30

  2. Extent of hippocampal atrophy predicts degree of deficit in recall.

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    Patai, Eva Zita; Gadian, David G; Cooper, Janine M; Dzieciol, Anna M; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-10-13

    Which specific memory functions are dependent on the hippocampus is still debated. The availability of a large cohort of patients who had sustained relatively selective hippocampal damage early in life enabled us to determine which type of mnemonic deficit showed a correlation with extent of hippocampal injury. We assessed our patient cohort on a test that provides measures of recognition and recall that are equated for difficulty and found that the patients' performance on the recall tests correlated significantly with their hippocampal volumes, whereas their performance on the equally difficult recognition tests did not and, indeed, was largely unaffected regardless of extent of hippocampal atrophy. The results provide new evidence in favor of the view that the hippocampus is essential for recall but not for recognition.

  3. Selective Reduction of AMPA Currents onto Hippocampal Interneurons Impairs Network Oscillatory Activity

    Science.gov (United States)

    Le Magueresse, Corentin; Monyer, Hannah

    2012-01-01

    Reduction of excitatory currents onto GABAergic interneurons in the forebrain results in impaired spatial working memory and altered oscillatory network patterns in the hippocampus. Whether this phenotype is caused by an alteration in hippocampal interneurons is not known because most studies employed genetic manipulations affecting several brain regions. Here we performed viral injections in genetically modified mice to ablate the GluA4 subunit of the AMPA receptor in the hippocampus (GluA4HC−/− mice), thereby selectively reducing AMPA receptor-mediated currents onto a subgroup of hippocampal interneurons expressing GluA4. This regionally selective manipulation led to a strong spatial working memory deficit while leaving reference memory unaffected. Ripples (125–250 Hz) in the CA1 region of GluA4HC−/− mice had larger amplitude, slower frequency and reduced rate of occurrence. These changes were associated with an increased firing rate of pyramidal cells during ripples. The spatial selectivity of hippocampal pyramidal cells was comparable to that of controls in many respects when assessed during open field exploration and zigzag maze running. However, GluA4 ablation caused altered modulation of firing rate by theta oscillations in both interneurons and pyramidal cells. Moreover, the correlation between the theta firing phase of pyramidal cells and position was weaker in GluA4HC−/− mice. These results establish the involvement of AMPA receptor-mediated currents onto hippocampal interneurons for ripples and theta oscillations, and highlight potential cellular and network alterations that could account for the altered working memory performance. PMID:22675480

  4. Hippocampal and diencephalic pathology in developmental amnesia.

    Science.gov (United States)

    Dzieciol, Anna M; Bachevalier, Jocelyne; Saleem, Kadharbatcha S; Gadian, David G; Saunders, Richard; Chong, W K Kling; Banks, Tina; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2017-01-01

    Developmental amnesia (DA) is a selective episodic memory disorder associated with hypoxia-induced bilateral hippocampal atrophy of early onset. Despite the systemic impact of hypoxia-ischaemia, the resulting brain damage was previously reported to be largely limited to the hippocampus. However, the thalamus and the mammillary bodies are parts of the hippocampal-diencephalic network and are therefore also at risk of injury following hypoxic-ischaemic events. Here, we report a neuroimaging investigation of diencephalic damage in a group of 18 patients with DA (age range 11-35 years), and an equal number of controls. Importantly, we uncovered a marked degree of atrophy in the mammillary bodies in two thirds of our patients. In addition, as a group, patients had mildly reduced thalamic volumes. The size of the anterior-mid thalamic (AMT) segment was correlated with patients' visual memory performance. Thus, in addition to the hippocampus, the diencephalic structures also appear to play a role in the patients' memory deficit. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  5. Behavior-Dependent Activity and Synaptic Organization of Septo-hippocampal GABAergic Neurons Selectively Targeting the Hippocampal CA3 Area.

    Science.gov (United States)

    Joshi, Abhilasha; Salib, Minas; Viney, Tim James; Dupret, David; Somogyi, Peter

    2017-12-20

    Rhythmic medial septal (MS) GABAergic input coordinates cortical theta oscillations. However, the rules of innervation of cortical cells and regions by diverse septal neurons are unknown. We report a specialized population of septal GABAergic neurons, the Teevra cells, selectively innervating the hippocampal CA3 area bypassing CA1, CA2, and the dentate gyrus. Parvalbumin-immunopositive Teevra cells show the highest rhythmicity among MS neurons and fire with short burst duration (median, 38 ms) preferentially at the trough of both CA1 theta and slow irregular oscillations, coincident with highest hippocampal excitability. Teevra cells synaptically target GABAergic axo-axonic and some CCK interneurons in restricted septo-temporal CA3 segments. The rhythmicity of their firing decreases from septal to temporal termination of individual axons. We hypothesize that Teevra neurons coordinate oscillatory activity across the septo-temporal axis, phasing the firing of specific CA3 interneurons, thereby contributing to the selection of pyramidal cell assemblies at the theta trough via disinhibition. VIDEO ABSTRACT. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  6. Long-Term Treatment with Paroxetine Increases Verbal Declarative Memory and Hippocampal Volume in Posttraumatic Stress Disorder

    Science.gov (United States)

    Vermetten, Eric; Vythilingam, Meena; Southwick, Steven M.; Charney, Dennis S.; Bremner, J. Douglas

    2011-01-01

    Background Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. Methods Declarative memory was assessed with the Wechsler Memory Scale–Revised and Selective Reminding Test before and after 9–12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. Results Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. Conclusions These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD. PMID:14512209

  7. Hypothyroidism Causes Endoplasmic Reticulum Stress in Adult Rat Hippocampus: A Mechanism Associated with Hippocampal Damage

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    Alejandra Paola Torres-Manzo

    2018-01-01

    Full Text Available Thyroid hormones (TH are essential for hippocampal neuronal viability in adulthood, and their deficiency causes hypothyroidism, which is related to oxidative stress events and neuronal damage. Also, it has been hypothesized that hypothyroidism causes a glucose deprivation in the neuron. This study is aimed at evaluating the temporal participation of the endoplasmic reticulum stress (ERE in hippocampal neurons of adult hypothyroid rats and its association with the oxidative stress events. Adult Wistar male rats were divided into euthyroid and hypothyroid groups. Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism at three weeks postsurgery. Oxidative stress, redox environment, and antioxidant enzyme markers, as well as the expression of the ERE through the pathways of PERK, ATF6, and IRE1, were evaluated at the 3rd and 4th weeks postsurgery. We found a rise in ROS and nitrite production; also, catalase increased and glutathione peroxidase diminished their activities. These events promote an enhancement of the lipoperoxidation, as well as of γ-GT, myeloperoxidase, and caspase 3 activities. With respect to ERE, there were ATF6, IRE1, and GADD153 overexpressions with a reduction in mitochondrial activity and GSH2/GSSG ratio. We conclude that the endoplasmic reticulum stress might play a pivotal role in the activation of hypothyroidism-induced hippocampal cell death.

  8. Stimulus Similarity and Encoding Time Influence Incidental Recognition Memory in Adult Monkeys with Selective Hippocampal Lesions

    Science.gov (United States)

    Zeamer, Alyson; Meunier, Martine; Bachevalier, Jocelyne

    2011-01-01

    Recognition memory impairment after selective hippocampal lesions in monkeys is more profound when measured with visual paired-comparison (VPC) than with delayed nonmatching-to-sample (DNMS). To clarify this issue, we assessed the impact of stimuli similarity and encoding duration on the VPC performance in monkeys with hippocampal lesions and…

  9. Guanosine prevents behavioral alterations in the forced swimming test and hippocampal oxidative damage induced by acute restraint stress.

    Science.gov (United States)

    Bettio, Luis E B; Freitas, Andiara E; Neis, Vivian B; Santos, Danúbia B; Ribeiro, Camille M; Rosa, Priscila B; Farina, Marcelo; Rodrigues, Ana Lúcia S

    2014-12-01

    Guanosine is a guanine-based purine that modulates glutamate uptake and exerts neurotrophic and neuroprotective effects. In a previous study, our group demonstrated that this endogenous nucleoside displays antidepressant-like properties in a predictive animal model. Based on the role of oxidative stress in modulating depressive disorders as well as on the association between the neuroprotective and antioxidant properties of guanosine, here we investigated if its antidepressant-like effect is accompanied by a modulation of hippocampal oxidant/antioxidant parameters. Adult Swiss mice were submitted to an acute restraint stress protocol, which is known to cause behavioral changes that are associated with neuronal oxidative damage. Animals submitted to ARS exhibited an increased immobility time in the forced swimming test (FST) and the administration of guanosine (5mg/kg, p.o.) or fluoxetine (10mg/kg, p.o., positive control) before the exposure to stressor prevented this alteration. Moreover, the significantly increased levels of hippocampal malondialdehyde (MDA; an indicator of lipid peroxidation), induced by ARS were not observed in stressed mice treated with guanosine. Although no changes were found in the hippocampal levels of reduced glutathione (GSH), the group submitted to ARS procedure presented enhanced glutathione peroxidase (GPx), glutathione reductase (GR), superoxide dismutase (SOD) activities and reduced catalase (CAT) activity in the hippocampus. Guanosine was able to prevent the alterations in GPx, GR, CAT activities, and in SOD/CAT activity ratio, but potentiated the increase in SOD activity elicited by ARS. Altogether, the present findings indicate that the observed antidepressant-like effects of guanosine might be related, at least in part, to its capability of modulating antioxidant defenses and mitigating hippocampal oxidative damage induced by ARS. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Abnormalities of hippocampal-cortical connectivity in temporal lobe epilepsy patients with hippocampal sclerosis

    Science.gov (United States)

    Li, Wenjing; He, Huiguang; Lu, Jingjing; Wang, Chunheng; Li, Meng; Lv, Bin; Jin, Zhengyu

    2011-03-01

    Hippocampal sclerosis (HS) is the most common damage seen in the patients with temporal lobe epilepsy (TLE). In the present study, the hippocampal-cortical connectivity was defined as the correlation between the hippocampal volume and cortical thickness at each vertex throughout the whole brain. We aimed to investigate the differences of ipsilateral hippocampal-cortical connectivity between the unilateral TLE-HS patients and the normal controls. In our study, the bilateral hippocampal volumes were first measured in each subject, and we found that the ipsilateral hippocampal volume significantly decreased in the left TLE-HS patients. Then, group analysis showed significant thinner average cortical thickness of the whole brain in the left TLE-HS patients compared with the normal controls. We found significantly increased ipsilateral hippocampal-cortical connectivity in the bilateral superior temporal gyrus, the right cingulate gyrus and the left parahippocampal gyrus of the left TLE-HS patients, which indicated structural vulnerability related to the hippocampus atrophy in the patient group. However, for the right TLE-HS patients, no significant differences were found between the patients and the normal controls, regardless of the ipsilateral hippocampal volume, the average cortical thickness or the patterns of hippocampal-cortical connectivity, which might be related to less atrophies observed in the MRI scans. Our study provided more evidence for the structural abnormalities in the unilateral TLE-HS patients.

  11. Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy.

    Science.gov (United States)

    Geva, Sharon; Cooper, Janine M; Gadian, David G; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2016-08-01

    One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task), between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. We discuss the role of the hippocampus and its interactions with the prefrontal cortex in serving working memory. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Impairment on a self-ordered working memory task in patients with early-acquired hippocampal atrophy

    Directory of Open Access Journals (Sweden)

    Sharon Geva

    2016-08-01

    Full Text Available One of the features of both adult-onset and developmental forms of amnesia resulting from bilateral medial temporal lobe damage, or even from relatively selective damage to the hippocampus, is the sparing of working memory. Recently, however, a number of studies have reported deficits on working memory tasks in patients with damage to the hippocampus and in macaque monkeys with neonatal hippocampal lesions. These studies suggest that successful performance on working memory tasks with high memory load require the contribution of the hippocampus. Here we compared performance on a working memory task (the Self-ordered Pointing Task, between patients with early onset hippocampal damage and a group of healthy controls. Consistent with the findings in the monkeys with neonatal lesions, we found that the patients were impaired on the task, but only on blocks of trials with intermediate memory load. Importantly, only intermediate to high memory load blocks yielded significant correlations between task performance and hippocampal volume. Additionally, we found no evidence of proactive interference in either group, and no evidence of an effect of time since injury on performance. We discuss the role of the hippocampus and its interactions with the prefrontal cortex in serving working memory.

  13. Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running.

    Science.gov (United States)

    Johnson, R A; Rhodes, J S; Jeffrey, S L; Garland, T; Mitchell, G S

    2003-01-01

    Voluntary wheel running in rats increases hippocampal brain-derived neurotrophic factor (BDNF) expression, a neurochemical important for neuronal survival, differentiation, connectivity and synaptic plasticity. Here, we report the effects of wheel running on BDNF and neurotrophin-3 (NT-3) protein levels in normal control mice, and in mice selectively bred (25 generations) for increased voluntary wheel running. We hypothesized that increased voluntary wheel running in selected (S) mice would increase CNS BDNF and NT-3 protein levels more than in control (C) mice. Baseline hippocampal BDNF levels (mice housed without running wheels) were similar in S and C mice. Following seven nights of running, hippocampal BDNF increased significantly more in S versus C mice, and levels were correlated with distance run (considering C and S mice together). Spinal and cerebellar BDNF and hippocampal NT-3 levels were not significantly affected by wheel running in any group, but there was a small, positive correlation between spinal C3-C6 BDNF levels and distance run (considering C and S mice together). This is the first study to demonstrate that mice which choose to run more have greater elevations in hippocampal BDNF, suggesting enhanced potential for exercise-induced hippocampal neuroplasticity.

  14. Xenon Reduces Neuronal Hippocampal Damage and Alters the Pattern of Microglial Activation after Experimental Subarachnoid Hemorrhage: A Randomized Controlled Animal Trial

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    Michael Veldeman

    2017-09-01

    Full Text Available ObjectiveThe neuroprotective properties of the noble gas xenon have already been demonstrated using a variety of injury models. Here, we examine for the first time xenon’s possible effect in attenuating early brain injury (EBI and its influence on posthemorrhagic microglial neuroinflammation in an in vivo rat model of subarachnoid hemorrhage (SAH.MethodsSprague-Dawley rats (n = 22 were randomly assigned to receive either Sham surgery (n = 9; divided into two groups or SAH induction via endovascular perforation (n = 13, divided into two groups. Of those randomized for SAH, 7 animals were postoperatively ventilated with 50 vol% oxygen/50 vol% xenon for 1 h and 6 received 50 vol% oxygen/50 vol% nitrogen (control. The animals were sacrificed 24 h after SAH. Of each animal, a cerebral coronal section (−3.60 mm from bregma was selected for assessment of histological damage 24 h after SAH. A 5-point neurohistopathological severity score was applied to assess neuronal cell damage in H&E and NeuN stained sections in a total of four predefined anatomical regions of interest. Microglial activation was evaluated by a software-assisted cell count of Iba-1 stained slices in three cortical regions of interest.ResultsA diffuse cellular damage was apparent in all regions of the ipsilateral hippocampus 24 h after SAH. Xenon-treated animals presented with a milder damage after SAH. This effect was found to be particularly pronounced in the medial regions of the hippocampus, CA3 (p = 0.040, and dentate gyrus (DG p = 0.040. However, for the CA1 and CA2 regions, there were no statistical differences in neuronal damage according to our histological scoring. A cell count of activated microglia was lower in the cortex of xenon-treated animals. This difference was especially apparent in the left piriform cortex (p = 0.017.ConclusionIn animals treated with 50 vol% xenon (for 1 h after SAH, a less pronounced neuronal damage was

  15. Extensive immune-mediated hippocampal damage in mice surviving infection with neuroadapted Sindbis virus

    International Nuclear Information System (INIS)

    Kimura, Takashi; Griffin, Diane E.

    2003-01-01

    Viral infections of the central nervous system and immune responses to these infections cause a variety of neurological diseases. Infection of weanling mice with Sindbis virus causes acute nonfatal encephalomyelitis followed by clearance of infectious virus, but persistence of viral RNA. Infection with a neuroadapted strain of Sindbis virus (NSV) causes fatal encephalomyelitis, but passive transfer of immune serum after infection protects from fatal disease and infectious virus is cleared. To determine whether persistent NSV RNA is associated with neurological damage, we examined the brains of recovered mice and found progressive loss of the hippocampal gyrus, adjacent white matter, and deep cerebral cortex associated with mononuclear cell infiltration. Mice deficient in CD4 + T cells showed less tissue loss, while mice lacking CD8 + T cells showed lesions comparable to those in immunocompetent mice. Mice deficient in both CD4 + and CD8 + T cells developed severe tissue loss similar to immunocompetent mice and this was associated with extensive infiltration of macrophages. The number of CD4 + cells and macrophage/microglial cells, but not CD8 + cells, infiltrating the hippocampal gyrus was correlated with the number of terminal deoxynucleotidyltransferase-mediated dUTP nick end-labeling positive pyramidal neurons. These results suggest that CD4 + T cells can promote progressive neuronal death and tissue injury, despite clearance of infectious virus

  16. Effects of hippocampal lesions on the monkey's ability to learn large sets of object-place associations.

    Science.gov (United States)

    Belcher, Annabelle M; Harrington, Rebecca A; Malkova, Ludise; Mishkin, Mortimer

    2006-01-01

    Earlier studies found that recognition memory for object-place associations was impaired in patients with relatively selective hippocampal damage (Vargha-Khadem et al., Science 1997; 277:376-380), but was unaffected after selective hippocampal lesions in monkeys (Malkova and Mishkin, J Neurosci 2003; 23:1956-1965). A potentially important methodological difference between the two studies is that the patients were required to remember a set of 20 object-place associations for several minutes, whereas the monkeys had to remember only two such associations at a time, and only for a few seconds. To approximate more closely the task given to the patients, we trained monkeys on several successive sets of 10 object-place pairs each, with each set requiring learning across days. Despite the increased associative memory demands, monkeys given hippocampal lesions were unimpaired relative to their unoperated controls, suggesting that differences other than set size and memory duration underlie the different outcomes in the human and animal studies. (c) 2005 Wiley-Liss, Inc.

  17. Impaired representation of geometric relationships in humans with damage to the hippocampal formation.

    Science.gov (United States)

    Finke, Carsten; Ostendorf, Florian; Braun, Mischa; Ploner, Christoph J

    2011-01-01

    The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks.

  18. Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane

    International Nuclear Information System (INIS)

    Huang, Zhenlie; Ichihara, Sahoko; Oikawa, Shinji; Chang, Jie; Zhang, Lingyi; Hu, Shijie; Huang, Hanlin; Ichihara, Gaku

    2015-01-01

    1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn 2+ )-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p < 0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn 2+ -Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. - Highlights: • 1-BP modified hippocampal phosphoproteome in rat and 23 altered proteins were identified. • 1-BP changed phosphorylation of GRP78

  19. Hippocampal phosphoproteomics of F344 rats exposed to 1-bromopropane

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    Huang, Zhenlie [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Ichihara, Sahoko [Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507 (Japan); Oikawa, Shinji [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Mie 514-8507 (Japan); Chang, Jie [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Graduate School of Regional Innovation Studies, Mie University, Tsu 514-8507 (Japan); Zhang, Lingyi [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510 (Japan); Hu, Shijie [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Huang, Hanlin, E-mail: huanghl@gdoh.org [Guangdong Provincial Key Laboratory of Occupational Disease Prevention and Treatment, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510-300 (China); Ichihara, Gaku, E-mail: gak@rs.tus.ac.jp [Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Nagoya 466-8550 (Japan); Department of Occupational and Environmental Health, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510 (Japan)

    2015-01-15

    1-Bromopropane (1-BP) is neurotoxic in both experimental animals and human. To identify phosphorylated modification on the unrecognized post-translational modifications of proteins and investigate their role in 1-BP-induced neurotoxicity, changes in hippocampal phosphoprotein expression levels were analyzed quantitatively in male F344 rats exposed to 1-BP inhalation at 0, 400, or 1000 ppm for 8 h/day for 1 or 4 weeks. Hippocampal protein extracts were analyzed qualitatively and quantitatively by Pro-Q Diamond gel staining and SYPRO Ruby staining coupled with two-dimensional difference in gel electrophoresis (2D-DIGE), respectively, as well as by matrix-assisted laser-desorption ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) to identify phosphoproteins. Changes in selected proteins were further confirmed by Manganese II (Mn{sup 2+})-Phos-tag SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Bax and cytochrome c protein levels were determined by western blotting. Pro-Q Diamond gel staining combined with 2D-DIGE identified 26 phosphoprotein spots (p < 0.05), and MALDI-TOF/MS identified 18 up-regulated proteins and 8 down-regulated proteins. These proteins are involved in the biological process of response to stimuli, metabolic processes, and apoptosis signaling. Changes in the expression of phosphorylated 14-3-3 θ were further confirmed by Mn{sup 2+}-Phos-tag SDS-PAGE. Western blotting showed overexpression of Bax protein in the mitochondria with down-regulation in the cytoplasm, whereas cytochrome c expression was high in the cytoplasm but low in the mitochondria after 1-BP exposure. Our results suggest that the pathogenesis of 1-BP-induced hippocampal damage involves inhibition of antiapoptosis process. Phosphoproteins identified in this study can potentially serve as biomarkers for 1-BP-induced neurotoxicity. - Highlights: • 1-BP modified hippocampal phosphoproteome in rat and 23 altered proteins were identified. • 1-BP changed phosphorylation

  20. Impaired representation of geometric relationships in humans with damage to the hippocampal formation.

    Directory of Open Access Journals (Sweden)

    Carsten Finke

    Full Text Available The pivotal role of the hippocampus for spatial memory is well-established. However, while neurophysiological and imaging studies suggest a specialization of the hippocampus for viewpoint-independent or allocentric memory, results from human lesion studies have been less conclusive. It is currently unclear whether disproportionate impairment in allocentric memory tasks reflects impairment of cognitive functions that are not sufficiently supported by regions outside the medial temporal lobe or whether the deficits observed in some studies are due to experimental factors. Here, we have investigated whether hippocampal contributions to spatial memory depend on the spatial references that are available in a certain behavioral context. Patients with medial temporal lobe lesions affecting systematically the right hippocampal formation performed a series of three oculomotor tasks that required memory of a spatial cue either in retinal coordinates or relative to a single environmental reference across a delay of 5000 ms. Stimulus displays varied the availability of spatial references and contained no complex visuo-spatial associations. Patients showed a selective impairment in a condition that critically depended on memory of the geometric relationship between spatial cue and environmental reference. We infer that regions of the medial temporal lobe, most likely the hippocampal formation, contribute to behavior in conditions that exceed the potential of viewpoint-dependent or egocentric representations. Apparently, this already applies to short-term memory of simple geometric relationships and does not necessarily depend on task difficulty or integration of landmarks into more complex representations. Deficient memory of basic geometric relationships may represent a core deficit that contributes to impaired performance in allocentric spatial memory tasks.

  1. Volumetric MRI and 1H MRS study of hippocampus in unilateral MCAO patients: Relationship between hippocampal secondary damage and cognitive disorder following stroke

    International Nuclear Information System (INIS)

    Tang, Xiangyu; Wang, Chengyuan; Xia, Liming; Zhu, Wenhao; Zhao, Lingyun; Zhu, Wenzhen

    2012-01-01

    Objective: To determine whether hippocampi alter in patients at the recovery stage of middle cerebral artery occlusion (MCAO) and whether the changes of hippocampi involve in the cognitive impairment in such patients. Meterials and methods: Forty-four patients with unilateral infarction solely in MCAO territory and 44 age-, sex- and education background-matched healthy volunteers were enrolled in this study. All subjects underwent 3-dimensional fast spoiled gradient-echo (3D FSPGR) and sing-voxel proton magnetic resonance spectroscopy ( 1 H MRS) protocols at a 1.5 T MR scanner. The ratios of n-acetylaspartate/creatine (NAA/Cr) and myo-inositol/creatine (mI/Cr) were obtained by using software integrated in the MR scanner. The hippocampal volumes were estimated by manually measurement. Results: The volume and NAA/Cr ratio were found significantly decreased and mI/Cr ratio significantly increased in the hippocampus ipsilateral to occluded middle cerebral artery (MCA) as compared with values in the contralateral hippocampus or healthy control. A reduced NAA/Cr ratio was also observed in contralateral hippocampus compared to controls. The shrinkage ratio of hippocampus ipsilateral to MCAO was found related to the Mini–Mental State Examination (MMSE) score. Conclusion: Our study identified that the hippocampal secondary damage occurred in patients after MCAO, and it could be evaluated noninvasively by volumetric magnetic resonance imaging (MRI) and 1 H MRS. Moreover, the hippocampal secondary damage in MCAO patients indeed contributed to their cognitive impairment

  2. Prevention of Hippocampal Neuronal Damage and Cognitive Function Deficits in Vascular Dementia by Dextromethorphan.

    Science.gov (United States)

    Xu, Xiaofeng; Zhang, Bin; Lu, Kaili; Deng, Jiangshan; Zhao, Fei; Zhao, Bing-Qiao; Zhao, Yuwu

    2016-07-01

    Dextromethorphan (DM) is a non-competitive antagonist of NMDA receptors and a widely used component of cough medicine. Recently, its indication has been extended experimentally to a wide range of disorders including inflammation-mediated central nervous system disorders such as Parkinson disease (PD) and multiple sclerosis (MS). In this study, we investigate whether DM treatment has protective effects on the hippocampal neuron damage induced by bilateral occlusion of the common carotid arteries (two-vessel occlusion [2VO]), an animal model of vascular dementia (VaD). Sprague-Dawley (SD) (10 weeks of age) rats were subjected to the 2VO, and DM was injected intraperitoneally once per day for 37 days. Neuron death, glial activation, and cognitive function were assessed at 37 days after 2VO (0.2 mg/kg, i.p., "DM-0.2" and 2 mg/kg, i.p., "DM-2"). DM-2 treatment provided protection against neuronal death and glial activation in the hippocampal CA1 subfield and reduced cognitive impairment induced by 2VO in rats. The study also demonstrates that activation of the Nrf2-HO-1 pathway and upregulation of superoxide dismutase (SOD) play important roles in these effects. These results suggest that DM is effective in treating VaD and protecting against oxidative stress, which is strongly implicated in the pathogenesis of VaD. Therefore, the present study suggests that DM treatment may represent a new and promising protective strategy for treating VaD.

  3. Hippocampal Volume Reduction in Humans Predicts Impaired Allocentric Spatial Memory in Virtual-Reality Navigation.

    Science.gov (United States)

    Guderian, Sebastian; Dzieciol, Anna M; Gadian, David G; Jentschke, Sebastian; Doeller, Christian F; Burgess, Neil; Mishkin, Mortimer; Vargha-Khadem, Faraneh

    2015-10-21

    The extent to which navigational spatial memory depends on hippocampal integrity in humans is not well documented. We investigated allocentric spatial recall using a virtual environment in a group of patients with severe hippocampal damage (SHD), a group of patients with "moderate" hippocampal damage (MHD), and a normal control group. Through four learning blocks with feedback, participants learned the target locations of four different objects in a circular arena. Distal cues were present throughout the experiment to provide orientation. A circular boundary as well as an intra-arena landmark provided spatial reference frames. During a subsequent test phase, recall of all four objects was tested with only the boundary or the landmark being present. Patients with SHD were impaired in both phases of this task. Across groups, performance on both types of spatial recall was highly correlated with memory quotient (MQ), but not with intelligence quotient (IQ), age, or sex. However, both measures of spatial recall separated experimental groups beyond what would be expected based on MQ, a widely used measure of general memory function. Boundary-based and landmark-based spatial recall were both strongly related to bilateral hippocampal volumes, but not to volumes of the thalamus, putamen, pallidum, nucleus accumbens, or caudate nucleus. The results show that boundary-based and landmark-based allocentric spatial recall are similarly impaired in patients with SHD, that both types of recall are impaired beyond that predicted by MQ, and that recall deficits are best explained by a reduction in bilateral hippocampal volumes. In humans, bilateral hippocampal atrophy can lead to profound impairments in episodic memory. Across species, perhaps the most well-established contribution of the hippocampus to memory is not to episodic memory generally but to allocentric spatial memory. However, the extent to which navigational spatial memory depends on hippocampal integrity in humans is

  4. Errors, error detection, error correction and hippocampal-region damage: data and theories.

    Science.gov (United States)

    MacKay, Donald G; Johnson, Laura W

    2013-11-01

    This review and perspective article outlines 15 observational constraints on theories of errors, error detection, and error correction, and their relation to hippocampal-region (HR) damage. The core observations come from 10 studies with H.M., an amnesic with cerebellar and HR damage but virtually no neocortical damage. Three studies examined the detection of errors planted in visual scenes (e.g., a bird flying in a fish bowl in a school classroom) and sentences (e.g., I helped themselves to the birthday cake). In all three experiments, H.M. detected reliably fewer errors than carefully matched memory-normal controls. Other studies examined the detection and correction of self-produced errors, with controls for comprehension of the instructions, impaired visual acuity, temporal factors, motoric slowing, forgetting, excessive memory load, lack of motivation, and deficits in visual scanning or attention. In these studies, H.M. corrected reliably fewer errors than memory-normal and cerebellar controls, and his uncorrected errors in speech, object naming, and reading aloud exhibited two consistent features: omission and anomaly. For example, in sentence production tasks, H.M. omitted one or more words in uncorrected encoding errors that rendered his sentences anomalous (incoherent, incomplete, or ungrammatical) reliably more often than controls. Besides explaining these core findings, the theoretical principles discussed here explain H.M.'s retrograde amnesia for once familiar episodic and semantic information; his anterograde amnesia for novel information; his deficits in visual cognition, sentence comprehension, sentence production, sentence reading, and object naming; and effects of aging on his ability to read isolated low frequency words aloud. These theoretical principles also explain a wide range of other data on error detection and correction and generate new predictions for future test. Copyright © 2013 Elsevier Ltd. All rights reserved.

  5. Radiation Dose–Dependent Hippocampal Atrophy Detected With Longitudinal Volumetric Magnetic Resonance Imaging

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    Seibert, Tyler M.; Karunamuni, Roshan [Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California (United States); Bartsch, Hauke [Department of Radiology, University of California, San Diego, La Jolla, California (United States); Kaifi, Samar [Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California (United States); Krishnan, Anitha Priya [Department of Radiology, University of California, San Diego, La Jolla, California (United States); Dalia, Yoseph; Burkeen, Jeffrey; Murzin, Vyacheslav; Moiseenko, Vitali [Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California (United States); Kuperman, Joshua; White, Nathan S. [Department of Radiology, University of California, San Diego, La Jolla, California (United States); Brewer, James B. [Department of Radiology, University of California, San Diego, La Jolla, California (United States); Department of Neurosciences, University of California, San Diego, La Jolla, California (United States); Farid, Nikdokht [Department of Radiology, University of California, San Diego, La Jolla, California (United States); McDonald, Carrie R. [Department of Psychiatry, University of California, San Diego, La Jolla, California (United States); Hattangadi-Gluth, Jona A., E-mail: jhattangadi@ucsd.edu [Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California (United States)

    2017-02-01

    Purpose: After radiation therapy (RT) to the brain, patients often experience memory impairment, which may be partially mediated by damage to the hippocampus. Hippocampal sparing in RT planning is the subject of recent and ongoing clinical trials. Calculating appropriate hippocampal dose constraints would be improved by efficient in vivo measurements of hippocampal damage. In this study we sought to determine whether brain RT was associated with dose-dependent hippocampal atrophy. Methods and Materials: Hippocampal volume was measured with magnetic resonance imaging (MRI) in 52 patients who underwent fractionated, partial brain RT for primary brain tumors. Study patients had high-resolution, 3-dimensional volumetric MRI before and 1 year after RT. Images were processed using software with clearance from the US Food and Drug Administration and Conformité Européene marking for automated measurement of hippocampal volume. Automated results were inspected visually for accuracy. Tumor and surgical changes were censored. Mean hippocampal dose was tested for correlation with hippocampal atrophy 1 year after RT. Average hippocampal volume change was also calculated for hippocampi receiving high (>40 Gy) or low (<10 Gy) mean RT dose. A multivariate analysis was conducted with linear mixed-effects modeling to evaluate other potential predictors of hippocampal volume change, including patient (random effect), age, hemisphere, sex, seizure history, and baseline volume. Statistical significance was evaluated at α = 0.05. Results: Mean hippocampal dose was significantly correlated with hippocampal volume loss (r=−0.24, P=.03). Mean hippocampal volume was significantly reduced 1 year after high-dose RT (mean −6%, P=.009) but not after low-dose RT. In multivariate analysis, both RT dose and patient age were significant predictors of hippocampal atrophy (P<.01). Conclusions: The hippocampus demonstrates radiation dose–dependent atrophy after treatment for brain

  6. Volumetric MRI and {sup 1}H MRS study of hippocampus in unilateral MCAO patients: Relationship between hippocampal secondary damage and cognitive disorder following stroke

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    Tang, Xiangyu; Wang, Chengyuan; Xia, Liming [Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao 1095, Wuhan 430030 (China); Zhu, Wenhao [Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao 1095, Wuhan 430030 (China); Zhao, Lingyun [Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao 1095, Wuhan 430030 (China); Zhu, Wenzhen, E-mail: zhuwenzhen@hotmail.com [Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao 1095, Wuhan 430030 (China)

    2012-10-15

    Objective: To determine whether hippocampi alter in patients at the recovery stage of middle cerebral artery occlusion (MCAO) and whether the changes of hippocampi involve in the cognitive impairment in such patients. Meterials and methods: Forty-four patients with unilateral infarction solely in MCAO territory and 44 age-, sex- and education background-matched healthy volunteers were enrolled in this study. All subjects underwent 3-dimensional fast spoiled gradient-echo (3D FSPGR) and sing-voxel proton magnetic resonance spectroscopy ({sup 1}H MRS) protocols at a 1.5 T MR scanner. The ratios of n-acetylaspartate/creatine (NAA/Cr) and myo-inositol/creatine (mI/Cr) were obtained by using software integrated in the MR scanner. The hippocampal volumes were estimated by manually measurement. Results: The volume and NAA/Cr ratio were found significantly decreased and mI/Cr ratio significantly increased in the hippocampus ipsilateral to occluded middle cerebral artery (MCA) as compared with values in the contralateral hippocampus or healthy control. A reduced NAA/Cr ratio was also observed in contralateral hippocampus compared to controls. The shrinkage ratio of hippocampus ipsilateral to MCAO was found related to the Mini–Mental State Examination (MMSE) score. Conclusion: Our study identified that the hippocampal secondary damage occurred in patients after MCAO, and it could be evaluated noninvasively by volumetric magnetic resonance imaging (MRI) and {sup 1}H MRS. Moreover, the hippocampal secondary damage in MCAO patients indeed contributed to their cognitive impairment.

  7. Curcumin protects neuronal cells against status-epilepticus-induced hippocampal damage through induction of autophagy and inhibition of necroptosis.

    Science.gov (United States)

    Wang, Jin; Liu, Yuan; Li, Xiao-Hui; Zeng, Xiang-Chang; Li, Jian; Zhou, Jun; Xiao, Bo; Hu, Kai

    2017-05-01

    Status epilepticus, the most severe form of epilepsy, is characterized by progressive functional and structural damage in the hippocampus, ultimately leading to the development and clinical appearance of spontaneous, recurrent seizures. Although the pathogenesis underlying epileptogenesis processes remains unclear, a substantial body of evidence has shown that status epilepticus acts as an important initial factor in triggering epileptogenesis. Notably, besides classical cell death mechanisms such as apoptosis and necrosis, 2 novel regulators of cell fate known as necroptosis and autophagy, are demonstrated to be involved in neuronal damage in various neurodegenerative and neuropsychiatric disorders. However, whether necroptosis and autophagy play a role in post-status-epilepticus rat hippocampus and other epilepsy mechanisms deserves further research effort. In addition, research is needed to determine whether compounds from traditional Chinese herbs possess antiepileptic effects through the modulation of necroptosis and autophagy. In this study, we found that curcumin, a polyphenolic phytochemical extracted from the Curcuma longa plant, protects neuronal cells against status-epilepticus-induced hippocampal neuronal damage in the lithium-pilocarpine-induced status epilepticus rat model through induction of autophagy and inhibition of necroptosis.

  8. Remote semantic memory is impoverished in hippocampal amnesia.

    Science.gov (United States)

    Klooster, Nathaniel B; Duff, Melissa C

    2015-12-01

    The necessity of the hippocampus for acquiring new semantic concepts is a topic of considerable debate. However, it is generally accepted that any role the hippocampus plays in semantic memory is time limited and that previously acquired information becomes independent of the hippocampus over time. This view, along with intact naming and word-definition matching performance in amnesia, has led to the notion that remote semantic memory is intact in patients with hippocampal amnesia. Motivated by perspectives of word learning as a protracted process where additional features and senses of a word are added over time, and by recent discoveries about the time course of hippocampal contributions to on-line relational processing, reconsolidation, and the flexible integration of information, we revisit the notion that remote semantic memory is intact in amnesia. Using measures of semantic richness and vocabulary depth from psycholinguistics and first and second language-learning studies, we examined how much information is associated with previously acquired, highly familiar words in a group of patients with bilateral hippocampal damage and amnesia. Relative to healthy demographically matched comparison participants and a group of brain-damaged comparison participants, the patients with hippocampal amnesia performed significantly worse on both productive and receptive measures of vocabulary depth and semantic richness. These findings suggest that remote semantic memory is impoverished in patients with hippocampal amnesia and that the hippocampus may play a role in the maintenance and updating of semantic memory beyond its initial acquisition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  9. Deficits in memory and visuospatial learning correlate with regional hippocampal atrophy in MS.

    Science.gov (United States)

    Longoni, Giulia; Rocca, Maria A; Pagani, Elisabetta; Riccitelli, Gianna C; Colombo, Bruno; Rodegher, Mariaemma; Falini, Andrea; Comi, Giancarlo; Filippi, Massimo

    2015-01-01

    The hippocampus has a critical role in episodic memory and visuospatial learning and consolidation. We assessed the patterns of whole and regional hippocampal atrophy in a large group of multiple sclerosis (MS) patients, and their correlations with neuropsychological impairment. From 103 MS patients and 28 healthy controls (HC), brain dual-echo and high-resolution 3D T1-weighted images were acquired using a 3.0-Tesla scanner. All patients underwent a neuropsychological assessment of hippocampal-related cognitive functions, including Paired Associate Word Learning, Short Story, delayed recall of Rey-Osterrieth Complex Figure and Paced Auditory Serial Attention tests. The hippocampi were manually segmented and volumes derived. Regional atrophy distribution was assessed using a radial mapping analysis. Correlations between hippocampal atrophy and clinical, neuropsychological and MRI metrics were also evaluated. Hippocampal volume was reduced in MS patients vs HC (p right and hippocampus). In MS patients, radial atrophy affected CA1 subfield and subiculum of posterior hippocampus, bilaterally. The dentate hilus (DG:H) of the right hippocampal head was also affected. Regional hippocampal atrophy correlated with brain T2 and T1 lesion volumes, while no correlation was found with disability. Damage to the CA1 and subiculum was significantly correlated to the performances at hippocampal-targeted neuropsychological tests. These results show that hippocampal subregions have a different vulnerability to MS-related damage, with a relative sparing of the head of the left hippocampus. The assessment of regional hippocampal atrophy may help explain deficits of specific cognitive functions in MS patients, including memory and visuospatial abilities.

  10. Hippocampal lesions, contextual retrieval, and autoshaping in pigeons.

    Science.gov (United States)

    Richmond, Jenny; Colombo, Michael

    2002-02-22

    Both pigeons and rats with damage to the hippocampus are slow to acquire an autoshaped response and emit fewer overall responses than control animals. Experiment 1 explored the possibility that the autoshaping deficit was due to an impairment in contextual retrieval. Pigeons were trained for 14 days on an autoshaping task in which a red stimulus was followed by reinforcement in context A, and a green stimulus was followed by reinforcement in context B. On day 15, the subjects were given a context test in which the red and green stimuli were presented simultaneously in context A and then later in context B. Both control and hippocampal animals showed context specificity, that is, they responded more to the red stimulus in context A and to the green stimulus in context B. In Experiment 2 we video-recorded the control and hippocampal animals performing the autoshaping task. Hippocampal animals tended to miss-peck the key more often than control animals. In addition, the number of missed pecks increased across days for hippocampal animals but not for control animals, suggesting that while the control animals increased their pecking accuracy, the hippocampal animals actually decreased their pecking accuracy. Our findings suggest that impairments in moving through space may underlie the hippocampal autoshaping deficit.

  11. Neurogenic function in rats with unilateral hippocampal sclerosis that experienced early-life status epilepticus

    Science.gov (United States)

    Dunleavy, Mark; Schindler, Clara K; Shinoda, Sachiko; Crilly, Shane; Henshall, David C

    2014-01-01

    Status epilepticus in the adult brain invariably causes an increase in hippocampal neurogenesis and the appearance of ectopic cells and this has been implicated as a causal factor in epileptogenesis. The effect of status epilepticus on neurogenesis in the developing brain is less well characterized and models of early-life seizures typically do not reproduce the hippocampal damage common to human mesial temporal sclerosis. We recently reported that evoking status epilepticus by intra-amygdala microinjection of kainic acid in post-natal (P) day 10 rats caused substantial acute neuronal death within the ipsilateral hippocampus and rats later developed unilateral hippocampal sclerosis and spontaneous recurrent seizures. Here, we examined the expression of a selection of genes associated with neurogenesis and assessed neurogenic function in this model. Protein levels of several markers of neurogenesis including polysialic acid neural cell adhesion molecule, neuroD and doublecortin were reduced in the hippocampus three days after status epilepticus in P10 rats. In contrast, protein levels of neurogenesis markers were similar to control in rats at P55. Pulse-chase experiments using thymidine analogues suggested there was a reduction in new neurons at 72 h after status epilepticus in P10 rats, whereas numbers of new neurons labelled in epileptic rats at P55 with hippocampal sclerosis were similar to controls. The present study suggests that status epilepticus in the immature brain suppresses neurogenesis but the neurogenic potential is retained in animals that later develop hippocampal sclerosis. PMID:25755841

  12. Hippocampal atrophy on MRI is predictive of histopathological patterns and surgical prognosis in mesial temporal lobe epilepsy with hippocampal sclerosis.

    Science.gov (United States)

    Jardim, Anaclara Prada; Corso, Jeana Torres; Garcia, Maria Teresa Fernandes Castilho; Gaça, Larissa Botelho; Comper, Sandra Mara; Lancellotti, Carmen Lúcia Penteado; Centeno, Ricardo Silva; Carrete, Henrique; Cavalheiro, Esper Abrão; Scorza, Carla Alessandra; Yacubian, Elza Márcia Targas

    2016-12-01

    To correlate hippocampal volumes obtained from brain structural imaging with histopathological patterns of hippocampal sclerosis (HS), in order to predict surgical outcome. Patients with mesial temporal lobe epilepsy (MTLE) with HS were selected. Clinical data were assessed pre-operatively and surgical outcome in the first year post surgery. One block of mid hippocampal body was selected for HS classification according to ILAE criteria. NeuN-immunoreactive cell bodies were counted within hippocampal subfields, in four randomly visual fields, and cell densities were transformed into z-score values. FreeSurfer processing of 1.5T brain structural images was used for subcortical and cortical volumetric estimation of the ipsilateral hippocampus. Univariate analysis of variance and Pearson's correlation test were applied for statistical analyses. Sixty-two cases (31 female, 32 right HS) were included. ILAE type 1 HS was identified in 48 patients, type 2 in eight, type 3 in two, and four had no-HS. Better results regarding seizure control, i.e. ILAE 1, were achieved by patients with type 1 HS (58.3%). Patients with types 1 and 2 had smaller hippocampal volumes compared to those with no-HS (p<0.001 and p=0.004, respectively). Positive correlation was encountered between hippocampal volumes and CA1, CA3, CA4, and total estimated neuronal densities. CA2 was the only sector which did not correlate its neuronal density with hippocampal volume (p=0.390). This is the first study correlating hippocampal volume on MRI submitted to FreeSurfer processing with ILAE patterns of HS and neuronal loss within each hippocampal subfield, a fundamental finding to anticipate surgical prognosis for patients with drug-resistant MTLE and HS. Copyright © 2016 Elsevier B.V. All rights reserved.

  13. Neuroprotective effect of curcumin on hippocampal injury in 6-OHDA-induced Parkinson's disease rat.

    Science.gov (United States)

    Yang, Jiaqing; Song, Shilei; Li, Jian; Liang, Tao

    2014-06-01

    Clinically, Parkinson's disease (PD)-related neuronal lesions commonly occur. The purpose of this study is to investigate potential therapeutic effect of curcumin against hippocampal damage of 6-hydroxydopamine (6-OHDA)-PD rat model. These results showed that curcumin significantly increased the body weight of 6-OHDA-impaired rats (Pcurcumin-treated PD rats were effectively ameliorated as shown in open field test (Pcurcumin increased the contents of monoaminergic neurotransmitters (PCurcumin effectively alleviated the 6-OHDA-induced hippocampal damage as observed in hematoxylin-eosin (H&E) staining. Furthermore, curcumin obviously up-regulated hippocampal brain derived neurotrophic factor (BDNF), TrkB, phosphatidylinositide 3-kinases (PI3K) protein expressions, respectively as shown in Western blot analysis. These findings demonstrated that curcumin mediated the neuroprotection against 6-OHDA-induced hippocampus neurons in rats, which the underlying mechanism is involved in activating BDNF/TrkB-dependent pathway for promoting neural regeneration of hippocampal tissue. Copyright © 2014 Elsevier GmbH. All rights reserved.

  14. Unilateral hippocampal inactivation or lesion selectively impairs remote contextual fear memory.

    Science.gov (United States)

    Zhou, Heng; Zhou, Qixin; Xu, Lin

    2016-10-01

    Contextual fear memory depends on the hippocampus, but the role of unilateral hippocampus in this type of memory remains unclear. Herein, pharmacological inactivation or excitotoxic lesions were used to study the role of unilateral hippocampus in the stages of contextual fear memory. The pharmacological experiments revealed that compared with the control groups, unilateral hippocampal blockade did not impair 1-day recent memory following learning, whereas bilateral hippocampal blockade significantly impaired this memory. The lesion experiments showed that compared with the control groups, the formed contextual fear memory was retained for 7 days and that 30-day remote memory was markedly reduced in unilateral hippocampal lesion groups. These results indicate that an intact bilateral hippocampus is required for the formation of remote memory and that unilateral hippocampus is sufficient for recent contextual fear memory.

  15. Specific responses of human hippocampal neurons are associated with better memory.

    Science.gov (United States)

    Suthana, Nanthia A; Parikshak, Neelroop N; Ekstrom, Arne D; Ison, Matias J; Knowlton, Barbara J; Bookheimer, Susan Y; Fried, Itzhak

    2015-08-18

    A population of human hippocampal neurons has shown responses to individual concepts (e.g., Jennifer Aniston) that generalize to different instances of the concept. However, recordings from the rodent hippocampus suggest an important function of these neurons is their ability to discriminate overlapping representations, or pattern separate, a process that may facilitate discrimination of similar events for successful memory. In the current study, we explored whether human hippocampal neurons can also demonstrate the ability to discriminate between overlapping representations and whether this selectivity could be directly related to memory performance. We show that among medial temporal lobe (MTL) neurons, certain populations of neurons are selective for a previously studied (target) image in that they show a significant decrease in firing rate to very similar (lure) images. We found that a greater proportion of these neurons can be found in the hippocampus compared with other MTL regions, and that memory for individual items is correlated to the degree of selectivity of hippocampal neurons responsive to those items. Moreover, a greater proportion of hippocampal neurons showed selective firing for target images in good compared with poor performers, with overall memory performance correlated with hippocampal selectivity. In contrast, selectivity in other MTL regions was not associated with memory performance. These findings show that a substantial proportion of human hippocampal neurons encode specific memories that support the discrimination of overlapping representations. These results also provide previously unidentified evidence consistent with a unique role of the human hippocampus in orthogonalization of representations in declarative memory.

  16. Adaptive measurement selection for progressive damage estimation

    Science.gov (United States)

    Zhou, Wenfan; Kovvali, Narayan; Papandreou-Suppappola, Antonia; Chattopadhyay, Aditi; Peralta, Pedro

    2011-04-01

    Noise and interference in sensor measurements degrade the quality of data and have a negative impact on the performance of structural damage diagnosis systems. In this paper, a novel adaptive measurement screening approach is presented to automatically select the most informative measurements and use them intelligently for structural damage estimation. The method is implemented efficiently in a sequential Monte Carlo (SMC) setting using particle filtering. The noise suppression and improved damage estimation capability of the proposed method is demonstrated by an application to the problem of estimating progressive fatigue damage in an aluminum compact-tension (CT) sample using noisy PZT sensor measurements.

  17. Context-dependent effects of hippocampal damage on memory in the shock-probe test.

    Science.gov (United States)

    Lehmann, Hugo; Carfagnini, Adrienne; Yamin, Stephanie; Mumby, Dave G

    2005-01-01

    We assessed the role of the hippocampus in anterograde memory, using the shock-probe test. Rats with sham or neurotoxic lesions of the hippocampus were given a shock-probe acquisition session during which each time they contacted a probe they received a shock; 24 h later, the rats were given a second shock-probe session to test their retention, but in this instance the probe was not electrified. Rats were tested in either the same context as the one used during acquisition or in a different context. The hippocampal lesions impaired avoidance of the probe and burying on the retention test, suggesting that the lesions induced anterograde amnesia. However, the impairment was context dependent. The hippocampal lesions impaired avoidance only when the rats were tested in the context in which they received the conditioning. The results of the shock-probe test suggest that the anterograde amnesia following hippocampal lesions is due mainly to an inability to associate the context with the shock more than to an inability to associate the probe with shock. Copyright (c) 2004 Wiley-Liss, Inc.

  18. Restoration of hippocampal growth hormone reverses stress-induced hippocampal impairment

    Directory of Open Access Journals (Sweden)

    Caitlin M. Vander Weele

    2013-06-01

    Full Text Available Though growth hormone (GH is synthesized by hippocampal neurons, where its expression is influenced by stress exposure, its function is poorly characterized. Here, we show that a regimen of chronic stress that impairs hippocampal function in rats also leads to a profound decrease in hippocampal GH levels. Restoration of hippocampal GH in the dorsal hippocampus via viral-mediated gene transfer completely reversed stress-related impairment of two hippocampus-dependent behavioral tasks, auditory trace fear conditioning and contextual fear conditioning, without affecting hippocampal function in unstressed control rats. GH overexpression reversed stress-induced decrements in both fear acquisition and long-term fear memory. These results suggest that loss of hippocampal GH contributes to hippocampal dysfunction following prolonged stress and demonstrate that restoring hippocampal GH levels following stress can promote stress resilience.

  19. Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis.

    Science.gov (United States)

    Coradazzi, Marino; Gulino, Rosario; Fieramosca, Francesco; Falzacappa, Lucia Verga; Riggi, Margherita; Leanza, Giampiero

    2016-12-01

    Noradrenergic neurons in the locus coeruleus play a role in learning and memory, and their loss is an early event in Alzheimer's disease pathogenesis. Moreover, noradrenaline may sustain hippocampal neurogenesis; however, whether are these events related is still unknown. Four to five weeks following the selective immunotoxic ablation of locus coeruleus neurons, young adult rats underwent reference and working memory tests, followed by postmortem quantitative morphological analyses to assess the extent of the lesion, as well as the effects on proliferation and/or survival of neural progenitors in the hippocampus. When tested in the Water Maze task, lesioned animals exhibited no reference memory deficit, whereas working memory abilities were seen significantly impaired, as compared with intact or sham-lesioned controls. Stereological analyses confirmed a dramatic noradrenergic neuron loss associated to reduced proliferation, but not survival or differentiation, of 5-bromo-2'deoxyuridine-positive progenitors in the dentate gyrus. Thus, ascending noradrenergic afferents may be involved in more complex aspects of cognitive performance (i.e., working memory) possibly via newly generated progenitors in the hippocampus. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Effect of dorsal hippocampal lesion compared to dorsal hippocampal blockade by atropine on reference memory in vision deprived rats.

    Science.gov (United States)

    Dhume, R A; Noronha, A; Nagwekar, M D; Mascarenhas, J F

    1989-10-01

    In order to study the primacy of the hippocampus in place learning function 24 male adult albino rats were hippocampally-lesioned in dorsal hippocampus involving fornical damage (group I); sham operated for comparison with group I (group II); cannulated for instillation of atropine sulphate in the same loci as group I (group III); and cannulated for instillation of saline which served as control for group III (group IV). All the animals were enucleated and their reference memory (long-term memory) was tested, using open 4-arm radial maze. There was loss of reference memory in groups I and III. However, hippocampally-lesioned animals, showed recovery of reference memory deficit within a short period of 10 days or so. Whereas atropinized animals showed persistent reference memory deficit as long as the instillation effect continued. The mechanism involved in the recovery of reference memory in hippocampally-lesioned animals and persistent deficit of reference memory in atropinized animals has been postulated to explain the primacy of hippocampus in the place learning function under normal conditions.

  1. Adult hippocampal neurogenesis in natural populations of mammals.

    Science.gov (United States)

    Amrein, Irmgard

    2015-05-01

    This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  2. Selective impairment of subcategories of long-term memory in mice with hippocampal lesions accessed by the olfactory tubing maze.

    Science.gov (United States)

    Chaillan, F A; Marchetti, E; Soumireu-Mourat, B; Roman, F S

    2005-03-30

    A new apparatus, the olfactory tubing maze for mice, was developed recently to study learning and memory processes in mice in regard to their ethological abilities. As in humans, BALB/c mice with selective bilateral lesions of the hippocampal formation showed selective impairment of subcategories of long-term memory when tested with the olfactory tubing maze. After three learning sessions, control mice reached a high percentage of correct responses. They consistently made the olfactory-reward associations, but antero-dorsal and postero-ventral hippocampal-lesioned mice did not. However, all lesioned mice learned the paradigm and the timing of the task as fast and as well as control mice. These data suggest that the olfactory tubing maze can be used to study subcategories of memory, such as declarative and non-declarative memory, which are similar in some respects to those observed in humans. Consequently, possible memory effects of classical approaches (i.e., pharmacological or lesion studies) or genetic modifications in transgenic or gene-targeting mice can be effectively analyzed using this new apparatus.

  3. Classification of Alzheimer's disease patients with hippocampal shape wrapper-based feature selection and support vector machine

    Science.gov (United States)

    Young, Jonathan; Ridgway, Gerard; Leung, Kelvin; Ourselin, Sebastien

    2012-02-01

    It is well known that hippocampal atrophy is a marker of the onset of Alzheimer's disease (AD) and as a result hippocampal volumetry has been used in a number of studies to provide early diagnosis of AD and predict conversion of mild cognitive impairment patients to AD. However, rates of atrophy are not uniform across the hippocampus making shape analysis a potentially more accurate biomarker. This study studies the hippocampi from 226 healthy controls, 148 AD patients and 330 MCI patients obtained from T1 weighted structural MRI images from the ADNI database. The hippocampi are anatomically segmented using the MAPS multi-atlas segmentation method, and the resulting binary images are then processed with SPHARM software to decompose their shapes as a weighted sum of spherical harmonic basis functions. The resulting parameterizations are then used as feature vectors in Support Vector Machine (SVM) classification. A wrapper based feature selection method was used as this considers the utility of features in discriminating classes in combination, fully exploiting the multivariate nature of the data and optimizing the selected set of features for the type of classifier that is used. The leave-one-out cross validated accuracy obtained on training data is 88.6% for classifying AD vs controls and 74% for classifying MCI-converters vs MCI-stable with very compact feature sets, showing that this is a highly promising method. There is currently a considerable fall in accuracy on unseen data indicating that the feature selection is sensitive to the data used, however feature ensemble methods may overcome this.

  4. Feature Selection based on Machine Learning in MRIs for Hippocampal Segmentation

    Science.gov (United States)

    Tangaro, Sabina; Amoroso, Nicola; Brescia, Massimo; Cavuoti, Stefano; Chincarini, Andrea; Errico, Rosangela; Paolo, Inglese; Longo, Giuseppe; Maglietta, Rosalia; Tateo, Andrea; Riccio, Giuseppe; Bellotti, Roberto

    2015-01-01

    Neurodegenerative diseases are frequently associated with structural changes in the brain. Magnetic resonance imaging (MRI) scans can show these variations and therefore can be used as a supportive feature for a number of neurodegenerative diseases. The hippocampus has been known to be a biomarker for Alzheimer disease and other neurological and psychiatric diseases. However, it requires accurate, robust, and reproducible delineation of hippocampal structures. Fully automatic methods are usually the voxel based approach; for each voxel a number of local features were calculated. In this paper, we compared four different techniques for feature selection from a set of 315 features extracted for each voxel: (i) filter method based on the Kolmogorov-Smirnov test; two wrapper methods, respectively, (ii) sequential forward selection and (iii) sequential backward elimination; and (iv) embedded method based on the Random Forest Classifier on a set of 10 T1-weighted brain MRIs and tested on an independent set of 25 subjects. The resulting segmentations were compared with manual reference labelling. By using only 23 feature for each voxel (sequential backward elimination) we obtained comparable state-of-the-art performances with respect to the standard tool FreeSurfer.

  5. Structural hippocampal network alterations during healthy aging: A multi-modal MRI study

    Directory of Open Access Journals (Sweden)

    Amandine ePelletier

    2013-12-01

    Full Text Available While hippocampal atrophy has been described during healthy aging, few studies have examined its relationship with the integrity of White Matter (WM connecting tracts of the limbic system. This investigation examined WM structural damage specifically related to hippocampal atrophy in healthy aging subjects (n=129, using morphological MRI to assess hippocampal volume and Diffusion Tensor Imaging (DTI to assess WM integrity. Subjects with Mild Cognitive Impairment (MCI or dementia were excluded from the analysis. In our sample, increasing age was significantly associated with reduced hippocampal volume and reduced Fractional Anisotropy (FA at the level of the fornix and the cingulum bundle. The findings also demonstrate that hippocampal atrophy was specifically associated with reduced FA of the fornix bundle, but it was not related to alteration of the cingulum bundle. Our results indicate that the relationship between hippocampal atrophy and fornix FA values is not due to an independent effect of age on both structures. A recursive regression procedure was applied to evaluate sequential relationships between the alterations of these two brain structures. When both hippocampal atrophy and fornix FA values were included in the same model to predict age, fornix FA values remained significant whereas hippocampal atrophy was no longer significantly associated with age. According to this latter finding, hippocampal atrophy in healthy aging could be mediated by a loss of fornix connections. Structural alterations of this part of the limbic system, which have been associated with neurodegeneration in Alzheimer’s disease, result at least in part from the aging process.

  6. Selection of regularization parameter for l1-regularized damage detection

    Science.gov (United States)

    Hou, Rongrong; Xia, Yong; Bao, Yuequan; Zhou, Xiaoqing

    2018-06-01

    The l1 regularization technique has been developed for structural health monitoring and damage detection through employing the sparsity condition of structural damage. The regularization parameter, which controls the trade-off between data fidelity and solution size of the regularization problem, exerts a crucial effect on the solution. However, the l1 regularization problem has no closed-form solution, and the regularization parameter is usually selected by experience. This study proposes two strategies of selecting the regularization parameter for the l1-regularized damage detection problem. The first method utilizes the residual and solution norms of the optimization problem and ensures that they are both small. The other method is based on the discrepancy principle, which requires that the variance of the discrepancy between the calculated and measured responses is close to the variance of the measurement noise. The two methods are applied to a cantilever beam and a three-story frame. A range of the regularization parameter, rather than one single value, can be determined. When the regularization parameter in this range is selected, the damage can be accurately identified even for multiple damage scenarios. This range also indicates the sensitivity degree of the damage identification problem to the regularization parameter.

  7. Impaired Odor Recognition Memory in Patients with Hippocampal Lesions

    Science.gov (United States)

    Levy, Daniel A.; Squire, Larry R.; Hopkins, Ramona O.

    2004-01-01

    In humans, impaired recognition memory following lesions thought to be limited to the hippocampal region has been demonstrated for a wide variety of tasks. However, the importance of the human hippocampus for olfactory recognition memory has scarcely been explored. We evaluated the ability of memory-impaired patients with damage thought to be…

  8. Hypoxic pretreatment protects against neuronal damage of the rat hippocampus induced by severe hypoxia.

    Science.gov (United States)

    Gorgias, N; Maidatsi, P; Tsolaki, M; Alvanou, A; Kiriazis, G; Kaidoglou, K; Giala, M

    1996-04-01

    The present study investigates whether under conditions of successive hypoxic exposures pretreatment with mild (15% O(2)) or moderate (10% O(2)) hypoxia, protects hippocampal neurones against damage induced by severe (3% O(2)) hypoxia. The ultrastructural findings were also correlated with regional superoxide dismutase (SOD) activity changes. In unpretreated rats severe hypoxia induced ultrastructural changes consistent with the aspects of delayed neuronal death (DND). However, in preexposed animals hippocampal damage was attenuated in an inversely proportional way with the severity of the hypoxic pretreatment. The ultrastructural hypoxic tolerance findings were also closely related to increased regional SOD activity levels. Thus the activation of the endogenous antioxidant defense by hypoxic preconditioning, protects against hippocampal damage induced by severe hypoxia. The eventual contribution of increased endogenous adenosine and/or reduced excitotoxicity to induce hypoxic tolerance is discussed.

  9. Chronic corticosterone exposure reduces hippocampal glycogen level and induces depression-like behavior in mice.

    Science.gov (United States)

    Zhang, Hui-yu; Zhao, Yu-nan; Wang, Zhong-li; Huang, Yu-fang

    2015-01-01

    Long-term exposure to stress or high glucocorticoid levels leads to depression-like behavior in rodents; however, the cause remains unknown. Increasing evidence shows that astrocytes, the most abundant cells in the central nervous system (CNS), are important to the nervous system. Astrocytes nourish and protect the neurons, and serve as glycogen repositories for the brain. The metabolic process of glycogen, which is closely linked to neuronal activity, can supply sufficient energy substrates for neurons. The research team probed into the effects of chronic corticosterone (CORT) exposure on the glycogen level of astrocytes in the hippocampal tissues of male C57BL/6N mice in this study. The results showed that chronic CORT injection reduced hippocampal neurofilament light protein (NF-L) and synaptophysin (SYP) levels, induced depression-like behavior in male mice, reduced hippocampal glycogen level and glycogen synthase activity, and increased glycogen phosphorylase activity. The results suggested that the reduction of the hippocampal glycogen level may be the mechanism by which chronic CORT treatment damages hippocampal neurons and induces depression-like behavior in male mice.

  10. Both oophorectomy and obesity impaired solely hippocampal-dependent memory via increased hippocampal dysfunction.

    Science.gov (United States)

    Mantor, Duangkamol; Pratchayasakul, Wasana; Minta, Wanitchaya; Sutham, Wissuta; Palee, Siripong; Sripetchwandee, Jirapas; Kerdphoo, Sasiwan; Jaiwongkum, Thidarat; Sriwichaiin, Sirawit; Krintratun, Warunsorn; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2018-04-17

    Our previous study demonstrated that obesity aggravated peripheral insulin resistance and brain dysfunction in the ovariectomized condition. Conversely, the effect of obesity followed by oophorectomy on brain oxidative stress, brain apoptosis, synaptic function and cognitive function, particularly in hippocampal-dependent and hippocampal-independent memory, has not been investigated. Our hypothesis was that oophorectomy aggravated metabolic impairment, brain dysfunction and cognitive impairment in obese rats. Thirty-two female rats were fed with either a normal diet (ND, n = 16) or a high-fat diet (HFD, n = 16) for a total of 20 weeks. At week 13, rats in each group were subdivided into sham and ovariectomized subgroups (n = 8/subgroup). At week 20, all rats were tested for hippocampal-dependent and hippocampal-independent memory by using Morris water maze test (MWM) and Novel objective recognition (NOR) tests, respectively. We found that the obese-insulin resistant condition occurred in sham-HFD-fed rats (HFS), ovariectomized-ND-fed rats (NDO), and ovariectomized-HFD-fed rats (HFO). Increased hippocampal oxidative stress level, increased hippocampal apoptosis, increased hippocampal synaptic dysfunction, decreased hippocampal estrogen level and impaired hippocampal-dependent memory were observed in HFS, NDO, and HFO rats. However, the hippocampal-independent memory, cortical estrogen levels, cortical ROS production, and cortical apoptosis showed no significant difference between groups. These findings suggested that oophorectomy and obesity exclusively impaired hippocampal-dependent memory, possibly via increased hippocampal dysfunction. Nonetheless, oophorectomy did not aggravate these deleterious effects under conditions of obesity. Copyright © 2017. Published by Elsevier Inc.

  11. Bilateral reorganization of the dentate gyrus in hippocampal sclerosis

    Science.gov (United States)

    Thom, M; Martinian, L; Catarino, C; Yogarajah, M; Koepp, M J.; Caboclo, L; Sisodiya, S M.

    2009-01-01

    Background: Hippocampal sclerosis (HS) is the most common surgical pathology associated with mesial temporal lobe epilepsy (MTLE). HS is typically characterized by mossy fiber sprouting (MFS) and reorganization of neuropeptide Y (NPY) fiber networks in the dentate gyrus. One potential cause of postoperative seizure recurrence following temporal lobe surgery may be the presence of seizure-associated bilateral hippocampal damage. We aimed to investigate patterns of hippocampal abnormalities in a postmortem series as identified by NPY and dynorphin immunohistochemistry. Methods: Analysis of dentate gyrus fiber reorganization, using dynorphin (to demonstrate MFS) and NPY immunohistochemistry, was carried out in a postmortem epilepsy series of 25 cases (age range 21–96 years). In 9 patients, previously refractory seizures had become well controlled for up to 34 years prior to death. Results: Bilateral MFS or abnormal NPY patterns were seen in 15 patients including those with bilateral symmetric, asymmetric, and unilateral HS by conventional histologic criteria. MFS and NPY reorganization was present in all classical HS cases, more variably in atypical HS, present in both MTLE and non-MTLE syndromes and with seizure histories of up to 92 years, despite seizure remission in some patients. Conclusion: Synaptic reorganization in the dentate gyrus may be a bilateral, persistent process in epilepsy. It is unlikely to be sufficient to generate seizures and more likely to represent a seizure-induced phenomenon. GLOSSARY AED = antiepileptic drug; CA1p = CA1-predominant hippocampal sclerosis; CHS = classical hippocampal sclerosis; EFG = end folium gliosis; EFS = end folium sclerosis; GCD = granule cell dispersion; GCL = granule cell layer; HS = hippocampal sclerosis; MFS = mossy fiber sprouting; MTLE = mesial temporal lobe epilepsy; NPY = neuropeptide Y; ROI = region of interest; SE = status epilepticus; TLE = temporal lobe epilepsy. PMID:19710404

  12. Protease-activated receptor-1 negatively regulates proliferation of neural stem/progenitor cells derived from the hippocampal dentate gyrus of the adult mouse

    Directory of Open Access Journals (Sweden)

    Masayuki Tanaka

    2016-07-01

    Full Text Available Thrombin-activated protease-activated receptor (PAR-1 regulates the proliferation of neural cells following brain injury. To elucidate the involvement of PAR-1 in the neurogenesis that occurs in the adult hippocampus, we examined whether PAR-1 regulated the proliferation of neural stem/progenitor cells (NPCs derived from the murine hippocampal dentate gyrus. NPC cultures expressed PAR-1 protein and mRNA encoding all subtypes of PAR. Direct exposure of the cells to thrombin dramatically attenuated the cell proliferation without causing cell damage. This thrombin-induced attenuation was almost completely abolished by the PAR antagonist RWJ 56110, as well as by dabigatran and 4-(2-aminoethylbenzenesulfonyl fluoride (AEBSF, which are selective and non-selective thrombin inhibitors, respectively. Expectedly, the PAR-1 agonist peptide (AP SFLLR-NH2 also attenuated the cell proliferation. The cell proliferation was not affected by the PAR-1 negative control peptide RLLFT-NH2, which is an inactive peptide for PAR-1. Independently, we determined the effect of in vivo treatment with AEBSF or AP on hippocampal neurogenesis in the adult mouse. The administration of AEBSF, but not that of AP, significantly increased the number of newly-generated cells in the hippocampal subgranular zone. These data suggest that PAR-1 negatively regulated adult neurogenesis in the hippocampus by inhibiting the proliferative activity of the NPCs.

  13. Turmeric extract inhibits apoptosis of hippocampal neurons of trimethyltin-exposed rats.

    Science.gov (United States)

    Yuliani, S; Widyarini, S; Mustofa; Partadiredja, G

    2017-01-01

    The aim of the present study was to reveal the possible antiapoptotic effect of turmeric (Curcuma longa Linn.) on the hippocampal neurons of rats exposed to trimethyltin (TMT). Oxidative damage in the hippocampus can induce the apoptosis of neurons associated with the pathogenesis of dementiaMETHODS. The ethanolic turmeric extract and a citicoline (as positive control) solution were administered to the TMT-exposed rats for 28 days. The body weights of rats were recorded once a week. The hippocampal weights and imumunohistochemical expression of caspase 3 proteins in the CA1 and CA2-CA3 regions of the hippocampi were examined at the end of the experiment. Immunohistochemical analysis showed that the injection of TMT increased the expression of caspase 3 in the CA1 and CA2-CA3 regions of hippocampus. TMT also decreased the body and hippocampal weights. Furthermore, the administration of 200 mg/kg bw dose of turmeric extract decreased the caspase 3 expression in the CA2-CA3 pyramidal neurons but not in the CA1 neurons. It also prevented the decrease of the body and hippocampal weights. We suggest that the 200 mg/kg bw dose of turmeric extract may exert antiapoptotic effect on the hippocampal neurons of the TMT-exposed rats (Tab. 1, Fig. 3, Ref. 49).

  14. Prediction of dementia by hippocampal shape analysis

    DEFF Research Database (Denmark)

    Achterberg, Hakim C.; van der Lijn, Fedde; den Heijer, Tom

    2010-01-01

    This work investigates the possibility of predicting future onset of dementia in subjects who are cognitively normal, using hippocampal shape and volume information extracted from MRI scans. A group of 47 subjects who were non-demented normal at the time of the MRI acquisition, but were diagnosed...... with dementia during a 9 year follow-up period, was selected from a large population based cohort study. 47 Age and gender matched subjects who stayed cognitively intact were selected from the same cohort study as a control group. The hippocampi were automatically segmented and all segmentations were inspected...... and, if necessary, manually corrected by a trained observer. From this data a statistical model of hippocampal shape was constructed, using an entropy-based particle system. This shape model provided the input for a Support Vector Machine classifier to predict dementia. Cross validation experiments...

  15. Locomotor damage in rats after x-irradiation in Utero

    International Nuclear Information System (INIS)

    Mullenix, P.; Norton, S.; Culver, B.

    1975-01-01

    Alterations in gait were found in rats after whole-body irradiation with 125 R on day 14, 15, and 16 of gestation. No effects on locomotion were detected after irradiation on day 17 with 125 R or after irradiation on day 14 with 50 R. A technique was set up for quantitative evaluation of locomotion based on a modification of other methods. Walking patterns of irradiated rats were recorded, when they were adults, by requiring them to walk up a 10 0 incline through a corridor after their feet had been dipped in ink. Rats irradiated on gestational day 14 had an in-phase, hopping gait with the sine of the angle between the hind feet and the direction of progression over 0.9. Rats irradiated on gestational days 15 and 16 had an alternating, waddling gait with wider stance and broader angle than control rats. Histologic examination of serial sections of the brains of these rats showed that the 14-day rats lacked all telencephalic commissures except for a few fibers which crossed in some rats. There was a progressive improvement in the condition of the anterior and ventral hippocampal commissures up to day 17, but the corpus callosum and doral hippocampal commissure were lacking or markedly reduced in all day 17 rats. No animals showed damage to the mesencephalic posterior commissure. Since rats which used the in-phase mode of locomotion were never observed to use alternating gait, the possible causal relationship of the commissural damage to the altered locomotor patterns was considered. In view of the restricted period of damage found for the anterior and ventral hippocampal commissures and the restriction of altered locomotion to damage in the same period, primary involvement of the corpus callosum and dorsal hippocampal commissure could be excluded, but a possible role for the other telencephalic commissures remained

  16. Automatic planning on hippocampal avoidance whole-brain radiotherapy

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Shuo, E-mail: shuo0220@gmail.com; Zheng, Dandan; Zhang, Chi; Ma, Rongtao; Bennion, Nathan R.; Lei, Yu; Zhu, Xiaofeng; Enke, Charles A.; Zhou, Sumin

    2017-04-01

    Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle{sup 3} Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present study is to evaluate the performance of the Pinnacle{sup 3} Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle{sup 3} Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D{sub 2%} and D{sub 98%} of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D{sub 100%} and D{sub max} of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle{sup 3} Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The

  17. Automatic planning on hippocampal avoidance whole-brain radiotherapy

    International Nuclear Information System (INIS)

    Wang, Shuo; Zheng, Dandan; Zhang, Chi; Ma, Rongtao; Bennion, Nathan R.; Lei, Yu; Zhu, Xiaofeng; Enke, Charles A.; Zhou, Sumin

    2017-01-01

    Mounting evidence suggests that radiation-induced damage to the hippocampus plays a role in neurocognitive decline for patients receiving whole-brain radiotherapy (WBRT). Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) has been proposed to reduce the putative neurocognitive deficits by limiting the dose to the hippocampus. However, urgency of palliation for patients as well as the complexities of the treatment planning may be barriers to protocol enrollment to accumulate further clinical evidence. This warrants expedited quality planning of HA-WBRT. Pinnacle 3 Automatic treatment planning was designed to increase planning efficiency while maintaining or improving plan quality and consistency. The aim of the present study is to evaluate the performance of the Pinnacle 3 Auto-Planning on HA-WBRT treatment planning. Ten patients previously treated for brain metastases were selected. Hippocampal volumes were contoured on T1 magnetic resonance (MR) images, and planning target volumes (PTVs) were generated based on RTOG0933. The following 2 types of plans were generated by Pinnacle 3 Auto-Planning: the one with 2 coplanar volumetric modulated arc therapy (VMAT) arcs and the other with 9-field noncoplanar intensity-modulated radiation therapy (IMRT). D 2% and D 98% of PTV were used to calculate homogeneity index (HI). HI and Paddick Conformity index (CI) of PTV as well as D 100% and D max of the hippocampus were used to evaluate the plan quality. All the auto-plans met the dose coverage and constraint objectives based on RTOG0933. The auto-plans eliminated the necessity of generating pseudostructures by the planners, and it required little manual intervention which expedited the planning process. IMRT quality assurance (QA) results also suggest that all the auto-plans are practically acceptable on delivery. Pinnacle 3 Auto-Planning generates acceptable plans by RTOG0933 criteria without time-consuming planning process. The expedited quality planning achieved by

  18. Protective effects of endoplasmic reticulum stress preconditioning on hippocampal neurons in rats with status epilepticus

    Directory of Open Access Journals (Sweden)

    Yi ZHANG

    2014-12-01

    Full Text Available Objective To evaluate the protective effects of endoplasmic reticulum stress preconditioning induced by 2-deoxyglucose (2-DG on hippocampal neurons of rats with status epilepticus (SE and the possible mechanism.  Methods Ninety Sprague-Dawley (SD rats were randomly enrolled into preconditioning group (N = 30, SE group (N = 30 and control group (N = 30. Each group was divided into 6 subsets (N = 5 according to six time points (before seizure, 6 h, 12 h, 1 d, 2 d and 7 d after seizure. The preconditioning group was administered 2-DG intraperitoneally with a dose of 150 mg/kg for 7 days, and the lithium-pilocarpine induced SE rat model was established on both preconditioning group and SE group. The rats were sacrificed at the above six time points, and the brains were removed to make paraffin sections. Nissl staining was performed by toluidine blue to evaluate the hippocampal neuronal damage after seizure, and the number of survival neurons in hippocampal CA1 and CA3 regions of the rats were counted. Immunohistochemical staining was performed to detect the expressions of glucose regulated protein 78 (GRP78 and X-box binding protein 1 (XBP-1 in hippocampal CA3 region of the rats.  Results The number of survival neurons in preconditioning group was much more than that in SE group at 7 d after seizure (t = 5.353, P = 0.000, and was more obvious in CA1 region. There was no significant hippocampal neuronal damage in control group. The expressions of GRP78 and XBP-1 in CA3 region of hippocampus in SE group at 6 h after seizure were significantly higher than that in control group (P = 0.000, and then kept increasing until reaching the peak at 2 d (P = 0.000, for all. The expressions of GRP78 and XBP-1 in hippocampal CA3 region in preconditioning group were significantly higher than that in control group before seizure (P = 0.000, for all. The level of GRP78 maintained the highest at 24 h and 2 d after seizure (P = 0.000, for all, while the XBP-1 level

  19. Roles of hippocampal subfields in verbal and visual episodic memory.

    Science.gov (United States)

    Zammit, Andrea R; Ezzati, Ali; Zimmerman, Molly E; Lipton, Richard B; Lipton, Michael L; Katz, Mindy J

    2017-01-15

    Selective hippocampal (HC) subfield atrophy has been reported in older adults with mild cognitive impairment and Alzheimer's disease. The goal of this study was to investigate the associations between the volume of hippocampal subfields and visual and verbal episodic memory in cognitively normal older adults. This study was conducted on a subset of 133 participants from the Einstein Aging Study (EAS), a community-based study of non-demented older adults systematically recruited from the Bronx, N.Y. All participants completed comprehensive EAS neuropsychological assessment. Visual episodic memory was assessed using the Complex Figure Delayed Recall subtest from the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Verbal episodic memory was assessed using Delayed Recall from the Free and Cued Selective Reminding Test (FCSRT). All participants underwent 3T MRI brain scanning with subsequent automatic measurement of the hemispheric hippocampal subfield volumes (CA1, CA2-CA3, CA4-dente gyrus, presubiculum, and subiculum). We used linear regressions to model the association between hippocampal subfield volumes and visual and verbal episodic memory tests while adjusting for age, sex, education, and total intracranial volume. Participants had a mean age of 78.9 (SD=5.1) and 60.2% were female. Total hippocampal volume was associated with Complex Figure Delayed Recall (β=0.31, p=0.001) and FCSRT Delayed Recall (β=0.27, p=0.007); subiculum volume was associated with Complex Figure Delayed Recall (β=0.27, p=0.002) and FCSRT Delayed Recall (β=0.24, p=0.010); CA1 was associated with Complex Figure Delayed Recall (β=0.26, pepisodic memory. Our results suggest that hippocampal subfields have sensitive roles in the process of visual and verbal episodic memory. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Resveratrol Ameliorates Tau Hyperphosphorylation at Ser396 Site and Oxidative Damage in Rat Hippocampal Slices Exposed to Vanadate: Implication of ERK1/2 and GSK-3β Signaling Cascades.

    Science.gov (United States)

    Jhang, Kyoung A; Park, Jin-Sun; Kim, Hee-Sun; Chong, Young Hae

    2017-11-08

    The objective of this study was to investigate the effect of resveratrol (a natural polyphenolic phytostilbene) on tau hyperphosphorylation and oxidative damage induced by sodium orthovanadate (Na 3 VO 4 ), the prevalent species of vanadium (vanadate), in rat hippocampal slices. Our results showed that resveratrol significantly inhibited Na 3 VO 4 -induced hyperphosphorylation of tau at the Ser396 (p-S396-tau) site, which is upregulated in the hippocampus of Alzheimer's disease (AD) brains and principally linked to AD-associated cognitive dysfunction. Subsequent mechanistic studies revealed that reduction of ERK1/2 activation was involved in the inhibitory effect of resveratrol by inhibiting the ERK1/2 pathway with SL327 mimicking the aforementioned effect of resveratrol. Moreover, resveratrol potently induced GSK-3β Ser9 phosphorylation and reduced Na 3 VO 4 -induced p-S396-tau levels, which were markedly replicated by pharmacologic inhibition of GSK-3β with LiCl. These results indicate that resveratrol could suppress Na 3 VO 4 -induced p-S396-tau levels via downregulating ERK1/2 and GSK-3β signaling cascades in rat hippocampal slices. In addition, resveratrol diminished the increased extracellular reactive oxygen species generation and hippocampal toxicity upon long-term exposure to Na 3 VO 4 or FeCl 2 . Our findings strongly support the notion that resveratrol may serve as a potential nutraceutical agent for AD.

  1. Spatial memory and hippocampal function: Where are we now?

    Directory of Open Access Journals (Sweden)

    Mark Good

    2002-01-01

    Full Text Available The main aim of this paper is to provide an overview of current debates concerning the role of the mammalian hippocampus in learning with a particular emphasis on spatial learning. The review discusses recent debates on (1 the role of the primate hippocampus in recognition memory and object-in-place memory, (2 the role of the hippocampus in spatial navigation in both rats and humans, and (3 the effects of hippocampal damage on processing contextual information. Evidence from these lines of research have led many current theories to posit a function for the hippocampus that has as its organizing principle the association or binding of stimulus representations. Based on this principle, recent theories of hippocampal function have extended their application beyond the spatial domain to capture features of declarative and episodic memory processes.

  2. DDPH ameliorated oxygen and glucose deprivation-induced injury in rat hippocampal neurons via interrupting Ca2+ overload and glutamate release.

    Science.gov (United States)

    He, Zhi; Lu, Qing; Xu, Xulin; Huang, Lin; Chen, Jianguo; Guo, Lianjun

    2009-01-28

    Our previous work has demonstrated that DDPH (1-(2, 6-dimethylphenoxy)-2-(3, 4-dimethoxyphenylethylamino) propane hydrochloride), a competitive alpha(1)-adrenoceptor antagonist, could improve cognitive deficits, reduce histopathological damage and facilitate synaptic plasticity in vivo possibly via increasing NR2B (NMDA receptor 2B) expression and antioxidation of DDPH itself. The present study further evaluated effects of DDPH on OGD (Oxygen and glucose deprivation)-induced neuronal damage in rat primary hippocampal cells. The addition of DDPH to the cultured cells 12 h before OGD for 4 h significantly reduced neuronal damage as determined by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay and LDH (lactate dehydrogenase) release experiments. The effects of DDPH on intracellular calcium concentration were explored by Fura-2 based calcium imaging techniques and results showed that DDPH at the dosages of 5 microM and 10 microM suppressed the increase of intracellular calcium ([Ca(2+)](i)) stimulated by 50 mM KCl in Ca(2+)-containing extracellular solutions. However, DDPH couldn't suppress the increase of [Ca(2+)](i) induced by both 50 microM glutamate in Ca(2+)-containing extracellular solutions and 20 microM ATP (Adenosine Triphosphate) in Ca(2+)-free solution. These results indicated that DDPH prevented [Ca(2+)](i) overload in hippocampal neurons by blocking Ca(2+) influx (voltage-dependent calcium channel) but not Ca(2+) mobilization from the intracellular Ca(2+) store in endoplasm reticulum (ER). We also demonstrated that DDPH could decrease glutamate release when hippocampal cells were subjected to OGD. These observations demonstrated that DDPH protected hippocampal neurons against OGD-induced damage by preventing the Ca(2+) influx and decreasing glutamate release.

  3. Thalamo-Cortical Disruption Contributes to Short-Term Memory Deficits in Patients with Medial Temporal Lobe Damage.

    Science.gov (United States)

    Voets, Natalie L; Menke, Ricarda A L; Jbabdi, Saad; Husain, Masud; Stacey, Richard; Carpenter, Katherine; Adcock, Jane E

    2015-11-01

    Short-term (STM) and long-term memory (LTM) have largely been considered as separate brain systems reflecting fronto-parietal and medial temporal lobe (MTL) functions, respectively. This functional dichotomy has been called into question by evidence of deficits on aspects of working memory in patients with MTL damage, suggesting a potentially direct hippocampal contribution to STM. As the hippocampus has direct anatomical connections with the thalamus, we tested the hypothesis that damage to thalamic nuclei regulating cortico-cortical interactions may contribute to STM deficits in patients with hippocampal dysfunction. We used diffusion-weighted magnetic resonance imaging-based tractography to identify anatomical subdivisions in patients with MTL epilepsy. From these, we measured resting-state functional connectivity with detailed cortical divisions of the frontal, temporal, and parietal lobes. Whereas thalamo-temporal functional connectivity reflected LTM performance, thalamo-prefrontal functional connectivity specifically predicted STM performance. Notably, patients with hippocampal volume loss showed thalamic volume loss, most prominent in the pulvinar region, not detected in patients with normal hippocampal volumes. Aberrant thalamo-cortical connectivity in the epileptic hemisphere was mirrored in a loss of behavioral association with STM performance specifically in patients with hippocampal atrophy. These findings identify thalamo-cortical disruption as a potential mechanism contributing to STM deficits in the context of MTL damage. © The Author 2015. Published by Oxford University Press.

  4. 4β-Hydroxywithanolide E selectively induces oxidative DNA damage for selective killing of oral cancer cells.

    Science.gov (United States)

    Tang, Jen-Yang; Huang, Hurng-Wern; Wang, Hui-Ru; Chan, Ya-Ching; Haung, Jo-Wen; Shu, Chih-Wen; Wu, Yang-Chang; Chang, Hsueh-Wei

    2018-03-01

    Reactive oxygen species (ROS) induction had been previously reported in 4β-hydroxywithanolide (4βHWE)-induced selective killing of oral cancer cells, but the mechanism involving ROS and the DNA damage effect remain unclear. This study explores the role of ROS and oxidative DNA damage of 4βHWE in the selective killing of oral cancer cells. Changes in cell viability, morphology, ROS, DNA double strand break (DSB) signaling (γH2AX foci in immunofluorescence and DSB signaling in western blotting), and oxidative DNA damage (8-oxo-2'deoxyguanosine [8-oxodG]) were detected in 4βHWE-treated oral cancer (Ca9-22) and/or normal (HGF-1) cells. 4βHWE decreased cell viability, changed cell morphology and induced ROS generation in oral cancer cells rather than oral normal cells, which were recovered by a free radical scavenger N-acetylcysteine (NAC). For immunofluorescence, 4βHWE also accumulated more of the DSB marker, γH2AX foci, in oral cancer cells than in oral normal cells. For western blotting, DSB signaling proteins such as γH2AX and MRN complex (MRE11, RAD50, and NBS1) were overexpressed in 4βHWE-treated oral cancer cells in different concentrations and treatment time. In the formamidopyrimidine-DNA glycolyase (Fpg)-based comet assay and 8-oxodG-based flow cytometry, the 8-oxodG expressions were higher in 4βHWE-treated oral cancer cells than in oral normal cells. All the 4βHWE-induced DSB and oxidative DNA damage to oral cancer cells were recovered by NAC pretreatment. Taken together, the 4βHWE selectively induced DSB and oxidative DNA damage for the ROS-mediated selective killing of oral cancer cells. © 2017 Wiley Periodicals, Inc.

  5. Phenolic antioxidants attenuate hippocampal neuronal cell damage ...

    Indian Academy of Sciences (India)

    Unknown

    CP had lower Fe3+ reducing activity in comparison to WS and AV. Plant extracts given singly ... modulators of nervous system damage. In epilepsy, ex- ..... D 1978 Antimicrobial agents from higher plants, Glycy- rrhiza glabra L. I. Some ...

  6. ASIC-like, proton-activated currents in rat hippocampal neurons.

    Science.gov (United States)

    Baron, Anne; Waldmann, Rainer; Lazdunski, Michel

    2002-03-01

    The expression of mRNA for acid sensing ion channels (ASIC) subunits ASIC1a, ASIC2a and ASIC2b has been reported in hippocampal neurons, but the presence of functional hippocampal ASIC channels was never assessed. We report here the first characterization of ASIC-like currents in rat hippocampal neurons in primary culture. An extracellular pH drop induces a transient Na(+) current followed by a sustained non-selective cation current. This current is highly sensitive to pH with an activation threshold around pH 6.9 and a pH(0.5) of 6.2. About half of the total peak current is inhibited by the spider toxin PcTX1, which is specific for homomeric ASIC1a channels. The remaining PcTX1-resistant ASIC-like current is increased by 300 microM Zn(2+) and, whereas not fully activated at pH 5, it shows a pH(0.5) of 6.0 between pH 7.4 and 5. We have previously shown that Zn(2+) is a co-activator of ASIC2a-containing channels. Thus, the hippocampal transient ASIC-like current appears to be generated by a mixture of homomeric ASIC1a channels and ASIC2a-containing channels, probably heteromeric ASIC1a+2a channels. The sustained non-selective current suggests the involvement of ASIC2b-containing heteromeric channels. Activation of the hippocampal ASIC-like current by a pH drop to 6.9 or 6.6 induces a transient depolarization which itself triggers an initial action potential (AP) followed by a sustained depolarization and trains of APs. Zn(2+) increases the acid sensitivity of ASIC channels, and consequently neuronal excitability. It is probably an important co-activator of ASIC channels in the central nervous system.

  7. Curcumin ameliorates hippocampal neuron damage induced by human immunodeficiency virus-1★

    OpenAIRE

    Tang, Hongmei; Pan, Rui; Fang, Wenli; Xing, Yanyan; Chen, Dexi; Chen, Xiaobao; Yu, Yuanyuan; Wang, Junbing; Gong, Zheng; Xiong, Guoyin; Dong, Jun

    2013-01-01

    Our previous studies have shown that infection with the gp120 V3 loop can cause human immunodeficiency virus-1 associated neurocognitive disorders. Curcumin has been shown to improve these effects to some degree, but the precise mechanisms remain unknown. The present study analyzed the neuroprotective effect and mechanism of curcumin in relation to hippocampal neurons. Results showed that 1 nmol/L gp120 V3 loop suppressed the growth of synapses. After administration of 1 μmol/L curcumin, syna...

  8. Electroconvulsive stimulation results in long-term survival of newly generated hippocampal neurons in rats

    DEFF Research Database (Denmark)

    Olesen, Mikkel Vestergaard; Wörtwein, Gitta; Folke, Jonas

    2017-01-01

    Electroconvulsive stimulation (ECS) is one of the strongest stimulators of hippocampal neurogenesis in rodents that represents a plausible mechanism for the efficacy of electroconvulsive therapy (ECT) in major depressive disorder. Using design-based stereological cell counting, we recently...... in neurogenesis facilitates the behavioral outcome of the forced swim test (FST), an animal model of depression. The results showed that ECS in conjunction with CRS stimulates hippocampal neurogenesis, and that a significant quantity of the newly formed hippocampal neurons survives up to 12 months. The new Brd......U-positive neurons showed time-dependent attrition of ∼40% from day 1 to 3 months, with no further decline between 3 and 12 months. ECS did not affect the number of pre-existing dentate granule neurons or the volume of the dentate granule cell layer, suggesting no damaging effect of the treatment. Finally, we found...

  9. Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

    Science.gov (United States)

    von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

    2012-08-01

    Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and

  10. Amnesia due to bilateral hippocampal glioblastoma

    International Nuclear Information System (INIS)

    Shimauchi, M.; Wakisaka, S.; Kinoshita, K.

    1989-01-01

    The authors report a unique case of glioblastoma which caused permanent amnesia. Magnetic resonance imaging showed the lesion to be limited to the hippocampal formation bilaterally. Although glioblastoma extends frequently into fiber pathways and expands into the opposite cerebral hemisphere, making a 'butterfly' lesion, it is unusual for it to invade the limbic system selectively to this extent. (orig.)

  11. The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

    Science.gov (United States)

    Babalola, P A; Fitz, N F; Gibbs, R B; Flaherty, P T; Li, P-K; Johnson, D A

    2012-10-01

    Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (pmemory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Cudarflavone B Provides Neuroprotection against Glutamate-Induced Mouse Hippocampal HT22 Cell Damage through the Nrf2 and PI3K/Akt Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Dong-Sung Lee

    2014-07-01

    Full Text Available Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS diseases such as Alzheimer’s disease, Parkinson’s disease, and ischemia. Nrf2 signaling-mediated heme oxygenase (HO-1 expression acts against oxidants that are thought to play a key role in the pathogenesis of neuronal diseases. Cudraflavone B is a prenylated flavone isolated from C. tricuspidata which has shown anti-proliferative activity, mouse brain monoamine oxidase (MAO inhibitory effects, apoptotic actions in human gastric carcinoma cells and mouse melanoma cells, and hepatoprotective activity. In this study, cudraflavone B showed neuroprotective effects and reactive oxygen species (ROS inhibition against glutamate-induced neurotoxicity by inducing the expression of HO-1 in mouse hippocampal HT22 cells. Furthermore, cudraflavone B caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2 and increased the promoter activity of antioxidant response elements (ARE in mouse hippocampal HT22 cells. In addition, we found that the Nrf2-midiated HO-1 expression by cudraflavone B is involved in the cell protective response and ROS reductions, and cudraflavone B-induced expression of HO-1 was mediated through the phosphatidylinositol 3-kinase (PI3K/Akt pathway in HT22 cells. Our results demonstrated the potential application of naturally occurring cudraflavone B as a therapeutic agent from neurodegenerative disease.

  13. Bigger is better! Hippocampal volume and declarative memory performance in healthy young men.

    Science.gov (United States)

    Pohlack, Sebastian T; Meyer, Patric; Cacciaglia, Raffaele; Liebscher, Claudia; Ridder, Stephanie; Flor, Herta

    2014-01-01

    The importance of the hippocampus for declarative memory processes is firmly established. Nevertheless, the issue of a correlation between declarative memory performance and hippocampal volume in healthy subjects still remains controversial. The aim of the present study was to investigate this relationship in more detail. For this purpose, 50 healthy young male participants performed the California Verbal Learning Test. Hippocampal volume was assessed by manual segmentation of high-resolution 3D magnetic resonance images. We found a significant positive correlation between putatively hippocampus-dependent memory measures like short-delay retention, long-delay retention and discriminability and percent hippocampal volume. No significant correlation with measures related to executive processes was found. In addition, percent amygdala volume was not related to any of these measures. Our data advance previous findings reported in studies of brain-damaged individuals in a large and homogeneous young healthy sample and are important for theories on the neural basis of episodic memory.

  14. Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury

    International Nuclear Information System (INIS)

    Chen, Shang-Der; Lin, Tsu-Kung; Yang, Ding-I.; Lee, Su-Ying; Shaw, Fu-Zen; Liou, Chia-Wei; Chuang, Yao-Chung

    2015-01-01

    Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616. - Highlights: • Transient global ischemia increases expression of PINK1 and p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA decreases PINK1 expression but increases p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA augments oxidative stress and neuronal damage in hippocampal CA1 subfield

  15. Roles of PTEN-induced putative kinase 1 and dynamin-related protein 1 in transient global ischemia-induced hippocampal neuronal injury

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Shang-Der, E-mail: chensd@adm.cgmh.org.tw [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Lin, Tsu-Kung [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Yang, Ding-I. [Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan (China); Lee, Su-Ying [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Shaw, Fu-Zen [Department of Psychology, National Cheng Kung University, Tainan, Taiwan (China); Liou, Chia-Wei [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Chuang, Yao-Chung, E-mail: ycchuang@adm.cgmh.org.tw [Department of Neurology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China); Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taiwan (China)

    2015-05-01

    Recent studies showed that increased mitochondrial fission is an early event of cell death during cerebral ischemia and dynamin-related protein 1 (Drp1) plays an important role in mitochondrial fission, which may be regulated by PTEN-induced putative kinase 1 (PINK1), a mitochondrial serine/threonine-protein kinase thought to protect cells from stress-induced mitochondrial dysfunction and regulate mitochondrial fission. However, the roles of PINK1 and Drp1 in hippocampal injury caused by transient global ischemia (TGI) remain unknown. We therefore tested the hypothesis that TGI may induce PINK1 causing downregulation of Drp1 phosphorylation to enhance hippocampal neuronal survival, thus functioning as an endogenous neuroprotective mechanism. We found progressively increased PINK1 expression in the hippocampal CA1 subfield1-48 h following TGI, reaching the maximal level at 4 h. Despite lack of changes in the expression level of total Drp1 and phosphor-Drp1 at Ser637, TGI induced a time-dependent increase of Drp1 phosphorlation at Ser616 that peaked after 24 h. Notably, PINK1-siRNA increased p-Drp1(Ser616) protein level in hippocampal CA1 subfield 24 h after TGI. The PINK1 siRNA also aggravated the TGI-induced oxidative DNA damage with an increased 8-hydroxy-deoxyguanosine (8-OHdG) content in hippocampal CA1 subfield. Furthermore, PINK1 siRNA also augmented TGI-induced apoptosis as evidenced by the increased numbers of TUNEL-positive staining and enhanced DNA fragmentation. These findings indicated that PINK1 is an endogenous protective mediator vital for neuronal survival under ischemic insult through regulating Drp1 phosphorylation at Ser616. - Highlights: • Transient global ischemia increases expression of PINK1 and p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA decreases PINK1 expression but increases p-Drp1 at Ser616 in hippocampal CA1 subfield. • PINK1-siRNA augments oxidative stress and neuronal damage in hippocampal CA1 subfield.

  16. A grading system for hippocampal sclerosis based on the degree of hippocampal mossy fiber sprouting

    NARCIS (Netherlands)

    Gispen, W.H.; Proper, E.A.; Jansen, G.H.; Veelen, C.W. van; Rijen, P.C. van; Graan, P.N.E. de

    2001-01-01

    Abstract. In patients suffering from temporal lobe epilepsy (TLE) a highly variable degree of hippocampal sclerosis (HS) can be observed. For standard neuropathological evaluation after hippocampal resection, neuronal cell loss in the hippocampal subareas is assessed (Wyler score 0-4) [Wyler et al.

  17. Bark chemical analysis explains selective bark damage by rodents

    Czech Academy of Sciences Publication Activity Database

    Heroldová, Marta; Jánová, Eva; Suchomel, J.; Purchart, L.; Homolka, Miloslav

    2009-01-01

    Roč. 2, č. 2 (2009), s. 137-140 ISSN 1803-2451 R&D Projects: GA MZe QH72075 Institutional research plan: CEZ:AV0Z60930519 Keywords : bark damage * bark selection * bark chemical analysis * rowan * beech * spruce * mountain forest regeneration Subject RIV: GK - Forestry

  18. Possible Role of the Glycogen Synthase Kinase-3 Signaling Pathway in Trimethyltin-Induced Hippocampal Neurodegeneration in Mice

    Science.gov (United States)

    Kim, Sung-Ho; Kim, Jong-Choon; Wang, Hongbing; Shin, Taekyun; Moon, Changjong

    2013-01-01

    Trimethyltin (TMT) is an organotin compound with potent neurotoxic effects characterized by neuronal destruction in selective regions, including the hippocampus. Glycogen synthase kinase-3 (GSK-3) regulates many cellular processes, and is implicated in several neurodegenerative disorders. In this study, we evaluated the therapeutic effect of lithium, a selective GSK-3 inhibitor, on the hippocampus of adult C57BL/6 mice with TMT treatment (2.6 mg/kg, intraperitoneal [i.p.]) and on cultured hippocampal neurons (12 days in vitro) with TMT treatment (5 µM). Lithium (50 mg/kg, i.p., 0 and 24 h after TMT injection) significantly attenuated TMT-induced hippocampal cell degeneration, seizure, and memory deficits in mice. In cultured hippocampal neurons, lithium treatment (0–10 mM; 1 h before TMT application) significantly reduced TMT-induced cytotoxicity in a dose-dependent manner. Additionally, the dynamic changes in GSK-3/β-catenin signaling were observed in the mouse hippocampus and cultured hippocampal neurons after TMT treatment with or without lithium. Therefore, lithium inhibited the detrimental effects of TMT on the hippocampal neurons in vivo and in vitro, suggesting involvement of the GSK-3/β-catenin signaling pathway in TMT-induced hippocampal cell degeneration and dysfunction. PMID:23940567

  19. Changes in Context-Specificity during Memory Reconsolidation: Selective Effects of Hippocampal Lesions

    Science.gov (United States)

    Winocur, Gordon; Frankland, Paul W.; Sekeres, Melanie; Fogel, Stuart; Moscovitch, Morris

    2009-01-01

    After acquisition, memories associated with contextual fear conditioning pass through a labile phase, in which they are vulnerable to hippocampal lesions, to a more stable state, via consolidation, in which they engage extrahippocampal structures and are resistant to such disruption. The process is accompanied by changes in the form of the memory…

  20. Memory reconsolidation mediates the updating of hippocampal memory content

    Directory of Open Access Journals (Sweden)

    Jonathan L C Lee

    2010-11-01

    Full Text Available The retrieval or reactivation of a memory places it into a labile state, requiring a process of reconsolidation to restabilize it. This retrieval-induced plasticity is a potential mechanism for the modification of the existing memory. Following previous data supportive of a functional role for memory reconsolidation in the modification of memory strength, here I show that hippocampal memory reconsolidation also supports the updating of contextual memory content. Using a procedure that separates the learning of pure context from footshock-motivated contextual fear learning, I demonstrate doubly dissociable hippocampal mechanisms of initial context learning and subsequent updating of the neutral contextual representation to incorporate the footshock. Contextual memory consolidation was dependent upon BDNF expression in the dorsal hippocampus, whereas the footshock modification of the contextual representation required the expression of Zif268. These mechanisms match those previously shown to be selectively involved in hippocampal memory consolidation and reconsolidation, respectively. Moreover, memory reactivation is a necessary step in modifying memory content, as inhibition of hippocampal synaptic protein degradation also prevented the footshock-mediated memory modification. Finally, dorsal hippocampal knockdown of Zif268 impaired the reconsolidation of the pure contextual memory only under conditions of weak context memory training, as well as failing to disrupt contextual freezing when a strong contextual fear memory is reactivated by further conditioning. Therefore, an adaptive function of the reactivation and reconsolidation process is to enable the updating of memory content.

  1. Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Ning-Ning Song

    2017-06-01

    Full Text Available The central serotonin (5-HT system is the main target of selective serotonin reuptake inhibitors (SSRIs, the first-line antidepressants widely used in current general practice. One of the prominent features of chronic SSRI treatment in rodents is the enhanced adult neurogenesis in the hippocampus, which has been proposed to contribute to antidepressant effects. Therefore, tremendous effort has been made to decipher how central 5-HT regulates adult hippocampal neurogenesis. In this paper, we review how changes in the central serotonergic system alter adult hippocampal neurogenesis. We focus on data obtained from three categories of genetically engineered mouse models: (1 mice with altered central 5-HT levels from embryonic stages, (2 mice with deletion of 5-HT receptors from embryonic stages, and (3 mice with altered central 5-HT system exclusively in adulthood. These recent findings provide unique insights to interpret the multifaceted roles of central 5-HT on adult hippocampal neurogenesis and its associated effects on depression.

  2. Ablation of NMDA receptors enhances the excitability of hippocampal CA3 neurons.

    Directory of Open Access Journals (Sweden)

    Fumiaki Fukushima

    Full Text Available Synchronized discharges in the hippocampal CA3 recurrent network are supposed to underlie network oscillations, memory formation and seizure generation. In the hippocampal CA3 network, NMDA receptors are abundant at the recurrent synapses but scarce at the mossy fiber synapses. We generated mutant mice in which NMDA receptors were abolished in hippocampal CA3 pyramidal neurons by postnatal day 14. The histological and cytological organizations of the hippocampal CA3 region were indistinguishable between control and mutant mice. We found that mutant mice lacking NMDA receptors selectively in CA3 pyramidal neurons became more susceptible to kainate-induced seizures. Consistently, mutant mice showed characteristic large EEG spikes associated with multiple unit activities (MUA, suggesting enhanced synchronous firing of CA3 neurons. The electrophysiological balance between fast excitatory and inhibitory synaptic transmission was comparable between control and mutant pyramidal neurons in the hippocampal CA3 region, while the NMDA receptor-slow AHP coupling was diminished in the mutant neurons. In the adult brain, inducible ablation of NMDA receptors in the hippocampal CA3 region by the viral expression vector for Cre recombinase also induced similar large EEG spikes. Furthermore, pharmacological blockade of CA3 NMDA receptors enhanced the susceptibility to kainate-induced seizures. These results raise an intriguing possibility that hippocampal CA3 NMDA receptors may suppress the excitability of the recurrent network as a whole in vivo by restricting synchronous firing of CA3 neurons.

  3. Control theory-based regulation of hippocampal CA1 nonlinear dynamics.

    Science.gov (United States)

    Hsiao, Min-Chi; Song, Dong; Berger, Theodore W

    2008-01-01

    We are developing a biomimetic electronic neural prosthesis to replace regions of the hippocampal brain area that have been damaged by disease or insult. Our previous study has shown that the VLSI implementation of a CA3 nonlinear dynamic model can functionally replace the CA3 subregion of the hippocampal slice. As a result, the propagation of temporal patterns of activity from DG-->VLSI-->CA1 reproduces the activity observed experimentally in the biological DG-->CA3-->CA1 circuit. In this project, we incorporate an open-loop controller to optimize the output (CA1) response. Specifically, we seek to optimize the stimulation signal to CA1 using a predictive dentate gyrus (DG)-CA1 nonlinear model (i.e., DG-CA1 trajectory model) and a CA1 input-output model (i.e., CA1 plant model), such that the ultimate CA1 response (i.e., desired output) can be first predicted by the DG-CA1 trajectory model and then transformed to the desired stimulation through the inversed CA1 plant model. Lastly, the desired CA1 output is evoked by the estimated optimal stimulation. This study will be the first stage of formulating an integrated modeling-control strategy for the hippocampal neural prosthetic system.

  4. Concentration-dependent effects of fullerenol on cultured hippocampal neuron viability

    Directory of Open Access Journals (Sweden)

    Zha YY

    2012-06-01

    Full Text Available Ying-ying Zha,1 Bo Yang,1 Ming-liang Tang,2 Qiu-chen Guo,1 Ju-tao Chen,1 Long-ping Wen,3 Ming Wang11CAS Key Laboratory of Brain Function and Disease, School of Life Sciences, University of Science and Technology of China, Hefei, 2Suzhou Institute of NanoTech and NanoBionics, Chinese Academy of Sciences, Suzhou, 3Laboratory of Nano-biology, School of Life Sciences, University of Science and Technology of China, Hefei, People's Republic of ChinaBackground: Recent studies have shown that the biological actions and toxicity of the water-soluble compound, polyhydroxyfullerene (fullerenol, are related to the concentrations present at a particular site of action. This study investigated the effects of different concentrations of fullerenol on cultured rat hippocampal neurons.Methods and results: Fullerenol at low concentrations significantly enhanced hippocampal neuron viability as tested by MTT assay and Hoechst 33342/propidium iodide double stain detection. At high concentrations, fullerenol induced apoptosis confirmed by Comet assay and assessment of caspase proteins.Conclusion: These findings suggest that fullerenol promotes cell death and protects against cell damage, depending on the concentration present. The concentration-dependent effects of fullerenol were mainly due to its influence on the reduction-oxidation pathway.Keywords: fullerenol, nanomaterial, neurotoxicity, neuroprotection, hippocampal neuron

  5. Opposing Effects of α2- and β-Adrenergic Receptor Stimulation on Quiescent Neural Precursor Cell Activity and Adult Hippocampal Neurogenesis

    Science.gov (United States)

    Prosper, Boris W.; Marathe, Swanand; Husain, Basma F. A.; Kernie, Steven G.; Bartlett, Perry F.; Vaidya, Vidita A.

    2014-01-01

    Norepinephrine regulates latent neural stem cell activity and adult hippocampal neurogenesis, and has an important role in modulating hippocampal functions such as learning, memory and mood. Adult hippocampal neurogenesis is a multi-stage process, spanning from the activation and proliferation of hippocampal stem cells, to their differentiation into neurons. However, the stage-specific effects of noradrenergic receptors in regulating adult hippocampal neurogenesis remain poorly understood. In this study, we used transgenic Nestin-GFP mice and neurosphere assays to show that modulation of α2- and β-adrenergic receptor activity directly affects Nestin-GFP/GFAP-positive precursor cell population albeit in an opposing fashion. While selective stimulation of α2-adrenergic receptors decreases precursor cell activation, proliferation and immature neuron number, stimulation of β-adrenergic receptors activates the quiescent precursor pool and enhances their proliferation in the adult hippocampus. Furthermore, our data indicate no major role for α1-adrenergic receptors, as we did not observe any change in either the activation and proliferation of hippocampal precursors following selective stimulation or blockade of α1-adrenergic receptors. Taken together, our data suggest that under physiological as well as under conditions that lead to enhanced norepinephrine release, the balance between α2- and β-adrenergic receptor activity regulates precursor cell activity and hippocampal neurogenesis. PMID:24922313

  6. Selective logging and damage to unharvested trees in a hyrcanian forest of Iran

    OpenAIRE

    Farshad Keivan Behjou; Omid Ghafarzade Mollabashi

    2012-01-01

    Selective logging in mature hardwood stands of Caspian forests often causes physical damage to residual trees through felling and skidding operations, resulting in a decline in bole quality and subsequent loss of tree value. This study evaluated the logging damage to residual trees following logging operations. A total density of 5.1 trees/ha and 17.3 m3/ha of wood were harvested. On average, 9.8 trees were damaged for every tree extracted, including 8 trees destroyed or severely damaged. The...

  7. Logging damage using an individual tree selection practice in Appalachian hardwood stands

    Science.gov (United States)

    Neil I. Lamson; H. Clay Smith; Gary W. Miller

    1985-01-01

    Four West Virginia hardwood stands, managed using individual-tree selection for the past 30 years, were examined after the third and, in one instance, the fourth periodic harvest to determine the severity of logging damage. On existing skid roads, trees were removed with a rubber-tired skidder or a crawler tractor with a rubber-tired arch. Logging damage reduced...

  8. Subregional Hippocampal Morphology and Psychiatric Outcome in Adolescents Who Were Born Very Preterm and at Term.

    Directory of Open Access Journals (Sweden)

    James H Cole

    Full Text Available The hippocampus has been reported to be structurally and functionally altered as a sequel of very preterm birth (<33 weeks gestation, possibly due its vulnerability to hypoxic-ischemic damage in the neonatal period. We examined hippocampal volumes and subregional morphology in very preterm born individuals in mid- and late adolescence and their association with psychiatric outcome.Structural brain magnetic resonance images were acquired at two time points (baseline and follow-up from 65 ex-preterm adolescents (mean age = 15.5 and 19.6 years and 36 term-born controls (mean age=15.0 and 19.0 years. Hippocampal volumes and subregional morphometric differences were measured from manual tracings and with three-dimensional shape analysis. Psychiatric outcome was assessed with the Rutter Parents' Scale at baseline, the General Health Questionnaire at follow-up and the Peters Delusional Inventory at both time points.In contrast to previous studies we did not find significant difference in the cross-sectional or longitudinal hippocampal volumes between individuals born preterm and controls, despite preterm individual having significantly smaller whole brain volumes. Shape analysis at baseline revealed subregional deformations in 28% of total bilateral hippocampal surface, reflecting atrophy, in ex-preterm individuals compared to controls, and in 22% at follow-up. In ex-preterm individuals, longitudinal changes in hippocampal shape accounted for 11% of the total surface, while in controls they reached 20%. In the whole sample (both groups larger right hippocampal volume and bilateral anterior surface deformations at baseline were associated with delusional ideation scores at follow-up.This study suggests a dynamic association between cross-sectional hippocampal volumes, longitudinal changes and surface deformations and psychosis proneness.

  9. Sustained Na+/H+ exchanger activation promotes gliotransmitter release from reactive hippocampal astrocytes following oxygen-glucose deprivation.

    Directory of Open Access Journals (Sweden)

    Pelin Cengiz

    Full Text Available Hypoxia ischemia (HI-related brain injury is the major cause of long-term morbidity in neonates. One characteristic hallmark of neonatal HI is the development of reactive astrogliosis in the hippocampus. However, the impact of reactive astrogliosis in hippocampal damage after neonatal HI is not fully understood. In the current study, we investigated the role of Na(+/H(+ exchanger isoform 1 (NHE1 protein in mouse reactive hippocampal astrocyte function in an in vitro ischemia model (oxygen/glucose deprivation and reoxygenation, OGD/REOX. 2 h OGD significantly increased NHE1 protein expression and NHE1-mediated H(+ efflux in hippocampal astrocytes. NHE1 activity remained stimulated during 1-5 h REOX and returned to the basal level at 24 h REOX. NHE1 activation in hippocampal astrocytes resulted in intracellular Na(+ and Ca(2+ overload. The latter was mediated by reversal of Na(+/Ca(2+ exchange. Hippocampal astrocytes also exhibited a robust release of gliotransmitters (glutamate and pro-inflammatory cytokines IL-6 and TNFα during 1-24 h REOX. Interestingly, inhibition of NHE1 activity with its potent inhibitor HOE 642 not only reduced Na(+ overload but also gliotransmitter release from hippocampal astrocytes. The noncompetitive excitatory amino acid transporter inhibitor TBOA showed a similar effect on blocking the glutamate release. Taken together, we concluded that NHE1 plays an essential role in maintaining H(+ homeostasis in hippocampal astrocytes. Over-stimulation of NHE1 activity following in vitro ischemia disrupts Na(+ and Ca(2+ homeostasis, which reduces Na(+-dependent glutamate uptake and promotes release of glutamate and cytokines from reactive astrocytes. Therefore, blocking sustained NHE1 activation in reactive astrocytes may provide neuroprotection following HI.

  10. Comparison of Hippocampal Volume in Dementia Subtypes

    International Nuclear Information System (INIS)

    Vijayakumar, Avinash; Vijayakumar, Abhishek

    2012-01-01

    Aims. To examine the relationship between different types of dementia and hippocampal volume. Methods. Hippocampal volume was measured using FL3D sequence magnetic resonance imaging in 26 Alzheimer's, vascular dementia, mixed dementia, and normal pressure hydrocephalus patients and 15 healthy controls and also hippocampal ratio, analyzed. Minimental scale was used to stratify patients on cognitive function impairments. Results. Hippocampal volume and ratio was reduced by 25% in Alzheimer's disease, 21% in mixed dementia, 11% in vascular dementia and 5% in normal pressure hydrocephalus in comparison to control. Also an asymmetrical decrease in volume of left hippocampus was noted. The severity of dementia increased in accordance to decreasing hippocampal volume. Conclusion. Measurement in hippocampal volume may facilitate in differentiating different types of dementia and in disease progression. There was a correlation between hippocampal volume and severity of cognitive impairment

  11. Distribution of seratonin-1A receptors in the monkey and the postmortem human hippocampal region. A quantitative autoradiographic study using the selective agonist (3H)8-PH-DPAT

    International Nuclear Information System (INIS)

    Koehler, Christer; Radesaeter, A.C.; Lang, Walter; Chan-Palay, Victoria

    1986-01-01

    Serotonin-1A receptors were visualized and their anatomical distribution mapped within the monkey and the human hippocampus by using in vitro receptor autoradiography of the selective agonist ( 3 H)8-OH-N, N-dipropyl-2-aminotetralin (( 3 H)8-OH-DPAT). The results show high densities of serotonin-1A receptors hetergeneously distributed in different subfields and layers of the monkey and the human hippocampal region. High densities are found in the molecular layer of area dentata, all layers of regio superior and the subiculum, parasubiculum, and layers 2, and 4 through 6 of the entorhinal area. In the human hippocampus, a distinct band of ( 3 H)8-OH-DPAT binding sites is present in the subgranular zone of the area dentata. The similar anatomical distribution of ( 3 H)8-OH-DPAT binding sites in the monkey and the human hippocampal region suggests that the serotonin-1A receptor is phylogenetically well preserved and indicates that this receptor may mediate action(s) of serotonin in the primate, including the human hippocampal region. (author)

  12. Mutant APP and Amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease.

    Science.gov (United States)

    Reddy, P Hemachandra; Yin, XiangLin; Manczak, Maria; Kumar, Subodh; Jangampalli Adi, Pradeepkiran; Vijayan, Murali; Reddy, Arubala P

    2018-04-25

    The purpose of our study was to determine the toxic effects of hippocampal mutant APP and amyloid beta (Aβ) in human mutant APP (mAPP) cDNA transfected with primary mouse hippocampal neurons (HT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative RT-PCR, immunoblotting & immunofluorescence, and transmission electron microscopy, we assessed mRNA and protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2, and assessed mitochondrial number and length in mAPP-HT22 cells that express Swedish/Indiana mutations. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial ATP. Increased levels of mRNA and protein levels of mitochondrial fission genes, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1α, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), mitophagy (PINK1 & TERT, BCL2 & BNIPBL), synaptic (synaptophysin & PSD95) and dendritic (MAP2) genes were found in mAPP-HT22 cells relative to WT-HT22 cells. Cell survival was significantly reduced mAPP-HT22 cells. GTPase-Dp1 enzymatic activity was increased in mAPP-HT22 cells. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells. These findings suggest that hippocampal accumulation of mutant APP and Aβ is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and mitochondrial structural and functional changes in mutant APP hippocampal cells. These observations strongly suggest that accumulation of mAPP and A

  13. Reduced hippocampal volume is associated with overgeneralization of negative context in individuals with PTSD.

    Science.gov (United States)

    Levy-Gigi, Einat; Szabo, Csilla; Richter-Levin, Gal; Kéri, Szabolcs

    2015-01-01

    Previous studies demonstrated reduced hippocampal volume in individuals with posttraumatic stress disorder (PTSD). However, the functional role the hippocampus plays in PTSD symptomatology is still unclear. The aim of the present study was to explore generalization learning and its connection to hippocampal volume in individuals with and without PTSD. Animal and human models argue that hippocampal deficit may result in failure to process contextual information. Therefore we predicted associations between reduced hippocampal volume and overgeneralization of context in individuals with PTSD. We conducted MRI scans of bilateral hippocampal and amygdala formations as well as intracranial and total brain volumes. Generalization was measured using a novel-learning paradigm, which separately evaluates generalization of cue and context in conditions of negative and positive outcomes. As expected, MRI scans indicated reduced hippocampal volume in PTSD compared to non-PTSD participants. Behavioral results revealed a selective deficit in context generalization learning in individuals with PTSD, F(1, 43) = 8.27, p < .01, η(p)² = .16. Specifically, as predicted, while generalization of cue was spared in both groups, individuals with PTSD showed overgeneralization of negative context. Hence, they could not learn that a previously negative context is later associated with a positive outcome, F(1, 43) = 7.33, p = .01, η(p)² = .15. Most importantly, overgeneralization of negative context significantly correlated with right and left hippocampal volume (r = .61, p = .000; r = .5, p = .000). Finally, bilateral hippocampal volume provided the strongest prediction of overgeneralization of negative context. Reduced hippocampal volume may account for the difficulty of individuals with PTSD to differentiate negative and novel conditions and hence may facilitate reexperiencing symptoms. PsycINFO Database Record (c) 2015 APA, all rights reserved.

  14. Novel Roles for the Insulin-Regulated Glucose Transporter-4 in Hippocampally Dependent Memory.

    Science.gov (United States)

    Pearson-Leary, Jiah; McNay, Ewan C

    2016-11-23

    The insulin-regulated glucose transporter-4 (GluT4) is critical for insulin- and contractile-mediated glucose uptake in skeletal muscle. GluT4 is also expressed in some hippocampal neurons, but its functional role in the brain is unclear. Several established molecular modulators of memory processing regulate hippocampal GluT4 trafficking and hippocampal memory formation is limited by both glucose metabolism and insulin signaling. Therefore, we hypothesized that hippocampal GluT4 might be involved in memory processes. Here, we show that, in male rats, hippocampal GluT4 translocates to the plasma membrane after memory training and that acute, selective intrahippocampal inhibition of GluT4-mediated glucose transport impaired memory acquisition, but not memory retrieval. Other studies have shown that prolonged systemic GluT4 blockade causes insulin resistance. Unexpectedly, we found that prolonged hippocampal blockade of glucose transport through GluT4-upregulated markers of hippocampal insulin signaling prevented task-associated depletion of hippocampal glucose and enhanced both working and short-term memory while also impairing long-term memory. These effects were accompanied by increased expression of hippocampal AMPA GluR1 subunits and the neuronal GluT3, but decreased expression of hippocampal brain-derived neurotrophic factor, consistent with impaired ability to form long-term memories. Our findings are the first to show the cognitive impact of brain GluT4 modulation. They identify GluT4 as a key regulator of hippocampal memory processing and also suggest differential regulation of GluT4 in the hippocampus from that in peripheral tissues. The role of insulin-regulated glucose transporter-4 (GluT4) in the brain is unclear. In the current study, we demonstrate that GluT4 is a critical component of hippocampal memory processes. Memory training increased hippocampal GluT4 translocation and memory acquisition was impaired by GluT4 blockade. Unexpectedly, whereas long

  15. The relationship between hippocampal asymmetry and temperament in adolescent borderline and antisocial personality pathology.

    Science.gov (United States)

    Jovev, Martina; Whittle, Sarah; Yücel, Murat; Simmons, Julian Guy; Allen, Nicholas B; Chanen, Andrew M

    2014-02-01

    Investigating etiological processes early in the life span represents an important step toward a better understanding of the development of personality pathology. The current study evaluated the interaction between an individual difference risk factor (i.e., temperament) and a biological risk factor for aggressive behavior (i.e., atypical [larger] rightward hippocampal asymmetry) in predicting the emergence of borderline personality disorder (BPD) and antisocial personality disorder symptoms during early adolescence. The sample consisted of 153 healthy adolescents (M = 12.6 years, SD = 0.4, range = 11.4-13.7) who were selected from a larger sample to maximize variation in temperament. Interactions between four temperament factors (effortful control, negative affectivity, surgency, and affiliativeness), based on the Early Adolescent Temperament Questionnaire-Revised, and volumetric measures of hippocampal asymmetry were examined as cross-sectional predictors of BPD and antisocial personality disorder symptoms. Boys were more likely to have elevated BPD symptoms if they were high on affiliation and had larger rightward hippocampal asymmetry. In boys, low affiliation was a significant predictor of BPD symptoms in the presence of low rightward hippocampal asymmetry. For girls, low effortful control was associated with elevated BPD symptoms in the presence of atypical rightward hippocampal asymmetry. This study builds on previous work reporting significant associations between atypical hippocampal asymmetry and poor behavioral regulation.

  16. Novel genetic loci associated with hippocampal volume.

    Science.gov (United States)

    Hibar, Derrek P; Adams, Hieab H H; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L; Hofer, Edith; Renteria, Miguel E; Bis, Joshua C; Arias-Vasquez, Alejandro; Ikram, M Kamran; Desrivières, Sylvane; Vernooij, Meike W; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H; Beiser, Alexa; Bernard, Manon; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Gutman, Boris A; Hass, Johanna; Haukvik, Unn K; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre F; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; McKay, David R; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C; Nyquist, Paul; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Saremi, Arvin; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Craen, Anton J M; De Geus, Eco J C; De Jager, Philip L; De Zubicaray, Greig I; Deary, Ian J; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Hulshoff Pol, Hilleke E; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J A; Van Haren, Neeltje E M; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Vellas, Bruno; Veltman, Dick J; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, Ronald H; Zonderman, Alan B; Martin, Nicholas G; Van Duijn, Cornelia M; Wright, Margaret J; Longstreth, W T; Schumann, Gunter; Grabe, Hans J; Franke, Barbara; Launer, Lenore J; Medland, Sarah E; Seshadri, Sudha; Thompson, Paul M; Ikram, M Arfan

    2017-01-18

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (r g =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

  17. Novel genetic loci associated with hippocampal volume

    OpenAIRE

    Hibar, Derrek P.; Adams, Hieab H. H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C.; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivieres, Sylvane; Vernooij, Meike W.; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf

    2017-01-01

    International audience; The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal ...

  18. Amnesia due to bilateral hippocampal glioblastoma. MRI finding

    Energy Technology Data Exchange (ETDEWEB)

    Shimauchi, M.; Wakisaka, S.; Kinoshita, K. (Miyazaki Medical Coll., Kiyotake (Japan). Dept. of Neurosurgery)

    1989-11-01

    The authors report a unique case of glioblastoma which caused permanent amnesia. Magnetic resonance imaging showed the lesion to be limited to the hippocampal formation bilaterally. Although glioblastoma extends frequently into fiber pathways and expands into the opposite cerebral hemisphere, making a 'butterfly' lesion, it is unusual for it to invade the limbic system selectively to this extent. (orig.).

  19. Selective axonal growth of embryonic hippocampal neurons according to topographic features of various sizes and shapes

    Directory of Open Access Journals (Sweden)

    Christine E Schmidt

    2010-12-01

    Full Text Available David Y Fozdar1*, Jae Y Lee2*, Christine E Schmidt2–6, Shaochen Chen1,3–5,7,1Departments of Mechanical Engineering, 2Chemical Engineering, 3Biomedical Engineering; 4Center for Nano Molecular Science and Technology; 5Texas Materials Institute; 6Institute of Neuroscience; 7Microelectronics Research Center, The University of Texas at Austin, Austin, TX, USA *Contributed equally to this workPurpose: Understanding how surface features influence the establishment and outgrowth of the axon of developing neurons at the single cell level may aid in designing implantable scaffolds for the regeneration of damaged nerves. Past studies have shown that micropatterned ridge-groove structures not only instigate axon polarization, alignment, and extension, but are also preferred over smooth surfaces and even neurotrophic ligands.Methods: Here, we performed axonal-outgrowth competition assays using a proprietary four-quadrant topography grid to determine the capacity of various micropatterned topographies to act as stimuli sequestering axon extension. Each topography in the grid consisted of an array of microscale (approximately 2 µm or submicroscale (approximately 300 nm holes or lines with variable dimensions. Individual rat embryonic hippocampal cells were positioned either between two juxtaposing topographies or at the borders of individual topographies juxtaposing unpatterned smooth surface, cultured for 24 hours, and analyzed with respect to axonal selection using conventional imaging techniques.Results: Topography was found to influence axon formation and extension relative to smooth surface, and the distance of neurons relative to topography was found to impact whether the topography could serve as an effective cue. Neurons were also found to prefer submicroscale over microscale features and holes over lines for a given feature size.Conclusion: The results suggest that implementing physical cues of various shapes and sizes on nerve guidance conduits

  20. Organotypic hippocampal slice cultures for studies of brain damage, neuroprotection and neurorepair

    DEFF Research Database (Denmark)

    Noraberg, Jens; Poulsen, Frantz Rom; Blaabjerg, Morten

    2005-01-01

    Slices of developing brain tissue can be grown for several weeks as so-called organotypic slice cultures. Here we summarize and review studies using hippocampal slice cultures to investigate mechanisms and treatment strategies for the neurodegenerative disorders like stroke (cerebral ischemia......), Alzheimer's disease (AD) and epilepsia. Studies of non-excitotoxic neurotoxic compounds and the experimental use of slice cultures in studies of HIV neurotoxicity, traumatic brain injury (TBI) and neurogenesis are included. For cerebral ischemia, experimental models with oxygen-glucose deprivation (OGD......) and exposure to glutamate receptor agonists (excitotoxins) are reviewed. For epilepsia, focus is on induction of seizures with effects on neuronal loss, axonal sprouting and neurogenesis. For Alzheimer's disease, the review centers on the use of beta-amyloid (Abeta) in different models, while the section...

  1. Behavioral inhibition in childhood predicts smaller hippocampal volume in adolescent offspring of parents with panic disorder

    Science.gov (United States)

    Schwartz, C E; Kunwar, P S; Hirshfeld-Becker, D R; Henin, A; Vangel, M G; Rauch, S L; Biederman, J; Rosenbaum, J F

    2015-01-01

    Behavioral inhibition (BI) is a genetically influenced behavioral profile seen in 15–20% of 2-year-old children. Children with BI are timid with people, objects and situations that are novel or unfamiliar, and are more reactive physiologically to these challenges as evidenced by higher heart rate, pupillary dilation, vocal cord tension and higher levels of cortisol. BI predisposes to the later development of anxiety, depression and substance abuse. Reduced hippocampal volumes have been observed in anxiety disorders, depression and posttraumatic stress disorder. Animal models have demonstrated that chronic stress can damage the hippocampal formation and implicated cortisol in these effects. We, therefore, hypothesized that the hippocampi of late adolescents who had been behaviorally inhibited as children would be smaller compared with those who had not been inhibited. Hippocampal volume was measured with high-resolution structural magnetic resonance imaging in 43 females and 40 males at 17 years of age who were determined to be BI+ or BI− based on behaviors observed in the laboratory as young children. BI in childhood predicted reduced hippocampal volumes in the adolescents who were offspring of parents with panic disorder, or panic disorder with comorbid major depression. We discuss genetic and environmental factors emanating from both child and parent that may explain these findings. To the best of our knowledge, this is the first study to demonstrate a relationship between the most extensively studied form of temperamentally based human trait anxiety, BI, and hippocampal structure. The reduction in hippocampal volume, as reported by us, suggests a role for the hippocampus in human trait anxiety and anxiety disorder that warrants further investigation. PMID:26196438

  2. Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Xiang Gao

    Full Text Available Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI. Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.

  3. Short-term exposure to a diet high in fat and sugar, or liquid sugar, selectively impairs hippocampal-dependent memory, with differential impacts on inflammation.

    Science.gov (United States)

    Beilharz, J E; Maniam, J; Morris, M J

    2016-06-01

    Chronic high-energy diets are known to induce obesity and impair memory; these changes have been associated with inflammation in brain areas crucial for memory. In this study, we investigated whether inflammation could also be related to diet-induced memory deficits, prior to obesity. We exposed rats to chow, chow supplemented with a 10% sucrose solution (Sugar) or a diet high in fat and sugar (Caf+Sugar) and assessed hippocampal-dependent and perirhinal-dependent memory at 1 week. Both high-energy diet groups displayed similar, selective hippocampal-dependent memory deficits despite the Caf+Sugar rats consuming 4-5 times more energy, and weighing significantly more than the other groups. Extreme weight gain and excessive energy intake are therefore not necessary for deficits in memory. Weight gain across the diet period however, was correlated with the memory deficits, even in the Chow rats. The Sugar rats had elevated expression of a number of inflammatory genes in the hippocampus and WAT compared to Chow and Caf+Sugar rats but not in the perirhinal cortex or hypothalamus. Blood glucose concentrations were also elevated in the Sugar rats, and were correlated with the hippocampal inflammatory markers. Together, these results indicate that liquid sugar can rapidly elevate markers of central and peripheral inflammation, in association with hyperglycemia, and this may be related to the memory deficits in the Sugar rats. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Hippocampal Atrophy Is Associated with Altered Hippocampus-Posterior Cingulate Cortex Connectivity in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis.

    Science.gov (United States)

    Shih, Y C; Tseng, C E; Lin, F-H; Liou, H H; Tseng, W Y I

    2017-03-01

    Unilateral mesial temporal lobe epilepsy and hippocampal sclerosis have structural and functional abnormalities in the mesial temporal regions. To gain insight into the pathophysiology of the epileptic network in mesial temporal lobe epilepsy with hippocampal sclerosis, we aimed to clarify the relationships between hippocampal atrophy and the altered connection between the hippocampus and the posterior cingulate cortex in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Fifteen patients with left mesial temporal lobe epilepsy with hippocampal sclerosis and 15 healthy controls were included in the study. Multicontrast MR imaging, including high-resolution T1WI, diffusion spectrum imaging, and resting-state fMRI, was performed to measure the hippocampal volume, structural connectivity of the inferior cingulum bundle, and intrinsic functional connectivity between the hippocampus and the posterior cingulate cortex, respectively. Compared with controls, patients had decreased left hippocampal volume (volume ratio of the hippocampus and controls, 0.366% ± 0.029%; patients, 0.277% ± 0.063%, corrected P = .002), structural connectivity of the bilateral inferior cingulum bundle (generalized fractional anisotropy, left: controls, 0.234 ± 0.020; patients, 0.193 ± 0.022, corrected P = .0001, right: controls, 0.226 ± 0.022; patients, 0.208 ± 0.017, corrected P = .047), and intrinsic functional connectivity between the left hippocampus and the left posterior cingulate cortex (averaged z-value: controls, 0.314 ± 0.152; patients, 0.166 ± 0.062). The left hippocampal volume correlated with structural connectivity positively (standardized β = 0.864, P = .001), but it had little correlation with intrinsic functional connectivity (standardized β = -0.329, P = .113). On the contralesional side, the hippocampal volume did not show any significant correlation with structural connectivity or intrinsic functional connectivity ( F 2,12 = 0.284, P = .757, R 2

  5. Palmitoylethanolamide Ameliorates Hippocampal Damage and Behavioral Dysfunction After Perinatal Asphyxia in the Immature Rat Brain

    Directory of Open Access Journals (Sweden)

    María I. Herrera

    2018-03-01

    Full Text Available Perinatal asphyxia (PA is an obstetric complication associated with an impaired gas exchange. This health problem continues to be a determinant of neonatal mortality and neurodevelopmental disorders. Palmitoylethanolamide (PEA has exerted neuroprotection in several models of brain injury and neurodegeneration. We aimed at evaluating the potential neuroprotective role of PEA in an experimental model, which induces PA in the immature rat brain. PA was induced by placing Sprague Dawley newborn rats in a water bath at 37°C for 19 min. Once their physiological conditions improved, they were given to surrogate mothers that had delivered normally within the last 24 h. The control group was represented by non-fostered vaginally delivered pups, mimicking the clinical situation. Treatment with PEA (10 mg/kg was administered within the first hour of life. Modifications in the hippocampus were analyzed with conventional electron microscopy, immunohistochemistry (for NeuN, pNF-H/M, MAP-2, and GFAP and western blot (for pNF H/M, MAP-2, and GFAP. Behavior was also studied throughout Open Field (OF Test, Passive Avoidance (PA Task and Elevated Plus Maze (EPM Test. After 1 month of the PA insult, we observed neuronal nucleus degeneration in CA1 using electron microscopy. Immunohistochemistry revealed a significant increase in pNF-H/M and decrease in MAP-2 in CA1 reactive area. These changes were also observed when analyzing the level of expression of these markers by western blot. Vertical exploration impairments and anxiety-related behaviors were encountered in the OF and EPM tests. PEA treatment attenuated PA-induced hippocampal damage and its corresponding behavioral alterations. These results contribute to the elucidation of PEA neuroprotective role after PA and the future establishment of therapeutic strategies for the developing brain.

  6. Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory.

    Science.gov (United States)

    Vetere, Gisella; Barbato, Christian; Pezzola, Silvia; Frisone, Paola; Aceti, Massimiliano; Ciotti, MariaTeresa; Cogoni, Carlo; Ammassari-Teule, Martine; Ruberti, Francesca

    2014-12-01

    Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc.

  7. Transsylvian selective amygdalohippocampectomy in children with hippocampal sclerosis: seizure, intellectual and memory outcome.

    Science.gov (United States)

    Beaton, Anne E; Durnford, Andrew; Heffer-Rahn, Phillip E; Kirkham, Fenella; Griffin, Angela; Gray, William P; Gray, W L S

    2012-11-01

    This study investigates the efficacy of transylvian selective amygdalohippocampectomy (TS SAH) in children with medically intractable epilepsy due to unilateral hippocampal sclerosis. Post-surgical seizure control, intellectual and memory outcomes are examined. This study reports on pre- and post-surgical clinical data from 10 patients who underwent TS SAH between 2002 and 2010 after 24 months follow-up. Pre- and post-operative change in seizure frequency, AED use, intellect and memory are compared. At 12 months and 24 months post-surgery, 9/10 (90%) and 7/8 (87.5%) patients respectively, were seizure free (Engel I). No patients were classed as Engel III or IV. No significant improvement or decline at a group level was found on measures of intellect or verbal or visual memory. One hundred per cent improved or remained within 1 SD of their pre-operatives score on verbal and perceptual reasoning learning and reasoning measures. Significant improvement was found post-operatively for both immediate and delayed facial memory. Our findings of good post-surgical seizure control and favourable cognitive outcome provides evidence against previous findings that SAH in children may not be effective. Copyright © 2012 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  8. GSK3β isoform-selective regulation of depression, memory and hippocampal cell proliferation.

    Science.gov (United States)

    Pardo, M; Abrial, E; Jope, R S; Beurel, E

    2016-03-01

    Abnormally active glycogen synthase kinase-3 (GSK3) contributes to pathological processes in multiple psychiatric and neurological disorders. Modeled in mice, this includes increasing susceptibility to dysregulation of mood-relevant behaviors, impairing performance in several cognitive tasks and impairing adult hippocampal neural precursor cell (NPC) proliferation. These deficits are all evident in GSK3α/β knockin mice, in which serine-to-alanine mutations block the inhibitory serine phosphorylation regulation of both GSK3 isoforms, leaving GSK3 hyperactive. It was unknown if both GSK3 isoforms perform redundant actions in these processes, or if hyperactivity of one GSK3 isoform has a predominant effect. To test this, we examined GSK3α or GSK3β knockin mice in which only one isoform was mutated to a hyperactive form. Only GSK3β, not GSK3α, knockin mice displayed heightened vulnerability to the learned helplessness model of depression-like behavior. Three cognitive measures impaired in GSK3α/β knockin mice showed differential regulation by GSK3 isoforms. Novel object recognition was impaired in GSK3β, not in GSK3α, knockin mice, whereas temporal order memory was not impaired in GSK3α or GSK3β knockin mice, and co-ordinate spatial processing was impaired in both GSK3α and GSK3β knockin mice. Adult hippocampal NPC proliferation was severely impaired in GSK3β knockin mice, but not impaired in GSK3α knockin mice. Increased activity of GSK3β, in the absence of overexpression or disease pathology, is sufficient to impair mood regulation, novel object recognition and hippocampal NPC proliferation, whereas hyperactive GSK3α individually does not impair these processes. These results show that hyperactivity of the two GSK3 isoforms execute non-redundant effects on these processes. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  9. Hippocampal Sclerosis in Older Patients

    Science.gov (United States)

    Cykowski, Matthew D.; Powell, Suzanne Z.; Schulz, Paul E.; Takei, Hidehiro; Rivera, Andreana L.; Jackson, Robert E.; Roman, Gustavo; Jicha, Gregory A.; Nelson, Peter T.

    2018-01-01

    Context Autopsy studies of the older population (≥65 years of age), and particularly of the “oldest-old” (≥85 years of age), have identified a significant proportion (~20%) of cognitively impaired patients in which hippocampal sclerosis is the major substrate of an amnestic syndrome. Hippocampal sclerosis may also be comorbid with frontotemporal lobar degeneration, Alzheimer disease, and Lewy body disease. Until recently, the terms hippocampal sclerosis of aging or hippocampal sclerosis dementia were applied in this context. Recent discoveries have prompted a conceptual expansion of hippocampal sclerosis of aging because (1) cellular inclusions of TAR DNA-binding protein 43 kDa (TDP-43) are frequent; (2) TDP-43 pathology may be found outside hippocampus; and (3) brain arteriolosclerosis is a common, possibly pathogenic, component. Objective To aid pathologists with recent recommendations for diagnoses of common neuropathologies in older persons, particularly hippocampal sclerosis, and highlight the recent shift in diagnostic terminology from HS-aging to cerebral age-related TDP-43 with sclerosis (CARTS). Data Sources Peer-reviewed literature and 5 autopsy examples that illustrate common age-related neuropathologies, including CARTS, and emphasize the importance of distinguishing CARTS from late-onset frontotemporal lobar degeneration with TDP-43 pathology and from advanced Alzheimer disease with TDP-43 pathology. Conclusions In advanced old age, the substrates of cognitive impairment are often multifactorial. This article demonstrates common and frequently comorbid neuropathologic substrates of cognitive impairment in the older population, including CARTS, to aid those practicing in this area of pathology. PMID:28467211

  10. Genetic deletion of melanin-concentrating hormone neurons impairs hippocampal short-term synaptic plasticity and hippocampal-dependent forms of short-term memory.

    Science.gov (United States)

    Le Barillier, Léa; Léger, Lucienne; Luppi, Pierre-Hervé; Fort, Patrice; Malleret, Gaël; Salin, Paul-Antoine

    2015-11-01

    The cognitive role of melanin-concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero-lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long-term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal-dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long-term potentiation and depression in the CA1 area of the hippocampus. Post-tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre-synaptic forms of short-term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short-term memory T-maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short-term memory by impairing short-term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short-term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.

  11. Contribution of Hippocampal 5-HT3 Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats.

    Science.gov (United States)

    Wu, Zhong-Min; Yang, Li-Hua; Cui, Rong; Ni, Gui-Lian; Wu, Feng-Tian; Liang, Yong

    2017-05-01

    One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT 3 receptor in the development of PTSD, even though 5-HT 3 receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT 3 receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT 3 agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT 3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT 3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT 3 receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.

  12. Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: implications for glucocorticoid neurotoxicity.

    Science.gov (United States)

    Virgin, C E; Ha, T P; Packan, D R; Tombaugh, G C; Yang, S H; Horner, H C; Sapolsky, R M

    1991-10-01

    Glucocorticoids (GCs), the adrenal steroid hormones secreted during stress, can damage the hippocampus and impair its capacity to survive coincident neurological insults. This GC endangerment of the hippocampus is energetic in nature, as it can be prevented when neurons are supplemented with additional energy substrates. This energetic endangerment might arise from the ability of GCs to inhibit glucose transport into both hippocampal neurons and astrocytes. The present study explores the GC inhibition in astrocytes. (1) GCs inhibited glucose transport approximately 15-30% in both primary and secondary hippocampal astrocyte cultures. (2) The parameters of inhibition agreed with the mechanisms of GC inhibition of glucose transport in peripheral tissues: A minimum of 4 h of GC exposure were required, and the effect was steroid specific (i.e., it was not triggered by estrogen, progesterone, or testosterone) and tissue specific (i.e., it was not triggered by GCs in cerebellar or cortical cultures). (3) Similar GC treatment caused a decrease in astrocyte survival during hypoglycemia and a decrease in the affinity of glutamate uptake. This latter observation suggests that GCs might impair the ability of astrocytes to aid neurons during times of neurologic crisis (i.e., by impairing their ability to remove damaging glutamate from the synapse).

  13. Hippocampal sclerosis in advanced age: clinical and pathological features

    Science.gov (United States)

    Schmitt, Frederick A.; Lin, Yushun; Abner, Erin L.; Jicha, Gregory A.; Patel, Ela; Thomason, Paula C.; Neltner, Janna H.; Smith, Charles D.; Santacruz, Karen S.; Sonnen, Joshua A.; Poon, Leonard W.; Gearing, Marla; Green, Robert C.; Woodard, John L.; Van Eldik, Linda J.; Kryscio, Richard J.

    2011-01-01

    Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer’s disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer’s Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n = 106). For individuals aged ≥95 years at death (n = 179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of ‘definite’ Alzheimer’s disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n = 10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar

  14. Hippocampal sclerosis in advanced age: clinical and pathological features.

    Science.gov (United States)

    Nelson, Peter T; Schmitt, Frederick A; Lin, Yushun; Abner, Erin L; Jicha, Gregory A; Patel, Ela; Thomason, Paula C; Neltner, Janna H; Smith, Charles D; Santacruz, Karen S; Sonnen, Joshua A; Poon, Leonard W; Gearing, Marla; Green, Robert C; Woodard, John L; Van Eldik, Linda J; Kryscio, Richard J

    2011-05-01

    Hippocampal sclerosis is a relatively common neuropathological finding (∼10% of individuals over the age of 85 years) characterized by cell loss and gliosis in the hippocampus that is not explained by Alzheimer's disease. Hippocampal sclerosis pathology can be associated with different underlying causes, and we refer to hippocampal sclerosis in the aged brain as hippocampal sclerosis associated with ageing. Much remains unknown about hippocampal sclerosis associated with ageing. We combined three different large autopsy cohorts: University of Kentucky Alzheimer's Disease Centre, the Nun Study and the Georgia Centenarian Study to obtain a pool of 1110 patients, all of whom were evaluated neuropathologically at the University of Kentucky. We focused on the subset of cases with neuropathology-confirmed hippocampal sclerosis (n=106). For individuals aged≥95 years at death (n=179 in our sample), each year of life beyond the age of 95 years correlated with increased prevalence of hippocampal sclerosis pathology and decreased prevalence of 'definite' Alzheimer's disease pathology. Aberrant TAR DNA protein 43 immunohistochemistry was seen in 89.9% of hippocampal sclerosis positive patients compared with 9.7% of hippocampal sclerosis negative patients. TAR DNA protein 43 immunohistochemistry can be used to demonstrate that the disease is usually bilateral even when hippocampal sclerosis pathology is not obvious by haematoxylin and eosin stains. TAR DNA protein 43 immunohistochemistry was negative on brain sections from younger individuals (n=10) after hippocampectomy due to seizures, who had pathologically confirmed hippocampal sclerosis. There was no association between cases with hippocampal sclerosis associated with ageing and apolipoprotein E genotype. Age of death and clinical features of hippocampal sclerosis associated with ageing (with or without aberrant TAR DNA protein 43) were distinct from previously published cases of frontotemporal lobar degeneration TAR

  15. Bilateral reorganization of the dentate gyrus in hippocampal sclerosis: a postmortem study.

    Science.gov (United States)

    Thom, M; Martinian, L; Catarino, C; Yogarajah, M; Koepp, M J; Caboclo, L; Sisodiya, S M

    2009-09-29

    Hippocampal sclerosis (HS) is the most common surgical pathology associated with mesial temporal lobe epilepsy (MTLE). HS is typically characterized by mossy fiber sprouting (MFS) and reorganization of neuropeptide Y (NPY) fiber networks in the dentate gyrus. One potential cause of postoperative seizure recurrence following temporal lobe surgery may be the presence of seizure-associated bilateral hippocampal damage. We aimed to investigate patterns of hippocampal abnormalities in a postmortem series as identified by NPY and dynorphin immunohistochemistry. Analysis of dentate gyrus fiber reorganization, using dynorphin (to demonstrate MFS) and NPY immunohistochemistry, was carried out in a postmortem epilepsy series of 25 cases (age range 21-96 years). In 9 patients, previously refractory seizures had become well controlled for up to 34 years prior to death. Bilateral MFS or abnormal NPY patterns were seen in 15 patients including those with bilateral symmetric, asymmetric, and unilateral HS by conventional histologic criteria. MFS and NPY reorganization was present in all classical HS cases, more variably in atypical HS, present in both MTLE and non-MTLE syndromes and with seizure histories of up to 92 years, despite seizure remission in some patients. Synaptic reorganization in the dentate gyrus may be a bilateral, persistent process in epilepsy. It is unlikely to be sufficient to generate seizures and more likely to represent a seizure-induced phenomenon.

  16. Functional implications of hippocampal degeneration in early Alzheimer's disease: a combined DTI and PET study

    International Nuclear Information System (INIS)

    Yakushev, Igor; Mueller, Matthias J.; Schermuly, Ingrid; Fellgiebel, Andreas; Schreckenberger, Matthias; Cumming, Paul; Stoeter, Peter; Gerhard, Alex

    2011-01-01

    Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. Twenty patients with early AD (Mini-Mental State Examination 25.7 ± 1.7) were studied with [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p< 0.005). The same correlation pattern was found for right hippocampal diffusivity (p< 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment. (orig.)

  17. Microarray profile of seizure damage-refractory hippocampal CA3 in a mouse model of epileptic preconditioning.

    Science.gov (United States)

    Hatazaki, S; Bellver-Estelles, C; Jimenez-Mateos, E M; Meller, R; Bonner, C; Murphy, N; Matsushima, S; Taki, W; Prehn, J H M; Simon, R P; Henshall, D C

    2007-12-05

    A neuroprotected state can be acquired by preconditioning brain with a stimulus that is subthreshold for damage (tolerance). Acquisition of tolerance involves coordinate, bi-directional changes to gene expression levels and the re-programmed phenotype is determined by the preconditioning stimulus. While best studied in ischemic brain there is evidence brief seizures can confer tolerance against prolonged seizures (status epilepticus). Presently, we developed a model of epileptic preconditioning in mice and used microarrays to gain insight into the transcriptional phenotype within the target hippocampus at the time tolerance had been acquired. Epileptic tolerance was induced by an episode of non-damaging seizures in adult C57Bl/6 mice using a systemic injection of kainic acid. Neuron and DNA damage-positive cell counts 24 h after status epilepticus induced by intraamygdala microinjection of kainic acid revealed preconditioning given 24 h prior reduced CA3 neuronal death by approximately 45% compared with non-tolerant seizure mice. Microarray analysis of over 39,000 transcripts (Affymetrix 430 2.0 chip) from microdissected CA3 subfields was undertaken at the point at which tolerance was acquired. Results revealed a unique profile of small numbers of equivalently up- and down-regulated genes with biological functions that included transport and localization, ubiquitin metabolism, apoptosis and cell cycle control. Select microarray findings were validated post hoc by real-time polymerase chain reaction and Western blotting. The present study defines a paradigm for inducing epileptic preconditioning in mice and first insight into the global transcriptome of the seizure-damage refractory brain.

  18. Residual tree damage during selection cuts using two skidding systems in the Missouri Ozarks

    Science.gov (United States)

    Robert L. Ficklin; John P. Dwyer; Bruce E. Cutter; Tom Draper

    1997-01-01

    Today, there is an interest in using alternative silvicultural systems like selection and two-aged management, because the public finds these systems more acceptable than clearcutting. However, repeated entries into forest stands to remove timber increase the risk of residual stand damage. Harvest techniques are desirable that (1) reduce the risk of stand damage and (2...

  19. Alkaloid fraction of Uncaria rhynchophylla protects against N-methyl-D-aspartate-induced apoptosis in rat hippocampal slices.

    Science.gov (United States)

    Lee, Jongseok; Son, Dongwook; Lee, Pyeongjae; Kim, Sun-Yeou; Kim, Hocheol; Kim, Chang-Ju; Lim, Eunhee

    2003-09-04

    Uncaria rhynchophylla is a medicinal herb which has sedative and anticonvulsive effects and has been applied in the treatment of epilepsy in Oriental medicine. In this study, the effect of alkaloid fraction of U. rhynchophylla against N-methyl-D-aspartate (NMDA)-induced neuronal cell death was investigated. Pretreatment with an alkaloid fraction of U. rhynchophylla for 1 h decreased the degree of neuronal damage induced by NMDA exposure in cultured hippocampal slices and also inhibited NMDA-induced enhanced expressions of apoptosis-related genes such as c-jun, p53, and bax. In the present study, the alkaloid fraction of U. rhynchophylla was shown to have a protective property against NMDA-induced cytotoxicity by suppressing the NMDA-induced apoptosis in rat hippocampal slices.

  20. Vitamin C deficiency in early postnatal life impairs spatial memory and reduces the number of hippocampal neurons in guinea pigs

    DEFF Research Database (Denmark)

    Tveden-Nyborg, Pernille Yde; Johansen, Louise Kruse; Raida, Zindy

    2009-01-01

    C deficiency and neuronal damage in newborn guinea pigs. DESIGN: Thirty 6- to 7-d-old guinea pigs were randomly assigned to 2 groups to receive either a vitamin C-sufficient diet or the same diet containing a low concentration of vitamin C (but adequate to prevent scurvy) for 2 mo. Spatial memory...... was assessed by the Morris Water Maze, and hippocampal neuron numbers were quantified by stereologic techniques. RESULTS: The results showed a reduction in spatial memory (P ... a lower total number of neurons in hippocampal subdivisions (dentate gyrus, cornu ammonis 1, and cornu ammonis 2-3) than did the normal controls (P impaired neuronal development and a functional decrease...

  1. Hippocampal dosimetry correlates with the change in neurocognitive function after hippocampal sparing during whole brain radiotherapy: a prospective study

    International Nuclear Information System (INIS)

    Tsai, Ping-Fang; Yang, Chi-Cheng; Chuang, Chi-Cheng; Huang, Ting-Yi; Wu, Yi-Ming; Pai, Ping-Ching; Tseng, Chen-Kan; Wu, Tung-Ho; Shen, Yi-Liang; Lin, Shinn-Yn

    2015-01-01

    Whole brain radiotherapy (WBRT) has been the treatment of choice for patients with brain metastases. However, change/decline of neurocognitive functions (NCFs) resulting from impaired hippocampal neurogenesis might occur after WBRT. It is reported that conformal hippocampal sparing would provide the preservation of NCFs. Our study aims to investigate the hippocampal dosimetry and to demonstrate the correlation between hippocampal dosimetry and neurocognitive outcomes in patients receiving hippocampal sparing during WBRT (HS-WBRT). Forty prospectively recruited cancer patients underwent HS-WBRT for therapeutic or prophylactic purposes. Before receiving HS-WBRT, all participants received a battery of baseline neurocognitive assessment, including memory, executive functions and psychomotor speed. The follow-up neurocognitive assessment at 4 months after HS-WBRT was also performed. For the delivery of HS-WBRT, Volumetric Modulated Arc Therapy (VMAT) with two full arcs and two non-coplanar partial arcs was employed. For each treatment planning, dose volume histograms were generated for left hippocampus, right hippocampus, and the composite hippocampal structure respectively. Biologically equivalent doses in 2-Gy fractions (EQD 2 ) assuming an alpha/beta ratio of 2 Gy were computed. To perform analyses addressing the correlation between hippocampal dosimetry and the change in scores of NCFs, pre- and post-HS-WBRT neurocognitive assessments were available in 24 patients in this study. Scores of NCFs were quite stable before and after HS-WBRT in terms of hippocampus-dependent memory. Regarding verbal memory, the corresponding EQD 2 values of 0, 10, 50, 80 % irradiating the composite hippocampal structure with <12.60 Gy, <8.81, <7.45 Gy and <5.83 Gy respectively were significantly associated with neurocognitive preservation indicated by the immediate recall of Word List Test of Wechsler Memory Scale-III. According to logistic regression analyses, it was noted that

  2. Hippocampal theta activity is selectively associated with contingency detection but not discrimination in rabbit discrimination-reversal eyeblink conditioning.

    Science.gov (United States)

    Nokia, Miriam S; Wikgren, Jan

    2010-04-01

    The relative power of the hippocampal theta-band ( approximately 6 Hz) activity (theta ratio) is thought to reflect a distinct neural state and has been shown to affect learning rate in classical eyeblink conditioning in rabbits. We sought to determine if the theta ratio is mostly related to the detection of the contingency between the stimuli used in conditioning or also to the learning of more complex inhibitory associations when a highly demanding delay discrimination-reversal eyeblink conditioning paradigm is used. A high hippocampal theta ratio was not only associated with a fast increase in conditioned responding in general but also correlated with slow emergence of discriminative responding due to sustained responding to the conditioned stimulus not paired with an unconditioned stimulus. The results indicate that the neural state reflected by the hippocampal theta ratio is specifically linked to forming associations between stimuli rather than to the learning of inhibitory associations needed for successful discrimination. This is in line with the view that the hippocampus is responsible for contingency detection in the early phase of learning in eyeblink conditioning. (c) 2009 Wiley-Liss, Inc.

  3. Alzheimer's Disease Diagnostic Performance of a Multi-Atlas Hippocampal Segmentation Method using the Harmonized Hippocampal Protocol

    DEFF Research Database (Denmark)

    Anker, Cecilie Benedicte; Sørensen, Lauge; Pai, Akshay

    PURPOSE Hippocampal volumetry is the most widely used structural MRI biomarker of Alzheimer’s disease (AD), and state-of-the-art, automatic hippocampal segmentation can be obtained using longitudinal FreeSurfer. In this study, we compare the diagnostic AD performance of a single time point, multi...

  4. Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons.

    Science.gov (United States)

    Sendrowski, Krzysztof; Sobaniec, Wojciech; Stasiak-Barmuta, Anna; Sobaniec, Piotr; Popko, Janusz

    2015-04-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of β-amyloid (Aβ) peptides in the brain. Deposits of Aβ initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Aβ-injured hippocampal neurons in culture. Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Aβ(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Aβ(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 μM Aβ(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 μM Aβ(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Our results suggest the protective potential of both studied nootropics against Aβ-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  5. A β Damages Learning and Memory in Alzheimer's Disease Rats with Kidney-Yang Deficiency

    OpenAIRE

    Qi, Dongmei; Qiao, Yongfa; Zhang, Xin; Yu, Huijuan; Cheng, Bin; Qiao, Haifa

    2012-01-01

    Previous studies demonstrated that Alzheimer's disease was considered as the consequence produced by deficiency of Kidney essence. However, the mechanism underlying the symptoms also remains elusive. Here we report that spatial learning and memory, escape, and swimming capacities were damaged significantly in Kidney-yang deficiency rats. Indeed, both hippocampal A β 40 and 42 increases in Kidney-yang deficiency contribute to the learning and memory impairments. Specifically, damage of synapti...

  6. Hippocampal MR volumetry

    Science.gov (United States)

    Haller, John W.; Botteron, K.; Brunsden, Barry S.; Sheline, Yvette I.; Walkup, Ronald K.; Black, Kevin J.; Gado, Mokhtar; Vannier, Michael W.

    1994-09-01

    Goal: To estimate hippocampal volumes from in vivo 3D magnetic resonance (MR) brain images and determine inter-rater and intra- rater repeatability. Objective: The precision and repeatability of hippocampal volume estimates using stereologic measurement methods is sought. Design: Five normal control and five schizophrenic subjects were MR scanned using a MPRAGE protocol. Fixed grid stereologic methods were used to estimate hippocampal volumes on a graphics workstation. The images were preprocessed using histogram analysis to standardize 3D MR image scaling from 16 to 8 bits and image volumes were interpolated to 0.5 mm3 isotropic voxels. The following variables were constant for the repeated stereologic measures: grid size, inter-slice distance (1.5 mm), voxel dimensions (0.5 mm3), number of hippocampi measured (10), total number of measurements per rater (40), and number of raters (5). Two grid sizes were tested to determine the coefficient of error associated with the number of sampled 'hits' (approximately 140 and 280) on the hippocampus. Starting slice and grid position were randomly varied to assure unbiased volume estimates. Raters were blind to subject identity, diagnosis, and side of the brain from which the image volumes were extracted and the order of subject presentation was randomized for each of the raters. Inter- and intra-rater intraclass correlation coefficients (ICC) were determined. Results: The data indicate excellent repeatability of fixed grid stereologic hippocampal volume measures when using an inter-slice distance of 1.5 mm and a 6.25 mm2 grid (inter-rater ICCs equals 0.86 - 0.97, intra- rater ICCs equals 0.85 - 0.97). One major advantage of the current study was the use of 3D MR data which significantly improved visualization of hippocampal boundaries by providing the ability to access simultaneous orthogonal views while counting stereological marks within the hippocampus. Conclusion: Stereological estimates of 3D volumes from 2D MR

  7. MRI-Based Measurement of Hippocampal Volume in Patients With Combat-Related Posttraumatic Stress Disorder

    Science.gov (United States)

    Bremner, J. Douglas; Randall, Penny; Scott, Tammy M.; Bronen, Richard A.; Seibyl, John P.; Southwick, Steven M.; Delaney, Richard C.; McCarthy, Gregory; Charney, Dennis S.; Innis, Robert B.

    2011-01-01

    Objective Studies in nonhuman primates suggest that high levels of cortisol associated with stress have neurotoxic effects on the hippocampus, a brain structure involved in memory. The authors previously showed that patients with combat-related posttraumatic stress disorder (PTSD) had deficits in short-term memory. The purpose of this study was to compare the hippocampal volume of patients with PTSD to that of subjects without psychiatric disorder. Method Magnetic resonance imaging was used to measure the volume of the hippocampus in 26 Vietnam combat veterans with PTSD and 22 comparison subjects selected to be similar to the patients in age, sex, race, years of education, socioeconomic status, body size, and years of alcohol abuse. Results The PTSD patients had a statistically significant 8% smaller right hippocampal volume relative to that of the comparison subjects, but there was no difference in the volume of other brain regions (caudate and temporal lobe). Deficits in short-term verbal memory as measured with the Wechsler Memory Scale were associated with smaller right hippocampal volume in the PTSD patients only. Conclusions These findings are consistent with a smaller right hippocampal volume in PTSD that is associated with functional deficits in verbal memory. PMID:7793467

  8. Effects of Single and Repeated Exposure to a 50-Hz 2-mT Electromagnetic Field on Primary Cultured Hippocampal Neurons.

    Science.gov (United States)

    Zeng, Ying; Shen, Yunyun; Hong, Ling; Chen, Yanfeng; Shi, Xiaofang; Zeng, Qunli; Yu, Peilin

    2017-06-01

    The prevalence of domestic and industrial electrical appliances has raised concerns about the health risk of extremely low-frequency magnetic fields (ELF-MFs). At present, the effects of ELF-MFs on the central nervous system are still highly controversial, and few studies have investigated its effects on cultured neurons. Here, we evaluated the biological effects of different patterns of ELF-MF exposure on primary cultured hippocampal neurons in terms of viability, apoptosis, genomic instability, and oxidative stress. The results showed that repeated exposure to 50-Hz 2-mT ELF-MF for 8 h per day after different times in culture decreased the viability and increased the production of intracellular reactive oxidative species in hippocampal neurons. The mechanism was potentially related to the up-regulation of Nox2 expression. Moreover, none of the repeated exposure patterns had significant effects on DNA damage, apoptosis, or autophagy, which suggested that ELF-MF exposure has no severe biological consequences in cultured hippocampal neurons.

  9. Cortisol, Cytokines, and Hippocampal Volume in the Elderly

    Directory of Open Access Journals (Sweden)

    Keith Daniel Sudheimer

    2014-07-01

    Full Text Available Separate bodies of literature report that elevated pro-inflammatory cytokines and cortisol negatively affect hippocampal structure and cognitive functioning, particularly in older adults. Although interactions between cytokines and cortisol occur through a variety of known mechanisms, few studies consider how their interactions affect brain structure. In this preliminary study, we assess the impact of interactions between circulating levels of IL-1Beta, IL-6, IL-8, IL-10, IL-12, TNF-alpha, and waking cortisol on hippocampal volume. Twenty-eight community-dwelling older adults underwent blood draws for quantification of circulating cytokines and saliva collections to quantify the cortisol awakening response. Hippocampal volume measurements were made using structural magnetic resonance imaging. Elevated levels of waking cortisol in conjunction with higher concentrations of IL-6 and TNF-alpha were associated with smaller hippocampal volumes. In addition, independent of cortisol, higher levels of IL-1beta and TNF-alpha were also associated with smaller hippocampal volumes. These data provide preliminary evidence that higher cortisol, in conjunction with higher IL-6 and TNF-alpha, are associated with smaller hippocampal volume in older adults. We suggest that the dynamic balance between the hypothalamic-pituitary adrenal axis and inflammation processes may explain hippocampal volume reductions in older adults better than either set of measures do in isolation.

  10. Differential response of hippocampal subregions to stress and learning.

    Directory of Open Access Journals (Sweden)

    Darby F Hawley

    Full Text Available The hippocampus has two functionally distinct subregions-the dorsal portion, primarily associated with spatial navigation, and the ventral portion, primarily associated with anxiety. In a prior study of chronic unpredictable stress (CUS in rodents, we found that it selectively enhanced cellular plasticity in the dorsal hippocampal subregion while negatively impacting it in the ventral. In the present study, we determined whether this adaptive plasticity in the dorsal subregion would confer CUS rats an advantage in a spatial task-the radial arm water maze (RAWM. RAWM exposure is both stressful and requires spatial navigation, and therefore places demands simultaneously upon both hippocampal subregions. Therefore, we used Western blotting to investigate differential expression of plasticity-associated proteins (brain derived neurotrophic factor [BDNF], proBDNF and postsynaptic density-95 [PSD-95] in the dorsal and ventral subregions following RAWM exposure. Lastly, we used unbiased stereology to compare the effects of CUS on proliferation, survival and neuronal differentiation of cells in the dorsal and ventral hippocampal subregions. We found that CUS and exposure to the RAWM both increased corticosterone, indicating that both are stressful; nevertheless, CUS animals had significantly better long-term spatial memory. We also observed a subregion-specific pattern of protein expression following RAWM, with proBDNF increased in the dorsal and decreased in the ventral subregion, while PSD-95 was selectively upregulated in the ventral. Finally, consistent with our previous study, we found that CUS most negatively affected neurogenesis in the ventral (compared to the dorsal subregion. Taken together, our data support a dual role for the hippocampus in stressful experiences, with the more resilient dorsal portion undergoing adaptive plasticity (perhaps to facilitate escape from or neutralization of the stressor, and the ventral portion involved in

  11. Childhood trauma and hippocampal and amygdalar volumes in first-episode psychosis.

    Science.gov (United States)

    Hoy, Katrina; Barrett, Suzanne; Shannon, Ciaran; Campbell, Clodagh; Watson, David; Rushe, Teresa; Shevlin, Mark; Bai, Feng; Cooper, Stephen; Mulholland, Ciaran

    2012-11-01

    A history of childhood trauma is common in individuals who later develop psychosis. Similar neuroanatomical abnormalities are observed in people who have been exposed to childhood trauma and people with psychosis. However, the relationship between childhood trauma and such abnormalities in psychosis has not been investigated. This study aimed to explore the association between the experience of childhood trauma and hippocampal and amygdalar volumes in a first-episode psychosis (FEP) population. The study employed an observational retrospective design. Twenty-one individuals, who had previously undergone magnetic resonance imaging procedures as part of the longitudinal Northern Ireland First-Episode Psychosis Study, completed measures assessing traumatic experiences and were included in the analysis. Data were subject to correlation analyses (r and r (pb)). Potential confounding variables (age at FEP and delay to scan from recruitment) were selected a priori for inclusion in multiple regression analyses. There was a high prevalence of lifetime (95%) and childhood (76%) trauma in the sample. The experience of childhood trauma was a significant predictor of left hippocampal volume, although age at FEP also significantly contributed to this model. There was no significant association between predictor variables and right hippocampal volume. The experience of childhood trauma was a significant predictor of right and total amygdalar volumes and the hippocampal/amygdalar complex volume as a whole. The findings indicate that childhood trauma is associated with neuroanatomical measures in FEP. Future research controlling for childhood traumatic experiences may contribute to explaining brain morphology in people with psychosis.

  12. Hippocampal sclerosis in children younger than 2 years

    Energy Technology Data Exchange (ETDEWEB)

    Kadom, Nadja [Children' s National Medical Center, Department of Diagnostic Imaging and Radiology, Washington, DC (United States); Tsuchida, Tammy; Gaillard, William D. [Children' s National Medical Center, Department of Neurology, Washington, DC (United States)

    2011-10-15

    Hippocampal sclerosis (HS) is rarely considered as a diagnosis in children younger than 2 years. To describe imaging features in conjunction with clinical information in patients with hippocampal sclerosis who are younger than 2 years. We retrospectively reviewed MR brain imaging and clinical information in five children in whom the diagnosis of HS was made both clinically and by MRI prior to 2 years of age. Imaging features establishing the diagnosis of hippocampal sclerosis were bright T2 signal and volume loss, while the internal architecture of the hippocampal formation was preserved in almost all children. Clinically, all children had an infectious trigger. It is necessary for radiologists to consider HS in children with certain clinical features to plan an MRI protocol that is appropriate for detection of hippocampal pathology. (orig.)

  13. Hippocampal sclerosis in children younger than 2 years

    International Nuclear Information System (INIS)

    Kadom, Nadja; Tsuchida, Tammy; Gaillard, William D.

    2011-01-01

    Hippocampal sclerosis (HS) is rarely considered as a diagnosis in children younger than 2 years. To describe imaging features in conjunction with clinical information in patients with hippocampal sclerosis who are younger than 2 years. We retrospectively reviewed MR brain imaging and clinical information in five children in whom the diagnosis of HS was made both clinically and by MRI prior to 2 years of age. Imaging features establishing the diagnosis of hippocampal sclerosis were bright T2 signal and volume loss, while the internal architecture of the hippocampal formation was preserved in almost all children. Clinically, all children had an infectious trigger. It is necessary for radiologists to consider HS in children with certain clinical features to plan an MRI protocol that is appropriate for detection of hippocampal pathology. (orig.)

  14. Hand gestures support word learning in patients with hippocampal amnesia.

    Science.gov (United States)

    Hilverman, Caitlin; Cook, Susan Wagner; Duff, Melissa C

    2018-06-01

    Co-speech hand gesture facilitates learning and memory, yet the cognitive and neural mechanisms supporting this remain unclear. One possibility is that motor information in gesture may engage procedural memory representations. Alternatively, iconic information from gesture may contribute to declarative memory representations mediated by the hippocampus. To investigate these alternatives, we examined gesture's effects on word learning in patients with hippocampal damage and declarative memory impairment, with intact procedural memory, and in healthy and in brain-damaged comparison groups. Participants learned novel label-object pairings while producing gesture, observing gesture, or observing without gesture. After a delay, recall and object identification were assessed. Unsurprisingly, amnesic patients were unable to recall the labels at test. However, they correctly identified objects at above chance levels, but only if they produced a gesture at encoding. Comparison groups performed well above chance at both recall and object identification regardless of gesture. These findings suggest that gesture production may support word learning by engaging nondeclarative (procedural) memory. © 2018 Wiley Periodicals, Inc.

  15. Dietary lipids are differentially associated with hippocampal-dependent relational memory in prepubescent children.

    Science.gov (United States)

    Baym, Carol L; Khan, Naiman A; Monti, Jim M; Raine, Lauren B; Drollette, Eric S; Moore, R Davis; Scudder, Mark R; Kramer, Arthur F; Hillman, Charles H; Cohen, Neal J

    2014-05-01

    Studies in rodents and older humans have shown that the hippocampus-a brain structure critical to relational/associative memory-has remarkable plasticity as a result of lifestyle factors (eg, exercise). However, the effect of dietary intake on hippocampal-dependent memory during childhood has remained unexamined. We investigated the cross-sectional relation of dietary components characteristic of the Western diet, including saturated fatty acids (SFAs), omega-3 (n-3) fatty acids, and refined sugar, with hippocampal-dependent relational memory in prepubescent children. Participants aged 7-9 y (n = 52) reported their dietary intake by using the Youth-Adolescent Food-Frequency Questionnaire and completed memory tasks designed to assess relational (hippocampal-dependent) and item (hippocampal-independent) memory. Performance on the memory tasks was assessed with both direct (accuracy) and indirect (eye movement) measures. Partial correlations adjusted for body mass index showed a positive relation between relational memory accuracy and intake of omega-3 fatty acids and a negative relation of both relational and item memory accuracy with intake of SFAs. Potential confounding factors of age, sex, intelligence quotient, socioeconomic status, pubertal timing, and aerobic fitness (maximal oxygen volume) were not significantly related to any of the dietary intake measures. Eye movement measures of relational memory (preferential viewing to the target stimulus) showed a negative relation with intake of added sugar. SFA intake was negatively associated with both forms of memory, whereas omega-3 fatty acid intake was selectively positively associated with hippocampal-dependent relational memory. These findings are among the first to show a link between habitual dietary intake and cognitive health as pertaining to hippocampal function in childhood. The Fitness Improves Thinking Kids (FITKids) and FITKids2 trials were registered at www.clinicaltrials.gov as NCT01334359 and NCT

  16. Inflammation subverts hippocampal synaptic plasticity in experimental multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Robert Nisticò

    Full Text Available Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS and its mouse model, experimental autoimmune encephalomyelitis (EAE. In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP induction was favored over long-term depression (LTD in EAE, as shown by a significant rightward shift in the frequency-synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS.

  17. Inflammation Subverts Hippocampal Synaptic Plasticity in Experimental Multiple Sclerosis

    Science.gov (United States)

    Mandolesi, Georgia; Piccinin, Sonia; Berretta, Nicola; Pignatelli, Marco; Feligioni, Marco; Musella, Alessandra; Gentile, Antonietta; Mori, Francesco; Bernardi, Giorgio; Nicoletti, Ferdinando; Mercuri, Nicola B.; Centonze, Diego

    2013-01-01

    Abnormal use-dependent synaptic plasticity is universally accepted as the main physiological correlate of memory deficits in neurodegenerative disorders. It is unclear whether synaptic plasticity deficits take place during neuroinflammatory diseases, such as multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). In EAE mice, we found significant alterations of synaptic plasticity rules in the hippocampus. When compared to control mice, in fact, hippocampal long-term potentiation (LTP) induction was favored over long-term depression (LTD) in EAE, as shown by a significant rightward shift in the frequency–synaptic response function. Notably, LTP induction was also enhanced in hippocampal slices from control mice following interleukin-1β (IL-1β) perfusion, and both EAE and IL-1β inhibited GABAergic spontaneous inhibitory postsynaptic currents (sIPSC) without affecting glutamatergic transmission and AMPA/NMDA ratio. EAE was also associated with selective loss of GABAergic interneurons and with reduced gamma-frequency oscillations in the CA1 region of the hippocampus. Finally, we provided evidence that microglial activation in the EAE hippocampus was associated with IL-1β expression, and hippocampal slices from control mice incubated with activated microglia displayed alterations of GABAergic transmission similar to those seen in EAE brains, through a mechanism dependent on enhanced IL-1β signaling. These data may yield novel insights into the basis of cognitive deficits in EAE and possibly of MS. PMID:23355887

  18. Novel derivative of Paeonol, Paeononlsilatie sodium, alleviates behavioral damage and hippocampal dendritic injury in Alzheimer's disease concurrent with cofilin1/phosphorylated-cofilin1 and RAC1/CDC42 alterations in rats.

    Directory of Open Access Journals (Sweden)

    Fei Han

    Full Text Available Alzheimer's disease (AD is a typical hippocampal amnesia and the most common senile dementia. Many studies suggest that cognitive impairments are more closely correlated with synaptic loss than the burden of amyloid deposits in AD progression. To date, there is no effective treatment for this disease. Paeonol has been widely employed in traditional Chinese medicine. This compound improves learning behavior in an animal model; however, the mechanism remains unclear. In this study, Paeononlsilatie sodium (Pa, a derivative of Paeonol, attenuated D-galactose (D-gal and AlCl3-induced behavioral damages in rats based on evaluations of the open field test (OFT, elevated plus maze test (EPMT, and Morris water maze test (MWMT. Pa increased the dendritic complexity and the density of dendritic spines. Correlation analysis indicated that morphological changes in neuronal dendrites are closely correlated with behavioral changes. Pa treatment reduced the production of Aβ, affected the phosphorylation and redistribution of cofilin1 and inhibited rod-like formation in hippocampal neurons. The induction of D-gal and AlCl3 promoted the expression of RAC1/CDC42 expression; however, the tendency of gene expression was inhibited by pretreatment with Pa. Taken together, our results suggest that Pa may represent a novel therapeutic agent for the improvement of cognitive and emotional behaviors and dendritic morphology in an AD animal model.

  19. The effects of hormones and physical exercise on hippocampal structural plasticity.

    Science.gov (United States)

    Triviño-Paredes, Juan; Patten, Anna R; Gil-Mohapel, Joana; Christie, Brian R

    2016-04-01

    The hippocampus plays an integral role in certain aspects of cognition. Hippocampal structural plasticity and in particular adult hippocampal neurogenesis can be influenced by several intrinsic and extrinsic factors. Here we review how hormones (i.e., intrinsic modulators) and physical exercise (i.e., an extrinsic modulator) can differentially modulate hippocampal plasticity in general and adult hippocampal neurogenesis in particular. Specifically, we provide an overview of the effects of sex hormones, stress hormones, and metabolic hormones on hippocampal structural plasticity and adult hippocampal neurogenesis. In addition, we also discuss how physical exercise modulates these forms of hippocampal plasticity, giving particular emphasis on how this modulation can be affected by variables such as exercise regime, duration, and intensity. Understanding the neurobiological mechanisms underlying the modulation of hippocampal structural plasticity by intrinsic and extrinsic factors will impact the design of new therapeutic approaches aimed at restoring hippocampal plasticity following brain injury or neurodegeneration. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Functional implications of hippocampal degeneration in early Alzheimer's disease: a combined DTI and PET study

    Energy Technology Data Exchange (ETDEWEB)

    Yakushev, Igor; Mueller, Matthias J.; Schermuly, Ingrid; Fellgiebel, Andreas [University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz (Germany); Schreckenberger, Matthias [University Medical Center Mainz, Department of Nuclear Medicine, Mainz (Germany); Cumming, Paul [University of Munich, Department of Nuclear Medicine, Munich (Germany); Stoeter, Peter [University Medical Center Mainz, Institute of Neuroradiology, Mainz (Germany); Gerhard, Alex [University Medical Center Mainz, Department of Psychiatry and Psychotherapy, Mainz (Germany); University of Manchester, Wolfson Molecular Imaging Centre, Manchester (United Kingdom)

    2011-12-15

    Hypometabolism of the posterior cingulate cortex (PCC) in early Alzheimer's disease (AD) is thought to arise in part due to AD-specific neuronal damage to the hippocampal formation. Here, we explored the association between microstructural alterations within the hippocampus and whole-brain glucose metabolism in subjects with AD, also in relation to episodic memory impairment. Twenty patients with early AD (Mini-Mental State Examination 25.7 {+-} 1.7) were studied with [{sup 18}F]fluorodeoxyglucose (FDG) positron emission tomography and diffusion tensor imaging. Episodic memory performance was assessed using the free delayed verbal recall task (DVR). Voxel-wise relative FDG uptake was correlated to diffusivity indices of the hippocampus, followed by extraction of FDG uptake values from significant clusters. Linear regression analysis was performed to test for unique contributions of diffusivity and metabolic indices in the prediction of memory function. Diffusivity in the left anterior hippocampus negatively correlated with FDG uptake primarily in the left anterior hippocampus, parahippocampal gyrus and the PCC (p< 0.005). The same correlation pattern was found for right hippocampal diffusivity (p< 0.05). In linear regression analysis, left anterior hippocampal diffusivity and FDG uptake from the PCC cluster were the only significant predictors for performance on DVR, together explaining 60.6% of the variance. We found an inverse association between anterior hippocampal diffusivity and PCC glucose metabolism, which was in turn strongly related to episodic memory performance in subjects with early AD. These findings support the diaschisis hypothesis of AD and implicate a dysfunction of structures along the hippocampal output pathways as a significant contributor to the genesis of episodic memory impairment. (orig.)

  1. Interactions between entorhinal axons and target hippocampal neurons: a role for glutamate in the development of hippocampal circuitry.

    Science.gov (United States)

    Mattson, M P; Lee, R E; Adams, M E; Guthrie, P B; Kater, S B

    1988-11-01

    A coculture system consisting of input axons from entorhinal cortex explants and target hippocampal pyramidal neurons was used to demonstrate that glutamate, released spontaneously from afferent axons, can influence both dendritic geometry of target neurons and formation of presumptive synaptic sites. Dendritic outgrowth was reduced in hippocampal neurons growing on entorhinal axons when compared with neurons growing off the axons. Presumptive presynaptic sites were observed in association with hippocampal neuron dendrites and somas. HPLC analysis showed that glutamate was released from the explants in an activity- and Ca2(+)-dependent manner. The general glutamate receptor antagonist D-glutamylglycine significantly increased dendritic outgrowth in pyramidal neurons associated with entorhinal axons and reduced presumptive presynaptic sites. Tetrodotoxin and reduction of extracellular Ca2+ also promoted dendritic outgrowth and reduced the formation of presumptive synaptic sites. The results suggest that the neurotransmitter glutamate may play important roles in the development of hippocampal circuitry.

  2. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

    D.P. Hibar (Derrek); H.H.H. Adams (Hieab); N. Jahanshad (Neda); G. Chauhan (Ganesh); J.L. Stein; E. Hofer (Edith); M.E. Rentería (Miguel); J.C. Bis (Joshua); A. Arias-Vásquez (Alejandro); Ikram, M.K. (M. Kamran); S. Desrivières (Sylvane); M.W. Vernooij (Meike); L. Abramovic (Lucija); S. Alhusaini (Saud); N. Amin (Najaf); M. Andersson (Micael); K. Arfanakis (Konstantinos); B. Aribisala (Benjamin); N.J. Armstrong (Nicola J.); L. Athanasiu (Lavinia); T. Axelsson (Tomas); A.H. Beecham (Ashley); A. Beiser (Alexa); M. Bernard (Manon); S.H. Blanton (Susan H.); M.M. Bohlken (Marc M.); M.P.M. Boks (Marco); L.B.C. Bralten (Linda); A.M. Brickman (Adam M.); Carmichael, O. (Owen); M.M. Chakravarty (M. Mallar); Q. Chen (Qiang); C.R.K. Ching (Christopher); V. Chouraki (Vincent); G. Cuellar-Partida (Gabriel); F. Crivello (Fabrice); A. den Braber (Anouk); Doan, N.T. (Nhat Trung); S.M. Ehrlich (Stefan); S. Giddaluru (Sudheer); A.L. Goldman (Aaron L.); R.F. Gottesman (Rebecca); O. Grimm (Oliver); M.D. Griswold (Michael); T. Guadalupe (Tulio); Gutman, B.A. (Boris A.); J. Hass (Johanna); U.K. Haukvik (Unn); D. Hoehn (David); A.J. Holmes (Avram); M. Hoogman (Martine); D. Janowitz (Deborah); T. Jia (Tianye); Jørgensen, K.N. (Kjetil N.); N. Karbalai (Nazanin); D. Kasperaviciute (Dalia); S. Kim (Shinseog); M. Klein (Marieke); B. Kraemer (Bernd); P.H. Lee (Phil); D.C. Liewald (David C.); L.M. Lopez (Lorna); M. Luciano (Michelle); C. MacAre (Christine); Marquand, A.F. (Andre F.); M. Matarin (Mar); R. Mather; M. Mattheisen (Manuel); McKay, D.R. (David R.); Milaneschi, Y. (Yuri); S. Muñoz Maniega (Susana); K. Nho (Kwangsik); A.C. Nugent (Allison); P. Nyquist (Paul); Loohuis, L.M.O. (Loes M. Olde); J. Oosterlaan (Jaap); M. Papmeyer (Martina); Pirpamer, L. (Lukas); B. Pütz (Benno); A. Ramasamy (Adaikalavan); Richards, J.S. (Jennifer S.); S.L. Risacher (Shannon); R. Roiz-Santiañez (Roberto); N. Rommelse (Nanda); S. Ropele (Stefan); E.J. Rose (Emma); N.A. Royle (Natalie); T. Rundek (Tatjana); P.G. Sämann (Philipp); Saremi, A. (Arvin); C.L. Satizabal (Claudia L.); L. Schmaal (Lianne); N.J. Schork (Nicholas); Shen, L. (Li); J. Shin (Jean); Shumskaya, E. (Elena); A.V. Smith (Albert Vernon); R. Sprooten (Roy); L.T. Strike (Lachlan); A. Teumer (Alexander); D. Tordesillas-Gutierrez (Diana); R. Toro (Roberto); D. Trabzuni (Danyah); S. Trompet (Stella); D. Vaidya (Dhananjay); J. van der Grond (Jeroen); S.J. van der Lee (Sven); Van Der Meer, D. (Dennis); M.M.J. Van Donkelaar (Marjolein M. J.); K.R. van Eijk (Kristel); T.G.M. van Erp (Theo G.); Van Rooij, D. (Daan); E. Walton (Esther); L.T. Westlye (Lars); C.D. Whelan (Christopher); B.G. Windham (B Gwen); A.M. Winkler (Anderson); K. Wittfeld (Katharina); G. Woldehawariat (Girma); A. Björnsson (Asgeir); Wolfers, T. (Thomas); L.R. Yanek (Lisa); Yang, J. (Jingyun); A.P. Zijdenbos; M.P. Zwiers (Marcel); I. Agartz (Ingrid); L. Almasy (Laura); D.J. Ames (David); Amouyel, P. (Philippe); O.A. Andreassen (Ole); S. Arepalli (Sampath); A.A. Assareh; S. Barral (Sandra); M.E. Bastin (Mark); Becker, D.M. (Diane M.); J.T. Becker (James); D.A. Bennett (David A.); J. Blangero (John); H. van Bokhoven (Hans); D.I. Boomsma (Dorret); H. Brodaty (Henry); R.M. Brouwer (Rachel); H.G. Brunner; M. Buckner; J.K. Buitelaar (Jan); K. Bulayeva (Kazima); W. Cahn (Wiepke); V.D. Calhoun Vince D. (V.); D.M. Cannon (Dara); G. Cavalleri (Gianpiero); Cheng, C.-Y. (Ching-Yu); S. Cichon (Sven); M.R. Cookson (Mark); A. Corvin (Aiden); B. Crespo-Facorro (Benedicto); J.E. Curran (Joanne); M. Czisch (Michael); A.M. Dale (Anders); G.E. Davies (Gareth); A.J. de Craen (Anton); E.J.C. de Geus (Eco); P.L. de Jager (Philip); G.I. de Zubicaray (Greig); I.J. Deary (Ian J.); S. Debette (Stéphanie); C. DeCarli (Charles); N. Delanty; C. Depondt (Chantal); A.L. DeStefano (Anita); A. Dillman (Allissa); S. Djurovic (Srdjan); D.J. Donohoe (Dennis); D.A. Drevets (Douglas); Duggirala, R. (Ravi); M.D. Dyer (Matthew); C. Enzinger (Christian); S. Erk; T. Espeseth (Thomas); Fedko, I.O. (Iryna O.); Fernández, G. (Guillén); L. Ferrucci (Luigi); S.E. Fisher (Simon); D. Fleischman (Debra); I. Ford (Ian); M. Fornage (Myriam); T. Foroud (Tatiana); P.T. Fox (Peter); C. Francks (Clyde); Fukunaga, M. (Masaki); Gibbs, J.R. (J. Raphael); D.C. Glahn (David); R.L. Gollub (Randy); H.H.H. Göring (Harald H.); R.C. Green (Robert C.); O. Gruber (Oliver); V. Gudnason (Vilmundur); S. Guelfi (Sebastian); Håberg, A.K. (Asta K.); N.K. Hansell (Narelle); J. Hardy (John); C.A. Hartman (C.); Hashimoto, R. (Ryota); K. Hegenscheid (Katrin); J. Heinz (Judith); S. Le Hellard (Stephanie); D.G. Hernandez (Dena); D.J. Heslenfeld (Dirk); Ho, B.-C. (Beng-Choon); P.J. Hoekstra (Pieter); W. Hoffmann (Wolfgang); A. Hofman (Albert); F. Holsboer (Florian); G. Homuth (Georg); N. Hosten (Norbert); J.J. Hottenga (Jouke Jan); M.J. Huentelman (Matthew); H.H. Pol; Ikeda, M. (Masashi); Jack, C.R. (Clifford R.); S. Jenkinson (Sarah); R. Johnson (Robert); Jönsson, E.G. (Erik G.); J.W. Jukema; R. Kahn (René); Kanai, R. (Ryota); I. Kloszewska (Iwona); Knopman, D.S. (David S.); P. Kochunov (Peter); Kwok, J.B. (John B.); S. Lawrie (Stephen); H. Lemaître (Herve); X. Liu (Xinmin); D.L. Longo (Dan L.); O.L. Lopez (Oscar L.); S. Lovestone (Simon); Martinez, O. (Oliver); J.-L. Martinot (Jean-Luc); V.S. Mattay (Venkata S.); McDonald, C. (Colm); A.M. McIntosh (Andrew); McMahon, F.J. (Francis J.); McMahon, K.L. (Katie L.); P. Mecocci (Patrizia); I. Melle (Ingrid); Meyer-Lindenberg, A. (Andreas); S. Mohnke (Sebastian); Montgomery, G.W. (Grant W.); D.W. Morris (Derek W); T.H. Mosley (Thomas H.); T.W. Mühleisen (Thomas); B. Müller-Myhsok (B.); M.A. Nalls (Michael); M. Nauck (Matthias); T.E. Nichols (Thomas); W.J. Niessen (Wiro); M.M. Nöthen (Markus); L. Nyberg (Lars); Ohi, K. (Kazutaka); R.L. Olvera (Rene); R.A. Ophoff (Roel); M. Pandolfo (Massimo); T. Paus (Tomas); Z. Pausova (Zdenka); B.W.J.H. Penninx (Brenda); Pike, G.B. (G. Bruce); S.G. Potkin (Steven); B.M. Psaty (Bruce); S. Reppermund; M. Rietschel (Marcella); J.L. Roffman (Joshua); N. Seiferth (Nina); J.I. Rotter (Jerome I.); M. Ryten (Mina); Sacco, R.L. (Ralph L.); P.S. Sachdev (Perminder); A.J. Saykin (Andrew); R. Schmidt (Reinhold); Schmidt, H. (Helena); C.J. Schofield (Christopher); Sigursson, S. (Sigurdur); Simmons, A. (Andrew); A. Singleton (Andrew); S.M. Sisodiya (Sanjay); Smith, C. (Colin); J.W. Smoller; H. Soininen (H.); V.M. Steen (Vidar); D.J. Stott (David J.); J. Sussmann (Jessika); A. Thalamuthu (Anbupalam); A.W. Toga (Arthur W.); B. Traynor (Bryan); J.C. Troncoso (Juan); M. Tsolaki (Magda); C. Tzourio (Christophe); A.G. Uitterlinden (André); Hernández, M.C.V. (Maria C. Valdés); M.P. van der Brug (Marcel); A. van der Lugt (Aad); N.J. van der Wee (Nic); N.E.M. van Haren (Neeltje E.); D. van 't Ent (Dennis); M.J.D. van Tol (Marie-José); B.N. Vardarajan (Badri); B. Vellas (Bruno); D.J. Veltman (Dick); H. Völzke (Henry); H.J. Walter (Henrik); J. Wardlaw (Joanna); A.M.J. Wassink (Annemarie); M.E. Weale (Michael); Weinberger, D.R. (Daniel R.); Weiner, M.W. (Michael W.); Wen, W. (Wei); E. Westman (Eric); T.J.H. White (Tonya); Wong, T.Y. (Tien Y.); Wright, C.B. (Clinton B.); R.H. Zielke (Ronald H.); A.B. Zonderman; N.G. Martin (Nicholas); C.M. van Duijn (Cornelia); M.J. Wright (Margaret); W.T. Longstreth Jr; G. Schumann (Gunter); H.J. Grabe (Hans Jörgen); B. Franke (Barbara); L.J. Launer (Lenore); S.E. Medland (Sarah Elizabeth); S. Seshadri (Sudha); P.M. Thompson (Paul); M.K. Ikram (Kamran)

    2017-01-01

    textabstractThe hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic

  3. Bacteremia causes hippocampal apoptosis in experimental pneumococcal meningitis

    DEFF Research Database (Denmark)

    Andersen, Christian Østergaard; Leib, S.L.; Rowland, Ian J

    2010-01-01

    ABSTRACT: BACKGROUND: Bacteremia and systemic complications both play important roles in brain pathophysiological alterations and the outcome of pneumococcal meningitis. Their individual contributions to the development of brain damage, however, still remain to be defined. METHODS: Using an adult...... rat pneumococcal meningitis model, the impact of bacteremia accompanying meningitis on the development of hippocampal injury was studied. The study comprised of the three groups: I. Meningitis (n=11), II. meningitis with attenuated bacteremia resulting from iv injection of serotype......-specific pneumococcal antibodies (n=14), and III. uninfected controls (n=6). RESULTS: Pneumococcal meningitis resulted in a significantly higher apoptosis score 0.22 (0.18-0.35) compared to uninfected controls (0.02 (0.00-0.02), Mann Whitney test, P=0.0003). Also, meningitis with an attenuation of bacteremia...

  4. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

    Hibar, Derrek P.; Adams, Hieab H. H.; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L.; Hofer, Edith; Renteria, Miguel E.; Bis, Joshua C.; Arias-Vasquez, Alejandro; Ikram, M. Kamran; Desrivières, Sylvane; Vernooij, Meike W.; Abramovic, Lucija; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S.; Armstrong, Nicola J.; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H.; Beiser, Alexa; Bernard, Manon; Blanton, Susan H.; Bohlken, Marc M.; Boks, Marco P.; Bralten, Janita; Brickman, Adam M.; Carmichael, Owen; Chakravarty, M. Mallar; Chen, Qiang; Ching, Christopher R. K.; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L.; Gottesman, Rebecca F.; Grimm, Oliver; Griswold, Michael E.; Guadalupe, Tulio; Gutman, Boris A.; Hass, Johanna; Haukvik, Unn K.; Hoehn, David; Holmes, Avram J.; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N.; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H.; Liewald, David C. M.; Lopez, Lorna M.; Luciano, Michelle; Macare, Christine; Marquand, Andre F.; Matarin, Mar; Mather, Karen A.; Mattheisen, Manuel; McKay, David R.; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C.; Nyquist, Paul; Loohuis, Loes M. Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S.; Risacher, Shannon L.; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J.; Royle, Natalie A.; Rundek, Tatjana; Sämann, Philipp G.; Saremi, Arvin; Satizabal, Claudia L.; Schmaal, Lianne; Schork, Andrew J.; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V.; Sprooten, Emma; Strike, Lachlan T.; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; van der Grond, Jeroen; van der Lee, Sven J.; van der Meer, Dennis; van Donkelaar, Marjolein M. J.; van Eijk, Kristel R.; van Erp, Theo G. M.; van Rooij, Daan; Walton, Esther; Westlye, Lars T.; Whelan, Christopher D.; Windham, Beverly G.; Winkler, Anderson M.; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R.; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P.; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A.; Arepalli, Sampath; Assareh, Amelia A.; Barral, Sandra; Bastin, Mark E.; Becker, Diane M.; Becker, James T.; Bennett, David A.; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I.; Brodaty, Henry; Brouwer, Rachel M.; Brunner, Han G.; Buckner, Randy L.; Buitelaar, Jan K.; Bulayeva, Kazima B.; Cahn, Wiepke; Calhoun, Vince D.; Cannon, Dara M.; Cavalleri, Gianpiero L.; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R.; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E.; Czisch, Michael; Dale, Anders M.; Davies, Gareth E.; de Craen, Anton J. M.; de Geus, Eco J. C.; de Jager, Philip L.; de Zubicaray, Greig I.; Deary, Ian J.; Debette, Stéphanie; Decarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C.; Duggirala, Ravi; Dyer, Thomas D.; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O.; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E.; Fleischman, Debra A.; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M.; Fox, Peter T.; Francks, Clyde; Fukunaga, Masaki; Gibbs, J. Raphael; Glahn, David C.; Gollub, Randy L.; Göring, Harald H. H.; Green, Robert C.; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K.; Hansell, Narelle K.; Hardy, John; Hartman, Catharina A.; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G.; Heslenfeld, Dirk J.; Ho, Beng-Choon; Hoekstra, Pieter J.; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Pol, Hilleke E. Hulshoff; Ikeda, Masashi; Jack, Clifford R.; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G.; Jukema, J. Wouter; Kahn, René S.; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S.; Kochunov, Peter; Kwok, John B.; Lawrie, Stephen M.; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L.; Lopez, Oscar L.; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S.; McDonald, Colm; McIntosh, Andrew M.; McMahon, Francis J.; McMahon, Katie L.; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W.; Morris, Derek W.; Mosley, Thomas H.; Mühleisen, Thomas W.; Müller-Myhsok, Bertram; Nalls, Michael A.; Nauck, Matthias; Nichols, Thomas E.; Niessen, Wiro J.; Nöthen, Markus M.; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L.; Ophoff, Roel A.; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W. J. H.; Pike, G. Bruce; Potkin, Steven G.; Psaty, Bruce M.; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L.; Romanczuk-Seiferth, Nina; Rotter, Jerome I.; Ryten, Mina; Sacco, Ralph L.; Sachdev, Perminder S.; Saykin, Andrew J.; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R.; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M.; Smith, Colin; Smoller, Jordan W.; Soininen, Hilkka; Steen, Vidar M.; Stott, David J.; Sussmann, Jessika E.; Thalamuthu, Anbupalam; Toga, Arthur W.; Traynor, Bryan J.; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G.; Hernández, Maria C. Valdés; van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J. A.; van Haren, Neeltje E. M.; van 't Ent, Dennis; van Tol, Marie-Jose; Vardarajan, Badri N.; Vellas, Bruno; Veltman, Dick J.; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M.; Wassink, Thomas H.; Weale, Michael E.; Weinberger, Daniel R.; Weiner, Michael W.; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y.; Wright, Clinton B.; Zielke, Ronald H.; Zonderman, Alan B.; Martin, Nicholas G.; van Duijn, Cornelia M.; Wright, Margaret J.; Longstreth, W. T.; Schumann, Gunter; Grabe, Hans J.; Franke, Barbara; Launer, Lenore J.; Medland, Sarah E.; Seshadri, Sudha; Thompson, Paul M.; Ikram, M. Arfan

    2017-01-01

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of

  5. Brain-derived neurotrophic factor mediates estradiol-induced dendritic spine formation in hippocampal neurons

    Science.gov (United States)

    Murphy, Diane D.; Cole, Nelson B.; Segal, Menahem

    1998-01-01

    Dendritic spines are of major importance in information processing and memory formation in central neurons. Estradiol has been shown to induce an increase of dendritic spine density on hippocampal neurons in vivo and in vitro. The neurotrophin brain-derived neurotrophic factor (BDNF) recently has been implicated in neuronal maturation, plasticity, and regulation of GABAergic interneurons. We now demonstrate that estradiol down-regulates BDNF in cultured hippocampal neurons to 40% of control values within 24 hr of exposure. This, in turn, decreases inhibition and increases excitatory tone in pyramidal neurons, leading to a 2-fold increase in dendritic spine density. Exogenous BDNF blocks the effects of estradiol on spine formation, and BDNF depletion with a selective antisense oligonucleotide mimics the effects of estradiol. Addition of BDNF antibodies also increases spine density, and diazepam, which facilitates GABAergic neurotransmission, blocks estradiol-induced spine formation. These observations demonstrate a functional link between estradiol, BDNF as a potent regulator of GABAergic interneurons, and activity-dependent formation of dendritic spines in hippocampal neurons. PMID:9736750

  6. Visual performance of pigeons following hippocampal lesions.

    Science.gov (United States)

    Bingman, V P; Hodos, W

    1992-11-15

    The effect of hippocampal lesions on performance in two psychophysical measures of spatial vision (acuity and size-difference threshold) was examined in 7 pigeons. No difference between the preoperative and postoperative thresholds of the experimental birds was found. The visual performance of pigeons in the psychophysical tasks failed to reveal a role of the hippocampal formation in vision. The results argue strongly that the behavioral deficits found in pigeons with hippocampal lesions when tested in a variety of memory-related spatial tasks is not based on a defect in spatial vision but impaired spatial cognition.

  7. Hippocampal “Time Cells”: Time versus Path Integration

    Science.gov (United States)

    Kraus, Benjamin J.; Robinson, Robert J.; White, John A.; Eichenbaum, Howard; Hasselmo, Michael E.

    2014-01-01

    SUMMARY Recent studies have reported the existence of hippocampal “time cells,” neurons that fire at particular moments during periods when behavior and location are relatively constant. However, an alternative explanation of apparent time coding is that hippocampal neurons “path integrate” to encode the distance an animal has traveled. Here, we examined hippocampal neuronal firing patterns as rats ran in place on a treadmill, thus “clamping” behavior and location, while we varied the treadmill speed to distinguish time elapsed from distance traveled. Hippocampal neurons were strongly influenced by time and distance, and less so by minor variations in location. Furthermore, the activity of different neurons reflected integration over time and distance to varying extents, with most neurons strongly influenced by both factors and some significantly influenced by only time or distance. Thus, hippocampal neuronal networks captured both the organization of time and distance in a situation where these dimensions dominated an ongoing experience. PMID:23707613

  8. Hippocampal-neocortical functional reorganization underlies children's cognitive development.

    Science.gov (United States)

    Qin, Shaozheng; Cho, Soohyun; Chen, Tianwen; Rosenberg-Lee, Miriam; Geary, David C; Menon, Vinod

    2014-09-01

    The importance of the hippocampal system for rapid learning and memory is well recognized, but its contributions to a cardinal feature of children's cognitive development-the transition from procedure-based to memory-based problem-solving strategies-are unknown. Here we show that the hippocampal system is pivotal to this strategic transition. Longitudinal functional magnetic resonance imaging (fMRI) in 7-9-year-old children revealed that the transition from use of counting to memory-based retrieval parallels increased hippocampal and decreased prefrontal-parietal engagement during arithmetic problem solving. Longitudinal improvements in retrieval-strategy use were predicted by increased hippocampal-neocortical functional connectivity. Beyond childhood, retrieval-strategy use continued to improve through adolescence into adulthood and was associated with decreased activation but more stable interproblem representations in the hippocampus. Our findings provide insights into the dynamic role of the hippocampus in the maturation of memory-based problem solving and establish a critical link between hippocampal-neocortical reorganization and children's cognitive development.

  9. Hippocampal adaptive response following extensive neuronal loss in an inducible transgenic mouse model.

    Directory of Open Access Journals (Sweden)

    Kristoffer Myczek

    Full Text Available Neuronal loss is a common component of a variety of neurodegenerative disorders (including Alzheimer's, Parkinson's, and Huntington's disease and brain traumas (stroke, epilepsy, and traumatic brain injury. One brain region that commonly exhibits neuronal loss in several neurodegenerative disorders is the hippocampus, an area of the brain critical for the formation and retrieval of memories. Long-lasting and sometimes unrecoverable deficits caused by neuronal loss present a unique challenge for clinicians and for researchers who attempt to model these traumas in animals. Can these deficits be recovered, and if so, is the brain capable of regeneration following neuronal loss? To address this significant question, we utilized the innovative CaM/Tet-DT(A mouse model that selectively induces neuronal ablation. We found that we are able to inflict a consistent and significant lesion to the hippocampus, resulting in hippocampally-dependent behavioral deficits and a long-lasting upregulation in neurogenesis, suggesting that this process might be a critical part of hippocampal recovery. In addition, we provide novel evidence of angiogenic and vasculature changes following hippocampal neuronal loss in CaM/Tet-DTA mice. We posit that angiogenesis may be an important factor that promotes neurogenic upregulation following hippocampal neuronal loss, and both factors, angiogenesis and neurogenesis, can contribute to the adaptive response of the brain for behavioral recovery.

  10. Dietary lipids are differentially associated with hippocampal-dependent relational memory in prepubescent children1234

    Science.gov (United States)

    Khan, Naiman A; Monti, Jim M; Raine, Lauren B; Drollette, Eric S; Moore, R Davis; Scudder, Mark R; Kramer, Arthur F; Hillman, Charles H; Cohen, Neal J

    2014-01-01

    Background: Studies in rodents and older humans have shown that the hippocampus—a brain structure critical to relational/associative memory—has remarkable plasticity as a result of lifestyle factors (eg, exercise). However, the effect of dietary intake on hippocampal-dependent memory during childhood has remained unexamined. Objective: We investigated the cross-sectional relation of dietary components characteristic of the Western diet, including saturated fatty acids (SFAs), omega-3 (n−3) fatty acids, and refined sugar, with hippocampal-dependent relational memory in prepubescent children. Design: Participants aged 7–9 y (n = 52) reported their dietary intake by using the Youth-Adolescent Food-Frequency Questionnaire and completed memory tasks designed to assess relational (hippocampal-dependent) and item (hippocampal-independent) memory. Performance on the memory tasks was assessed with both direct (accuracy) and indirect (eye movement) measures. Results: Partial correlations adjusted for body mass index showed a positive relation between relational memory accuracy and intake of omega-3 fatty acids and a negative relation of both relational and item memory accuracy with intake of SFAs. Potential confounding factors of age, sex, intelligence quotient, socioeconomic status, pubertal timing, and aerobic fitness (maximal oxygen volume) were not significantly related to any of the dietary intake measures. Eye movement measures of relational memory (preferential viewing to the target stimulus) showed a negative relation with intake of added sugar. Conclusions: SFA intake was negatively associated with both forms of memory, whereas omega-3 fatty acid intake was selectively positively associated with hippocampal-dependent relational memory. These findings are among the first to show a link between habitual dietary intake and cognitive health as pertaining to hippocampal function in childhood. The Fitness Improves Thinking Kids (FITKids) and FITKids2 trials were

  11. How does the brain deal with cumulative stress? A review with focus on developmental stress, HPA axis function and hippocampal structure in humans.

    Science.gov (United States)

    Frodl, Thomas; O'Keane, Veronica

    2013-04-01

    There is evidence that excessive stress exposure of the brain, mediated through the neurotoxic effects of cortisol and possibly neuroinflammation, causes damage to brain structure and function: the glucocorticoid cascade hypothesis. Functional changes of hypothalamic-pituitary-adrenal (HPA) axis as well as alterations in brain structures like the hippocampus have been consistently reported in major depression. However, there has not been a lot of emphasis on bringing findings from studies on early childhood stress, HPA axis functioning and hippocampal imaging together. This is the subject for this systematic review of the literature on how developmental stress, specifically childhood maltreatment, may impact on HPA axis function and hippocampal structure. We will also review the literature on the relationship between HPA axis function and hippocampal volume in healthy, depressed and other disease states. There is evidence that prenatal stress and childhood maltreatment is associated with an abnormally developing HPA system, as well as hippocampal volume reduction. Smaller hippocampal volumes are associated with increased cortisol secretion during the day. We conclude that a model integrating childhood maltreatment, cortisol abnormalities and hippocampal volume may need to take other factors into account, such as temperament, genetics or the presence of depression; to provide a cohesive explanation of all the findings. Finally, we have to conclude that the cascade hypothesis, mainly based on preclinical studies, has not been translated enough into humans. While there is evidence that early life maltreatment results in structural hippocampal changes and these are in turn more prominent in subjects with higher continuous cortisol secretion it is less clear which role early life maltreatment plays in HPA axis alteration. Copyright © 2012 Elsevier Inc. All rights reserved.

  12. Stretch-induced Ca2+ independent ATP release in hippocampal astrocytes.

    Science.gov (United States)

    Xiong, Yingfei; Teng, Sasa; Zheng, Lianghong; Sun, Suhua; Li, Jie; Guo, Ning; Li, Mingli; Wang, Li; Zhu, Feipeng; Wang, Changhe; Rao, Zhiren; Zhou, Zhuan

    2018-02-28

    Similar to neurons, astrocytes actively participate in synaptic transmission via releasing gliotransmitters. The Ca 2+ -dependent release of gliotransmitters includes glutamate and ATP. Following an 'on-cell-like' mechanical stimulus to a single astrocyte, Ca 2+ independent single, large, non-quantal, ATP release occurs. Astrocytic ATP release is inhibited by either selective antagonist treatment or genetic knockdown of P2X7 receptor channels. Our work suggests that ATP can be released from astrocytes via two independent pathways in hippocampal astrocytes; in addition to the known Ca 2+ -dependent vesicular release, larger non-quantal ATP release depends on P2X7 channels following mechanical stretch. Astrocytic ATP release is essential for brain functions such as synaptic long-term potentiation for learning and memory. However, whether and how ATP is released via exocytosis remains hotly debated. All previous studies of non-vesicular ATP release have used indirect assays. By contrast, two recent studies report vesicular ATP release using more direct assays. In the present study, using patch clamped 'ATP-sniffer cells', we re-investigated astrocytic ATP release at single-vesicle resolution in hippocampal astrocytes. Following an 'on-cell-like' mechanical stimulus of a single astrocyte, a Ca 2+ independent single large non-quantal ATP release occurred, in contrast to the Ca 2+ -dependent multiple small quantal ATP release in a chromaffin cell. The mechanical stimulation-induced ATP release from an astrocyte was inhibited by either exposure to a selective antagonist or genetic knockdown of P2X7 receptor channels. Functional P2X7 channels were expressed in astrocytes in hippocampal brain slices. Thus, in addition to small quantal ATP release, larger non-quantal ATP release depends on P2X7 channels in astrocytes. © 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.

  13. Magnesium chloride alone or in combination with diazepam fails to prevent hippocampal damage following transient forebrain ischemia

    Directory of Open Access Journals (Sweden)

    H. Milani

    1999-10-01

    Full Text Available In the central nervous system, magnesium ion (Mg2+ acts as an endogenous modulator of N-methyl-D-aspartate (NMDA-coupled calcium channels, and may play a major role in the pathomechanisms of ischemic brain damage. In the present study, we investigated the effects of magnesium chloride (MgCl2, 2.5, 5.0 or 7.5 mmol/kg, either alone or in combination with diazepam (DZ, on ischemia-induced hippocampal cell death. Male Wistar rats (250-300 g were subjected to transient forebrain ischemia for 15 min using the 4-vessel occlusion model. MgCl2 was applied systemically (sc in single (1x, 2 h post-ischemia or multiple doses (4x, 1, 2, 24 and 48 h post-ischemia. DZ was always given twice, at 1 and 2 h post-ischemia. Thus, ischemia-subjected rats were assigned to one of the following treatments: vehicle (0.1 ml/kg, N = 34, DZ (10 mg/kg, N = 24, MgCl2 (2.5 mmol/kg, N = 10, MgCl2 (5.0 mmol/kg, N = 17, MgCl2 (7.5 mmol/kg, N = 9 or MgCl2 (5 mmol/kg + DZ (10 mg/kg, N = 14. Seven days after ischemia the brains were analyzed histologically. Fifteen minutes of ischemia caused massive pyramidal cell loss in the subiculum (90.3% and CA1 (88.4% sectors of the hippocampus (P0.05. Both DZ alone and DZ + MgCl2 reduced rectal temperature significantly (P<0.05. No animal death was observed after drug treatment. These data indicate that exogenous magnesium, when administered systemically post-ischemia even in different multiple dose schedules, alone or with diazepam, is not useful against the histopathological effects of transient global cerebral ischemia in rats.

  14. Role of adult hippocampal neurogenesis in stress resilience

    Directory of Open Access Journals (Sweden)

    Brunno R. Levone

    2015-01-01

    Full Text Available There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders.

  15. Spatio-temporal specialization of GABAergic septo-hippocampal neurons for rhythmic network activity.

    Science.gov (United States)

    Unal, Gunes; Crump, Michael G; Viney, Tim J; Éltes, Tímea; Katona, Linda; Klausberger, Thomas; Somogyi, Peter

    2018-03-03

    Medial septal GABAergic neurons of the basal forebrain innervate the hippocampus and related cortical areas, contributing to the coordination of network activity, such as theta oscillations and sharp wave-ripple events, via a preferential innervation of GABAergic interneurons. Individual medial septal neurons display diverse activity patterns, which may be related to their termination in different cortical areas and/or to the different types of innervated interneurons. To test these hypotheses, we extracellularly recorded and juxtacellularly labeled single medial septal neurons in anesthetized rats in vivo during hippocampal theta and ripple oscillations, traced their axons to distant cortical target areas, and analyzed their postsynaptic interneurons. Medial septal GABAergic neurons exhibiting different hippocampal theta phase preferences and/or sharp wave-ripple related activity terminated in restricted hippocampal regions, and selectively targeted a limited number of interneuron types, as established on the basis of molecular markers. We demonstrate the preferential innervation of bistratified cells in CA1 and of basket cells in CA3 by individual axons. One group of septal neurons was suppressed during sharp wave-ripples, maintained their firing rate across theta and non-theta network states and mainly fired along the descending phase of CA1 theta oscillations. In contrast, neurons that were active during sharp wave-ripples increased their firing significantly during "theta" compared to "non-theta" states, with most firing during the ascending phase of theta oscillations. These results demonstrate that specialized septal GABAergic neurons contribute to the coordination of network activity through parallel, target area- and cell type-selective projections to the hippocampus.

  16. Persistent schema-dependent hippocampal-neocortical connectivity during memory encoding and postencoding rest in humans.

    Science.gov (United States)

    van Kesteren, Marlieke T R; Fernández, Guillén; Norris, David G; Hermans, Erno J

    2010-04-20

    The hippocampus is thought to promote gradual incorporation of novel information into long-term memory by binding, reactivating, and strengthening distributed cortical-cortical connections. Recent studies implicate a key role in this process for hippocampally driven crosstalk with the (ventro)medial prefrontal cortex (vmPFC), which is proposed to become a central node in such representational networks over time. The existence of a relevant prior associative network, or schema, may moreover facilitate this process. Thus, hippocampal-vmPFC crosstalk may support integration of new memories, particularly in the absence of a relevant prior schema. To address this issue, we used functional magnetic resonance imaging (fMRI) and prior schema manipulation to track hippocampal-vmPFC connectivity during encoding and postencoding rest. We manipulated prior schema knowledge by exposing 30 participants to the first part of a movie that was temporally scrambled for 15 participants. The next day, participants underwent fMRI while encoding the movie's final 15 min in original order and, subsequently, while resting. Schema knowledge and item recognition performance show that prior schema was successfully and selectively manipulated. Intersubject synchronization (ISS) and interregional partial correlation analyses furthermore show that stronger prior schema was associated with more vmPFC ISS and less hippocampal-vmPFC interregional connectivity during encoding. Notably, this connectivity pattern persisted during postencoding rest. These findings suggest that additional crosstalk between hippocampus and vmPFC is required to compensate for difficulty integrating novel information during encoding and provide tentative support for the notion that functionally relevant hippocampal-neocortical crosstalk persists during off-line periods after learning.

  17. Parahippocampal Involvement in Mesial Temporal Lobe Epilepsy with Hippocampal Sclerosis: A Proof of Concept from Memory-Guided Saccades

    Directory of Open Access Journals (Sweden)

    Silvia Colnaghi

    2017-11-01

    Full Text Available ObjectiveMesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS may involve extrahippocampal areas of structural damage and dysfunction. The accuracy of medium-term spatial memory can be tested by memory-guided saccades (MGS to evaluate a functional impairment of the parahippocampal cortex (PHC, while voxel-based morphometry (VBM analysis can be used to detect a structural damage of the latter region.MethodsMGS with 3- and 30-s memorization delays were compared between 7 patients affected by right MTLE-HS (r-MTLE-HS, 6 patients affected by left MTLE-HS, and 13 healthy controls. The same subjects underwent brain MRI for a VBM analysis. Correlation analysis was performed between the results of VBM and MGS and with patients’ clinical data.ResultsRight MTLE-HS patients showed impaired accuracy of leftward MGS with a 30-s memorization delay; their gray-matter volume was reduced in the right hippocampus and inferior temporal gyrus, and bilaterally in the cerebellum. Left MTLE-HS patients had normal MGS accuracy; their gray-matter volume was reduced in the left hippocampus, in the right-inferior temporal gyrus and corpus callosus, and bilaterally in the insular cortex and in the cerebellum. The difference between right and left parahippocampal volumes correlated with MGS accuracy, while right and left hippocampal volumes did not. Hippocampal and parahippocampal volume did not correlate with clinical variables such as febrile seizures, age at disease onset, disease duration, and seizure frequency.ConclusionMGS abnormalities suggested the functional involvement of the right PHC in patients with r-MTLE-HS, supporting a right lateralization of spatial memory control and showing a relation between functional impairment and degree of atrophy.

  18. Chronic copper exposure causes spatial memory impairment, selective loss of hippocampal synaptic proteins, and activation of PKR/eIF2α pathway in mice.

    Science.gov (United States)

    Ma, Quan; Ying, Ming; Sui, Xiaojing; Zhang, Huimin; Huang, Haiyan; Yang, Linqing; Huang, Xinfeng; Zhuang, Zhixiong; Liu, Jianjun; Yang, Xifei

    2015-01-01

    Copper is an essential element for human growth and development; however, excessive intake of copper could contribute to neurotoxicity. Here we show that chronic exposure to copper in drinking water impaired spatial memory with simultaneous selective loss of hippocampal pre-synaptic protein synapsin 1, and post-synaptic density protein (PSD)-93/95 in mice. Copper exposure was shown to elevate the levels of nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) in hippocampus, two markers of oxidative stress. Concurrently, we also found that copper exposure activated double stranded RNA-dependent protein kinase (PKR) as evidenced by increased ratio of phosphorylated PKR at Thr451 and total PKR and increased the phosphorylation of its downstream signaling molecule eukaryotic initiation factor 2α (eIF2α) at Ser51 in hippocampus. Consistent with activation of PKR/eIF2α signaling pathway which was shown to mediate synaptic deficit and cognitive impairment, the levels of activating transcription factor 4 (ATF-4), a downstream signaling molecule of eIF2α and a repressor of CREB-mediated gene expression, were significantly increased, while the activity of cAMP response elements binding protein (CREB) was inactivated as suggested by decreased phosphorylation of CREB at Ser133 by copper exposure. In addition, the expression of the pro-apoptotic target molecule C/EBP homology protein (CHOP) of ATF-4 was upregulated and hippocampal neuronal apoptosis was induced by copper exposure. Taken together, we propose that chronic copper exposure might cause spatial memory impairment, selective loss of synaptic proteins, and neuronal apoptosis through the mechanisms involving activation of PKR/eIF2α signaling pathway.

  19. Berberine prevents nigrostriatal dopaminergic neuronal loss and suppresses hippocampal apoptosis in mice with Parkinson's disease.

    Science.gov (United States)

    Kim, Mia; Cho, Ki-Ho; Shin, Mal-Soon; Lee, Jae-Min; Cho, Han-Sam; Kim, Chang-Ju; Shin, Dong-Hoon; Yang, Hyeon Jeong

    2014-04-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of nigral dopaminergic neurons and a reduction in striatal dopaminergic fibers, which result in tremors, rigidity, bradykinesia and gait disturbance. In addition to motor dysfunction, dementia is a widely recognized symptom of patients with PD. Berberine, an isoquinoline alkaloid isolated from Berberis vulgaris L., is known to exert anxiolytic, analgesic, anti-inflammatory, antipsychotic, antidepressant and anti-amnesic effects. In the present study, we investigated the effects of berberine on short-term memory in relation to dopamine depletion and hippocampal neurogenesis using a mouse model of PD, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/P) treatment. Mice in the berberine-treated groups were orally administered berberine once a day for a total of 5 weeks. Our results revealed that the injection of MPTP/P induced dopaminergic neuronal death in the substantia nigra and fiber loss in the striatum. This resulted in impaired motor balance and coordination, as assessed by the beam walking test. We further demonstrated that MPTP/P-induced apoptosis in the hippocampus deteriorated short-term memory, as shown by the step-down avoidance task. By contrast, neurogenesis in the hippocampal dentate gyrus, which is a compensatory adaptive response to excessive apoptosis, was increased upon PD induction. However, treatment with berberine enhanced motor balance and coordination by preventing dopaminergic neuronal damage. Treatment with berberine also improved short-term memory by inhibiting apoptosis in the hippocampus. Berberine demonstrated maximal potency at 50 mg/kg. Based on these data, treatment with berberine may serve as a potential therapeutic strategy for the alleviation of memory impairment and motor dysfunction in patients with PD.

  20. Creativity, Comprehension, Conversation and the Hippocampal Region: New Data and Theory

    Directory of Open Access Journals (Sweden)

    Donald G. MacKay

    2016-04-01

    Full Text Available This article examines conceptual frameworks for explaining relations between creativity and the hippocampal region (HR and reports two new experimental studies. In both studies, seventeen people participated in extensive face-to-face interviews: sixteen normal individuals and H.M., an amnesic with cerebellar and HR damage but virtually no neocortical damage. The results indicated that HR damage impairs aspects of everyday language comprehension and production that require creativity—defined as the ability to form new internal representations that satisfy relevant constraints for being useful or valuable in the real world. Study 1 demonstrated deficits in H.M.’s comprehension of creative but not routine aspects of the interviews—extending to the real world twelve prior demonstrations that H.M. understands routine but not novel aspects of experimentally constructed sentences, deficits that reflected his HR damage, but not his cerebellar damage, his explicit or declarative memory problems, inability to comprehend or recall the instructions, forgetting, poor visual acuity, motoric slowing, time pressure, deficits in visual scanning or attentional allocation, lack of motivation, and excessive memory load in the tasks. Study 2 demonstrated similar deficits in H.M.’s ability to produce creative but not routine aspects of conversational discourse, extending findings in five prior sentence production experiments to real-world creativity. Both types of deficits impaired communication in the interviews, results that support some theories of creativity and the HR but not others.

  1. Short-term sleep deprivation stimulates hippocampal neurogenesis in rats following global cerebral ischemia/reperfusion.

    Directory of Open Access Journals (Sweden)

    Oumei Cheng

    Full Text Available Sleep deprivation (SD plays a complex role in central nervous system (CNS diseases. Recent studies indicate that short-term SD can affect the extent of ischemic damage. The aim of this study was to investigate whether short-term SD could stimulate hippocampal neurogenesis in a rat model of global cerebral ischemia/reperfusion (GCIR.One hundred Sprague-Dawley rats were randomly divided into Sham, GCIR and short-term SD groups based on different durations of SD; the short-term SD group was randomly divided into three subgroups: the GCIR+6hSD*3d-treated, GCIR+12hSD-treated and GCIR+12hSD*3d-treated groups. The GCIR rat model was induced via the bilateral occlusion of the common carotid arteries and hemorrhagic hypotension. The rats were sleep-deprived starting at 48 h following GCIR. A Morris water maze test was used to assess learning and memory ability; cell proliferation and differentiation were analyzed via 5-bromodeoxyuridine (BrdU and neuron-specific enolase (NSE, respectively, at 14 and 28 d; the expression of hippocampal BDNF was measured after 7 d.The different durations of short-term SD designed in our experiment exhibited improvement in cognitive function as well as increased hippocampal BDNF expression. Additionally, the short-term SD groups also showed an increased number of BrdU- and BrdU/NSE-positive cells compared with the GCIR group. Of the three short-term SD groups, the GCIR+12hSD*3d-treated group experienced the most substantial beneficial effects.Short-term SD, especially the GCIR+12hSD*3d-treated method, stimulates neurogenesis in the hippocampal dentate gyrus (DG of rats that undergo GCIR, and BDNF may be an underlying mechanism in this process.

  2. Hippocampal and Amygdalar Volumes in Dissociative Identity Disorder

    Science.gov (United States)

    Vermetten, Eric; Schmahl, Christian; Lindner, Sanneke; Loewenstein, Richard J.; Bremner, J. Douglas

    2011-01-01

    Objective Smaller hippocampal volume has been reported in several stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD), borderline personality disorder with early abuse, and depression with early abuse. Patients with borderline personality disorder and early abuse have also been found to have smaller amygdalar volume. The authors examined hippocampal and amygdalar volumes in patients with dissociative identity disorder, a disorder that has been associated with a history of severe childhood trauma. Method The authors used magnetic resonance imaging to measure the volumes of the hippocampus and amygdala in 15 female patients with dissociative identity disorder and 23 female subjects without dissociative identity disorder or any other psychiatric disorder. The volumetric measurements for the two groups were compared. Results Hippocampal volume was 19.2% smaller and amygdalar volume was 31.6% smaller in the patients with dissociative identity disorder, compared to the healthy subjects. The ratio of hippocampal volume to amygdalar volume was significantly different between groups. Conclusions The findings are consistent with the presence of smaller hippocampal and amygdalar volumes in patients with dissociative identity disorder, compared with healthy subjects. PMID:16585437

  3. Hippocampal and amygdalar volumes in dissociative identity disorder.

    Science.gov (United States)

    Vermetten, Eric; Schmahl, Christian; Lindner, Sanneke; Loewenstein, Richard J; Bremner, J Douglas

    2006-04-01

    Smaller hippocampal volume has been reported in several stress-related psychiatric disorders, including posttraumatic stress disorder (PTSD), borderline personality disorder with early abuse, and depression with early abuse. Patients with borderline personality disorder and early abuse have also been found to have smaller amygdalar volume. The authors examined hippocampal and amygdalar volumes in patients with dissociative identity disorder, a disorder that has been associated with a history of severe childhood trauma. The authors used magnetic resonance imaging to measure the volumes of the hippocampus and amygdala in 15 female patients with dissociative identity disorder and 23 female subjects without dissociative identity disorder or any other psychiatric disorder. The volumetric measurements for the two groups were compared. Hippocampal volume was 19.2% smaller and amygdalar volume was 31.6% smaller in the patients with dissociative identity disorder, compared to the healthy subjects. The ratio of hippocampal volume to amygdalar volume was significantly different between groups. The findings are consistent with the presence of smaller hippocampal and amygdalar volumes in patients with dissociative identity disorder, compared with healthy subjects.

  4. Induction and repair of DNA double-strand breaks in hippocampal neurons of mice of different age after exposure to 60Co γ-rays in vivo and in vitro

    Science.gov (United States)

    Kozhina, R. A.; Chausov, V. N.; Kuzmina, E. A.; Boreyko, A. V.

    2018-04-01

    One of the central problems of modern radiobiology is the study of DNA damage induction and repair mechanisms in central nervous system cells, in particular, in hippocampal cells. The study of the regularities of molecular damage formation and repair in the hippocampus cells is of special interest, because these cells, unlike most cells of the central nervous system (CNS), keep proliferative activity, i.e. ability to neurogenesis. Age-related changes in hippocampus play an important role, which could lead to radiosensitivity changes in neurons to the ionizing radiation exposure. Regularities in DNA double-strand breaks (DSB) induction and repair in different aged mice hippocampal cells in vivo and in vitro under the action of γ-rays 60Co were studied with DNA comet-assay. The obtained dose dependences of DNA DSB induction are linear both in vivo and in vitro. It is established that in young animals' cells, the degree of DNA damage is higher than in older animals. It is shown that repair kinetics is basically different for exposure in vivo and in vitro.

  5. Verbal learning and memory outcome in selective amygdalohippocampectomy versus temporal lobe resection in patients with hippocampal sclerosis.

    Science.gov (United States)

    Foged, Mette Thrane; Vinter, Kirsten; Stauning, Louise; Kjær, Troels W; Ozenne, Brice; Beniczky, Sándor; Paulson, Olaf B; Madsen, Flemming Find; Pinborg, Lars H

    2018-02-01

    With the advent of new very selective techniques like thermal laser ablation to treat drug-resistant focal epilepsy, the controversy of resection size in relation to seizure outcome versus cognitive deficits has gained new relevance. The purpose of this study was to test the influence of the selective amygdalohippocampectomy (SAH) versus nonselective temporal lobe resection (TLR) on seizure outcome and cognition in patients with mesial temporal lobe epilepsy (MTLE) and histopathological verified hippocampal sclerosis (HS). We identified 108 adults (>16years) with HS, operated between 1995 and 2009 in Denmark. Exclusion criteria are the following: Intelligence below normal range, right hemisphere dominance, other native languages than Danish, dual pathology, and missing follow-up data. Thus, 56 patients were analyzed. The patients were allocated to SAH (n=22) or TLR (n=34) based on intraoperative electrocorticography. Verbal learning and verbal memory were tested pre- and postsurgery. Seizure outcome did not differ between patients operated using the SAH versus the TLR at 1year (p=0.951) nor at 7years (p=0.177). Verbal learning was more affected in patients resected in the left hemisphere than in the right (p=0.002). In patients with left-sided TLR, a worsening in verbal memory performance was found (p=0.011). Altogether, 73% were seizure-free for 1year and 64% for 7years after surgery. In patients with drug-resistant focal MTLE, HS and no magnetic resonance imaging (MRI) signs of dual pathology, selective amygdalohippocampectomy results in sustained seizure freedom and better memory function compared with patients operated with nonselective temporal lobe resection. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. A comprehensive analysis of earthquake damage patterns using high dimensional model representation feature selection

    Science.gov (United States)

    Taşkin Kaya, Gülşen

    2013-10-01

    Recently, earthquake damage assessment using satellite images has been a very popular ongoing research direction. Especially with the availability of very high resolution (VHR) satellite images, a quite detailed damage map based on building scale has been produced, and various studies have also been conducted in the literature. As the spatial resolution of satellite images increases, distinguishability of damage patterns becomes more cruel especially in case of using only the spectral information during classification. In order to overcome this difficulty, textural information needs to be involved to the classification to improve the visual quality and reliability of damage map. There are many kinds of textural information which can be derived from VHR satellite images depending on the algorithm used. However, extraction of textural information and evaluation of them have been generally a time consuming process especially for the large areas affected from the earthquake due to the size of VHR image. Therefore, in order to provide a quick damage map, the most useful features describing damage patterns needs to be known in advance as well as the redundant features. In this study, a very high resolution satellite image after Iran, Bam earthquake was used to identify the earthquake damage. Not only the spectral information, textural information was also used during the classification. For textural information, second order Haralick features were extracted from the panchromatic image for the area of interest using gray level co-occurrence matrix with different size of windows and directions. In addition to using spatial features in classification, the most useful features representing the damage characteristic were selected with a novel feature selection method based on high dimensional model representation (HDMR) giving sensitivity of each feature during classification. The method called HDMR was recently proposed as an efficient tool to capture the input

  7. Inter-relationships among Diet, Obesity and Hippocampal-dependent Cognitive Function

    OpenAIRE

    Davidson, Terry L.; Hargrave, Sara L.; Swithers, Susan E.; Sample, Camille H.; Fu, Xue; Kinzig, Kimberly P.; Zheng, Wei

    2013-01-01

    Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD...

  8. Methamphetamine-induced changes in the mice hippocampal neuropeptide Y system: implications for memory impairment

    DEFF Research Database (Denmark)

    Gonçalves, J; Baptista, S; Olesen, MV

    2012-01-01

    Methamphetamine (METH) is a psychostimulant drug that causes irreversible brain damage leading to several neurological and psychiatric abnormalities, including cognitive deficits. Neuropeptide Y (NPY) is abundant in the mammalian central nervous system (CNS) and has several important functions......, being involved in learning and memory processing. It has been demonstrated that METH induces significant alteration in mice striatal NPY, Y(1) and Y(2) receptor mRNA levels. However, the impact of this drug on the hippocampal NPY system and its consequences remain unknown. Thus, in this study, we...

  9. Effects of melatonin on prenatal dexamethasone-induced epigenetic alterations in hippocampal morphology and reelin and glutamic acid decarboxylase 67 levels.

    Science.gov (United States)

    Lui, Chun-Chung; Hsu, Mei-Hsin; Kuo, Ho-Chang; Chen, Chih-Cheng; Sheen, Jiunn-Ming; Yu, Hong-Ren; Tiao, Mao-Meng; Tain, You-Lin; Chang, Kow-Aung; Huang, Li-Tung

    2015-01-01

    Prenatal glucocorticoid exposure causes brain damage in adult offspring; however, the underlying mechanisms remain unclear. Melatonin has been shown to have beneficial effects in compromised pregnancies. Pregnant Sprague-Dawley rats were administered vehicle (VEH) or dexamethasone between gestation days 14 and 21. The programming effects of prenatal dexamethasone exposure on the brain were assessed at postnatal days (PND) 7, 42, and ∼120. Melatonin was administered from PND21 to the rats exposed to dexamethasone, and the outcome was assessed at ∼PND120. In total, there were four groups: VEH, vehicle plus melatonin (VEHM), prenatal dexamethasone-exposure (DEX), and prenatal dexamethasone exposure plus melatonin (DEXM). Spatial memory, gross hippocampal morphology, and hippocampal biochemistry were examined. Spatial memory assessed by the Morris water maze showed no significant differences among the four groups. Brain magnetic resonance imaging showed that all rats with prenatal dexamethasone exposure (DEX + DEXM) exhibited increased T2-weighted signals in the hippocampus. There were no significant differences in the levels of mRNA expression of hippocampal reln, which encodes reelin, and GAD1, which encodes glutamic acid decarboxylase 67, at PND7. At both PND42 and ∼PND120, reln and GAD1 mRNA expression levels were decreased. At ∼PND120, melatonin restored the reduced levels of hippocampal reln and GAD1 mRNA expression in the DEXM group. In addition, melatonin restored the reln mRNA expression levels by (1) reducing DNA methyltransferase 1 (DNMT1) mRNA expression and (2) reducing the binding of DNMT1 and the methyl-CpG binding protein 2 (MeCP2) to the reln promoter. The present study showed that prenatal dexamethasone exposure induced gross alterations in hippocampal morphology and reduced the levels of hippocampal mRNA expression of reln and GAD1. Spatial memory was unimpaired. Thus, melatonin had a beneficial effect in restoring hippocampal reln m

  10. Dehydroepiandrosterone protects male and female hippocampal neurons and neuroblastoma cells from glucose deprivation.

    Science.gov (United States)

    Vieira-Marques, Claudia; Arbo, Bruno Dutra; Ruiz-Palmero, Isabel; Ortiz-Rodriguez, Ana; Ghorbanpoor, Samar; Kucharski, Luiz Carlos; Arevalo, Maria A; Garcia-Segura, Luis Miguel; Ribeiro, Maria Flávia M

    2016-08-01

    Dehydroepiandrosterone (DHEA) modulates neurogenesis, neuronal function, neuronal survival and metabolism, enhancing mitochondrial oxidative capacity. Glucose deprivation and hypometabolism have been implicated in the mechanisms that mediate neuronal damage in neurological disorders, and some studies have shown that these mechanisms are sexually dimorphic. It was also demonstrated that DHEA is able to attenuate the hypometabolism that is related to some neurodegenerative diseases, eliciting neuroprotective effects in different experimental models of neurodegeneration. The aim of this study was to evaluate the effect of DHEA on the viability of male and female hippocampal neurons and SH-SY5Y neuroblastoma cells exposed to glucose deprivation. It was observed that after 12h of pre-treatment, DHEA was able to protect SH-SY5Y cells from glucose deprivation for 6h (DHEA 10(-12), 10(-8) and 10(-6)M) and 8h (DHEA 10(-8)M). In contrast, DHEA was not neuroprotective against glucose deprivation for 12 or 24h. DHEA (10(-8)M) also protected SH-SY5Y cells when added together or even 1h after the beginning of glucose deprivation (6h). Furthermore, DHEA (10(-8)M) also protected primary neurons from both sexes against glucose deprivation. In summary, our findings indicate that DHEA is neuroprotective against glucose deprivation in human neuroblastoma cells and in male and female mouse hippocampal neurons. These results suggest that DHEA could be a promising candidate to be used in clinical studies aiming to reduce neuronal damage in people from both sexes. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Point application with Angong Niuhuang sticker protects hippocampal and cortical neurons in rats with cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Dong-shu Zhang

    2015-01-01

    Full Text Available Angong Niuhuang pill, a Chinese materia medica preparation, can improve neurological functions after acute ischemic stroke. Because of its inconvenient application and toxic components (Cinnabaris and Realgar, we used transdermal enhancers to deliver Angong Niuhuang pill by modern technology, which expanded the safe dose range and clinical indications. In this study, Angong Niuhuang stickers administered at different point application doses (1.35, 2.7, and 5.4 g/kg were administered to the Dazhui (DU14, Qihai (RN6 and Mingmen (DU4 of rats with chronic cerebral ischemia, for 4 weeks. The Morris water maze was used to determine the learning and memory ability of rats. Hematoxylin-eosin staining and Nissl staining were used to observe neuronal damage of the cortex and hippocampal CA1 region in rats with chronic cerebral ischemia. The middle- and high-dose point application of Angong Niuhuang stickers attenuated neuronal damage in the cortex and hippocampal CA1 region, and improved the memory of rats with chronic cerebral ischemia with an efficacy similar to interventions by electroacupuncture at Dazhui (DU14, Qihai (RN6 and Mingmen (DU4. Our experimental findings indicate that point application with Angong Niuhuang stickers can improve cognitive function after chronic cerebral ischemia in rats and is neuroprotective with an equivalent efficacy to acupuncture.

  12. Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice.

    Directory of Open Access Journals (Sweden)

    Sindhu K Madathil

    Full Text Available Traumatic brain injury (TBI survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1, a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal overexpression of IGF-1 using the controlled cortical impact (CCI injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI.

  13. Astrocyte-Specific Overexpression of Insulin-Like Growth Factor-1 Protects Hippocampal Neurons and Reduces Behavioral Deficits following Traumatic Brain Injury in Mice

    Science.gov (United States)

    Madathil, Sindhu K.; Carlson, Shaun W.; Brelsfoard, Jennifer M.; Ye, Ping; D’Ercole, A. Joseph; Saatman, Kathryn E.

    2013-01-01

    Traumatic brain injury (TBI) survivors often suffer from long-lasting cognitive impairment that stems from hippocampal injury. Systemic administration of insulin-like growth factor-1 (IGF-1), a polypeptide growth factor known to play vital roles in neuronal survival, has been shown to attenuate posttraumatic cognitive and motor dysfunction. However, its neuroprotective effects in TBI have not been examined. To this end, moderate or severe contusion brain injury was induced in mice with conditional (postnatal) overexpression of IGF-1 using the controlled cortical impact (CCI) injury model. CCI brain injury produces robust reactive astrocytosis in regions of neuronal damage such as the hippocampus. We exploited this regional astrocytosis by linking expression of hIGF-1 to the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter, effectively targeting IGF-1 delivery to vulnerable neurons. Following brain injury, IGF-1Tg mice exhibited a progressive increase in hippocampal IGF-1 levels which was coupled with enhanced hippocampal reactive astrocytosis and significantly greater GFAP levels relative to WT mice. IGF-1 overexpression stimulated Akt phosphorylation and reduced acute (1 and 3d) hippocampal neurodegeneration, culminating in greater neuron survival at 10d after CCI injury. Hippocampal neuroprotection achieved by IGF-1 overexpression was accompanied by improved motor and cognitive function in brain-injured mice. These data provide strong support for the therapeutic efficacy of increased brain levels of IGF-1 in the setting of TBI. PMID:23826235

  14. Selective Excitation of Lamb-Waves for Damage Detection in Composites

    Science.gov (United States)

    Petculescu, G.; Krishnaswamy, S.; Achenbach, J. D.

    2006-03-01

    Sensors based on periodic arrays of coherent piezoelectric sources (comb design) are used to selectively excite and detect Lamb waves in aluminum and AS4/3601 unidirectional carbon-epoxy plates. 110 μm PVDF film poled in the thickness direction is used as piezoelectric material. An algorithm to eliminate the effect of coupling in amplitude measurements, using individual Lamb modes excited/detected by the same transducer pair, is described. A multiple-impact test showing a decrease in amplitude and group velocity as damage progresses is used as an example.

  15. Adaptive emotional memory: the key hippocampal-amygdalar interaction.

    Science.gov (United States)

    Desmedt, Aline; Marighetto, Aline; Richter-Levin, Gal; Calandreau, Ludovic

    2015-01-01

    For centuries philosophical and clinical studies have emphasized a fundamental dichotomy between emotion and cognition, as, for instance, between behavioral/emotional memory and explicit/representative memory. However, the last few decades cognitive neuroscience have highlighted data indicating that emotion and cognition, as well as their underlying neural networks, are in fact in close interaction. First, it turns out that emotion can serve cognition, as exemplified by its critical contribution to decision-making or to the enhancement of episodic memory. Second, it is also observed that reciprocally cognitive processes as reasoning, conscious appraisal or explicit representation of events can modulate emotional responses, like promoting or reducing fear. Third, neurobiological data indicate that reciprocal amygdalar-hippocampal influences underlie such mutual regulation of emotion and cognition. While supporting this view, the present review discusses experimental data, obtained in rodents, indicating that the hippocampal and amygdalar systems not only regulate each other and their functional outcomes, but also qualify specific emotional memory representations through specific activations and interactions. Specifically, we review consistent behavioral, electrophysiological, pharmacological, biochemical and imaging data unveiling a direct contribution of both the amygdala and hippocampal-septal system to the identification of the predictor of a threat in different situations of fear conditioning. Our suggestion is that these two brain systems and their interplay determine the selection of relevant emotional stimuli, thereby contributing to the adaptive value of emotional memory. Hence, beyond the mutual quantitative regulation of these two brain systems described so far, we develop the idea that different activations of the hippocampus and amygdala, leading to specific configurations of neural activity, qualitatively impact the formation of emotional memory

  16. Progressive contralateral hippocampal atrophy following surgery for medically refractory temporal lobe epilepsy.

    Science.gov (United States)

    Elliott, Cameron A; Gross, Donald W; Wheatley, B Matt; Beaulieu, Christian; Sankar, Tejas

    2016-09-01

    Determine the extent and time course of volumetric changes in the contralateral hippocampus following surgery for medically refractory temporal lobe epilepsy (TLE). Serial T1-weighted MRI brain scans were obtained in 26 TLE patients pre- and post-temporal lobe epilepsy surgery as well as in 12 control subjects of similar age. Patients underwent either anterior temporal lobectomy (ATL) or selective amygdalohippocampectomy (SAH). Blinded, manual hippocampal volumetry (head, body, and tail) was performed in two groups: 1) two scan group [ATL (n=6); SAH (n=10)], imaged pre-surgery and on average at 5.4 years post-surgery; and 2) longitudinal group [ATL (n=8); SAH (n=2)] imaged pre-surgery and on post-operative day 1, 2, 3, 6, 60, 120 and a delayed time point (average 2.4 years). In the two scan group, there was atrophy by 12% of the unresected contralateral hippocampus (p<0.001), with atrophy being most pronounced (27%) in the hippocampal body (p<0.001) with no significant differences seen for the hippocampal head or tail. In the longitudinal group, significant atrophy was also observed for the whole hippocampus and the body with atrophy seen as early as post-operative day #1 which progressed significantly over the first post-operative week (1.3%/day and 3.0%./day, respectively) before stabilizing over the long-term to a 13% reduction in total volume. There was no significant difference in atrophy compared by surgical approach (ATL vs. SAH; p=0.94) or side (p=0.31); however, atrophy was significantly more pronounced in patients with ongoing post-operative seizures (hippocampal body, p=0.019; whole hippocampus, p=0.048). There were no detectable post-operative neuropsychological deficits attributable to contralateral hippocampal atrophy. Significant contralateral hippocampal atrophy occurs following TLE surgery, which begins immediately and progresses over the first post-operative week. The observation that seizure free patients had significantly less atrophy of the

  17. Cryptic sexual dimorphism in spatial memory and hippocampal oxytocin receptors in prairie voles (Microtus ochrogaster).

    Science.gov (United States)

    Rice, Marissa A; Hobbs, Lauren E; Wallace, Kelly J; Ophir, Alexander G

    2017-09-01

    Sex differences are well documented and are conventionally associated with intense sex-specific selection. For example, spatial memory is frequently better in males, presumably due to males' tendency to navigate large spaces to find mates. Alternatively, monogamy (in which sex-specific selection is relatively relaxed) should diminish or eliminate differences in spatial ability and the mechanisms associated with this behavior. Nevertheless, phenotypic differences between monogamous males and females persist, sometimes cryptically. We hypothesize that sex-specific cognitive demands are present in monogamous species that will influence neural and behavioral phenotypes. The effects of these demands should be observable in spatial learning performance and neural structures associated with spatial learning and memory. We analyzed spatial memory performance, hippocampal volume and cell density, and hippocampal oxytocin receptor (OTR) expression in the socially monogamous prairie vole. Compared to females, males performed better in a spatial memory and spatial learning test. Although we found no sex difference in hippocampal volume or cell density, male OTR density was significantly lower than females, suggesting that performance may be regulated by sub-cellular mechanisms within the hippocampus that are less obvious than classic neuroanatomical features. Our results suggest an expanded role for oxytocin beyond facilitating social interactions, which may function in part to integrate social and spatial information. Copyright © 2017 Elsevier Inc. All rights reserved.

  18. Afferent input selects NMDA receptor subtype to determine the persistency of hippocampal LTP in freely behaving mice

    Directory of Open Access Journals (Sweden)

    Jesús Javier Ballesteros

    2016-10-01

    Full Text Available The glutamatergic N-methyl-D-aspartate receptor (NMDAR is critically involved in many forms of hippocampus-dependent memory that may be enabled by synaptic plasticity. Behavioral studies with NMDAR antagonists and NMDAR subunit (GluN2 mutants revealed distinct contributions from GluN2A- and GluN2B-containing NMDARs to rapidly and slowly acquired memory performance. Furthermore, studies of synaptic plasticity, in genetically modified mice in vitro, suggest that GluN2A and GluN2B may contribute in different ways to the induction and longevity of synaptic plasticity. In contrast to the hippocampal slice preparation, in behaving mice, the afferent frequencies that induce synaptic plasticity are very restricted and specific. In fact, it is the stimulus pattern, and not variations in afferent frequency that determine the longevity of long-term potentiation (LTP. Here, we explored the contribution of GluN2A and GluN2B to LTP of differing magnitudes and persistencies in freely behaving mice. We applied differing high-frequency stimulation (HFS patterns at 100 Hz to the hippocampal CA1 region, to induce NMDAR-dependent LTP in wild-type (WT mice, that endured for 24h (late (L-LTP. In GluN2A-KO mice, E-LTP (HFS, 50 pulses was significantly reduced in magnitude and duration, whereas LTP (HFS, 2 x 50 pulses and L-LTP (HFS, 4 x 50 pulses were unaffected compared to responses in WT animals. By contrast, pharmacological antagonism of GluN2B in WT had no effect on E-LTP but significantly prevented LTP. E- LTP and LTP were significantly impaired by GluN2B antagonism in GluN2A-KO mice. These data indicate that the pattern of afferent stimulation is decisive for the recruitment of distinct GluN2A and GluN2B signaling pathways that in turn determine the persistency of hippocampal LTP. Whereas brief bursts of patterned stimulation preferentially recruit GluN2A and lead to weak and short-lived forms of LTP, prolonged, more intense, afferent activation recruits GluN2B

  19. Tissue-selective effects of nucleolar stress and rDNA damage in developmental disorders.

    Science.gov (United States)

    Calo, Eliezer; Gu, Bo; Bowen, Margot E; Aryan, Fardin; Zalc, Antoine; Liang, Jialiang; Flynn, Ryan A; Swigut, Tomek; Chang, Howard Y; Attardi, Laura D; Wysocka, Joanna

    2018-02-01

    Many craniofacial disorders are caused by heterozygous mutations in general regulators of housekeeping cellular functions such as transcription or ribosome biogenesis. Although it is understood that many of these malformations are a consequence of defects in cranial neural crest cells, a cell type that gives rise to most of the facial structures during embryogenesis, the mechanism underlying cell-type selectivity of these defects remains largely unknown. By exploring molecular functions of DDX21, a DEAD-box RNA helicase involved in control of both RNA polymerase (Pol) I- and II-dependent transcriptional arms of ribosome biogenesis, we uncovered a previously unappreciated mechanism linking nucleolar dysfunction, ribosomal DNA (rDNA) damage, and craniofacial malformations. Here we demonstrate that genetic perturbations associated with Treacher Collins syndrome, a craniofacial disorder caused by heterozygous mutations in components of the Pol I transcriptional machinery or its cofactor TCOF1 (ref. 1), lead to relocalization of DDX21 from the nucleolus to the nucleoplasm, its loss from the chromatin targets, as well as inhibition of rRNA processing and downregulation of ribosomal protein gene transcription. These effects are cell-type-selective, cell-autonomous, and involve activation of p53 tumour-suppressor protein. We further show that cranial neural crest cells are sensitized to p53-mediated apoptosis, but blocking DDX21 loss from the nucleolus and chromatin rescues both the susceptibility to apoptosis and the craniofacial phenotypes associated with Treacher Collins syndrome. This mechanism is not restricted to cranial neural crest cells, as blood formation is also hypersensitive to loss of DDX21 functions. Accordingly, ribosomal gene perturbations associated with Diamond-Blackfan anaemia disrupt DDX21 localization. At the molecular level, we demonstrate that impaired rRNA synthesis elicits a DNA damage response, and that rDNA damage results in tissue-selective and

  20. Comparison with hippocampal atrophy and hypoperfusion in Alzheimer's disease

    International Nuclear Information System (INIS)

    Chung, YA; Kim, SH; Chung, SK; Juh, RH; Sohn, HS; Suh, TS; Choe, BY

    2004-01-01

    Objective: Hypoperfusion and hippocampal atropy of the medial temporal lobe are peculiarity of Alzheimer's disease (AD). The manual ROI (region of interest) technique for hippocampal volume estimation is specific and sensitive for the detection of hippocampal atrophy. In patients with AD reported a significant correlation between hippocampal volume and hypoperfusion. This study investigated correlations between atrophy distinct medial temporal lobe structure and hypoperfusion in hippocampal volumetry. Methods: The hippocampi were individually outlined on Tl-weighted volumetry MRI and calculated with MATLAB in 12 patients with AD. All volume measurements were performed by a segmentation technique with a combination of tracing and thresholding. The volume of a given structure in each slice was obtained by automatically counting the number of pixels within the segmented regions and multiplying the number by a voxel size. In order to permit direct regional comparisons, both of each patient's Tc- 99m ECD SPECT was then registered to the patient's MRI. Delineation continued anteriorly in each contiguous slice reaching the head of the hippocampus, which was distinguished from the overlying amygdala by the presence of the alveus or uncal recess. The right hippocampus (RH) was measured first, followed by the left hippocampus (LH). The accuracy of registration was investigated in a validation study with developed brain phantom. Results:The mean total intracranial volume of the AD was significantly smaller volume (1492.9 cm 3 ) and hypo perfused than those in normal subjects. The mean hippocampal volumes were 2.01 cm 3 and l.99 cm 3 for the RH and LH. The correlations between volume and hypoperfusion in the affected hippocampi were found to be significant; especially the medial temporal lobe is markedly hypo perfused. Conclusion: Volumetry is the most sensitive tool for the detection of hippocampal abnormality in AD, and significant correlation between asymmetry in

  1. Canine hippocampal formation composited into three-dimensional structure using MPRAGE.

    Science.gov (United States)

    Jung, Mi-Ae; Nahm, Sang-Soep; Lee, Min-Su; Lee, In-Hye; Lee, Ah-Ra; Jang, Dong-Pyo; Kim, Young-Bo; Cho, Zang-Hee; Eom, Ki-Dong

    2010-07-01

    This study was performed to anatomically illustrate the living canine hippocampal formation in three-dimensions (3D), and to evaluate its relationship to surrounding brain structures. Three normal beagle dogs were scanned on a MR scanner with inversion recovery segmented 3D gradient echo sequence (known as MP-RAGE: Magnetization Prepared Rapid Gradient Echo). The MRI data was manually segmented and reconstructed into a 3D model using the 3D slicer software tool. From the 3D model, the spatial relationships between hippocampal formation and surrounding structures were evaluated. With the increased spatial resolution and contrast of the MPRAGE, the canine hippocampal formation was easily depicted. The reconstructed 3D image allows easy understanding of the hippocampal contour and demonstrates the structural relationship of the hippocampal formation to surrounding structures in vivo.

  2. Cognitive deficits caused by prefrontal cortical and hippocampal neural disinhibition.

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    Bast, Tobias; Pezze, Marie; McGarrity, Stephanie

    2017-10-01

    We review recent evidence concerning the significance of inhibitory GABA transmission and of neural disinhibition, that is, deficient GABA transmission, within the prefrontal cortex and the hippocampus, for clinically relevant cognitive functions. Both regions support important cognitive functions, including attention and memory, and their dysfunction has been implicated in cognitive deficits characterizing neuropsychiatric disorders. GABAergic inhibition shapes cortico-hippocampal neural activity, and, recently, prefrontal and hippocampal neural disinhibition has emerged as a pathophysiological feature of major neuropsychiatric disorders, especially schizophrenia and age-related cognitive decline. Regional neural disinhibition, disrupting spatio-temporal control of neural activity and causing aberrant drive of projections, may disrupt processing within the disinhibited region and efferent regions. Recent studies in rats showed that prefrontal and hippocampal neural disinhibition (by local GABA antagonist microinfusion) dysregulates burst firing, which has been associated with important aspects of neural information processing. Using translational tests of clinically relevant cognitive functions, these studies showed that prefrontal and hippocampal neural disinhibition disrupts regional cognitive functions (including prefrontal attention and hippocampal memory function). Moreover, hippocampal neural disinhibition disrupted attentional performance, which does not require the hippocampus but requires prefrontal-striatal circuits modulated by the hippocampus. However, some prefrontal and hippocampal functions (including inhibitory response control) are spared by regional disinhibition. We consider conceptual implications of these findings, regarding the distinct relationships of distinct cognitive functions to prefrontal and hippocampal GABA tone and neural activity. Moreover, the findings support the proposition that prefrontal and hippocampal neural disinhibition

  3. Longitudinal study of hippocampal volumes in heavy cannabis users.

    Science.gov (United States)

    Koenders, L; Lorenzetti, V; de Haan, L; Suo, C; Vingerhoets, Wam; van den Brink, W; Wiers, R W; Meijer, C J; Machielsen, Mwj; Goudriaan, A E; Veltman, D J; Yücel, M; Cousijn, J

    2017-08-01

    Cannabis exposure, particularly heavy cannabis use, has been associated with neuroanatomical alterations in regions rich with cannabinoid receptors such as the hippocampus in some but not in other (mainly cross-sectional) studies. However, it remains unclear whether continued heavy cannabis use alters hippocampal volume, and whether an earlier age of onset and/or a higher dosage exacerbate these changes. Twenty heavy cannabis users (mean age 21 years, range 18-24 years) and 23 matched non-cannabis using healthy controls were submitted to a comprehensive psychological assessment and magnetic resonance imaging scan at baseline and at follow-up (average of 39 months post-baseline; standard deviation=2.4). Cannabis users started smoking around 16 years and smoked on average five days per week. A novel aspect of the current study is that hippocampal volume estimates were obtained from manual tracing the hippocampus on T1-weighted anatomical magnetic resonance imaging scans, using a previously validated protocol. Compared to controls, cannabis users did not show hippocampal volume alterations at either baseline or follow-up. Hippocampal volumes increased over time in both cannabis users and controls, following similar trajectories of increase. Cannabis dose and age of onset of cannabis use did not affect hippocampal volumes. Continued heavy cannabis use did not affect hippocampal neuroanatomical changes in early adulthood. This contrasts with prior evidence on alterations in this region in samples of older adult cannabis users. In young adults using cannabis at this level, cannabis use may not be heavy enough to affect hippocampal neuroanatomy.

  4. Pathological changes in hippocampal neuronal circuits underlie age-associated neurodegeneration and memory loss: positive clue toward SAD.

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    Moorthi, P; Premkumar, P; Priyanka, R; Jayachandran, K S; Anusuyadevi, M

    2015-08-20

    defect in neuronal-circuits of hippocampus (DG-CA4-CA1-Sub) that were significantly damaged leading to memory impairment. Interestingly, RSV was observed to culminate pathological events in the hippocampal neuronal circuit during aging, proving them as potent therapeutic drug against age-associated neurodegeneration and memory loss. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

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    Dicker Bridget L

    2007-06-01

    Full Text Available Abstract Background Alzheimer's disease (AD is characterized by a decline in cognitive function and accumulation of amyloid-β peptide (Aβ in extracellular plaques. Mutations in amyloid precursor protein (APP and presenilins alter APP metabolism resulting in accumulation of Aβ42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of cerebral Aβ deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human Aβ42 and Aβ40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. Results Adeno-associated viral (AAV vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits. Conclusion The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in

  6. Delayed hippocampal neuronal death in young gerbil following transient global cerebral ischemia is related to higher and longer-term expression of p63 in the ischemic hippocampus

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    Eun Joo Bae

    2015-01-01

    Full Text Available The tumor suppressor p63 is one of p53 family members and plays a vital role as a regulator of neuronal apoptosis in the development of the nervous system. However, the role of p63 in mature neuronal death has not been addressed yet. In this study, we first compared ischemia-induced effects on p63 expression in the hippocampal regions (CA1- 3 between the young and adult gerbils subjected to 5 minutes of transient global cerebral ischemia. Neuronal death in the hippocampal CA1 region of young gerbils was significantly slow compared with that in the adult gerbils after transient global cerebral ischemia. p63 immunoreactivity in the hippocampal CA1 pyramidal neurons in the sham-operated young group was significantly low compared with that in the sham-operated adult group. p63 immunoreactivity was apparently changed in ischemic hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. In the ischemia-operated adult groups, p63 immunoreactivity in the hippocampal CA1 pyramidal neurons was significantly decreased at 4 days post-ischemia; however, p63 immunoreactivity in the ischemia-operated young group was significantly higher than that in the ischemia-operated adult group. At 7 days post-ischemia, p63 immunoreactivity was decreased in the hippocampal CA1 pyramidal neurons in both ischemia-operated young and adult groups. Change patterns of p63 level in the hippocampal CA1 region of adult and young gerbils after ischemic damage were similar to those observed in the immunohistochemical results. These findings indicate that higher and longer-term expression of p63 in the hippocampal CA1 region of the young gerbils after ischemia/reperfusion may be related to more delayed neuronal death compared to that in the adults.

  7. Parkia biglobosa Improves Mitochondrial Functioning and Protects against Neurotoxic Agents in Rat Brain Hippocampal Slices

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    Kayode Komolafe

    2014-01-01

    Full Text Available Objective. Methanolic leaf extracts of Parkia biglobosa, PBE, and one of its major polyphenolic constituents, catechin, were investigated for their protective effects against neurotoxicity induced by different agents on rat brain hippocampal slices and isolated mitochondria. Methods. Hippocampal slices were preincubated with PBE (25, 50, 100, or 200 µg/mL or catechin (1, 5, or 10 µg/mL for 30 min followed by further incubation with 300 µM H2O2, 300 µM SNP, or 200 µM PbCl2 for 1 h. Effects of PBE and catechin on SNP- or CaCl2-induced brain mitochondrial ROS formation and mitochondrial membrane potential (ΔΨm were also determined. Results. PBE and catechin decreased basal ROS generation in slices and blunted the prooxidant effects of neurotoxicants on membrane lipid peroxidation and nonprotein thiol contents. PBE rescued hippocampal cellular viability from SNP damage and caused a significant boost in hippocampus Na+, K+-ATPase activity but with no effect on the acetylcholinesterase activity. Both PBE and catechin also mitigated SNP- or CaCl2-dependent mitochondrial ROS generation. Measurement by safranine fluorescence however showed that the mild depolarization of the ΔΨm by PBE was independent of catechin. Conclusion. The results suggest that the neuroprotective effect of PBE is dependent on its constituent antioxidants and mild mitochondrial depolarization propensity.

  8. New learning of music after bilateral medial temporal lobe damage: evidence from an amnesic patient.

    Science.gov (United States)

    Valtonen, Jussi; Gregory, Emma; Landau, Barbara; McCloskey, Michael

    2014-01-01

    Damage to the hippocampus impairs the ability to acquire new declarative memories, but not the ability to learn simple motor tasks. An unresolved question is whether hippocampal damage affects learning for music performance, which requires motor processes, but in a cognitively complex context. We studied learning of novel musical pieces by sight-reading in a newly identified amnesic, LSJ, who was a skilled amateur violist prior to contracting herpes simplex encephalitis. LSJ has suffered virtually complete destruction of the hippocampus bilaterally, as well as extensive damage to other medial temporal lobe structures and the left anterior temporal lobe. Because of LSJ's rare combination of musical training and near-complete hippocampal destruction, her case provides a unique opportunity to investigate the role of the hippocampus for complex motor learning processes specifically related to music performance. Three novel pieces of viola music were composed and closely matched for factors contributing to a piece's musical complexity. LSJ practiced playing two of the pieces, one in each of the two sessions during the same day. Relative to a third unpracticed control piece, LSJ showed significant pre- to post-training improvement for the two practiced pieces. Learning effects were observed both with detailed analyses of correctly played notes, and with subjective whole-piece performance evaluations by string instrument players. The learning effects were evident immediately after practice and 14 days later. The observed learning stands in sharp contrast to LSJ's complete lack of awareness that the same pieces were being presented repeatedly, and to the profound impairments she exhibits in other learning tasks. Although learning in simple motor tasks has been previously observed in amnesic patients, our results demonstrate that non-hippocampal structures can support complex learning of novel musical sequences for music performance.

  9. New Learning of Music after Bilateral Medial Temporal Lobe Damage: Evidence from an Amnesic Patient

    Science.gov (United States)

    Valtonen, Jussi; Gregory, Emma; Landau, Barbara; McCloskey, Michael

    2014-01-01

    Damage to the hippocampus impairs the ability to acquire new declarative memories, but not the ability to learn simple motor tasks. An unresolved question is whether hippocampal damage affects learning for music performance, which requires motor processes, but in a cognitively complex context. We studied learning of novel musical pieces by sight-reading in a newly identified amnesic, LSJ, who was a skilled amateur violist prior to contracting herpes simplex encephalitis. LSJ has suffered virtually complete destruction of the hippocampus bilaterally, as well as extensive damage to other medial temporal lobe structures and the left anterior temporal lobe. Because of LSJ’s rare combination of musical training and near-complete hippocampal destruction, her case provides a unique opportunity to investigate the role of the hippocampus for complex motor learning processes specifically related to music performance. Three novel pieces of viola music were composed and closely matched for factors contributing to a piece’s musical complexity. LSJ practiced playing two of the pieces, one in each of the two sessions during the same day. Relative to a third unpracticed control piece, LSJ showed significant pre- to post-training improvement for the two practiced pieces. Learning effects were observed both with detailed analyses of correctly played notes, and with subjective whole-piece performance evaluations by string instrument players. The learning effects were evident immediately after practice and 14 days later. The observed learning stands in sharp contrast to LSJ’s complete lack of awareness that the same pieces were being presented repeatedly, and to the profound impairments she exhibits in other learning tasks. Although learning in simple motor tasks has been previously observed in amnesic patients, our results demonstrate that non-hippocampal structures can support complex learning of novel musical sequences for music performance. PMID:25232312

  10. New Learning of Music after Bilateral Medial Temporal Lobe Damage: Evidence from an Amnesic Patient

    Directory of Open Access Journals (Sweden)

    Jussi eValtonen

    2014-09-01

    Full Text Available Damage to the hippocampus impairs the ability to acquire new declarative memories, but not the ability to learn simple motor tasks. An unresolved question is whether hippocampal damage affects learning for music performance, which requires motor processes, but in a cognitively complex context. We studied learning of novel musical pieces by sight-reading in a newly-identified amnesic, LSJ, who was a skilled amateur violist prior to contracting herpes simplex encephalitis. LSJ has suffered virtually complete destruction of the hippocampus bilaterally, as well as extensive damage to other medial temporal lobe structures and the left anterior temporal lobe. Because of LSJ’s rare combination of musical training and near-complete hippocampal destruction, her case provides a unique opportunity to investigate the role of the hippocampus for complex motor learning processes specifically related to music performance. Three novel pieces of viola music were composed, closely matched for factors contributing to a piece’s musical complexity. LSJ practiced playing two of the pieces, one in each of two sessions during the same day. Relative to a third unpracticed control piece, LSJ showed significant pre- to post-training improvement for the two practiced pieces. Learning effects were observed both with detailed analyses of correctly played notes, and with subjective whole-piece performance evaluations by string instrument players. The learning effects were evident immediately after practice and 14 days later. The observed learning stands in sharp contrast to LSJ’s complete lack of awareness that the same pieces were being presented repeatedly, and to the profound impairments she exhibits in other learning tasks. Although learning in simple motor tasks has been previously observed in amnesic patients, our results demonstrate that non-hippocampal structures can support complex learning of novel musical sequences for music performance.

  11. The hippocampal formation: morphological changes induced by thyroid, gonadal and adrenal hormones.

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    Gould, E; Woolley, C S; McEwen, B S

    1991-01-01

    The hippocampal formation is of considerable interest due to its proposed role in a number of important functions, including learning and memory processes. Manipulations of thyroid, gonadal and adrenal hormones have been shown to influence hippocampal physiology as well as learning and memory. The cellular events which underlie these hormone-induced functional changes are largely unexplored. However, studies suggest that hormonal manipulations during development and in adulthood result in dramatic morphological changes within the hippocampal formation. Because neuronal physiology has been suggested to depend upon neuronal morphology, we have been determining the morphologic sensitivity of hippocampal neurons to thyroid and steroid hormones in an effort to elucidate possible structural mechanisms to account for differences in hippocampal function. In this review, hormone-induced structural changes in the developing and adult hippocampal formation are discussed, with particular emphasis on their functional relevance. Sex differences, as well as the developmental effects of thyroid hormone and glucocorticoids, are described. Moreover, the effects of ovarian steroids, thyroid hormone and glucocorticoids on neuronal morphology in the hippocampal formation of the adult rat are reviewed. These hormone-induced structural changes may account, at least in part, for previously reported hormone-induced changes in hippocampal function.

  12. Higher-order conditioning is impaired by hippocampal lesions.

    Science.gov (United States)

    Gilboa, Asaf; Sekeres, Melanie; Moscovitch, Morris; Winocur, Gordon

    2014-09-22

    Behavior in the real world is rarely motivated by primary conditioned stimuli that have been directly associated with potent unconditioned reinforcers. Instead, motivation and choice behavior are driven by complex chains of higher-order associations that are only indirectly linked to intrinsic reward and often exert their influence outside awareness. Second-order conditioning (SOC) [1] is a basic associative-learning mechanism whereby stimuli acquire motivational salience by proxy, in the absence of primary incentives [2, 3]. Memory-systems theories consider first-order conditioning (FOC) and SOC to be prime examples of hippocampal-independent nondeclarative memory [4, 5]. Accordingly, neurobiological models of SOC focus almost exclusively on nondeclarative neural systems that support motivational salience and reward value. Transfer of value from a conditioned stimulus to a neutral stimulus is thought to require the basolateral amygdala [6, 7] and the ventral striatum [2, 3], but not the hippocampus. We developed a new paradigm to measure appetitive SOC of tones in rats. Hippocampal lesions severely impaired both acquisition and expression of SOC despite normal FOC. Unlike controls, rats with hippocampal lesions could not discriminate between positive and negative secondary conditioned tones, although they exhibited general familiarity with previously presented tones compared with new tones. Importantly, normal rats' behavior, in contrast to that of hippocampal groups, also revealed different confidence levels as indexed by effort, a central characteristic of hippocampal relational memory. The results indicate, contrary to current systems models, that representations of intrinsic relationships between reward value, stimulus identity, and motivation require hippocampal mediation when these relationships are of a higher order. Copyright © 2014 Elsevier Ltd. All rights reserved.

  13. Intermediate levels of hippocampal activity appear optimal for associative memory formation.

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    Xiao Liu

    Full Text Available BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly attributed to unsuccessful memory formation, whereas the supra-optimal levels of hippocampal activity related to unsuccessful memory formation have been rarely studied. It is still unclear under what circumstances such supra-optimal levels of hippocampal activity occur. To clarify this issue, we aimed at creating a condition, in which supra-optimal hippocampal activity is associated with encoding failure. We assumed that such supra-optimal activity occurs when task-relevant information is embedded in task-irrelevant, distracting information, which can be considered as noise. METHODOLOGY/PRINCIPAL FINDINGS: In the present fMRI study, we probed neural correlates of associative memory formation in a full-factorial design with associative memory (subsequently remembered versus forgotten and noise (induced by high versus low distraction as factors. Results showed that encoding failure was associated with supra-optimal activity in the high-distraction condition and with sub-optimal activity in the low distraction condition. Thus, we revealed evidence for a bell-shape function relating hippocampal activity with associative encoding success. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that intermediate levels of hippocampal activity are optimal while both too low and too high levels appear detrimental for associative memory formation. Supra-optimal levels of hippocampal activity seem to occur when task-irrelevant information is added to task-relevant signal. If such task-irrelevant noise is reduced adequately, hippocampal activity is lower and thus optimal for associative memory formation.

  14. Hippocampal sclerosis: correlation of MR imaging findings with surgical outcome

    International Nuclear Information System (INIS)

    Kim, Yoon Hee; Chang, Kee Hyun; Kim, Kyung Won; Han, Moon Hee; Park, Sung Ho; Nam, Hyun Woo; Choi, Kyu Ho; Cho, Woo Ho

    2001-01-01

    Atrophy and a high T2 signal of the hippocampus are known to be the principal MR imaging findings of hippocampal sclerosis. The purpose of this study was to determine whether or not individual MRI findings correlate with surgical outcome in patients with this condition. Preoperative MR imaging findings in 57 consecutive patients with pathologically-proven hippocampal sclerosis who underwent anterior temporal lobectomy and were followed-up for 24 months or more were retrospectively reviewed, and the results were compared with the postsurgical outcome (Engel classification). The MR images included routine sagittal T1-weighted and axial T2-weighted spin-echo images, and oblique coronal T1-weighted 3D gradient-echo and T2-weighted 2D fast spin-echo images obtained on either a 1.5 T or 1.0 T unit. The images were visually evaluated by two neuroradiologists blinded to the outcome; their focus was the presence or absence of atrophy and a high T2 hippocampal signal. Hippocampal atrophy was seen in 96% of cases (55/57) [100% (53/53) of the good outcome group (Engel class I and II), and 50% (2/4) of the poor outcome group (class III and IV)]. A high T2 hippocampal signal was seen in 61% of cases (35/57) [62% (33/53) of the good outcome group and 50% (2/4) of the poor outcome group]. All 35 patients with a high T2 signal had hippocampal atrophy. 'Normal' hippocampus, as revealed by MR imaging, occurred in 4% of patients (2/57), both of whom showed a poor outcome (Engel class III). The presence or absence of hippocampal atrophy correlated well with surgical outcome (p 0.05). Compared with a high T2 hippocampal signal, hippocampal atrophy is more common and correlates better with surgical outcome. For the prediction of this, it thus appears to be the more useful indicator

  15. Morphological Variations of Hippocampal Formation in Epilepsy

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    J Gordon Millichap

    2013-02-01

    Full Text Available Researchers at Hospital Sao Paulo and other centers in Brazil compared the hippocampal formation (HF morphology of healthy asymptomatic individuals (n=30 with that of patients with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS(n=68, of patients with malformations of cortical development (MCD(n=34, and of patients with morphological HF variations without other structural signs (pure MVHF(n=12.

  16. Abnormalities of hippocampal signal intensity in patients with familial mesial temporal lobe epilepsy

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    Coan A.C.

    2004-01-01

    Full Text Available Mesial temporal lobe epilepsy (MTLE is associated with hippocampal atrophy and hippocampal signal abnormalities. In our series of familial MTLE (FMTLE, we found a high proportion of hippocampal abnormalities. To quantify signal abnormalities in patients with FMTLE we studied 152 individuals (46 of them asymptomatic with FMTLE. We used NIH-Image® for volumetry and signal quantification in coronal T1 inversion recovery and T2 for all cross-sections of the hippocampus. Values diverging by 2 or more SD from the control mean were considered abnormal. T2 hippocampal signal abnormalities were found in 52% of all individuals: 54% of affected subjects and 48% of asymptomatic subjects. T1 hippocampal signal changes were found in 34% of all individuals: 42.5% of affected subjects and 15% of asymptomatic subjects. Analysis of the hippocampal head (first three slices revealed T2 abnormalities in 73% of all individuals (74% of affected subjects and 72% of asymptomatic subjects and T1 abnormalities in 59% (67% of affected subjects and 41% of asymptomatic subjects. Affected individuals had smaller volumes than controls (P < 0.0001. There was no difference in hippocampal volumes between asymptomatic subjects and controls, although 39% of asymptomatic patients had hippocampal atrophy. Patients with an abnormal hippocampal signal (133 individuals had smaller ipsilateral volume, but no linear correlation could be determined. Hippocampal signal abnormalities in FMTLE were more frequently found in the hippocampal head in both affected and asymptomatic family members, including those with normal volumes. These results indicate that subtle abnormalities leading to an abnormal hippocampal signal in FMTLE are not necessarily related to seizures and may be determined by genetic factors.

  17. Hippocampal multimodal structural changes and subclinical depression in healthy individuals.

    Science.gov (United States)

    Spalletta, Gianfranco; Piras, Fabrizio; Caltagirone, Carlo; Fagioli, Sabrina

    2014-01-01

    Several neuroimaging studies report reduced hippocampal volume in depressed patients. However, it is still unclear if hippocampal changes in healthy individuals can be considered a risk factor for progression to clinical depression. Here, we investigated subclinical depression and its hippocampal correlates in a non-clinical sample of healthy individuals, with particular regard to gender differences. One-hundred-two participants underwent a comprehensive clinical assessment, a high-resolution T1-weighted magnetic resonance imaging and diffusion tensor imaging protocol using a 3T MRI scanner. Data of macro-(volume) and micro-(mean diffusivity, MD) structural changes of the hippocampus were analyzed with reference to the Beck Depression Inventory score. Results of multivariate regression analyses revealed reduced bilateral volume, along with increased bilateral MD in hippocampal formation predicting subclinical depressive phenomenology only in healthy males. Conversely, subclinical depressive phenomenology in healthy female was accounted for by only lower educational level, in the absence of any hippocampal structure variations. To date, this is the only evidence reporting a relationship between subclinical depressive phenomenology and changes in hippocampal formation in healthy individuals. Our findings demonstrated that reduced volume, along with increased MD in hippocampal formation, is significantly associated with subclinical depressive phenomenology in healthy males. This encourages to study the hypothesis that early macro- and microstructural changes in hippocampi associated with subclinical depression may constitute a risk factor of developing depressive disorders in males. © 2013 Elsevier B.V. All rights reserved.

  18. Treatment planning and 3D dose verification of whole brain radiation therapy with hippocampal avoidance in rats

    International Nuclear Information System (INIS)

    Yoon, S W; Miles, D; Reinsvold, M; Kirsch, D; Oldham, M; Cramer, C

    2017-01-01

    Despite increasing use of stereotactic radiosurgery, whole brain radiotherapy (WBRT) continues to have a therapeutic role in a selected subset of patients. Selectively avoiding the hippocampus during such treatment (HA-WBRT) emerged as a strategy to reduce the cognitive morbidity associated with WBRT and gave rise to a recently published the phase II trial (RTOG 0933) and now multiple ongoing clinical trials. While conceptually hippocampal avoidance is supported by pre-clinical evidence showing that the hippocampus plays a vital role in memory, there is minimal pre-clinic data showing that selectively avoiding the hippocampus will reduce radiation-induced cognitive decline. Largely the lack of pre-clinical evidence can be attributed to the technical hurdles associated with delivering precise conformal treatment the rat brain. In this work we develop a novel conformal HA-WBRT technique for Wistar rats, utilizing a 225kVp micro-irradiator with precise 3D-printed radiation blocks designed to spare hippocampus while delivering whole brain dose. The technique was verified on rodent-morphic Presage ® 3D dosimeters created from micro-CT scans of Wistar rats with Duke Large Field-of-View Optical Scanner (DLOS) at 1mm isotropic voxel resolution. A 4-field box with parallel opposed AP-PA and two lateral opposed fields was explored with conformal hippocampal sparing aided by 3D-printed radiation blocks. The measured DVH aligned reasonably well with that calculated from SmART Plan Monte Carlo simulations with simulated blocks for 4-field HA-WBRT with both demonstrating hippocampal sparing of 20% volume receiving less than 30% the prescription dose. (paper)

  19. Spatial learning depends on both the addition and removal of new hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    David Dupret

    2007-08-01

    Full Text Available The role of adult hippocampal neurogenesis in spatial learning remains a matter of debate. Here, we show that spatial learning modifies neurogenesis by inducing a cascade of events that resembles the selective stabilization process characterizing development. Learning promotes survival of relatively mature neurons, apoptosis of more immature cells, and finally, proliferation of neural precursors. These are three interrelated events mediating learning. Thus, blocking apoptosis impairs memory and inhibits learning-induced cell survival and cell proliferation. In conclusion, during learning, similar to the selective stabilization process, neuronal networks are sculpted by a tightly regulated selection and suppression of different populations of newly born neurons.

  20. Memory impairment in multiple sclerosis: Relevance of hippocampal activation and hippocampal connectivity

    NARCIS (Netherlands)

    Hulst, H.E.; Schoonheim, M.M.; van Geest, Q.; Uitdehaag, B.M.J.; Barkhof, F.; Geurts, J.J.G.

    2015-01-01

    Background: Memory impairment is frequent in multiple sclerosis (MS), but it is unclear what functional brain changes underlie this cognitive deterioration. Objective: To investigate functional hippocampal activation and connectivity, in relation to memory performance in MS. Methods: Structural and

  1. Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

    Science.gov (United States)

    Mucio-Ramírez, Samuel; Makeyev, Oleksandr

    2017-01-01

    Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats ( n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals ( p  = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses ( p  = 0.71) nor due to the delay after the last stimulation dose ( p  = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200  μ s, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

  2. Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

    Directory of Open Access Journals (Sweden)

    Samuel Mucio-Ramírez

    2017-01-01

    Full Text Available Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n=36 due to the single dose or five doses (given every 24 hours of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71. Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71 nor due to the delay after the last stimulation dose (p = 0.96. Obtained results suggest that stimulation at current parameters (50 mA, 200 μs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

  3. Reward Expectancy Strengthens CA1 Theta and Beta Band Synchronization and Hippocampal-Ventral Striatal Coupling.

    Science.gov (United States)

    Lansink, Carien S; Meijer, Guido T; Lankelma, Jan V; Vinck, Martin A; Jackson, Jadin C; Pennartz, Cyriel M A

    2016-10-12

    The use of information from the hippocampal memory system in motivated behavior depends on its communication with the ventral striatum. When an animal encounters cues that signal subsequent reward, its reward expectancy is raised. It is unknown, however, how this process affects hippocampal dynamics and their influence on target structures, such as ventral striatum. We show that, in rats, reward-predictive cues result in enhanced hippocampal theta and beta band rhythmic activity during subsequent action, compared with uncued goal-directed navigation. The beta band component, also labeled theta's harmonic, involves selective hippocampal CA1 cell groups showing frequency doubling of firing periodicity relative to theta rhythmicity and it partitions the theta cycle into segments showing clear versus poor spike timing organization. We found that theta phase precession occurred over a wider range than previously reported. This was apparent from spikes emitted near the peak of the theta cycle exhibiting large "phase precessing jumps" relative to spikes in foregoing cycles. Neither this phenomenon nor the regular manifestation of theta phase precession was affected by reward expectancy. Ventral striatal neuronal firing phase-locked not only to hippocampal theta, but also to beta band activity. Both hippocampus and ventral striatum showed increased synchronization between neuronal firing and local field potential activity during cued compared with uncued goal approaches. These results suggest that cue-triggered reward expectancy intensifies hippocampal output to target structures, such as the ventral striatum, by which the hippocampus may gain prioritized access to systems modulating motivated behaviors. Here we show that temporally discrete cues raising reward expectancy enhance both theta and beta band activity in the hippocampus once goal-directed navigation has been initiated. These rhythmic activities are associated with increased synchronization of neuronal firing

  4. Neuroprotective effects of the AMPA antagonist PNQX in oxygen-glucose deprivation in mouse hippocampal slice cultures and global cerebral ischemia in gerbils

    DEFF Research Database (Denmark)

    Montero, Maria; Nielsen, Marianne; Rønn, Lars Christian B

    2007-01-01

    PNQX (9-methyl-amino-6-nitro-hexahydro-benzo(F)quinoxalinedione) is a selective AMPA antagonist with demonstrated neuroprotective effects in focal ischemia in rats. Here we report corresponding effects in mouse hippocampal slice cultures subjected to oxygen and glucose deprivation (OGD) and in tr......PNQX (9-methyl-amino-6-nitro-hexahydro-benzo(F)quinoxalinedione) is a selective AMPA antagonist with demonstrated neuroprotective effects in focal ischemia in rats. Here we report corresponding effects in mouse hippocampal slice cultures subjected to oxygen and glucose deprivation (OGD......) and in transient global cerebral ischemia in gerbils. For in vitro studies, hippocampal slice cultures derived from 7-day-old mice and grown for 14 days, were submersed in oxygen-glucose deprived medium for 30 min and exposed to PNQX for 24 h, starting together with OGD, immediately after OGD, or 2 h after OGD...... stained for the neurodegeneration marker Fluoro-Jade B and immunostained for the astroglial marker glial fibrillary acidic protein revealed a significant PNQX-induced decrease in neuronal cell death and astroglial activation. We conclude that, PNQX provided neuroprotection against both global cerebral...

  5. Associative reinstatement memory measures hippocampal function in Parkinson's Disease.

    Science.gov (United States)

    Cohn, Melanie; Giannoylis, Irene; De Belder, Maya; Saint-Cyr, Jean A; McAndrews, Mary Pat

    2016-09-01

    In Parkinson's Disease (PD), hippocampal atrophy is associated with rapid cognitive decline. Hippocampal function is typically assessed using memory tests but current clinical tools (e.g., free recall) also rely on executive functions or use material that is not optimally engaging hippocampal memory networks. Because of the ubiquity of executive dysfunction in PD, our ability to detect true memory deficits is suboptimal. Our previous behavioural and neuroimaging work in other populations suggests that an experimental memory task - Associative Reinstatement Memory (ARM) - may prove useful in investigating hippocampal function in PD. In this study, we investigated whether ARM is compromised in PD and we assessed its convergent and divergent validity by comparing it to standardized measures of memory and of attention and executive functioning in PD, respectively. Using fMRI, we also investigated whether performance in PD relates to degree of hippocampal engagement. Fifteen participants with PD and 13 age-matched healthy controls completed neuropsychological testing as well as an ARM fMRI recognition paradigm in which they were instructed to identify word pairs comprised of two studied words (intact or rearranged pairs) and those containing at least one new word (new or half new pairs). ARM is measured by the differences in hit rates between intact and rearranged pairs. Behaviourally, ARM was poorer in PD relative to controls and was correlated with verbal memory measures, but not with attention or executive functioning in the PD group. Hippocampal activation associated with ARM was reduced in PD relative to controls and covaried with ARM scores in both groups. To conclude, ARM is a sensitive measure of hippocampal memory function that is unaffected by attention or executive dysfunction in PD. Our study highlights the benefit of integrating cognitive neuroscience frameworks and novel experimental tasks to improve the practice of clinical neuropsychology in PD

  6. Temporal lobe developmental malformations and epilepsy: dual pathology and bilateral hippocampal abnormalities.

    Science.gov (United States)

    Ho, S S; Kuzniecky, R I; Gilliam, F; Faught, E; Morawetz, R

    1998-03-01

    Temporal lobe developmental malformations (TLDM) with focal cortical dysplasia and balloon cells may coexist with mesial temporal sclerosis. The true incidence of this dual pathology is unknown. Our aim was to assess the frequency of amygdala (AM)-hippocampal abnormality in a homogeneous population with this specific developmental malformation. MRI-based volumetry of the AM and hippocampal formation (HF) in 30 patients with unilateral TLDM and intractable partial epilepsy was performed. A volume normalization process defined a normal range of HF and AM volumes in control subjects, and enabled the detection of bilateral volume loss. Normalized volumes detected HF atrophy in 26 patients (nine unilateral and 17 bilateral) and AM atrophy in 18 patients (three unilateral and 15 bilateral). Visual analysis detected unilateral HF abnormality in 21 patients and bilateral abnormality in two. When compared with a group of patients with temporal lobe epilepsy and pure hippocampal sclerosis (N = 92), where volumetry revealed bilateral HF atrophy in 18%, a significant difference in the frequency of bilateral HF atrophy was found (p Dual pathology is frequent in patients with TLDM (87%), and the AM-HF abnormality is often bilateral (57%). Our data suggest that more widespread and potentially epileptogenic lesions coexist with visibly detectable unilateral TLDM. This has implications for the selection of patients for temporal lobe surgery and may influence surgical strategies.

  7. Predicting memory performance in normal ageing using different measures of hippocampal size

    International Nuclear Information System (INIS)

    Lye, T.C.; Creasey, H.; Kril, J.J.; Grayson, D.A.; Piguet, O.; Bennett, H.P.; Ridley, L.J.; Broe, G.A.

    2006-01-01

    A number of different methods have been employed to correct hippocampal volumes for individual variation in head size. Researchers have previously used qualitative visual inspection to gauge hippocampal atrophy. The purpose of this study was to determine the best measure(s) of hippocampal size for predicting memory functioning in 102 community-dwelling individuals over 80 years of age. Hippocampal size was estimated using magnetic resonance imaging (MRI) volumetry and qualitative visual assessment. Right and left hippocampal volumes were adjusted by three different estimates of head size: total intracranial volume (TICV), whole-brain volume including ventricles (WB+V) and a more refined measure of whole-brain volume with ventricles extracted (WB). We compared the relative efficacy of these three volumetric adjustment methods and visual ratings of hippocampal size in predicting memory performance using linear regression. All four measures of hippocampal size were significant predictors of memory performance. TICV-adjusted volumes performed most poorly in accounting for variance in memory scores. Hippocampal volumes adjusted by either measure of whole-brain volume performed equally well, although qualitative visual ratings of the hippocampus were at least as effective as the volumetric measures in predicting memory performance in community-dwelling individuals in the ninth or tenth decade of life. (orig.)

  8. Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

    International Nuclear Information System (INIS)

    Zaja-Milatovic, Snjezana; Gupta, Ramesh C.; Aschner, Michael; Milatovic, Dejan

    2009-01-01

    Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p 2 -isoprostanes, F 2 -IsoPs; and F 4 -neuroprostanes, F 4 -NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p 2 -IsoPs, F 4 -NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

  9. Dissociable Contributions of Thalamic Nuclei to Recognition Memory: Novel Evidence from a Case of Medial Dorsal Thalamic Damage

    Science.gov (United States)

    Newsome, Rachel N.; Trelle, Alexandra N.; Fidalgo, Celia; Hong, Bryan; Smith, Victoria M.; Jacob, Alexander; Ryan, Jennifer D.; Rosenbaum, R. Shayna; Cowell, Rosemary A.; Barense, Morgan D.

    2018-01-01

    The thalamic nuclei are thought to play a critical role in recognition memory. Specifically, the anterior thalamic nuclei and medial dorsal nuclei may serve as critical output structures in distinct hippocampal and perirhinal cortex systems, respectively. Existing evidence indicates that damage to the anterior thalamic nuclei leads to impairments…

  10. Transient optogenetic inactivation of the medial entorhinal cortex biases the active population of hippocampal neurons.

    Science.gov (United States)

    Rueckemann, Jon W; DiMauro, Audrey J; Rangel, Lara M; Han, Xue; Boyden, Edward S; Eichenbaum, Howard

    2016-02-01

    The mechanisms that enable the hippocampal network to express the appropriate spatial representation for a particular circumstance are not well understood. Previous studies suggest that the medial entorhinal cortex (MEC) may have a role in reproducibly selecting the hippocampal representation of an environment. To examine how ongoing MEC activity is continually integrated by the hippocampus, we performed transient unilateral optogenetic inactivations of the MEC while simultaneously recording place cell activity in CA1. Inactivation of the MEC caused a partial remapping in the CA1 population without diminishing the degree of spatial tuning across the active cell assembly. These changes remained stable irrespective of intermittent disruption of MEC input, indicating that while MEC input is integrated over long time scales to bias the active population, there are mechanisms for stabilizing the population of active neurons independent of the MEC. We find that MEC inputs to the hippocampus shape its ongoing activity by biasing the participation of the neurons in the active network, thereby influencing how the hippocampus selectively represents information. © 2015 Wiley Periodicals, Inc.

  11. A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum.

    Science.gov (United States)

    McDonald, Robert J; Jones, Jana; Richards, Blake; Hong, Nancy S

    2006-09-01

    The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.

  12. PirB regulates asymmetries in hippocampal circuitry.

    Directory of Open Access Journals (Sweden)

    Hikari Ukai

    Full Text Available Left-right asymmetry is a fundamental feature of higher-order brain structure; however, the molecular basis of brain asymmetry remains unclear. We recently identified structural and functional asymmetries in mouse hippocampal circuitry that result from the asymmetrical distribution of two distinct populations of pyramidal cell synapses that differ in the density of the NMDA receptor subunit GluRε2 (also known as NR2B, GRIN2B or GluN2B. By examining the synaptic distribution of ε2 subunits, we previously found that β2-microglobulin-deficient mice, which lack cell surface expression of the vast majority of major histocompatibility complex class I (MHCI proteins, do not exhibit circuit asymmetry. In the present study, we conducted electrophysiological and anatomical analyses on the hippocampal circuitry of mice with a knockout of the paired immunoglobulin-like receptor B (PirB, an MHCI receptor. As in β2-microglobulin-deficient mice, the PirB-deficient hippocampus lacked circuit asymmetries. This finding that MHCI loss-of-function mice and PirB knockout mice have identical phenotypes suggests that MHCI signals that produce hippocampal asymmetries are transduced through PirB. Our results provide evidence for a critical role of the MHCI/PirB signaling system in the generation of asymmetries in hippocampal circuitry.

  13. Dopamine receptor D5 deficiency results in a selective reduction of hippocampal NMDA receptor subunit NR2B expression and impaired memory.

    Science.gov (United States)

    Moraga-Amaro, Rodrigo; González, Hugo; Ugalde, Valentina; Donoso-Ramos, Juan Pablo; Quintana-Donoso, Daisy; Lara, Marcelo; Morales, Bernardo; Rojas, Patricio; Pacheco, Rodrigo; Stehberg, Jimmy

    2016-04-01

    Pharmacological evidence associates type I dopamine receptors, including subtypes D1 and D5, with learning and memory. Analyses using genetic approaches have determined the relative contribution of dopamine receptor D1 (D1R) in cognitive tasks. However, the lack of drugs that can discriminate between D1R and D5R has made the pharmacological distinction between the two receptors difficult. Here, we aimed to determine the role of D5R in learning and memory. In this study we tested D5R knockout mice and wild-type littermates in a battery of behavioral tests, including memory, attention, locomotion, anxiety and motivational evaluations. Our results show that genetic deficiency of D5R significantly impairs performance in the Morris water maze paradigm, object location and object recognition memory, indicating a relevant role for D5R in spatial memory and recognition memory. Moreover, the lack of D5R resulted in decreased exploration and locomotion. In contrast, D5R deficiency had no impact on working memory, anxiety and depressive-like behavior, measured using the spontaneous alternation, open-field, tail suspension test, and forced swimming test. Electrophysiological analyses performed on hippocampal slices showed impairment in long-term-potentiation in mice lacking D5R. Further analyses at the molecular level showed that genetic deficiency of D5R results in a strong and selective reduction in the expression of the NMDA receptor subunit NR2B in the hippocampus. These findings demonstrate the relevant contribution of D5R in memory and suggest a functional interaction of D5R with hippocampal glutamatergic pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Caffeine Increases Hippocampal Sharp Waves in Vitro.

    Science.gov (United States)

    Watanabe, Yusuke; Ikegaya, Yuji

    2017-01-01

    Caffeine promotes memory consolidation. Memory consolidation is thought to depend at least in part on hippocampal sharp waves (SWs). In the present study, we investigated the effect of bath-application of caffeine in spontaneously occurring SWs in mouse acute hippocampal slices. Caffeine induced an about 100% increase in the event frequency of SWs at concentrations of 60 and 200 µM. The effect of caffeine was reversible after washout of caffeine and was mimicked by an adenosine A 1 receptor antagonist, but not by an A 2A receptor antagonist. Caffeine increased SWs even in dentate-CA3 mini-slices without the CA2 regions, in which adenosine A 1 receptors are abundantly expressed in the hippocampus. Thus, caffeine facilitates SWs by inhibiting adenosine A 1 receptors in the hippocampal CA3 region or the dentate gyrus.

  15. Correlation between volume and morphological changes in the hippocampal formation in Alzheimer's disease: rounding of the outline of the hippocampal body on coronal MR images

    International Nuclear Information System (INIS)

    Adachi, Michito; Sato, Takamichi; Kawakatsu, Shinobu; Ohshima, Fumi

    2012-01-01

    The aim of this study was to investigate whether the outline of the hippocampal body becomes rounded on coronal magnetic resonance imaging (MRI) as the volume of the hippocampal formation decreases in Alzheimer's disease (AD). Institutional review board approval of the study protocol was obtained, and all subjects provided informed consent for the mini-mental state examination (MMSE) and MRI. The MRI and MMSE were prospectively performed in all 103 subjects (27 men and 76 women; mean age ± standard deviation, 77.7 ± 7.8 years) who had AD or were concerned about having of dementia and who consulted our institute over 1 year. The subjects included 14 non-dementia cases (MMSE score ≥ 28) and 89 AD cases (MMSE score ≤ 27). The total volume of the bilateral hippocampal formation (VHF) was assessed with a tracing method, and the ratio of the VHF to the intracranial volume (RVHF) and the rounding ratio (RR) of the hippocampal body (mean ratio of its short dimension to the long dimension in the bilateral hippocampal body) were calculated. Using Spearman's correlation coefficient, the correlations between RR and VHF and between RR and RVHF were assessed. Correlation coefficients between RR and VHF and between RR and RVHF were -0.419 (p < 0.01) and -0.418 (p < 0.01), respectively. There was a significant negative correlation between RR and the volume of the hippocampal formation. The outline of the body of the hippocampal formation becomes rounded on coronal images as its volume decreases in AD. (orig.)

  16. Delayed recall, hippocampal volume and Alzheimer neuropathology: findings from the Nun Study.

    Science.gov (United States)

    Mortimer, J A; Gosche, K M; Riley, K P; Markesbery, W R; Snowdon, D A

    2004-02-10

    To examine the associations of hippocampal volume and the severity of neurofibrillary lesions determined at autopsy with delayed verbal recall performance evaluated an average of 1 year prior to death. Hippocampal volumes were computed using postmortem brain MRI from the first 56 scanned participants of the Nun Study. Quantitative neuropathologic studies included lesion counts, Braak staging, and determination of whether neuropathologic criteria for Alzheimer disease (AD) were met. Multiple regression was used to assess the association of hippocampal volume and neuropathologic lesions with the number of words (out of 10) recalled on the Consortium to Establish a Registry for Alzheimer's Disease Delayed Word Recall Test administered an average of 1 year prior to death. When entered separately, hippocampal volume, Braak stage, and the mean neurofibrillary tangle counts in the CA-1 region of the hippocampus and the subiculum were strongly associated with the number of words recalled after a delay, adjusting for age and education. When hippocampal volume was entered together with each neuropathologic index, only hippocampal volume retained a significant association with the delayed recall measure. The association between hippocampal volume and the number of words recalled was present in both demented and nondemented individuals as well as in those with and without substantial AD neurofibrillary pathology. The association of neurofibrillary tangles with delayed verbal recall may reflect associated hippocampal atrophy.

  17. VPS35 regulates developing mouse hippocampal neuronal morphogenesis by promoting retrograde trafficking of BACE1

    Directory of Open Access Journals (Sweden)

    Chun-Lei Wang

    2012-10-01

    VPS35, a major component of the retromer, plays an important role in the selective endosome-to-Golgi retrieval of membrane proteins. Dysfunction of retromer is a risk factor for neurodegenerative disorders, but its function in developing mouse brain remains poorly understood. Here we provide evidence for VPS35 promoting dendritic growth and maturation, and axonal protein transport in developing mouse hippocampal neurons. Embryonic hippocampal CA1 neurons suppressing Vps35 expression by in utero electroporation of its micro RNAs displayed shortened apical dendrites, reduced dendritic spines, and swollen commissural axons in the neonatal stage, those deficits reflecting a defective protein transport/trafficking in developing mouse neurons. Further mechanistic studies showed that Vps35 depletion in neurons resulted in an impaired retrograde trafficking of BACE1 (β1-secretase and altered BACE1 distribution. Suppression of BACE1 expression in CA1 neurons partially rescued both dendritic and axonal deficits induced by Vps35-deficiency. These results thus demonstrate that BACE1 acts as a critical cargo of retromer in vitro and in vivo, and suggest that VPS35 plays an essential role in regulating apical dendritic maturation and in preventing axonal spheroid formation in developing hippocampal neurons.

  18. Sleep deprivation causes memory deficits by negatively impacting neuronal connectivity in hippocampal area CA1

    Science.gov (United States)

    Havekes, Robbert; Park, Alan J; Tudor, Jennifer C; Luczak, Vincent G; Hansen, Rolf T; Ferri, Sarah L; Bruinenberg, Vibeke M; Poplawski, Shane G; Day, Jonathan P; Aton, Sara J; Radwańska, Kasia; Meerlo, Peter; Houslay, Miles D; Baillie, George S; Abel, Ted

    2016-01-01

    Brief periods of sleep loss have long-lasting consequences such as impaired memory consolidation. Structural changes in synaptic connectivity have been proposed as a substrate of memory storage. Here, we examine the impact of brief periods of sleep deprivation on dendritic structure. In mice, we find that five hours of sleep deprivation decreases dendritic spine numbers selectively in hippocampal area CA1 and increased activity of the filamentous actin severing protein cofilin. Recovery sleep normalizes these structural alterations. Suppression of cofilin function prevents spine loss, deficits in hippocampal synaptic plasticity, and impairments in long-term memory caused by sleep deprivation. The elevated cofilin activity is caused by cAMP-degrading phosphodiesterase-4A5 (PDE4A5), which hampers cAMP-PKA-LIMK signaling. Attenuating PDE4A5 function prevents changes in cAMP-PKA-LIMK-cofilin signaling and cognitive deficits associated with sleep deprivation. Our work demonstrates the necessity of an intact cAMP-PDE4-PKA-LIMK-cofilin activation-signaling pathway for sleep deprivation-induced memory disruption and reduction in hippocampal spine density. DOI: http://dx.doi.org/10.7554/eLife.13424.001 PMID:27549340

  19. Differential hippocampal gene expression is associated with climate-related natural variation in memory and the hippocampus in food-caching chickadees.

    Science.gov (United States)

    Pravosudov, V V; Roth, T C; Forister, M L; Ladage, L D; Kramer, R; Schilkey, F; van der Linden, A M

    2013-01-01

    There is significant and often heritable variation in cognition and its underlying neural mechanisms, yet specific genetic contributions to such variation are not well characterized. Black-capped chickadees present a good model to investigate the genetic basis of cognition because they exhibit tremendous climate-related variation in memory, hippocampal morphology and neurogenesis rates throughout the North American continent, and these cognitive traits appear to have a heritable basis. We examined the hippocampal transcriptome profiles of laboratory-reared chickadees from the two most divergent populations to test whether differential gene expression in the hippocampus is associated with population differences in spatial memory, hippocampal morphology and adult hippocampal neurogenesis rates. Using high-resolution mRNA sequencing coupled to a de novo transcriptome assembly, we generated 23 295 consensus sequences, which predicted 16 206 protein sequences with 13 982 showing high similarity to known protein sequences or conserved hypothetical proteins in other species. Of these, we identified differential expression in nearly 380 genes, with 47 genes specifically linked to neurogenesis, apoptosis, synaptic function, and learning and memory processes. Many of the other differentially expressed genes, however, may be associated with other functions. Our study presents the first avian hippocampal transcriptome, and it is the first study identifying differential gene expression associated with natural variation in cognition and the hippocampus. Our results provide additional support to the hypothesis that population differences in memory, hippocampal morphology and neurogenesis in chickadees have likely resulted from natural selection that appears to act on memory and its underlying neural mechanisms. © 2012 Blackwell Publishing Ltd.

  20. Separate elements of episodic memory subserved by distinct hippocampal-prefrontal connections.

    Science.gov (United States)

    Barker, Gareth R I; Banks, Paul J; Scott, Hannah; Ralph, G Scott; Mitrophanous, Kyriacos A; Wong, Liang-Fong; Bashir, Zafar I; Uney, James B; Warburton, E Clea

    2017-02-01

    Episodic memory formation depends on information about a stimulus being integrated within a precise spatial and temporal context, a process dependent on the hippocampus and prefrontal cortex. Investigations of putative functional interactions between these regions are complicated by multiple direct and indirect hippocampal-prefrontal connections. Here application of a pharmacogenetic deactivation technique enabled us to investigate the mnemonic contributions of two direct hippocampal-medial prefrontal cortex (mPFC) pathways, one arising in the dorsal CA1 (dCA1) and the other in the intermediate CA1 (iCA1). While deactivation of either pathway impaired episodic memory, the resulting pattern of mnemonic deficits was different: deactivation of the dCA1→mPFC pathway selectively disrupted temporal order judgments while iCA1→mPFC pathway deactivation disrupted spatial memory. These findings reveal a previously unsuspected division of function among CA1 neurons that project directly to the mPFC. Such subnetworks may enable the distinctiveness of contextual information to be maintained in an episodic memory circuit.

  1. Qualitative and Quantitative Hippocampal MRI Assessments in Intractable Epilepsy

    Directory of Open Access Journals (Sweden)

    Paramdeep Singh

    2013-01-01

    Full Text Available Aims. To acquire normative data of hippocampal volumes and T2 relaxation times, to evaluate and compare qualitative and quantitative assessments in evaluating hippocampi in patients with different durations of intractable epilepsy, and to propose an imaging protocol based on performance of these techniques. Methods. MRI analysis was done in 50 nonepileptic controls and 30 patients with intractable epilepsy on 1.5T scanner. Visual assessment and hippocampal volumetry were done on oblique coronal IR/T2W and T1W MP-RAGE images, respectively. T2 relaxation times were measured using 16-echo Carr-Purcell-Meiboom-Gill sequence. Volumetric data was normalized for variation in head size between individuals. Patients were divided into temporal ( and extratemporal ( groups based on clinical and EEG localization. Results. In controls, right hippocampal volume was slightly more than the left with no effect of age or gender. In TLE patients, hippocampal volumetry provided maximum concordance with EEG. Visual assessment of unilateral pathology concurred well with measured quantitative values but poorly in cases with bilateral pathologies. There were no significant differences of mean values between extratemporal group and controls group. Quantitative techniques detected mild abnormalities, undetected on visual assessment. Conclusions. Quantitative techniques are more sensitive to diagnose bilateral and mild unilateral hippocampal abnormalities.

  2. Hippocampal Structure Predicts Statistical Learning and Associative Inference Abilities during Development.

    Science.gov (United States)

    Schlichting, Margaret L; Guarino, Katharine F; Schapiro, Anna C; Turk-Browne, Nicholas B; Preston, Alison R

    2017-01-01

    Despite the importance of learning and remembering across the lifespan, little is known about how the episodic memory system develops to support the extraction of associative structure from the environment. Here, we relate individual differences in volumes along the hippocampal long axis to performance on statistical learning and associative inference tasks-both of which require encoding associations that span multiple episodes-in a developmental sample ranging from ages 6 to 30 years. Relating age to volume, we found dissociable patterns across the hippocampal long axis, with opposite nonlinear volume changes in the head and body. These structural differences were paralleled by performance gains across the age range on both tasks, suggesting improvements in the cross-episode binding ability from childhood to adulthood. Controlling for age, we also found that smaller hippocampal heads were associated with superior behavioral performance on both tasks, consistent with this region's hypothesized role in forming generalized codes spanning events. Collectively, these results highlight the importance of examining hippocampal development as a function of position along the hippocampal axis and suggest that the hippocampal head is particularly important in encoding associative structure across development.

  3. Fearfulness and feather damage in laying hens divergently selected for high and low feather pecking

    DEFF Research Database (Denmark)

    Rodenburg, T Bas; de Haas, Elske N; Nielsen, Birte Lindstrøm

    2010-01-01

    Feather pecking (FP) remains a major welfare and economic problem in laying hens. FP has been found to be related to other behavioural characteristics, such as fearfulness. There are indications that fearful birds are more likely to develop FP. Furthermore, FP can lead to increased fearfulness...... in the victims. To investigate further the relationship between FP and fearfulness, feather damage and behavioural fear responses were recorded in three White Leghorn lines of laying hens: a line selected for high FP (HFP line), a line selected for low FP (LFP line) and an unselected control line (10th...... in fear responses between the HFP and LFP lines were not found, neither in the TI-test, nor in the HA or NO test. As expected, birds from the HFP line had considerably more feather damage than birds from the LFP line and birds from the unselected control line were intermediate. Cages that withdrew from...

  4. Selecting for memory? The influence of selective attention on the mnemonic binding of contextual information.

    Science.gov (United States)

    Uncapher, Melina R; Rugg, Michael D

    2009-06-24

    Not all of what is experienced is remembered later. Behavioral evidence suggests that the manner in which an event is processed influences which aspects of the event will later be remembered. The present experiment investigated the neural correlates of "selective encoding," or the mechanisms that support the encoding of some elements of an event in preference to others. Event-related MRI data were acquired while volunteers selectively attended to one of two different contextual features of study items (color or location). A surprise memory test for the items and both contextual features was subsequently administered to determine the influence of selective attention on the neural correlates of contextual encoding. Activity in several cortical regions indexed later memory success selectively for color or location information, and this encoding-related activity was enhanced by selective attention to the relevant feature. Critically, a region in the hippocampus responded selectively to attended source information (whether color or location), demonstrating encoding-related activity for attended but not for nonattended source features. Together, the findings suggest that selective attention modulates the magnitude of activity in cortical regions engaged by different aspects of an event, and hippocampal encoding mechanisms seem to be sensitive to this modulation. Thus, the information that is encoded into a memory representation is biased by selective attention, and this bias is mediated by cortical-hippocampal interactions.

  5. Selecting for memory? The influence of selective attention on the mnemonic binding of contextual information

    Science.gov (United States)

    Uncapher, Melina R.; Rugg, Michael D.

    2009-01-01

    Not all of what is experienced is remembered later. Behavioral evidence suggests that the manner in which an event is processed influences which aspects of the event will later be remembered. The present experiment investigated the neural correlates of ‘selective encoding’, or the mechanisms that support the encoding of some elements of an event in preference to others. Event-related functional magnetic resonance imaging (fMRI) data were acquired while volunteers selectively attended to one of two different contextual features of study items (color or location). A surprise memory test for the items and both contextual features was subsequently administered to determine the influence of selective attention on the neural correlates of contextual encoding. Activity in several cortical regions indexed later memory success selectively for color or location information, and this encoding-related activity was enhanced by selective attention to the relevant feature. Critically, a region in the hippocampus responded selectively to attended source information (whether color or location), demonstrating encoding-related activity for attended but not for nonattended source features. Together, the findings suggest that selective attention modulates the magnitude of activity in cortical regions engaged by different aspects of an event, and hippocampal encoding mechanisms seem to be sensitive to this modulation. Thus, the information that is encoded into a memory representation is biased by selective attention, and this bias is mediated by cortico-hippocampal interactions. PMID:19553466

  6. Hippocampal MRI volumetry at 3 Tesla: reliability and practical guidance.

    Science.gov (United States)

    Jeukens, Cécile R L P N; Vlooswijk, Mariëlle C G; Majoie, H J Marian; de Krom, Marc C T F M; Aldenkamp, Albert P; Hofman, Paul A M; Jansen, Jacobus F A; Backes, Walter H

    2009-09-01

    Although volumetry of the hippocampus is considered to be an established technique, protocols reported in literature are not described in great detail. This article provides a complete and detailed protocol for hippocampal volumetry applicable to T1-weighted magnetic resonance (MR) images acquired at 3 Tesla, which has become the standard for structural brain research. The protocol encompasses T1-weighted image acquisition at 3 Tesla, anatomic guidelines for manual hippocampus delineation, requirements of delineation software, reliability measures, and criteria to assess and ensure sufficient reliability. Moreover, the validity of the correction for total intracranial volume size was critically assessed. The protocol was applied by 2 readers to the MR images of 36 patients with cryptogenic localization-related epilepsy, 4 patients with unilateral hippocampal sclerosis, and 20 healthy control subjects. The uncorrected hippocampal volumes were 2923 +/- 500 mm3 (mean +/- SD) (left) and 3120 +/- 416 mm3 (right) for the patient group and 3185 +/- 411 mm3 (left) and 3302 +/- 411 mm3 (right) for the healthy control group. The volume of the 4 pathologic hippocampi of the patients with unilateral hippocampal sclerosis was 2980 +/- 422 mm3. The inter-reader reliability values were determined: intraclass-correlation-coefficient (ICC) = 0.87 (left) and 0.86 (right), percentage volume difference (VD) = 7.0 +/- 4.7% (left) and 6.0 +/- 3.8% (right), and overlap ratio (OR) = 0.82 +/- 0.04 (left) and 0.82 +/- 0.03 (right). The positive Pearson correlation between hippocampal volume and total intracranial volume was found to be low: r = 0.48 (P = 0.03, left) and r = 0.62 (P = 0.004, right) and did not significantly reduce the volumetric variances, showing the limited benefit of the brain size correction. A protocol was described to determine hippocampal volumes based on 3 Tesla MR images with high inter-reader reliability. Although the reliability of hippocampal volumetry at 3 Tesla

  7. Updating the lamellar hypothesis of hippocampal organization

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    Robert S Sloviter

    2012-12-01

    Full Text Available In 1971, Andersen and colleagues proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a trisynaptic circuit lying within transverse hippocampal slices or lamellae [Andersen, Bliss, and Skrede. 1971. Lamellar organization of hippocampal pathways. Exp Brain Res 13, 222-238]. In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly infinite variety of unique outputs. The lamellar hypothesis derives primary support from the lamellar distribution of dentate granule cell axons (the mossy fibers, which innervate dentate hilar neurons and area CA3 pyramidal cells and interneurons within the confines of a thin transverse hippocampal segment. Following the initial formulation of the lamellar hypothesis, anatomical studies revealed that unlike granule cells, hilar mossy cells, CA3 pyramidal cells, and Layer II entorhinal cells all form axonal projections that are more divergent along the longitudinal axis than the clearly lamellar mossy fiber pathway. The existence of pathways with translamellar distribution patterns has been interpreted, incorrectly in our view, as justifying outright rejection of the lamellar hypothesis [Amaral and Witter. 1989. The three-dimensional organization of the hippocampal formation: a review of anatomical data. Neuroscience 31, 571-591]. We suggest that the functional implications of longitudinally-projecting axons depend not on whether they exist, but on what they do. The observation that focal granule cell layer discharges normally inhibit, rather than excite, distant granule cells suggests that longitudinal axons in the dentate gyrus may mediate "lateral" inhibition and define lamellar function, rather than undermine it. In this review, we attempt a reconsideration of the evidence that most directly impacts the physiological concept of hippocampal lamellar

  8. Adult hippocampal neurogenesis and cognitive aging

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    Román Darío Moreno Fernández

    2013-12-01

    Full Text Available Aging is a normal developmental process associated with neurobiological changes leading to cognitive alterations with preserved, impaired, and enhanced functions. Evidence from animal and human studies is reviewed to explore the potential role of hippocampal plasticity on age-related cognitive changes with special attention to adult hippocampal neurogenesis. Results from lesion and stimulation strategies, as well as correlation data, support either a direct or modulatory role for adult newborn neurons in cognition at advanced ages. Further research on this topic may help to develop new treatments and to improve the quality of life of older people.

  9. Hippocampal damage causes retrograde but not anterograde memory loss for context fear discrimination in rats.

    Science.gov (United States)

    Lee, Justin Q; Sutherland, Robert J; McDonald, Robert J

    2017-09-01

    There is a substantial body of evidence that the hippocampus (HPC) plays and essential role in context discrimination in rodents. Studies reporting anterograde amnesia (AA) used repeated, alternating, distributed conditioning and extinction sessions to measure context fear discrimination. In addition, there is uncertainty about the extent of damage to the HPC. Here, we induced conditioned fear prior to discrimination tests and rats sustained extensive, quantified pre- or post-training HPC damage. Unlike previous work, we found that extensive HPC damage spares context discrimination, we observed no AA. There must be a non-HPC system that can acquire long-term memories that support context fear discrimination. Post-training HPC damage caused retrograde amnesia (RA) for context discrimination, even when rats are fear conditioned for multiple sessions. We discuss the implications of these findings for understanding the role of HPC in long-term memory. © 2017 Wiley Periodicals, Inc.

  10. Cavernous angioma associated with ipsilateral hippocampal sclerosis

    International Nuclear Information System (INIS)

    Okujava, M.; Ebner, A.; Schmitt, J.; Woermann, F.G.

    2002-01-01

    We report two cases with extratemporal cavernous angioma (CA) and coexisting ipsilateral hippocampal sclerosis. Classically dual pathology is defined as the association of hippocampal sclerosis with an extrahippocampal lesion. Subtle changes in hippocampus might be overlooked in the presence of an unequivocal extrahippocampal abnormality. Seizure outcome after epilepsy surgery in cases with dual pathology is less favourable if only one of the lesions is removed. Dual pathology must always be considered in diagnostic imaging of patients with intractable epilepsy and CA. (orig.)

  11. Cavernous angioma associated with ipsilateral hippocampal sclerosis

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    Okujava, M [Institute of Radiology and Interventional Diagnostics, Tbilisi (Georgia); Ebner, A; Schmitt, J; Woermann, F G [Bethel Epilepsy Centre, Mara Hospital, Bielefeld (Germany)

    2002-07-01

    We report two cases with extratemporal cavernous angioma (CA) and coexisting ipsilateral hippocampal sclerosis. Classically dual pathology is defined as the association of hippocampal sclerosis with an extrahippocampal lesion. Subtle changes in hippocampus might be overlooked in the presence of an unequivocal extrahippocampal abnormality. Seizure outcome after epilepsy surgery in cases with dual pathology is less favourable if only one of the lesions is removed. Dual pathology must always be considered in diagnostic imaging of patients with intractable epilepsy and CA. (orig.)

  12. Transiently increasing cAMP levels selectively in hippocampal excitatory neurons during sleep deprivation prevents memory deficits caused by sleep loss

    NARCIS (Netherlands)

    Havekes, Robbert; Bruinenberg, Vibeke M.; Tudor, Jennifer C.; Ferri, Sarah L.; Baumann, Arnd; Meerlo, Peter; Abel, Ted

    2014-01-01

    The hippocampus is particularly sensitive to sleep loss. Although previous work has indicated that sleep deprivation impairs hippocampal cAMP signaling, it remains to be determined whether the cognitive deficits associated with sleep deprivation are caused by attenuated cAMP signaling in the

  13. Studies on hippocampal sclerosis by 1H MRS and MRI

    International Nuclear Information System (INIS)

    Qi Jing; Du Xiangke; Luan Guoming; Wang Dehang

    2000-01-01

    Objective: To determine the relative utility of 1 H MRS and MRI for pre-surgical diagnosis of hippocampal sclerosis by the study on metabolic abnormalities and anatomical alterations in the brain of patients with temporal lobe epilepsy (TLE). Methods: 1 H MRS and MRI were performed on 8 patients with pathologically confirmed hippocampal sclerosis and 8 healthy volunteers on 2.0 T 1 H MRS/MRI system. The values of NAA, Cr and Cho were calculated by integration of their peaks and the ratios of NAA/Cr, NAA/(Cr + Cho), and Cho/Cr were measured. The volumes of both hippocampal formations in every case were observed and the differences of hippocampal formation (DHF) were analyzed. Results: The ratios of NAA/Cr, NAA/(Cr + Cho), and Cho/Cr in ipsilateral side were 0.55, 1.77 and 1.38, and in control subjects were 0.77, 1.38 and 1.06 separately. The ratios of NAA/Cr and NAA/(Cr + Cho) were decreased on ipsilateral side (t = 2.15, 4.83 separately, P 1 H MRS and MRI, seven of eight cases could be lateralized. Conclusion: 1 H MRS is sensitive to the diagnosis of neuron abnormality and coincident well with the pathological results 1 H MRS and MRI correctly lateralize most patients with hippocampal sclerosis and complement each other in final lateralization. The combination of 1 H MRS and MRI can provide useful information for pre-surgical diagnosis of hippocampal sclerosis

  14. Morphological variations of hippocampal formation in epilepsy: image, clinical and electrophysiological data.

    Science.gov (United States)

    Hamad, Ana Paula Andrade; Carrete, Henrique; Bianchin, Marino Muxfeldt; Ferrari-Marinho, Taissa; Lin, Katia; Yacubian, Elza Márcia Targas; Vilanova, Luiz Celso Pereira; Garzon, Eliana; Caboclo, Luís Otávio; Sakamoto, Américo Ceiki

    2013-01-01

    Morphological variations of hippocampal formation (MVHF) are observed in patients with epilepsy but also in asymptomatic individuals. The precise role of these findings in epilepsy is not yet fully understood. This study analyzes the hippocampal formation (HF) morphology of asymptomatic individuals (n = 30) and of patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis (MTLE-HS) (n = 68), patients with malformations of cortical development (MCD) (n = 34), or patients with pure morphological variations of hippocampal formation (pure MVHF) (n = 12). Main clinical and electrophysiological data of patients with MVHF were also analyzed. Morphological variations of hippocampal formation are more frequently observed in patients with MCD than in patients with MTLE-HS or in asymptomatic individuals. Patients with pure morphological variations of hippocampal formation showed higher incidence of extratemporal seizure onset. Refractoriness seems to be more associated with other abnormalities, like HS or MCD, than with the HF variation itself. Thus, although morphological HF abnormalities might play a role in epileptogenicity, they seem to contribute less to refractoriness. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Hippocampal functional connectivity and episodic memory in early childhood.

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    Riggins, Tracy; Geng, Fengji; Blankenship, Sarah L; Redcay, Elizabeth

    2016-06-01

    Episodic memory relies on a distributed network of brain regions, with the hippocampus playing a critical and irreplaceable role. Few studies have examined how changes in this network contribute to episodic memory development early in life. The present addressed this gap by examining relations between hippocampal functional connectivity and episodic memory in 4- and 6-year-old children (n=40). Results revealed similar hippocampal functional connectivity between age groups, which included lateral temporal regions, precuneus, and multiple parietal and prefrontal regions, and functional specialization along the longitudinal axis. Despite these similarities, developmental differences were also observed. Specifically, 3 (of 4) regions within the hippocampal memory network were positively associated with episodic memory in 6-year-old children, but negatively associated with episodic memory in 4-year-old children. In contrast, all 3 regions outside the hippocampal memory network were negatively associated with episodic memory in older children, but positively associated with episodic memory in younger children. These interactions are interpreted within an interactive specialization framework and suggest the hippocampus becomes functionally integrated with cortical regions that are part of the hippocampal memory network in adults and functionally segregated from regions unrelated to memory in adults, both of which are associated with age-related improvements in episodic memory ability. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

    Science.gov (United States)

    Tuscher, Jennifer J; Szinte, Julia S; Starrett, Joseph R; Krentzel, Amanda A; Fortress, Ashley M; Remage-Healey, Luke; Frick, Karyn M

    2016-07-01

    The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents. Copyright © 2016 Elsevier Inc. All rights reserved.

  17. Taurine increases hippocampal neurogenesis in aging mice

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    Elias Gebara

    2015-05-01

    Full Text Available Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.

  18. Active sulforhodamine 101 uptake into hippocampal astrocytes.

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    Christian Schnell

    Full Text Available Sulforhodamine 101 (SR101 is widely used as a marker of astrocytes. In this study we investigated labeling of astrocytes by SR101 in acute slices from the ventrolateral medulla and the hippocampus of transgenic mice expressing EGFP under the control of the astrocyte-specific human GFAP promoter. While SR101 efficiently and specifically labeled EGFP-expressing astrocytes in hippocampus, we found that the same staining procedure failed to label astrocytes efficiently in the ventrolateral medulla. Although carbenoxolone is able to decrease the SR101-labeling of astrocytes in the hippocampus, it is unlikely that SR101 is taken up via gap-junction hemichannels because mefloquine, a blocker for pannexin and connexin hemichannels, was unable to prevent SR101-labeling of hippocampal astrocytes. However, SR101-labeling of the hippocampal astrocytes was significantly reduced by substrates of organic anion transport polypeptides, including estron-3-sulfate and dehydroepiandrosterone sulfate, suggesting that SR101 is actively transported into hippocampal astrocytes.

  19. Fukunaga-Koontz feature transformation for statistical structural damage detection and hierarchical neuro-fuzzy damage localisation

    Science.gov (United States)

    Hoell, Simon; Omenzetter, Piotr

    2017-07-01

    Considering jointly damage sensitive features (DSFs) of signals recorded by multiple sensors, applying advanced transformations to these DSFs and assessing systematically their contribution to damage detectability and localisation can significantly enhance the performance of structural health monitoring systems. This philosophy is explored here for partial autocorrelation coefficients (PACCs) of acceleration responses. They are interrogated with the help of the linear discriminant analysis based on the Fukunaga-Koontz transformation using datasets of the healthy and selected reference damage states. Then, a simple but efficient fast forward selection procedure is applied to rank the DSF components with respect to statistical distance measures specialised for either damage detection or localisation. For the damage detection task, the optimal feature subsets are identified based on the statistical hypothesis testing. For damage localisation, a hierarchical neuro-fuzzy tool is developed that uses the DSF ranking to establish its own optimal architecture. The proposed approaches are evaluated experimentally on data from non-destructively simulated damage in a laboratory scale wind turbine blade. The results support our claim of being able to enhance damage detectability and localisation performance by transforming and optimally selecting DSFs. It is demonstrated that the optimally selected PACCs from multiple sensors or their Fukunaga-Koontz transformed versions can not only improve the detectability of damage via statistical hypothesis testing but also increase the accuracy of damage localisation when used as inputs into a hierarchical neuro-fuzzy network. Furthermore, the computational effort of employing these advanced soft computing models for damage localisation can be significantly reduced by using transformed DSFs.

  20. Estrogen administration modulates hippocampal GABAergic subpopulations in the hippocampus of trimethyltin-treated rats

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    Valentina eCorvino

    2015-11-01

    Full Text Available Given the well-documented involvement of estrogens in the modulation of hippocampal functions in both physiological and pathological conditions, the present study investigates the effects of 17-beta estradiol (E2 administration in the rat model of hippocampal neurodegeneration induced by trimethyltin (TMT administration (8mg/kg, characterized by loss of pyramidal neurons in CA1, CA3/hilus hippocampal subfields associated with astroglial and microglial activation, seizures and cognitive impairment. After TMT/saline treatment, ovariectomized animals received two doses of E2 (0.2 mg/kg i.p. or vehicle, and were sacrificed 48h or 7 days after TMT-treatment. Our results indicate that in TMT-treated animals E2 administration induces the early (48h upregulation of genes involved in neuroprotection and synaptogenesis, namely Bcl2, trkB, Cadherin and cyclin-dependent-kinase-5. Increased expression levels of glutamic acid decarboxylase (gad 67, neuropeptide Y (Npy, parvalbumin , Pgc-1α and Sirtuin 1genes, the latter involved in parvalbumin (PV synthesis, were also evident. Unbiased stereology performed on rats sacrificed 7 days after TMT treatment showed that although E2 does not significantly influence the extent of TMT-induced neuronal death, significantly enhances the TMT-induced modulation of GABAergic interneuron population size in selected hippocampal subfields. In particular, E2 administration causes, in TMT treated rats, a significant increase in the number of GAD67-expressing interneurons in CA1 stratum oriens, CA3 pyramidal layer, hilus and dentate gyrus, accompanied by a parallel increase in NPY-expressing cells, essentially in the same regions, and of PV-positive cells in CA1 pyramidal layer. The present results add information concerning the role of in vivo E2 administration on mechanisms involved in cellular plasticity in the adult brain.

  1. Hippocampal Dysfunction Provoked by Mercury Chloride Exposure: Evaluation of Cognitive Impairment, Oxidative Stress, Tissue Injury and Nature of Cell Death

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    Walessa Alana Bragança Aragão

    2018-01-01

    Full Text Available Mercury (Hg is a highly toxic metal, which can be found in its inorganic form in the environment. This form presents lower liposolubility and lower absorption in the body. In order to elucidate the possible toxicity of inorganic Hg in the hippocampus, we investigated the potential of low doses of mercury chloride (HgCl2 to promote hippocampal dysfunction by employing a chronic exposure model. For this, 56 rats were exposed to HgCl2 (0.375 mg/kg/day via the oral route for 45 days. After the exposure period, the animals were submitted to the cognitive test of fear memory. The hippocampus was collected for the measurement of total Hg levels, analysis of oxidative stress, and evaluation of cytotoxicity, apoptosis, and tissue injury. It was observed that chronic exposure to inorganic Hg promotes an increase in mercury levels in this region and damage to short- and long-term memory. Furthermore, we found that this exposure model provoked oxidative stress, which led to cytotoxicity and cell death by apoptosis, affecting astrocytes and neurons in the hippocampus. Our study demonstrated that inorganic Hg, even with its low liposolubility, is able to produce deleterious effects in the central nervous system, resulting in cognitive impairment and hippocampal damage when administered for a long time at low doses in rats.

  2. Effect of chronic mild stress on hippocampal transcriptome in mice selected for high and low stress-induced analgesia and displaying different emotional behaviors.

    Science.gov (United States)

    Lisowski, Pawel; Juszczak, Grzegorz R; Goscik, Joanna; Wieczorek, Marek; Zwierzchowski, Lech; Swiergiel, Artur H

    2011-01-01

    There is increasing evidence that mood disorders may derive from the impact of environmental pressure on genetically susceptible individuals. Stress-induced hippocampal plasticity has been implicated in depression. We studied hippocampal transcriptomes in strains of mice that display high (HA) and low (LA) swim stress-induced analgesia and that differ in emotional behaviors and responses to different classes of antidepressants. Chronic mild stress (CMS) affected expression of a number of genes common for both strains. CMS also produced strain specific changes in expression suggesting that hippocampal responses to stress depend on genotype. Considerably larger number of genes, biological processes, molecular functions, biochemical pathways, and gene networks were affected by CMS in LA than in HA mice. The results suggest that potential drug targets against detrimental effects of stress include glutamate transporters, and cholinergic, cholecystokinin (CCK), glucocorticoids, and thyroid hormones receptors. Furthermore, some biological processes evoked by stress and different between the strains, such as apoptosis, neurogenesis and chromatin modifications, may be responsible for the long-term, irreversible effects of stress and suggest a role for epigenetic regulation of mood related stress responses. Copyright © 2010 Elsevier B.V. and ECNP. All rights reserved.

  3. Distinguishing cognitive state with multifractal complexity of hippocampal interspike interval sequences

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    Dustin eFetterhoff

    2015-09-01

    Full Text Available Fractality, represented as self-similar repeating patterns, is ubiquitous in nature and the brain. Dynamic patterns of hippocampal spike trains are known to exhibit multifractal properties during working memory processing; however, it is unclear whether the multifractal properties inherent to hippocampal spike trains reflect active cognitive processing. To examine this possibility, hippocampal neuronal ensembles were recorded from rats before, during and after a spatial working memory task following administration of tetrahydrocannabinol (THC, a memory-impairing component of cannabis. Multifractal detrended fluctuation analysis was performed on hippocampal interspike interval sequences to determine characteristics of monofractal long-range temporal correlations (LRTCs, quantified by the Hurst exponent, and the degree/magnitude of multifractal complexity, quantified by the width of the singularity spectrum. Our results demonstrate that multifractal firing patterns of hippocampal spike trains are a marker of functional memory processing, as they are more complex during the working memory task and significantly reduced following administration of memory impairing THC doses. Conversely, LRTCs are largest during resting state recordings, therefore reflecting different information compared to multifractality. In order to deepen conceptual understanding of multifractal complexity and LRTCs, these measures were compared to classical methods using hippocampal frequency content and firing variability measures. These results showed that LRTCs, multifractality, and theta rhythm represent independent processes, while delta rhythm correlated with multifractality. Taken together, these results provide a novel perspective on memory function by demonstrating that the multifractal nature of spike trains reflects hippocampal microcircuit activity that can be used to detect and quantify cognitive, physiological and pathological states.

  4. BDNF val(66)met affects hippocampal volume and emotion-related hippocampal memory activity

    NARCIS (Netherlands)

    Molendijk, M. L.; van Tol, M-J; Penninx, B. W. J. H.; van der Wee, N. J. A.; Aleman, A.; Veltman, D. J.; Spinhoven, P.; Elzinga, B. M.

    2012-01-01

    The val(66)met polymorphism on the BDNF gene has been reported to explain individual differences in hippocampal volume and memory-related activity. These findings, however, have not been replicated consistently and no studies to date controlled for the potentially confounding impact of early life

  5. Does white matter structure or hippocampal volume mediate associations between cortisol and cognitive ageing?

    Science.gov (United States)

    Cox, Simon R.; MacPherson, Sarah E.; Ferguson, Karen J.; Royle, Natalie A.; Maniega, Susana Muñoz; Hernández, Maria del C. Valdés; Bastin, Mark E.; MacLullich, Alasdair M.J.; Wardlaw, Joanna M.; Deary, Ian J.

    2015-01-01

    Elevated glucocorticoid (GC) levels putatively damage specific brain regions, which in turn may accelerate cognitive ageing. However, many studies are cross-sectional or have relatively short follow-up periods, making it difficult to relate GCs directly to changes in cognitive ability with increasing age. Moreover, studies combining endocrine, MRI and cognitive variables are scarce, measurement methods vary considerably, and formal tests of the underlying causal hypothesis (cortisol → brain → cognition) are absent. In this study, 90 men, aged 73 years, provided measures of fluid intelligence, processing speed and memory, diurnal and reactive salivary cortisol and two measures of white matter (WM) structure (WM hyperintensity volume from structural MRI and mean diffusivity averaged across 12 major tracts from diffusion tensor MRI), hippocampal volume, and also cognitive ability at age 11. We tested whether negative relationships between cognitive ageing differences (over more than 60 years) and salivary cortisol were significantly mediated by WM and hippocampal volume. Significant associations between reactive cortisol at 73 and cognitive ageing differences between 11 and 73 (r = −.28 to −.36, p cognition associations (cognitive ageing differences from childhood to the early 70s, partly via brain WM structure. PMID:26298692

  6. Regulation of Hippocampal 5-HT Release by P2X7 Receptors in Response to Optogenetic Stimulation of Median Raphe Terminals of Mice

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    Flóra Gölöncsér

    2017-10-01

    Full Text Available Serotonergic and glutamatergic neurons of median raphe region (MRR play a pivotal role in the modulation of affective and cognitive functions. These neurons synapse both onto themselves and remote cortical areas. P2X7 receptors (P2rx7 are ligand gated ion channels expressed by central presynaptic excitatory nerve terminals and involved in the regulation of neurotransmitter release. P2rx7s are implicated in various neuropsychiatric conditions such as schizophrenia and depression. Here we investigated whether 5-HT release released from the hippocampal terminals of MRR is subject to modulation by P2rx7s. To achieve this goal, an optogenetic approach was used to selectively activate subpopulation of serotonergic terminals derived from the MRR locally, and one of its target area, the hippocampus. Optogenetic activation of neurons in the MRR with 20 Hz was correlated with freezing and enhanced locomotor activity of freely moving mice and elevated extracellular levels of 5-HT, glutamate but not GABA in vivo. Similar optical stimulation (OS significantly increased [3H]5-HT and [3H]glutamate release in acute MRR and hippocampal slices. We examined spatial and temporal patterns of [3H]5-HT release and the interaction between the serotonin and glutamate systems. Whilst [3H]5-HT release from MRR neurons was [Ca2+]o-dependent and sensitive to TTX, CNQX and DL-AP-5, release from hippocampal terminals was not affected by the latter drugs. Hippocampal [3H]5-HT released by electrical but not OS was subject to modulation by 5- HT1B/D receptors agonist sumatriptan (1 μM, whereas the selective 5-HT1A agonist buspirone (0.1 μM was without effect. [3H]5-HT released by electrical and optical stimulation was decreased in mice genetically deficient in P2rx7s, and after perfusion with selective P2rx7 antagonists, JNJ-47965567 (0.1 μM, and AZ-10606120 (0.1 μM. Optical and electrical stimulation elevated the extracellular level of ATP. Our results demonstrate for the

  7. CNS bioavailability and radiation protection of normal hippocampal neurogenesis by a lipophilic Mn porphyrin-based superoxide dismutase mimic, MnTnBuOE-2-PyP5+

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    David Leu

    2017-08-01

    Full Text Available Although radiation therapy can be effective against cancer, potential damage to normal tissues limits the amount that can be safely administered. In central nervous system (CNS, radiation damage to normal tissues is presented, in part, as suppressed hippocampal neurogenesis and impaired cognitive functions. Mn porphyrin (MnP-based redox active drugs have demonstrated differential effects on cancer and normal tissues in experimental animals that lead to protection of normal tissues and radio- and chemo-sensitization of cancers. To test the efficacy of MnPs in CNS radioprotection, we first examined the tissue levels of three different MnPs – MnTE-2-PyP5+(MnE, MnTnHex-2-PyP5+(MnHex, and MnTnBuOE-2-PyP5+(MnBuOE. Nanomolar concentrations of MnHex and MnBuOE were detected in various brain regions after daily subcutaneous administration, and MnBuOE was well tolerated at a daily dose of 3 mg/kg. Administration of MnBuOE for one week before cranial irradiation and continued for one week afterwards supported production and long-term survival of newborn neurons in the hippocampal dentate gyrus. MnP-driven S-glutathionylation in cortex and hippocampus showed differential responses to MnP administration and radiation in these two brain regions. A better understanding of how preserved hippocampal neurogenesis correlates with cognitive functions following cranial irradiation will be helpful in designing better MnP-based radioprotection strategies. Keywords: Mn porphyrin, Bioavailability, BMX-001, Hippocampus, Neurogenesis, Radioprotection

  8. Role of adult neurogenesis in hippocampal-cortical memory consolidation

    Science.gov (United States)

    2014-01-01

    Acquired memory is initially dependent on the hippocampus (HPC) for permanent memory formation. This hippocampal dependency of memory recall progressively decays with time, a process that is associated with a gradual increase in dependency upon cortical structures. This process is commonly referred to as systems consolidation theory. In this paper, we first review how memory becomes hippocampal dependent to cortical dependent with an emphasis on the interactions that occur between the HPC and cortex during systems consolidation. We also review the mechanisms underlying the gradual decay of HPC dependency during systems consolidation from the perspective of memory erasures by adult hippocampal neurogenesis. Finally, we discuss the relationship between systems consolidation and memory precision. PMID:24552281

  9. Forest canopy damage and recovery in reduced-impact and conventional selective logging in eastern Para, Brazil.

    Science.gov (United States)

    Rodrigo Pereira Jr.; Johan Zweedea; Gregory P. Asnerb; Keller; Michael

    2002-01-01

    We investigated ground and canopy damage and recovery following conventional logging and reduced-impact logging (RIL) of moist tropical forest in the eastern Amazon of Brazil. Paired conventional and RIL blocks were selectively logged with a harvest intensity of approximately 23 m3 ha

  10. Hippocampal sleep features: relations to human memory function

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    Michele eFerrara

    2012-04-01

    Full Text Available The recent spread of intracranial EEG recordings techniques for presurgical evaluation of drug-resistant epileptic patients is providing new information on the activity of different brain structures during both wakefulness and sleep. The interest has been mainly focused on the medial temporal lobe, and in particular the hippocampal formation, whose peculiar local sleep features have been recently described, providing support to the idea that sleep is not a spatially global phenomenon. The study of the hippocampal sleep electrophysiology is particularly interesting because of its central role in the declarative memory formation. Recent data indicate that sleep contributes to memory formation. Therefore, it is relevant to understand whether specific pattern of activity taking place during sleep are related to memory consolidation processes. Fascinating similarities between different states of consciousness (wakefulness, REM sleep, NREM sleep in some electrophysiological mechanisms underlying cognitive processes have been reported. For instance, large-scale synchrony in gamma activity is important for waking memory and perception processes, and its changes during sleep may be the neurophysiological substrate of sleep-related deficits of declarative memory. Hippocampal activity seems to specifically support memory consolidation during sleep, through specific coordinated neurophysiological events (slow waves, spindles, ripples that would facilitate the integration of new information into the pre-existing cortical networks. A few studies indeed provided direct evidence that rhinal ripples as well as slow hippocampal oscillations are correlated with memory consolidation in humans. More detailed electrophysiological investigations assessing the specific relations between different types of memory consolidation and hippocampal EEG features are in order. These studies will add an important piece of knowledge to the elucidation of the ultimate sleep

  11. Hippocampal Sleep Features: Relations to Human Memory Function

    Science.gov (United States)

    Ferrara, Michele; Moroni, Fabio; De Gennaro, Luigi; Nobili, Lino

    2012-01-01

    The recent spread of intracranial electroencephalographic (EEG) recording techniques for presurgical evaluation of drug-resistant epileptic patients is providing new information on the activity of different brain structures during both wakefulness and sleep. The interest has been mainly focused on the medial temporal lobe, and in particular the hippocampal formation, whose peculiar local sleep features have been recently described, providing support to the idea that sleep is not a spatially global phenomenon. The study of the hippocampal sleep electrophysiology is particularly interesting because of its central role in the declarative memory formation. Recent data indicate that sleep contributes to memory formation. Therefore, it is relevant to understand whether specific patterns of activity taking place during sleep are related to memory consolidation processes. Fascinating similarities between different states of consciousness (wakefulness, REM sleep, non-REM sleep) in some electrophysiological mechanisms underlying cognitive processes have been reported. For instance, large-scale synchrony in gamma activity is important for waking memory and perception processes, and its changes during sleep may be the neurophysiological substrate of sleep-related deficits of declarative memory. Hippocampal activity seems to specifically support memory consolidation during sleep, through specific coordinated neurophysiological events (slow waves, spindles, ripples) that would facilitate the integration of new information into the pre-existing cortical networks. A few studies indeed provided direct evidence that rhinal ripples as well as slow hippocampal oscillations are correlated with memory consolidation in humans. More detailed electrophysiological investigations assessing the specific relations between different types of memory consolidation and hippocampal EEG features are in order. These studies will add an important piece of knowledge to the elucidation of the ultimate

  12. Spatial deficits in an amnesic patient with hippocampal damage: questioning the multiple trace theory.

    Science.gov (United States)

    Gomez, A; Rousset, S; Charnallet, A

    2012-06-01

    Mediotemporal lobe structures are involved in both spatial processing and long-term memory. Patient M.R. suffers from amnesia, due to bilateral hippocampal lesion and temporoparietal atrophy following carbon monoxide poisoning. We compared his performance in immediate spatial memory tasks with the performance of ten healthy matched participants. Using an immediate reproduction of path, we observed a dissociation between his performance in three allocentric tasks and in five egocentric-updating tasks. His performance was always impaired on tasks requiring the use of an egocentric-updating representation but remained preserved on allocentric tasks. These results fit with the hypothesis that the hippocampus plays a role in spatial memory, but they also suggest that allocentric deficits previously observed in amnesia might actually reflect deficits in egocentric-updating processes. Furthermore, the co-occurrence of deficits in episodic long-term memory and short-term egocentric-updating representation without any short-term allocentric deficit suggests a new link between the mnemonic and navigational roles of the hippocampus. The Cognitive Map theory, the Multiple Trace theory, as well as further models linking spatial and nonspatial functions of the hippocampus are discussed. Copyright © 2011 Wiley Periodicals, Inc.

  13. A reduction in hippocampal GABAA receptor alpha5 subunits disrupts the memory for location of objects in mice.

    Science.gov (United States)

    Prut, L; Prenosil, G; Willadt, S; Vogt, K; Fritschy, J-M; Crestani, F

    2010-07-01

    The memory for location of objects, which binds information about objects to discrete positions or spatial contexts of occurrence, is a form of episodic memory particularly sensitive to hippocampal damage. Its early decline is symptomatic for elderly dementia. Substances that selectively reduce alpha5-GABA(A) receptor function are currently developed as potential cognition enhancers for Alzheimer's syndrome and other dementia, consistent with genetic studies implicating these receptors that are highly expressed in hippocampus in learning performance. Here we explored the consequences of reduced GABA(A)alpha5-subunit contents, as occurring in alpha5(H105R) knock-in mice, on the memory for location of objects. This required the behavioral characterization of alpha5(H105R) and wild-type animals in various tasks examining learning and memory retrieval strategies for objects, locations, contexts and their combinations. In mutants, decreased amounts of alpha5-subunits and retained long-term potentiation in hippocampus were confirmed. They exhibited hyperactivity with conserved circadian rhythm in familiar actimeters, and normal exploration and emotional reactivity in novel places, allocentric spatial guidance, and motor pattern learning acquisition, inhibition and flexibility in T- and eight-arm mazes. Processing of object, position and context memories and object-guided response learning were spared. Genotype difference in object-in-place memory retrieval and in encoding and response learning strategies for object-location combinations manifested as a bias favoring object-based recognition and guidance strategies over spatial processing of objects in the mutants. These findings identify in alpha5(H105R) mice a behavioral-cognitive phenotype affecting basal locomotion and the memory for location of objects indicative of hippocampal dysfunction resulting from moderately decreased alpha5-subunit contents.

  14. Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function.

    Science.gov (United States)

    Xiao, Ena; Chen, Qiang; Goldman, Aaron L; Tan, Hao Yang; Healy, Kaitlin; Zoltick, Brad; Das, Saumitra; Kolachana, Bhaskar; Callicott, Joseph H; Dickinson, Dwight; Berman, Karen F; Weinberger, Daniel R; Mattay, Venkata S

    2017-11-01

    We explored the cumulative effect of several late-onset Alzheimer's disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry. In a sample of 231 healthy control subjects (19-55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level-dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics. We also studied effects on brain morphometry in an overlapping sample of 280 subjects. There was almost no significant association of LOAD-RPS with cognitive or morphometric measures. However, there was a significant negative relationship between LOAD-RPS and hippocampal function (familywise error [small volume correction-hippocampal region of interest] p risk score based on APOE haplotype, and for a combined LOAD-RPS + APOE haplotype risk profile score (p risk genes on hippocampal function even in healthy volunteers. The effect of LOAD-RPS on hippocampal function in the relative absence of any effect on cognitive and morphometric measures is consistent with the reported temporal characteristics of LOAD biomarkers with the earlier manifestation of synaptic dysfunction before morphometric and cognitive changes. Copyright © 2017 Society of Biological Psychiatry. All rights reserved.

  15. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Shanshan Sun

    2017-04-01

    Full Text Available Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD, a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen–glucose-deprivation/reperfusion (OGD/R model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XFe24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP+ ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance.

  16. Cannabidiol attenuates OGD/R-induced damage by enhancing mitochondrial bioenergetics and modulating glucose metabolism via pentose-phosphate pathway in hippocampal neurons.

    Science.gov (United States)

    Sun, Shanshan; Hu, Fangyuan; Wu, Jihong; Zhang, Shenghai

    2017-04-01

    Deficient bioenergetics and diminished redox conservation have been implicated in the development of cerebral ischemia/reperfusion injury. In this study, the mechanisms underlying the neuroprotective effects of cannabidiol (CBD), a nonpsychotropic compound derived from Cannabis sativa with FDA-approved antiepilepsy properties, were studied in vitro using an oxygen-glucose-deprivation/reperfusion (OGD/R) model in a mouse hippocampal neuronal cell line. CBD supplementation during reperfusion rescued OGD/R-induced cell death, attenuated intracellular ROS generation and lipid peroxidation, and simultaneously reversed the abnormal changes in antioxidant biomarkers. Using the Seahorse XF e 24 Extracellular Flux Analyzer, we found that CBD significantly improved basal respiration, ATP-linked oxygen consumption rate, and the spare respiratory capacity, and augmented glucose consumption in OGD/R-injured neurons. The activation of glucose 6-phosphate dehydrogenase and the preservation of the NADPH/NADP + ratio implies that the pentose-phosphate pathway is stimulated by CBD, thus protecting hippocampal neurons from OGD/R injury. This study is the first to document the neuroprotective effects of CBD against OGD/R insult, which depend in part on attenuating oxidative stress, enhancing mitochondrial bioenergetics, and modulating glucose metabolism via the pentose-phosphate pathway, thus preserving both energy and the redox balance. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Asymmetry of limbic structure (hippocampal formation and amygdaloidal complex at PTSD

    Directory of Open Access Journals (Sweden)

    Aida Sarač-Hadžihalilović

    2003-05-01

    Full Text Available Defining exact position of weak anatomic function which is find in a base of neurological and psychiatric disorder is just became the subject of intensive research interest. For this purposes it is important to implement structural and functional MRI techniques, also for further lightening and seeing subject of this work, more concretely connected to PTSD. Therefore, exactly MRI gives most sensitive volumetric measuring of hippocampal formation and amygdaloidal complex.The goal of this work was to research asymmetry of hippocampal formation and amygdaloidal complex to the PTSD patients.Results showed that at the axial slice length of hippocampal formation on the left and right side of all patients are significantly asymmetric. At the sagittal slice from the left side of hippocampal formation is in many cases longer than right about 50 %. At the coronal slice, there are no significant differences toward patient proportion according to symm. / asymm. of the hippocampal formation width at the right and left side. Difference in volume average of hippocampal formation between right and left side for axial and coronal slice is not statistically significant, but it is significant for sagittal slice. In about amygdaloidal complex patients with PTSD toward symm. / asymm. Amygdaloidal complex at the right and left side of axial and sagittal slice in all three measurement shows asymmetry, what is especially shown at sagittal slice. Difference in average length of amygdaloidal complex at the right and left side is not statistically significant for no one slice.Therefore, results of a new research that are used MRI, showed smaller hippocampal level at PTSD (researched by Van der Kolka 1996, Pitman 1996, Bremner et al., 1995.. Application of MRI technique in research of asymmetry of hippocampal formation and amygdaloidal complex, which we used in our research, we recommend as a template for future researches in a sense of lightening anatomic function that is

  18. Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing.

    Science.gov (United States)

    Neltner, Janna H; Abner, Erin L; Baker, Steven; Schmitt, Frederick A; Kryscio, Richard J; Jicha, Gregory A; Smith, Charles D; Hammack, Eleanor; Kukull, Walter A; Brenowitz, Willa D; Van Eldik, Linda J; Nelson, Peter T

    2014-01-01

    Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer's Disease Centre, Nun Study, and National Alzheimer's Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case-control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin-immunoreactive arterioles had thicker walls (P < 0.05), larger perimeters (P < 0

  19. The MRI study of hippocampal volume and shape in the youth and older

    International Nuclear Information System (INIS)

    Li Yuefeng; Jiang Ping; Tong Xinkang; Wang Dongqing; Peng Weibin; Wei Chuanshe; Yin Ruigen; Zhao Liang; Sun Weibin; Wang Zhengchao

    2009-01-01

    statistical significance (t=3.48,3.75, P<0.05). The number of layers and average areas of hippocampal head were less in older than in youth group, and the shape of hippocampus become short and narrow. Conclusion: According to the rule with landmarks that we selected, standardization measurement of the hippocampus may become possible and can be provided the basis of diagnosis and searching pathogenesis related to disease. (authors)

  20. Rubia cordifolia, Fagonia cretica linn and Tinospora cordifolia exert neuroprotection by modulating the antioxidant system in rat hippocampal slices subjected to oxygen glucose deprivation

    Directory of Open Access Journals (Sweden)

    Biswas Saibal K

    2004-08-01

    Full Text Available Abstract Background The major damaging factor during and after the ischemic/hypoxic insult is the generation of free radicals, which leads to apoptosis, necrosis and ultimately cell death. Rubia cordifolia (RC, Fagonia cretica linn (FC and Tinospora cordifolia (TC have been reported to contain a wide variety of antioxidants and have been in use in the eastern system of medicine for various disorders. However, their mechanism of action was largely unknown. We therefore selected these herbs for the present study to test their neuroprotective ability and the associated mechanism in rat hippocampal slices subjected to oxygen-glucose deprivation (OGD. Methods Hippocampal Slices were subjected to OGD (oxygen glucose deprivation and divided into 3 groups: control, OGD and OGD + drug treated. Cytosolic Cu-Zn superoxide dismutase (Cu-Zn SOD, reduced glutathione (GSH, glutathione peroxidase (GPx, nitric oxide (NO was measured as nitrite (NO2 in the supernatant and protein assays were performed in the respective groups at various time intervals. EPR was used to establish the antioxidant effect of RC, FC and TC with respect to superoxide anion (O2.-, hydroxyl radicals (. OH, nitric oxide (NO radical and peroxynitrite anion (ONOO generated from pyrogallol, menadione, DETA-NO and Sin-1 respectively. RT-PCR was performed for the three groups for GCLC, iNOS, Cu-Zn SOD and GAPDH gene expression. Results All the three herbs were effective in elevating the GSH levels, expression of the gamma-glutamylcysteine ligase and Cu-Zn SOD genes. The herbs also exhibited strong free radical scavenging properties against reactive oxygen and nitrogen species as studied by electron paramagnetic resonance spectroscopy. In addition all the three herbs significantly diminished the expression of iNOS gene after 48 hours which plays a major role in neuronal injury during hypoxia/ischemia. Conclusions RC, FC and TC therefore attenuate oxidative stress mediated cell injury during OGD

  1. Episodic autobiographical memory is associated with variation in the size of hippocampal subregions.

    Science.gov (United States)

    Palombo, Daniela J; Bacopulos, Agnes; Amaral, Robert S C; Olsen, Rosanna K; Todd, Rebecca M; Anderson, Adam K; Levine, Brian

    2018-02-01

    Striking individual differences exist in the human capacity to recollect past events, yet, little is known about the neural correlates of such individual differences. Studies investigating hippocampal volume in relation to individual differences in laboratory measures of episodic memory in young adults suggest that whole hippocampal volume is unrelated (or even negatively associated) with episodic memory. However, anatomical and functional specialization across hippocampal subregions suggests that individual differences in episodic memory may be linked to particular hippocampal subregions, as opposed to whole hippocampal volume. Given that the DG/CA 2/3 circuitry is thought to be especially critical for supporting episodic memory in humans, we predicted that the volume of this region would be associated with individual variability in episodic memory. This prediction was supported using high-resolution MRI of the hippocampal subfields and measures of real-world (autobiographical) episodic memory. In addition to the association with DG/CA 2/3 , we further observed a relationship between episodic autobiographical memory and subiculum volume, whereas no association was observed with CA 1 or with whole hippocampal volume. These findings provide insight into the possible neural substrates that mediate individual differences in real-world episodic remembering in humans. © 2017 Wiley Periodicals, Inc.

  2. Arteriolosclerosis that affects multiple brain regions is linked to hippocampal sclerosis of ageing

    Science.gov (United States)

    Neltner, Janna H.; Abner, Erin L.; Baker, Steven; Schmitt, Frederick A.; Kryscio, Richard J.; Jicha, Gregory A.; Smith, Charles D.; Hammack, Eleanor; Kukull, Walter A.; Brenowitz, Willa D.; Van Eldik, Linda J.

    2014-01-01

    Hippocampal sclerosis of ageing is a prevalent brain disease that afflicts older persons and has been linked with cerebrovascular pathology. Arteriolosclerosis is a subtype of cerebrovascular pathology characterized by concentrically thickened arterioles. Here we report data from multiple large autopsy series (University of Kentucky Alzheimer’s Disease Centre, Nun Study, and National Alzheimer’s Coordinating Centre) showing a specific association between hippocampal sclerosis of ageing pathology and arteriolosclerosis. The present analyses incorporate 226 cases of autopsy-proven hippocampal sclerosis of ageing and 1792 controls. Case–control comparisons were performed including digital pathological assessments for detailed analyses of blood vessel morphology. We found no evidence of associations between hippocampal sclerosis of ageing pathology and lacunar infarcts, large infarcts, Circle of Willis atherosclerosis, or cerebral amyloid angiopathy. Individuals with hippocampal sclerosis of ageing pathology did not show increased rates of clinically documented hypertension, diabetes, or other cardiac risk factors. The correlation between arteriolosclerosis and hippocampal sclerosis of ageing pathology was strong in multiple brain regions outside of the hippocampus. For example, the presence of arteriolosclerosis in the frontal cortex (Brodmann area 9) was strongly associated with hippocampal sclerosis of ageing pathology (P ageing (n = 15) and control (n = 42) cases. Following technical studies to optimize immunostaining methods for small blood vessel visualization, our analyses focused on sections immunostained for smooth muscle actin (a marker of arterioles) and CD34 (an endothelial marker), with separate analyses on grey and white matter. A total of 43 834 smooth muscle actin-positive vascular profiles and 603 798 CD34-positive vascular profiles were evaluated. In frontal cortex of cases with hippocampal sclerosis of ageing, smooth muscle actin

  3. Comparison of the dose-response relationship of radiation-induced apoptosis in the hippocampal dentate gyrus and intestinal crypt of adult mice

    International Nuclear Information System (INIS)

    Kim, J. S.; Yang, M.; Kim, J.; Lee, D.; Kim, J. C.; Shin, T.; Kim, S. H.; Moon, C.

    2012-01-01

    The present study compared the dose-response curves for the frequency of apoptosis in mouse hippocampal dentate gyrus (DG) and intestinal crypt using whole-body gamma irradiation. The incidence of gamma-ray-induced apoptosis was measured using the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end-labelling (TUNEL) method. TUNEL-positive apoptotic nuclei in the DG and intestinal crypt were increased in a dose-dependent pattern (0-2 Gy). The dose-response curves were linear-quadratic, with a significant relationship between the appearance of apoptosis and irradiation dose. The slopes of the dose-response curves in the DG were much steeper (∼5-6-fold) than those in the intestinal crypt within the range of 0-1 Gy exposure. Hippocampal DG might be a more effective and sensitive evaluation structure than the intestinal crypt to estimate the degree of radiation exposure in damaged organs of adult mice exposed to low irradiation dose. copy; The Author 2011. Published by Oxford Univ. Press. All rights reserved. (authors)

  4. Major depressive episodes over the course of 7 years and hippocampal subfield volumes at 7 tesla MRI: the PREDICT-MR study.

    Science.gov (United States)

    Wisse, L E M; Biessels, G J; Stegenga, B T; Kooistra, M; van der Veen, P H; Zwanenburg, J J M; van der Graaf, Y; Geerlings, M I

    2015-04-01

    Smaller hippocampal volumes have been associated with major depressive disorder (MDD). The hippocampus consists of several subfields that may be differentially related to MDD. We investigated the association of occurrence of major depressive episodes (MDEs), assessed five times over seven years, with hippocampal subfield and entorhinal cortex volumes at 7 tesla MRI. In this prospective study of randomly selected general practice attendees, MDEs according to DSM-IV-R criteria were assessed at baseline and after 6, 12, 39 and 84 months follow-up. At the last follow-up, a T2 (0.7 mm(3)) 7 tesla MRI scan was obtained in 47 participants (60±10 years). The subiculum, cornu ammonis (CA) 1 to 3, dentate gyrus&CA4 and entorhinal cortex volumes were manually segmented according a published protocol. Of the 47 participants, 13 had one MDE and 5 had multiple MDEs. ANCOVAs, adjusted for age, sex, education and intracranial volume, revealed no significant differences in hippocampal subfield or entorhinal cortex volumes between participants with and without an MDE in the preceding 84 months. Multiple episodes were associated with smaller subiculum volumes (B=-0.03 mL/episode; 95% CI -0.06; -0.003), but not with the other hippocampal subfield volumes, entorhinal cortex, or total hippocampal volume. A limitation of this study is the small sample size which makes replication necessary. In this exploratory study, we found that an increasing number of major depressive episodes was associated with smaller subiculum volumes in middle-aged and older persons, but not with smaller volumes in other hippocampal subfields or the entorhinal cortex. Copyright © 2014 Elsevier B.V. All rights reserved.

  5. Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia.

    Science.gov (United States)

    La Joie, Renaud; Perrotin, Audrey; de La Sayette, Vincent; Egret, Stéphanie; Doeuvre, Loïc; Belliard, Serge; Eustache, Francis; Desgranges, Béatrice; Chételat, Gaël

    2013-01-01

    Hippocampal atrophy is a well-known feature of Alzheimer's disease (AD), but sensitivity and specificity of hippocampal volumetry are limited. Neuropathological studies have shown that hippocampal subfields are differentially vulnerable to AD; hippocampal subfield volumetry may thus prove to be more accurate than global hippocampal volumetry to detect AD. CA1, subiculum and other subfields were manually delineated from 40 healthy controls, 18 AD, 17 amnestic Mild Cognitive Impairment (aMCI), and 8 semantic dementia (SD) patients using a previously developed high resolution MRI procedure. Non-parametric group comparisons and receiver operating characteristic (ROC) analyses were conducted. Complementary analyses were conducted to evaluate differences of hemispheric asymmetry and anterior-predominance between AD and SD patients and to distinguish aMCI patients with or without β-amyloid deposition as assessed by Florbetapir-TEP. Global hippocampi were atrophied in all three patient groups and volume decreases were maximal in the CA1 subfield (22% loss in aMCI, 27% in both AD and SD; all p volumetry was more accurate than global hippocampal measurement to distinguish patients from controls (areas under the ROC curve = 0.88 and 0.76, respectively; p = 0.05) and preliminary analyses suggest that it was independent from the presence of β-amyloid deposition. In patients with SD, whereas the degree of CA1 and subiculum atrophy was similar to that found in AD patients, hemispheric and anterior-posterior asymmetry were significantly more marked than in AD with greater involvement of the left and anterior hippocampal subfields. The findings suggest that CA1 measurement is more sensitive than global hippocampal volumetry to detect structural changes at the pre-dementia stage, although the predominance of CA1 atrophy does not appear to be specific to AD pathophysiological processes.

  6. Postnatal choline supplementation selectively attenuates hippocampal microRNA alterations associated with developmental alcohol exposure.

    Science.gov (United States)

    Balaraman, Sridevi; Idrus, Nirelia M; Miranda, Rajesh C; Thomas, Jennifer D

    2017-05-01

    Prenatal alcohol exposure can result in a range of physical, neuropathological, and behavioral alterations, collectively termed fetal alcohol spectrum disorders (FASD). We have shown that supplementation with the nutrient choline reduces the severity of developmental alcohol-associated deficits in hippocampal-dependent behaviors and normalizes some aspects of hippocampal cholinergic development and DNA methylation patterns. Alcohol's developmental effects may also be mediated, in part, by altering microRNAs (miRNAs) that serve as negative regulators of gene translation. To determine whether choline supplementation alters ethanol's long-lasting effects on miRNAs, Sprague-Dawley rats were exposed to 5.25 g/kg/day ethanol from postnatal days (PD) 4-9 via intubation; controls received sham intubations. Subjects were treated with choline chloride (100 mg/kg/day) or saline vehicle subcutaneously (s.c.) from PD 4-21. On PD 22, subjects were sacrificed, and RNA was isolated from the hippocampus. MiRNA expression was assessed with TaqMan Human MicroRNA Panel Low-Density Arrays. Ethanol significantly increased miRNA expression variance, an effect that was attenuated with choline supplementation. Cluster analysis of stably expressed miRNAs that exceeded an ANOVA p < 0.05 criterion indicated that for both male and female offspring, control and ethanol-exposed groups were most dissimilar from each other, with choline-supplemented groups in between. MiRNAs that expressed an average 2-fold change due to ethanol exposure were further analyzed to identify which ethanol-sensitive miRNAs were protected by choline supplementation. We found that at a false discovery rate (FDR)-adjusted criterion of p < 0.05, miR-200c was induced by ethanol exposure and that choline prevented this effect. Collectively, our data show that choline supplementation can normalize disturbances in miRNA expression following developmental alcohol exposure and can protect specific miRNAs from induction by

  7. Selective alteration of adult hippocampal neurogenesis and impaired spatial pattern separation performance in the RSK2-deficient mouse model of Coffin-Lowry syndrome.

    Science.gov (United States)

    Castillon, Charlotte; Lunion, Steeve; Desvignes, Nathalie; Hanauer, André; Laroche, Serge; Poirier, Roseline

    2018-07-01

    Adult neurogenesis is involved in certain hippocampus-dependent cognitive functions and is linked to psychiatric diseases including intellectual disabilities. The Coffin-Lowry syndrome (CLS) is a developmental disorder caused by mutations in the Rsk2 gene and characterized by intellectual disabilities associated with growth retardation. How RSK2-deficiency leads to cognitive dysfunctions in CLS is however poorly understood. Here, using Rsk2 Knock-Out mice, we characterized the impact of RSK2 deficiency on adult hippocampal neurogenesis in vivo. We report that the absence of RSK2 does not affect basal proliferation, differentiation and survival of dentate gyrus adult-born neurons but alters the maturation progression of young immature newborn neurons. Moreover, when RSK2-deficient mice were submitted to spatial learning, in contrast to wild-type mice, proliferation of adult generated neurons was decreased and no pro-survival effect of learning was observed. Thus, learning failed to recruit a selective population of young newborn neurons in association with deficient long-term memory recall. Given the proposed role of the dentate gyrus and of adult-generated newborn neurons in hippocampal-dependent pattern separation function, we explored this function in a delayed non-matching to place task and in an object-place pattern separation task and report severe deficits in spatial pattern separation in Rsk2-KO mice. Together, this study reveals a previously unknown role for RSK2 in the early stages of maturation and learning-dependent involvement of adult-born dentate gyrus neurons. These alterations associated with a deficit in the ability of RSK2-deficient mice to finely discriminate relatively similar spatial configurations, may contribute to cognitive dysfunction in CLS. Copyright © 2018 Elsevier Inc. All rights reserved.

  8. Hippocampal volumes are important predictors for memory function in elderly women

    Directory of Open Access Journals (Sweden)

    Adolfsdottir Steinunn

    2009-08-01

    Full Text Available Abstract Background Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOE-gene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46–77 years. Methods Brain morphometric analysis was performed with the automated segmentation work-flow implemented in FreeSurfer. Genetic analysis of the APOE genotype was determined with polymerase chain reaction (PCR on DNA from whole-blood. All individuals were subjected to extensive neuropsychological testing, including the California Verbal Learning Test-II (CVLT. To obtain robust and easily interpretable relationships between explanatory variables and verbal memory function we applied the recent method of conditional inference trees in addition to scatterplot matrices and simple pairwise linear least-squares regression analysis. Results APOE genotype had no significant impact on the CVLT results (scores on long delay free recall, CVLT-LD or the ICV-normalized hippocampal volumes. Hippocampal volumes were found to decrease with age and a right-larger-than-left hippocampal asymmetry was also found. These findings are in accordance with previous studies. CVLT-LD score was shown to correlate with hippocampal volume. Multivariate conditional inference analysis showed that gender and left hippocampal volume largely dominated predictive values for CVLT-LD scores in our sample. Left hippocampal volume dominated predictive values for females but not for males. APOE genotype did not alter the model significantly, and age was only partly influencing the results. Conclusion Gender and left hippocampal volumes are main predictors for verbal memory function in normal aging. APOE genotype did not affect the results in any part of our analysis.

  9. Choline-mediated modulation of hippocampal sharp wave-ripple complexes in vitro.

    Science.gov (United States)

    Fischer, Viktoria; Both, Martin; Draguhn, Andreas; Egorov, Alexei V

    2014-06-01

    The cholinergic system is critically involved in the modulation of cognitive functions, including learning and memory. Acetylcholine acts through muscarinic (mAChRs) and nicotinic receptors (nAChRs), which are both abundantly expressed in the hippocampus. Previous evidence indicates that choline, the precursor and degradation product of Acetylcholine, can itself activate nAChRs and thereby affects intrinsic and synaptic neuronal functions. Here, we asked whether the cellular actions of choline directly affect hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R) and can induce gamma oscillations. In addition, choline reduces synaptic transmission between hippocampal subfields CA3 and CA1. Surprisingly, these effects are mediated by activation of both mAChRs and α7-containing nAChRs. Most nicotinic effects became only apparent after local, fast application of choline, indicating rapid desensitization kinetics of nAChRs. Effects were still present following block of choline uptake and are, therefore, likely because of direct actions of choline at the respective receptors. Together, choline turns out to be a potent regulator of patterned network activity within the hippocampus. These actions may be of importance for understanding state transitions in normal and pathologically altered neuronal networks. In this study we asked whether choline, the precursor and degradation product of acetylcholine, directly affects hippocampal network activity. Using mouse hippocampal slices we found that choline efficiently suppresses spontaneously occurring sharp wave-ripple complexes (SPW-R). In addition, choline reduces synaptic transmission between hippocampal subfields. These effects are mediated by direct activation of muscarinic as well as nicotinic cholinergic pathways. Together, choline turns out to be a potent regulator of patterned activity within hippocampal

  10. Hippocampal EEG and behaviour in dog. I. Hippocampal EEG correlates of gross motor behaviour

    NARCIS (Netherlands)

    Arnolds, D.E.A.T.; Lopes da Silva, F.H.; Aitink, J.W.; Kamp, A.

    It was shown that rewarding spectral shifts (i.e. increase in amplitude or peak frequency of the hippocampal EEG) causes a solitary dog to show increased motor behaviour. Rewarded spectral shifts concurred with a variety of behavioural transitions. It was found that statistically significant

  11. Aerobic exercise increases hippocampal volume and improves memory in multiple sclerosis: preliminary findings.

    Science.gov (United States)

    Leavitt, V M; Cirnigliaro, C; Cohen, A; Farag, A; Brooks, M; Wecht, J M; Wylie, G R; Chiaravalloti, N D; DeLuca, J; Sumowski, J F

    2014-01-01

    Multiple sclerosis leads to prominent hippocampal atrophy, which is linked to memory deficits. Indeed, 50% of multiple sclerosis patients suffer memory impairment, with negative consequences for quality of life. There are currently no effective memory treatments for multiple sclerosis either pharmacological or behavioral. Aerobic exercise improves memory and promotes hippocampal neurogenesis in nonhuman animals. Here, we investigate the benefits of aerobic exercise in memory-impaired multiple sclerosis patients. Pilot data were collected from two ambulatory, memory-impaired multiple sclerosis participants randomized to non-aerobic (stretching) and aerobic (stationary cycling) conditions. The following baseline/follow-up measurements were taken: high-resolution MRI (neuroanatomical volumes), fMRI (functional connectivity), and memory assessment. Intervention was 30-minute sessions 3 times per week for 3 months. Aerobic exercise resulted in 16.5% increase in hippocampal volume and 53.7% increase in memory, as well as increased hippocampal resting-state functional connectivity. Improvements were specific, with no comparable changes in overall cerebral gray matter (+2.4%), non-hippocampal deep gray matter structures (thalamus, caudate: -4.0%), or in non-memory cognitive functioning (executive functions, processing speed, working memory: changes ranged from -11% to +4%). Non-aerobic exercise resulted in relatively no change in hippocampal volume (2.8%) or memory (0.0%), and no changes in hippocampal functional connectivity. This is the first evidence for aerobic exercise to increase hippocampal volume and connectivity and improve memory in multiple sclerosis. Aerobic exercise represents a cost-effective, widely available, natural, and self-administered treatment with no adverse side effects that may be the first effective memory treatment for multiple sclerosis patients.

  12. Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane

    Science.gov (United States)

    Ding, Xue-feng; Wu, Yan; Qu, Wen-rui; Fan, Ming; Zhao, Yong-qi

    2018-01-01

    Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation. PMID:29623929

  13. Associations between hippocampal morphometry and neuropathologic markers of Alzheimer's disease using 7 T MRI

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    Anna E. Blanken

    2017-01-01

    Full Text Available Hippocampal atrophy, amyloid plaques, and neurofibrillary tangles are established pathologic markers of Alzheimer's disease. We analyzed the temporal lobes of 9 Alzheimer's dementia (AD and 7 cognitively normal (NC subjects. Brains were scanned post-mortem at 7 Tesla. We extracted hippocampal volumes and radial distances using automated segmentation techniques. Hippocampal slices were stained for amyloid beta (Aβ, tau, and cresyl violet to evaluate neuronal counts. The hippocampal subfields, CA1, CA2, CA3, CA4, and subiculum were manually traced so that the neuronal counts, Aβ, and tau burden could be obtained for each region. We used linear regression to detect associations between hippocampal atrophy in 3D, clinical diagnosis and total as well as subfield pathology burden measures. As expected, we found significant correlations between hippocampal radial distance and mean neuronal count, as well as diagnosis. There were subfield specific associations between hippocampal radial distance and tau in CA2, and cresyl violet neuronal counts in CA1 and subiculum. These results provide further validation for the European Alzheimer's Disease Consortium Alzheimer's Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP.

  14. Stimulation of estradiol biosynthesis by tributyltin in rat hippocampal slices.

    Science.gov (United States)

    Munetsuna, Eiji; Hattori, Minoru; Yamazaki, Takeshi

    2014-01-01

    Hippocampal functions are influenced by steroid hormones, such as testosterone and estradiol. It has been demonstrated that hippocampus-derived steroid hormones play important roles in neuronal protection and synapse formation. Our research groups have demonstrated that estradiol is de novo synthesized in the rat hippocampus. However, the mechanism(s) regulating this synthesis remains unclear. It has been reported that tributyltin, an environmental pollutant, binds to the retinoid X receptor (RXR) and modifies estrogen synthesis in human granulosa-like tumor cells. This compound can penetrate the blood brain barrier, and tends to accumulate in the brain. Based on these facts, we hypothesized that tributyltin could influence the hippocampal estradiol synthesis. A concentration of 0.1 μM tributyltin induced an increase in the mRNA content of P450(17α) and P450arom in hippocampal slices, as determined using real-time PCR. The transcript levels of other steroidogenic enzymes and a steroidogenic acute regulatory protein were not affected. The estradiol level in rat hippocampal slices was subsequently determined using a radioimmunoassay. We found that the estradiol synthesis was stimulated by ∼2-fold following a 48-h treatment with 0.1 μM tributyltin, and this was accompanied by transcriptional activation of P450(17α) and P450arom. Tributyltin stimulated de novo hippocampal estradiol synthesis by modifying the transcription of specific steroidogenic enzymes.

  15. Food restriction reduces neurogenesis in the avian hippocampal formation.

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    Barbara-Anne Robertson

    Full Text Available The mammalian hippocampus is particularly vulnerable to chronic stress. Adult neurogenesis in the dentate gyrus is suppressed by chronic stress and by administration of glucocorticoid hormones. Post-natal and adult neurogenesis are present in the avian hippocampal formation as well, but much less is known about its sensitivity to chronic stressors. In this study, we investigate this question in a commercial bird model: the broiler breeder chicken. Commercial broiler breeders are food restricted during development to manipulate their growth curve and to avoid negative health outcomes, including obesity and poor reproductive performance. Beyond knowing that these chickens are healthier than fully-fed birds and that they have a high motivation to eat, little is known about how food restriction impacts the animals' physiology. Chickens were kept on a commercial food-restricted diet during the first 12 weeks of life, or released from this restriction by feeding them ad libitum from weeks 7-12 of life. To test the hypothesis that chronic food restriction decreases the production of new neurons (neurogenesis in the hippocampal formation, the cell proliferation marker bromodeoxyuridine was injected one week prior to tissue collection. Corticosterone levels in blood plasma were elevated during food restriction, even though molecular markers of hypothalamic-pituitary-adrenal axis activation did not differ between the treatments. The density of new hippocampal neurons was significantly reduced in the food-restricted condition, as compared to chickens fed ad libitum, similar to findings in rats at a similar developmental stage. Food restriction did not affect hippocampal volume or the total number of neurons. These findings indicate that in birds, like in mammals, reduction in hippocampal neurogenesis is associated with chronically elevated corticosterone levels, and therefore potentially with chronic stress in general. This finding is consistent with the

  16. Combined effects of marijuana and nicotine on memory performance and hippocampal volume.

    Science.gov (United States)

    Filbey, Francesca M; McQueeny, Tim; Kadamangudi, Shrinath; Bice, Collette; Ketcherside, Ariel

    2015-10-15

    Combined use of marijuana (MJ) and tobacco is highly prevalent in today's population. Individual use of either substance is linked to structural brain changes and altered cognitive function, especially with consistent reports of hippocampal volume deficits and poorer memory performance. However, the combined effects of MJ and tobacco on hippocampal structure and on learning and memory processes remain unknown. In this study, we examined both the individual and combined effects of MJ and tobacco on hippocampal volumes and memory performance in four groups of adults taken from two larger studies: MJ-only users (n=36), nicotine-only (Nic-only, n=19), combined marijuana and nicotine users (MJ+Nic, n=19) and non-using healthy controls (n=16). Total bilateral hippocampal volumes and memory performance (WMS-III logical memory) were compared across groups controlling for total brain size and recent alcohol use. Results found MJ and MJ+Nic groups had smaller total hippocampal volumes compared to Nic-only and controls. No significant difference between groups was found between immediate and delayed story recall. However, the controls showed a trend for larger hippocampal volumes being associated with better memory scores, while MJ+Nic users showed a unique inversion, whereby smaller hippocampal volume was associated with better memory. Overall, results suggest abnormalities in the brain-behavior relationships underlying memory processes with combined use of marijuana and nicotine use. Further research will need to address these complex interactions between MJ and nicotine. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

  17. Peripheral Etanercept Administration Normalizes Behavior, Hippocampal Neurogenesis, and Hippocampal Reelin and GABAA Receptor Expression in a Preclinical Model of Depression

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    Kyle J. Brymer

    2018-02-01

    Full Text Available Depression is a serious psychiatric disorder frequently comorbid with autoimmune disorders. Previous work in our lab has demonstrated that repeated corticosterone (CORT injections in rats reliably increase depressive-like behavior, impair hippocampal-dependent memory, reduce the number and complexity of adult-generated neurons in the dentate gyrus, decrease hippocampal reelin expression, and alter markers of GABAergic function. We hypothesized that peripheral injections of the TNF-α inhibitor etanercept could exert antidepressant effects through a restoration of many of these neurobiological changes. To test this hypothesis, we examined the effect of repeated CORT injections and concurrent injections of etanercept on measures of object-location and object-in-place memory, forced-swim test behavior, hippocampal neurogenesis, and reelin and GABA β2/3 immunohistochemistry. CORT increased immobility behavior in the forced swim test and impaired both object-location and object-in-place memory, and these effects were reversed by etanercept. CORT also decreased both the number and complexity of adult-generated neurons, but etanercept restored these measures back to control levels. Finally, CORT decreased the number of reelin and GABA β2/3-ir cells within the subgranular zone of the dentate gyrus, and etanercept restored these to control levels. These novel results demonstrate that peripheral etanercept has antidepressant effects that are accompanied by a restoration of cognitive function, hippocampal neurogenesis, and GABAergic plasticity, and suggest that a normalization of reelin expression in the dentate gyrus could be a key component underlying these novel antidepressant effects.

  18. Docosahexaenoic (DHA modulates phospholipid-hydroperoxide glutathione peroxidase (Gpx4 gene expression to ensure self-protection from oxidative damage in hippocampal cells

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    Veronica eCasañas-Sanchez

    2015-07-01

    Full Text Available Docosahexaenoic acid (DHA, 22:6n-3 is a unique polyunsaturated fatty acid particularly abundant in nerve cell membrane phospholipids. DHA is a pleiotropic molecule that, not only modulates the physicochemical properties and architecture of neuronal plasma membrane, but it is also involved in multiple facets of neuronal biology, from regulation of synaptic function to neuroprotection and modulation of gene expression. As a highly unsaturated fatty acid due to the presence of six double bonds, DHA is susceptible for oxidation, especially in the highly pro-oxidant environment of brain parenchyma. We have recently reported the ability of DHA to regulate the transcriptional program controlling neuronal antioxidant defenses in a hippocampal cell line, especially the glutathione/glutaredoxin system. Within this antioxidant system, DHA was particularly efficient in triggering the upregulation of Gpx4 gene, which encodes for the nuclear, cytosolic and mitochondrial isoforms of phospholipid-hydroperoxide glutathione peroxidase (PH-GPx/GPx4, the main enzyme protecting cell membranes against lipid peroxidation and capable to reduce oxidized phospholipids in situ. We show here that this novel property of DHA is also significant in the hippocampus of wild-type mice and APP/PS1 transgenic mice, a familial model of Alzheimer’s disease. By doing this, DHA stimulates a mechanism to self-protect from oxidative damage even in the neuronal scenario of high aerobic metabolism and in the presence of elevated levels of transition metals, which inevitably favor the generation of reactive oxygen species. Noticeably, DHA also upregulated a novel Gpx4 splicing variant, harboring part of the first intronic region, which according to the ‘sentinel RNA hypothesis’ would expand the ability of Gpx4 (and DHA to provide neuronal antioxidant defense independently of conventional nuclear splicing in cellular compartments, like dendritic zones, located away from nuclear

  19. Into the future with little past: exploring mental time travel in a patient with damage to the mammillary bodies/fornix.

    Science.gov (United States)

    Tedder, Jacqui; Miller, Laurie; Tu, Sicong; Hornberger, Michael; Lah, Suncica

    2016-02-01

    Remembering the past and imaging the future are both manifestations of 'mental time travel'. These processes have been found to be impaired in patients with bilateral hippocampal lesions. Here, we examined the question of whether future thinking is affected by other Papez circuit lesions, namely: damage to the mammillary bodies/fornix. Case (SL) was a 43-year-old woman who developed dense anterograde and retrograde amnesia suddenly, as a result of Wernicke-Korsakoff's syndrome. A region of interest volumetric Magnetic resonance imaging (MRI) analysis was performed. We assessed past and future thinking in SL and 11 control subjects of similar age and education with the adapted Autobiographical Interview (AI). Participants also completed a battery of neuropsychological tests. Volumetric MRI analyses revealed severely reduced fornix and mammillary body volumes, but intact hippocampi. SL showed substantial, albeit temporally graded retrograde memory deficits on the adapted AI. Strikingly, whilst SL could not provide any specific details of events from the past two weeks or past two years and had impaired recall of events from her late 30s, her descriptions of potential future events were normal in number of event details and plausibility. This dissociation of past and future events' performance after mammillary body and fornix damage is at odds with the findings of the majority of patients with adult onset hippocampal amnesia. It suggests that these non-hippocampal regions of the Papez circuit are only critical for past event retrieval and not for the generation of possible future events.

  20. Changes in Hippocampal Volume are Correlated with Cell Loss but Not with Seizure Frequency in Two Chronic Models of Temporal Lobe Epilepsy

    Science.gov (United States)

    Polli, Roberson S.; Malheiros, Jackeline M.; dos Santos, Renan; Hamani, Clement; Longo, Beatriz M.; Tannús, Alberto; Mello, Luiz E.; Covolan, Luciene

    2014-01-01

    Kainic acid (KA) or pilocarpine (PILO) have been used in rats to model human temporal lobe epilepsy (TLE) but the distribution and severity of structural lesions between these two models may differ. Magnetic resonance imaging (MRI) studies have used quantitative measurements of hippocampal T2 (T2HP) relaxation time and volume, but simultaneous comparative results have not been reported yet. The aim of this study was to compare the MRI T2HP and volume with histological data and frequency of seizures in both models. KA- and PILO-treated rats were imaged with a 2 T MRI scanner. T2HP and volume values were correlated with the number of cells, mossy fiber sprouting, and spontaneous recurrent seizures (SRS) frequency over the 9 months following status epilepticus (SE). Compared to controls, KA-treated rats had unaltered T2HP, pronounced reduction in hippocampal volume and concomitant cell reduction in granule cell layer, CA1 and CA3 at 3 months post SE. In contrast, hippocampal volume was unchanged in PILO-treated animals despite detectable increased T2HP and cell loss in granule cell layer, CA1 and CA3. In the following 6 months, MRI hippocampal volume remained stable with increase of T2HP signal in the KA-treated group. The number of CA1 and CA3 cells was smaller than age-matched CTL group. In contrast, PILO group had MRI volumetric reduction accompanied by reduction in the number of CA1 and CA3 cells. In this group, T2HP signal was unaltered at 6 or 9 months after status. Reductions in the number of cells were not progressive in both models. Notably, the SRS frequency was higher in PILO than in the KA model. The volumetry data correlated well with tissue damage in the epileptic brain, suggesting that MRI may be useful for tracking longitudinal hippocampal changes, allowing the assessment of individual variability and disease progression. Our results indicate that the temporal changes in hippocampal morphology are distinct for both models of TLE and that

  1. Fluoxetine Increases Hippocampal Neurogenesis and Induces Epigenetic Factors But Does Not Improve Functional Recovery after Traumatic Brain Injury

    Science.gov (United States)

    Wang, Yonggang; Neumann, Melanie; Hansen, Katharina; Hong, Shuwhey M.; Kim, Sharon; Noble-Haeusslein, Linda J.

    2011-01-01

    Abstract The selective serotonin reuptake inhibitor fluoxetine induces hippocampal neurogenesis, stimulates maturation and synaptic plasticity of adult hippocampal neurons, and reduces motor/sensory and memory impairments in several CNS disorders. In the setting of traumatic brain injury (TBI), its effects on neuroplasticity and function have yet to be thoroughly investigated. Here we examined the efficacy of fluoxetine after a moderate to severe TBI, produced by a controlled cortical impact. Three days after TBI or sham surgery, mice were treated with fluoxetine (10 mg/kg/d) or vehicle for 4 weeks. To evaluate the effects of fluoxetine on neuroplasticity, hippocampal neurogenesis and epigenetic modification were studied. Stereologic analysis of the dentate gyrus revealed a significant increase in doublecortin-positive cells in brain-injured animals treated with fluoxetine relative to controls, a finding consistent with enhanced hippocampal neurogenesis. Epigenetic modifications, including an increase in histone 3 acetylation and induction of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, were likewise seen by immunohistochemistry and quantitative Western immunoblots, respectively, in brain-injured animals treated with fluoxetine. To determine if fluoxetine improves neurological outcomes after TBI, gait function and spatial learning and memory were assessed by the CatWalk-assisted gait test and Barnes maze test, respectively. No differences in these parameters were seen between fluoxetine- and vehicle-treated animals. Thus while fluoxetine enhanced neuroplasticity in the hippocampus after TBI, its chronic administration did not restore locomotor function or ameliorate memory deficits. PMID:21175261

  2. Hippocampal disconnection in early Alzheimer's disease: a 7 tesla MRI study

    NARCIS (Netherlands)

    Wisse, L.E.; Reijmer, Y.D.; Telgte, A. ter; Kuijf, H.J.; Leemans, A.; Luijten, P.R.; Koek, H.L.; Geerlings, M.I.; Biessels, G.J.

    2015-01-01

    BACKGROUND: In patients with Alzheimer's disease (AD), atrophy of the entorhinal cortex (ERC) and hippocampal formation may induce degeneration of connecting white matter tracts. OBJECTIVE: We examined the association of hippocampal subfield and ERC atrophy at 7 tesla MRI with fornix and

  3. Intermediate levels of hippocampal activity appear optimal for associative memory formation.

    NARCIS (Netherlands)

    Liu, X.; Qin, S.; Rijpkema, M.J.P.; Luo, J.; Fernandez, G.S.E.

    2010-01-01

    BACKGROUND: It is well established that hippocampal activity is positively related to effective associative memory formation. However, in biological systems often optimal levels of activity are contrasted by both sub- and supra-optimal levels. Sub-optimal levels of hippocampal activity are commonly

  4. Hippocampal volume measurement in patients with Meniere's disease : a pilot study

    NARCIS (Netherlands)

    van Cruijsen, Nynke; Hiemstra, Wilma M.; Meiners, Linda C.; Wit, Hero P.; Albers, Frans W. J.

    2007-01-01

    Conclusion. No signs of chronic stress as in hippocampal atrophy were present in patients with Meniere's disease. Objective. To evaluate the effect of chronic stress (allostatic load) by measuring hippocampal volume in patients with Meniere's disease. Subjects and methods. Ten patients with

  5. Erythropoietin enhances hippocampal response during memory retrieval in humans

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla; O'Sullivan, Ursula; Harmer, Catherine J

    2007-01-01

    Although erythropoietin (Epo) is best known for its effects on erythropoiesis, recent evidence suggests that it also has neurotrophic and neuroprotective properties in animal models of hippocampal function. Such an action in humans would make it an intriguing novel compound for the treatment....... This is consistent with upregulation of hippocampal BDNF and neurotrophic actions found in animals and highlights Epo as a promising candidate for treatment of psychiatric disorders....

  6. The correlation of serum S100β protein levels and hippocampal Seladin-1 gene expression in a rat model of sporadic Alzheimer\\\\\\'s disease

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    Soheila Hosseinzadeh

    2015-11-01

    Full Text Available Background: Seladin-1 protein protects the neural cells against amyloid beta toxicity and its expression decreased in vulnerable regions of Alzheimer's disease (AD brains. On the other hand, changes in serum levels of S100 have been considered as a marker of brain damage in neurodegenerative diseases. Furthermore, this study was carried out to determine the relation between the change profile of serum S100β protein levels and hippocampal Seladin-1 gene expression in a rat model of sporadic AD. Methods: In this experimental study that established in Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Science, from March 2011 to April 2013, 72 animals were randomly divided into control, 4, 7, 14, and 21days ICV-STZ/Saline administrated rats. Alzheimer's model was induced by intracerebroventricular (ICV injections of streptozotocin (STZ [3 mg/kg] on days 1 and 3. Serum levels of S100β and hippocampal Seladin-1 gene expression were evalu-ated in experimental groups. The initial and step-through latencies (STL were deter-mined using passive avoidance test. Results: Serum levels of S100β were significantly different between the STZ-7 day and STZ-14 day groups in comparison with the control, saline and STZ-4 day groups. As well as, there was a significant difference between the STZ-7 day group in comparison with the STZ-14 day and STZ-21 day groups (P=0.0001. Hippocampal Seladin-1 gene expression in STZ-14 day and STZ-21 day groups significantly decreased as compared to the control, saline and STZ-4 day groups (P=0.0001. However, significant correla-tion was detected between serum S100β protein decrement and Seladin-1 down regula-tion (P=0.001. Also, the STL was significantly decreased in 21 days ICV-STZ adminis-trated rats as compared to the control or saline groups (P=0.001. Conclusion: Monitoring the changes of serum S100β protein levels by relationship with changes in hippocampal Seladin-1

  7. High postnatal susceptibility of hippocampal cytoskeleton in response to ethanol exposure during pregnancy and lactation.

    Science.gov (United States)

    Reis, Karina Pires; Heimfarth, Luana; Pierozan, Paula; Ferreira, Fernanda; Loureiro, Samanta Oliveira; Fernandes, Carolina Gonçalves; Carvalho, Rônan Vivian; Pessoa-Pureur, Regina

    2015-11-01

    Ethanol exposure to offspring during pregnancy and lactation leads to developmental disorders, including central nervous system dysfunction. In the present work, we have studied the effect of chronic ethanol exposure during pregnancy and lactation on the phosphorylating system associated with the astrocytic and neuronal intermediate filament (IF) proteins: glial fibrillary acidic protein (GFAP), and neurofilament (NF) subunits of low, medium, and high molecular weight (NFL, NFM, and NFH, respectively) in 9- and 21-day-old pups. Female rats were fed with 20% ethanol in their drinking water during pregnancy and lactation. The homeostasis of the IF phosphorylation was not altered in the cerebral cortex, cerebellum, or hippocampus of 9-day-old pups. However, GFAP, NFL, and NFM were hyperphosphorylated in the hippocampus of 21-day-old pups. PKA had been activated in the hippocampus, and Ser55 in the N-terminal region of NFL was hyperphosphorylated. In addition, JNK/MAPK was activated and KSP repeats in the C-terminal region of NFM were hyperphosphorylated in the hippocampus of 21-day-old pups. Decreased NFH immunocontent but an unaltered total NFH/phosphoNFH ratio suggested altered stoichiometry of NFs in the hippocampus of ethanol-exposed 21-day-old pups. In contrast to the high susceptibility of hippocampal cytoskeleton in developing rats, the homeostasis of the cytoskeleton of ethanol-fed adult females was not altered. Disruption of the cytoskeletal homeostasis in neural cells supports the view that regions of the brain are differentially vulnerable to alcohol insult during pregnancy and lactation, suggesting that modulation of JNK/MAPK and PKA signaling cascades target the hippocampal cytoskeleton in a window of vulnerability in 21-day-old pups. Our findings are relevant, since disruption of the cytoskeleton in immature hippocampus could contribute to later hippocampal damage associated with ethanol toxicity. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Hippocampal dentation: Structural variation and its association with episodic memory in healthy adults.

    Science.gov (United States)

    Fleming Beattie, Julia; Martin, Roy C; Kana, Rajesh K; Deshpande, Hrishikesh; Lee, Seongtaek; Curé, Joel; Ver Hoef, Lawrence

    2017-07-01

    While the hippocampus has long been identified as a structure integral to memory, the relationship between morphology and function has yet to be fully explained. We present an analysis of hippocampal dentation, a morphological feature previously unexplored in regard to its relationship with episodic memory. "Hippocampal dentation" in this case refers to surface convolutions, primarily present in the CA1/subiculum on the inferior aspect of the hippocampus. Hippocampal dentation was visualized using ultra-high resolution structural MRI and evaluated using a novel visual rating scale. The degree of hippocampal dentation was found to vary considerably across individuals, and was positively associated with verbal memory recall and visual memory recognition in a sample of 22 healthy adults. This study is the first to characterize the variation in hippocampal dentation in a healthy cohort and to demonstrate its association with aspects of episodic memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Neuropsychology, autobiographical memory and hippocampal volume in younger and older patients with chronic schizophrenia

    Directory of Open Access Journals (Sweden)

    Christina Josefa Herold

    2015-04-01

    Full Text Available Despite a wide range of studies on neuropsychology in schizophrenia, autobiographical memory (AM has been scarcely investigated in these patients. Hence less is known about AM in older patients and hippocampal contribution to autobiographical memories of varying remoteness. Therefore we investigated hippocampal volume and AM along with important neuropsychological domains in patients with chronic schizophrenia and the respective relationships between these parameters. We compared 25 older patients with chronic schizophrenia to 23 younger patients and an older healthy control group (N = 21 with respect to AM, additional neuropsychological parameters and hippocampal volume. Personal episodic and semantic memory was investigated using a semi-structured interview. Additional neuropsychological parameters were assessed by using a battery of standard neuropsychological tests. Structural magnetic resonance imaging data were analysed with an automated region-of-interest procedure. While hippocampal volume reduction and neuropsychological impairment were more pronounced in the older than in the younger patients, both groups showed equivalent reduced AM performance for recent personal episodes. In the patient group significant correlations between left hippocampal volume and recent autobiographical episodes as well as personal semantic memories arose. Verbal memory and working memory were significantly correlated with right hippocampal volume, executive functions, however, were associated with bilateral hippocampal volumes. These findings underline the complexity of AM and its impairments in the course of schizophrenia in comparison to rather progressive neuropsychological deficits and address the importance of hippocampal contribution.

  10. Neuropsychology, autobiographical memory, and hippocampal volume in "younger" and "older" patients with chronic schizophrenia.

    Science.gov (United States)

    Herold, Christina Josefa; Lässer, Marc Montgomery; Schmid, Lena Anna; Seidl, Ulrich; Kong, Li; Fellhauer, Iven; Thomann, Philipp Arthur; Essig, Marco; Schröder, Johannes

    2015-01-01

    Despite a wide range of studies on neuropsychology in schizophrenia, autobiographical memory (AM) has been scarcely investigated in these patients. Hence, less is known about AM in older patients and hippocampal contribution to autobiographical memories of varying remoteness. Therefore, we investigated hippocampal volume and AM along with important neuropsychological domains in patients with chronic schizophrenia and the respective relationships between these parameters. We compared 25 older patients with chronic schizophrenia to 23 younger patients and an older healthy control group (N = 21) with respect to AM, additional neuropsychological parameters, and hippocampal volume. Personal episodic and semantic memory was investigated using a semi-structured interview. Additional neuropsychological parameters were assessed by using a battery of standard neuropsychological tests. Structural magnetic resonance imaging data were analyzed with an automated region-of-interest procedure. While hippocampal volume reduction and neuropsychological impairment were more pronounced in the older than in the younger patients, both groups showed equivalent reduced AM performance for recent personal episodes. In the patient group, significant correlations between left hippocampal volume and recent autobiographical episodes as well as personal semantic memories arose. Verbal memory and working memory were significantly correlated with right hippocampal volume; executive functions, however, were associated with bilateral hippocampal volumes. These findings underline the complexity of AM and its impairments in the course of schizophrenia in comparison to rather progressive neuropsychological deficits and address the importance of hippocampal contribution.

  11. Imbalance of incidental encoding across tasks: an explanation for non-memory-related hippocampal activations?

    Science.gov (United States)

    Reas, Emilie T; Brewer, James B

    2013-11-01

    Functional neuroimaging studies have increasingly noted hippocampal activation associated with a variety of cognitive functions--such as decision making, attention, perception, incidental learning, prediction, and working memory--that have little apparent relation to declarative memory. Such findings might be difficult to reconcile with classical hippocampal lesion studies that show remarkable sparing of cognitive functions outside the realm of declarative memory. Even the oft-reported hippocampal activations during confident episodic retrieval are not entirely congruent with evidence that hippocampal lesions reliably impair encoding but inconsistently affect retrieval. Here we explore the conditions under which the hippocampus responds during episodic recall and recognition. Our findings suggest that anterior hippocampal activity may be related to the imbalance of incidental encoding across tasks and conditions rather than due to retrieval per se. Incidental encoding and hippocampal activity may be reduced during conditions where retrieval requires greater attentional engagement. During retrieval, anterior hippocampal activity decreases with increasing search duration and retrieval effort, and this deactivation corresponds with a coincident impaired encoding of the external environment (Israel, Seibert, Black, & Brewer, 2010; Reas & Brewer, 2013; Reas, Gimbel, Hales, & Brewer, 2011). In light of this emerging evidence, we discuss the proposal that some hippocampal activity observed during memory retrieval, or other non-memory conditions, may in fact be attributable to concomitant encoding activity that is regulated by the attentional demands of the principal task. PsycINFO Database Record (c) 2013 APA, all rights reserved.

  12. Comparison of the force exerted by hippocampal and DRG growth cones.

    Science.gov (United States)

    Amin, Ladan; Ercolini, Erika; Ban, Jelena; Torre, Vincent

    2013-01-01

    Mechanical properties such as force generation are fundamental for neuronal motility, development and regeneration. We used optical tweezers to compare the force exerted by growth cones (GCs) of neurons from the Peripheral Nervous System (PNS), such as Dorsal Root Ganglia (DRG) neurons, and from the Central Nervous System (CNS) such as hippocampal neurons. Developing GCs from dissociated DRG and hippocampal neurons were obtained from P1-P2 and P10-P12 rats. Comparing their morphology, we observed that the area of GCs of hippocampal neurons was 8-10 µm(2) and did not vary between P1-P2 and P10-P12 rats, but GCs of DRG neurons were larger and their area increased from P1-P2 to P10-P12 by 2-4 times. The force exerted by DRG filopodia was in the order of 1-2 pN and never exceeded 5 pN, while hippocampal filopodia exerted a larger force, often in the order of 5 pN. Hippocampal and DRG lamellipodia exerted lateral forces up to 20 pN, but lamellipodia of DRG neurons could exert a vertical force larger than that of hippocampal neurons. Force-velocity relationships (Fv) in both types of neurons had the same qualitative behaviour, consistent with a common autocatalytic model of force generation. These results indicate that molecular mechanisms of force generation of GC from CNS and PNS neurons are similar but the amplitude of generated force is influenced by their cytoskeletal properties.

  13. A mathematical model of aging-related and cortisol induced hippocampal dysfunction

    Directory of Open Access Journals (Sweden)

    Jones Janette JL

    2009-03-01

    Full Text Available Abstract Background The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD, the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML. We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated. Results The in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA, increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation. Conclusion Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people.

  14. Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Katrina, E-mail: Trinabena23@gmail.com; Lenards, Nishele; Holson, Janice

    2016-04-01

    The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient's neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to the hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient's data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain.

  15. Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study

    International Nuclear Information System (INIS)

    Lee, Katrina; Lenards, Nishele; Holson, Janice

    2016-01-01

    The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient's neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to the hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient's data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain.

  16. Low-intensity daily walking activity is associated with hippocampal volume in older adults.

    Science.gov (United States)

    Varma, Vijay R; Chuang, Yi-Fang; Harris, Gregory C; Tan, Erwin J; Carlson, Michelle C

    2015-05-01

    Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low-intensity walking activity, which may be related to leisure-time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher-intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low-intensity walking activity, independent of moderate- to vigorous-intensity activity and self-reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings

  17. Hippocampal Abnormalities and Seizure Recurrence

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-08-01

    Full Text Available Hippocampal volumetry and T2 relaxometry were performed on 84 consecutive patients (adolescents and adults with partial epilepsy submitted to antiepileptic drug (AED withdrawal after at least 2 years of seizure control, in a study at State University of Campinas-UNICAMP, Brazil.

  18. Hippocampal Functioning and Verbal Associative Memory in Adolescents with Congenital Hypothyroidism

    Directory of Open Access Journals (Sweden)

    Sarah Marie Wheeler

    2015-10-01

    Full Text Available Thyroid hormone (TH is essential for normal development of the hippocampus, which is critical for memory and particularly for learning and recalling associations between visual and verbal stimuli. Adolescents with congenital hypothyroidism (CH, who lack TH in late gestation and early life, demonstrate weak verbal recall abilities, reduced hippocampal volumes, and abnormal hippocampal functioning for visually associated material. However, it is not known if their hippocampus functions abnormally when remembering verbal associations. Our objective was to assess hippocampal functioning in CH using functional magnetic resonance imaging (fMRI. Fourteen adolescents with CH and 14 typically developing controls (TDC were studied. Participants studied pairs of words and then, during fMRI acquisition, made two types of recognition decisions: in one they judged whether the pairs were the same as when seen originally and in the other, whether individual words were seen before regardless of pairing. Hippocampal activation was greater for pairs than items in both groups, but this difference was only significant in TDC. When we directly compared the groups, the right anterior hippocampus was the primary region in which the TDC and CH groups differed for this pair memory effect. Results signify that adolescents with CH show abnormal hippocampal functioning during verbal memory processing.

  19. Hippocampal sparing radiotherapy for pediatric medulloblastoma: impact of treatment margins and treatment technique.

    Science.gov (United States)

    Brodin, N Patrik; Munck af Rosenschöld, Per; Blomstrand, Malin; Kiil-Berthlesen, Anne; Hollensen, Christian; Vogelius, Ivan R; Lannering, Birgitta; Bentzen, Søren M; Björk-Eriksson, Thomas

    2014-04-01

    We investigated how varying the treatment margin and applying hippocampal sparing and proton therapy impact the risk of neurocognitive impairment in pediatric medulloblastoma patients compared with current standard 3D conformal radiotherapy. We included 17 pediatric medulloblastoma patients to represent the variability in tumor location relative to the hippocampal region. Treatment plans were generated using 3D conformal radiotherapy, hippocampal sparing intensity-modulated radiotherapy, and spot-scanned proton therapy, using 3 different treatment margins for the conformal tumor boost. Neurocognitive impairment risk was estimated based on dose-response models from pediatric CNS malignancy survivors and compared among different margins and treatment techniques. Mean hippocampal dose and corresponding risk of cognitive impairment were decreased with decreasing treatment margins (P < .05). The largest risk reduction, however, was seen when applying hippocampal sparing proton therapy-the estimated risk of impaired task efficiency (95% confidence interval) was 92% (66%-98%), 81% (51%-95%), and 50% (30%-70%) for 3D conformal radiotherapy, intensity-modulated radiotherapy, and proton therapy, respectively, for the smallest boost margin and 98% (78%-100%), 90% (60%-98%), and 70% (39%-90%) if boosting the whole posterior fossa. Also, the distance between the closest point of the planning target volume and the center of the hippocampus can be used to predict mean hippocampal dose for a given treatment technique. We estimate a considerable clinical benefit of hippocampal sparing radiotherapy. In choosing treatment margins, the tradeoff between margin size and risk of neurocognitive impairment quantified here should be considered.

  20. Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

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    Shan Liu

    2014-01-01

    Full Text Available Tumor necrosis factor-α (TNF-α is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  1. Microglia modulate hippocampal neural precursor activity in response to exercise and aging.

    Science.gov (United States)

    Vukovic, Jana; Colditz, Michael J; Blackmore, Daniel G; Ruitenberg, Marc J; Bartlett, Perry F

    2012-05-09

    Exercise has been shown to positively augment adult hippocampal neurogenesis; however, the cellular and molecular pathways mediating this effect remain largely unknown. Previous studies have suggested that microglia may have the ability to differentially instruct neurogenesis in the adult brain. Here, we used transgenic Csf1r-GFP mice to investigate whether hippocampal microglia directly influence the activation of neural precursor cells. Our results revealed that an exercise-induced increase in neural precursor cell activity was mediated via endogenous microglia and abolished when these cells were selectively removed from hippocampal cultures. Conversely, microglia from the hippocampi of animals that had exercised were able to activate latent neural precursor cells when added to neurosphere preparations from sedentary mice. We also investigated the role of CX(3)CL1, a chemokine that is known to provide a more neuroprotective microglial phenotype. Intraparenchymal infusion of a blocking antibody against the CX(3)CL1 receptor, CX(3)CR1, but not control IgG, dramatically reduced the neurosphere formation frequency in mice that had exercised. While an increase in soluble CX(3)CL1 was observed following running, reduced levels of this chemokine were found in the aged brain. Lower levels of CX(3)CL1 with advancing age correlated with the natural decline in neural precursor cell activity, a state that could be partially alleviated through removal of microglia. These findings provide the first direct evidence that endogenous microglia can exert a dual and opposing influence on neural precursor cell activity within the hippocampus, and that signaling through the CX(3)CL1-CX(3)CR1 axis critically contributes toward this process.

  2. Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition.

    Science.gov (United States)

    Basu, Jayeeta; Zaremba, Jeffrey D; Cheung, Stephanie K; Hitti, Frederick L; Zemelman, Boris V; Losonczy, Attila; Siegelbaum, Steven A

    2016-01-08

    The cortico-hippocampal circuit is critical for storage of associational memories. Most studies have focused on the role in memory storage of the excitatory projections from entorhinal cortex to hippocampus. However, entorhinal cortex also sends inhibitory projections, whose role in memory storage and cortico-hippocampal activity remains largely unexplored. We found that these long-range inhibitory projections enhance the specificity of contextual and object memory encoding. At the circuit level, these γ-aminobutyric acid (GABA)-releasing projections target hippocampal inhibitory neurons and thus act as a disinhibitory gate that transiently promotes the excitation of hippocampal CA1 pyramidal neurons by suppressing feedforward inhibition. This enhances the ability of CA1 pyramidal neurons to fire synaptically evoked dendritic spikes and to generate a temporally precise form of heterosynaptic plasticity. Long-range inhibition from entorhinal cortex may thus increase the precision of hippocampal-based long-term memory associations by assessing the salience of mnemonormation to the immediate sensory input. Copyright © 2016, American Association for the Advancement of Science.

  3. Effects of Early-Life Adversity on Hippocampal Structures and Associated HPA Axis Functions.

    Science.gov (United States)

    Dahmen, Brigitte; Puetz, Vanessa B; Scharke, Wolfgang; von Polier, Georg G; Herpertz-Dahlmann, Beate; Konrad, Kerstin

    2018-01-01

    Early-life adversity (ELA) is one of the major risk factors for serious mental and physical health risks later in life. ELA has been associated with dysfunctional neurodevelopment, especially in brain structures such as the hippocampus, and with dysfunction of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis. Children who have experienced ELA are also more likely to suffer from mental health disorders such as depression later in life. The exact interplay of aberrant neurodevelopment and HPA axis dysfunction as risks for psychopathology is not yet clear. We investigated volume differences in the bilateral hippocampus and in stress-sensitive hippocampal subfields, behavior problems, and diurnal cortisol activity in 24 children who had experienced documented ELA (including out-of-home placement) in a circumscribed duration of adversity only in their first 3 years of life in comparison to data on 25 control children raised by their biological parents. Hippocampal volumes and stress-sensitive hippocampal subfields (Cornu ammonis [CA]1, CA3, and the granule-cell layer of the dentate gyrus [GCL-DG]) were significantly smaller in children who had experienced ELA, taking psychiatric diagnoses and dimensional psychopathological symptoms into account. ELA moderated the relationship between left hippocampal volume and cortisol: in the control group, hippocampal volumes were not related to diurnal cortisol, while in ELA children, a positive linear relationship between left hippocampal volume and diurnal cortisol was present. Our findings show that ELA is associated with altered development of the hippocampus, and an altered relationship between hippocampal volume and HPA axis activity in youth in care, even after they have lived in stable and caring foster family environments for years. Altered hippocampal development after ELA could thus be associated with a risk phenotype for the development of psychiatric disorders later in life. © 2017 S. Karger

  4. Tat-antioxidant 1 protects against stress-induced hippocampal HT-22 cells death and attenuate ischaemic insult in animal model.

    Science.gov (United States)

    Kim, So Mi; Hwang, In Koo; Yoo, Dae Young; Eum, Won Sik; Kim, Dae Won; Shin, Min Jea; Ahn, Eun Hee; Jo, Hyo Sang; Ryu, Eun Ji; Yong, Ji In; Cho, Sung-Woo; Kwon, Oh-Shin; Lee, Keun Wook; Cho, Yoon Shin; Han, Kyu Hyung; Park, Jinseu; Choi, Soo Young

    2015-06-01

    Oxidative stress-induced reactive oxygen species (ROS) are responsible for various neuronal diseases. Antioxidant 1 (Atox1) regulates copper homoeostasis and promotes cellular antioxidant defence against toxins generated by ROS. The roles of Atox1 protein in ischaemia, however, remain unclear. In this study, we generated a protein transduction domain fused Tat-Atox1 and examined the roles of Tat-Atox1 in oxidative stress-induced hippocampal HT-22 cell death and an ischaemic injury animal model. Tat-Atox1 effectively transduced into HT-22 cells and it protected cells against the effects of hydrogen peroxide (H2O2)-induced toxicity including increasing of ROS levels and DNA fragmentation. At the same time, Tat-Atox1 regulated cellular survival signalling such as p53, Bad/Bcl-2, Akt and mitogen-activate protein kinases (MAPKs). In the animal ischaemia model, transduced Tat-Atox1 protected against neuronal cell death in the hippocampal CA1 region. In addition, Tat-Atox1 significantly decreased the activation of astrocytes and microglia as well as lipid peroxidation in the CA1 region after ischaemic insult. Taken together, these results indicate that transduced Tat-Atox1 protects against oxidative stress-induced HT-22 cell death and against neuronal damage in animal ischaemia model. Therefore, we suggest that Tat-Atox1 has potential as a therapeutic agent for the treatment of oxidative stress-induced ischaemic damage. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  5. Kainate toxicity in energy-compromised rat hippocampal slices: differences between oxygen and glucose deprivation.

    Science.gov (United States)

    Schurr, A; Rigor, B M

    1993-06-18

    The effects of kainate (KA) on the recovery of neuronal function in rat hippocampal slices after hypoxia or glucose deprivation (GD) were investigated and compared to those of (R,S)-alpha-amino-3-hydroxy-5-methyl-4- isoxazoleproprionate (AMPA). KA and AMPA were found to be more toxic than either N-methyl-D-aspartate (NMDA), quinolinate, or glutamate, both under normal conditions and under states of energy deprivation. Doses as low as 1 microM KA or AMPA were sufficient to significantly reduce the recovery rate of neuronal function in slices after a standardized period of hypoxia or GD. The enhancement of hypoxic neuronal damage by both agonists could be partially blocked by the antagonist kynurenate, by the NMDA competitive antagonist AP5, and by elevating [Mg2+] in or by omitting Ca2+ from the perfusion medium. The AMPA antagonist glutamic acid diethyl ester was ineffective in preventing the enhanced hypoxic neuronal damage by either KA or AMPA. The antagonist of the glycine modulatory site on the NMDA receptor, 7-chlorokynurenate, did not block the KA toxicity but was able to block the toxicity of AMPA. 2,3-Dihydroxyquinoxaline completely blocked the KA- and AMPA-enhanced hypoxic neuronal damage. The KA-enhanced, GD-induced neuronal damage was prevented by Ca2+ depletion and partially antagonized by kynurenate but not by AP5 or elevated [Mg2+]. The results of the present study indicate that the KA receptor is involved in the mechanism of neuronal damage induced by hypoxia and GD, probably allowing Ca2+ influx and subsequent intracellular Ca2+ overload.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Development of a histologically validated segmentation protocol for the hippocampal body.

    Science.gov (United States)

    Steve, Trevor A; Yasuda, Clarissa L; Coras, Roland; Lail, Mohjevan; Blumcke, Ingmar; Livy, Daniel J; Malykhin, Nikolai; Gross, Donald W

    2017-08-15

    Recent findings have demonstrated that hippocampal subfields can be selectively affected in different disease states, which has led to efforts to segment the human hippocampus with in vivo magnetic resonance imaging (MRI). However, no studies have examined the histological accuracy of subfield segmentation protocols. The presence of MRI-visible anatomical landmarks with known correspondence to histology represents a fundamental prerequisite for in vivo hippocampal subfield segmentation. In the present study, we aimed to: 1) develop a novel method for hippocampal body segmentation, based on two MRI-visible anatomical landmarks (stratum lacunosum moleculare [SLM] & dentate gyrus [DG]), and assess its accuracy in comparison to the gold standard direct histological measurements; 2) quantify the accuracy of two published segmentation strategies in comparison to the histological gold standard; and 3) apply the novel method to ex vivo MRI and correlate the results with histology. Ultra-high resolution ex vivo MRI was performed on six whole cadaveric hippocampal specimens, which were then divided into 22 blocks and histologically processed. The hippocampal bodies were segmented into subfields based on histological criteria and subfield boundaries and areas were directly measured. A novel method was developed using mean percentage of the total SLM distance to define subfield boundaries. Boundary distances and subfield areas on histology were then determined using the novel method and compared to the gold standard histological measurements. The novel method was then used to determine ex vivo MRI measures of subfield boundaries and areas, which were compared to histological measurements. For direct histological measurements, the mean percentages of total SLM distance were: Subiculum/CA1 = 9.7%, CA1/CA2 = 78.4%, CA2/CA3 = 97.5%. When applied to histology, the novel method provided accurate measures for CA1/CA2 (ICC = 0.93) and CA2/CA3 (ICC = 0.97) boundaries, but not for the

  7. The hippocampal network model: A transdiagnostic metaconnectomic approach

    Directory of Open Access Journals (Sweden)

    Eithan Kotkowski

    Full Text Available Purpose: The hippocampus plays a central role in cognitive and affective processes and is commonly implicated in neurodegenerative diseases. Our study aimed to identify and describe a hippocampal network model (HNM using trans-diagnostic MRI data from the BrainMap® database. We used meta-analysis to test the network degeneration hypothesis (NDH (Seeley et al., 2009 by identifying structural and functional covariance in this hippocampal network. Methods: To generate our network model, we used BrainMap's VBM database to perform a region-to-whole-brain (RtWB meta-analysis of 269 VBM experiments from 165 published studies across a range of 38 psychiatric and neurological diseases reporting hippocampal gray matter density alterations. This step identified 11 significant gray matter foci, or nodes. We subsequently used meta-analytic connectivity modeling (MACM to define edges of structural covariance between nodes from VBM data as well as functional covariance using the functional task-activation database, also from BrainMap. Finally, we applied a correlation analysis using Pearson's r to assess the similarities and differences between the structural and functional covariance models. Key findings: Our hippocampal RtWB meta-analysis reported consistent and significant structural covariance in 11 key regions. The subsequent structural and functional MACMs showed a strong correlation between HNM nodes with a significant structural-functional covariance correlation of r = .377 (p = .000049. Significance: This novel method of studying network covariance using VBM and functional meta-analytic techniques allows for the identification of generalizable patterns of functional and structural abnormalities pertaining to the hippocampus. In accordance with the NDH, this framework could have major implications in studying and predicting spatial disease patterns using network-based assays. Keywords: Anatomic likelihood estimation, ALE, BrainMap, Functional

  8. Building hippocampal circuits to learn and remember: insights into the development of human memory.

    Science.gov (United States)

    Lavenex, Pierre; Banta Lavenex, Pamela

    2013-10-01

    The hippocampal formation is essential for the processing of episodic memories for autobiographical events that happen in unique spatiotemporal contexts. Interestingly, before 2 years of age, children are unable to form or store episodic memories for recall later in life, a phenomenon known as infantile amnesia. From 2 to 7 years of age, there are fewer memories than predicted based on a forgetting function alone, a phenomenon known as childhood amnesia. Here, we discuss the postnatal maturation of the primate hippocampal formation with the goal of characterizing the development of the neurobiological substrates thought to subserve the emergence of episodic memory. Distinct regions, layers and cells of the hippocampal formation exhibit different profiles of structural and molecular development during early postnatal life. The protracted period of neuronal addition and maturation in the dentate gyrus is accompanied by the late maturation of specific layers in different hippocampal regions that are located downstream from the dentate gyrus, particularly CA3. In contrast, distinct layers in several hippocampal regions, particularly CA1, which receive direct projections from the entorhinal cortex, exhibit an early maturation. In addition, hippocampal regions that are more highly interconnected with subcortical structures, including the subiculum, presubiculum, parasubiculum and CA2, mature even earlier. These findings, together with our studies of the development of human spatial memory, support the hypothesis that the differential maturation of distinct hippocampal circuits might underlie the differential emergence of specific "hippocampus-dependent" memory processes, culminating in the emergence of episodic memory concomitant with the maturation of all hippocampal circuits. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Selective amygdalohippocampectomy via trans-superior temporal gyrus keyhole approach

    OpenAIRE

    Mathon , Bertrand; Clemenceau , Stéphane

    2016-01-01

    International audience; BackgroundHippocampal sclerosis is the most common cause of drug-resistant epilepsy amenable for surgical treatment and seizure control. The rationale of the selective amygdalohippocampectomy is to spare cerebral tissue not included in the seizure generator.MethodDescribe the selective amygdalohippocampectomy through the trans-superior temporal gyrus keyhole approach.ConclusionSelective amygdalohippocampectomy for temporal lobe epilepsy is performed when the data (semi...

  10. Five-year retrospective changes in hippocampal atrophy and cognitive screening test performances in very mild Alzheimer's disease: the Tajiri Project

    International Nuclear Information System (INIS)

    Yamaguchi, S.; Meguro, K.; Shimada, M.; Ishizaki, J.; Yamadori, A.; Sekita, Y.

    2002-01-01

    The medial temporal lobe, especially the hippocampus, is important for normal cognitive function, especially for memory, and is the region with the earliest and most extensive pathological changes in Alzheimer's disease (AD). We investigated the atrophic changes of the hippocampus over a 5-year period and its relation to cognitive screening test performances in normal elderly subjects, those with very mild AD, and patients with AD. Fifty-seven elderly subjects without a moderate or greater degree of cerebrovascular disease as shown by MRI were randomly selected from the town of Tajiri. Thirty-three subjects with a clinical dementia rating (CDR) of 0 (normal), 18 CDR-0.5 (very mild AD) subjects, and six CDR-1 and 2 (AD) subjects underwent MRI and the Mini Mental State Examination (MMSE) twice during the period. Retrospective changes in the hippocampal width and the MMSE scores were evaluated. There were significant CDR group effects for the changes in the mean bilateral hippocampal widths and the MMSE scores. Normal subjects did not show cognitive decline, although there was a slight tendency for hippocampal atrophy. A significant and meaningful Spearman's correlation was noted between left hippocampal atrophy and the MMSE scores over the 5-year period for the CDR-0.5 group. These CDR-0.5 subjects met the MCI (mild cognitive impairment) criteria as proposed by the consensus paper. Findings suggested that normal elderly subjects maintain a high level of cognitive functions for at least 5 years, although hippocampal atrophy might occur. Atrophic change of the left hippocampus might be a good marker of the very early stage of AD. (orig.)

  11. Sinularin Selectively Kills Breast Cancer Cells Showing G2/M Arrest, Apoptosis, and Oxidative DNA Damage

    Directory of Open Access Journals (Sweden)

    Hurng-Wern Huang

    2018-04-01

    Full Text Available The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl-5-(3-carboxymethoxyphenyl-2-(4-sulfophenyl-2H- tetrazolium, inner salt (MTS assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231 cells, but showed less effect on breast normal (M10 cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose polymerase (PARP, caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS, mitochondrial membrane potential (MitoMP, mitochondrial superoxide, and 8-oxo-2′-deoxyguanosine (8-oxodG. In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.

  12. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews

    NARCIS (Netherlands)

    Keuker, J.I.H.; de Biurrun, G.; Luiten, P.G.M.; Fuchs, E.

    2004-01-01

    Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many

  13. Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

    Science.gov (United States)

    Shima, Takeru; Matsui, Takashi; Jesmin, Subrina; Okamoto, Masahiro; Soya, Mariko; Inoue, Koshiro; Liu, Yu-Fan; Torres-Aleman, Ignacio; McEwen, Bruce S; Soya, Hideaki

    2017-03-01

    Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

  14. A three-plane architectonic atlas of the rat hippocampal region.

    Science.gov (United States)

    Boccara, Charlotte N; Kjonigsen, Lisa J; Hammer, Ingvild M; Bjaalie, Jan G; Leergaard, Trygve B; Witter, Menno P

    2015-07-01

    The hippocampal region, comprising the hippocampal formation and the parahippocampal region, has been one of the most intensively studied parts of the brain for decades. Better understanding of its functional diversity and complexity has led to an increased demand for specificity in experimental procedures and manipulations. In view of the complex 3D structure of the hippocampal region, precisely positioned experimental approaches require a fine-grained architectural description that is available and readable to experimentalists lacking detailed anatomical experience. In this paper, we provide the first cyto- and chemoarchitectural description of the hippocampal formation and parahippocampal region in the rat at high resolution and in the three standard sectional planes: coronal, horizontal and sagittal. The atlas uses a series of adjacent sections stained for neurons and for a number of chemical marker substances, particularly parvalbumin and calbindin. All the borders defined in one plane have been cross-checked against their counterparts in the other two planes. The entire dataset will be made available as a web-based interactive application through the Rodent Brain WorkBench (http://www.rbwb.org) which, together with this paper, provides a unique atlas resource. © 2014 Wiley Periodicals, Inc.

  15. Pathophysiogenesis of Mesial Temporal Lobe Epilepsy: Is Prevention of Damage Antiepileptogenic?

    Science.gov (United States)

    Curia, G.; Lucchi, C.; Vinet, J.; Gualtieri, F.; Marinelli, C.; Torsello, A.; Costantino, L.; Biagini*,, G.

    2014-01-01

    Temporal lobe epilepsy (TLE) is frequently associated with hippocampal sclerosis, possibly caused by a primary brain injury that occurred a long time before the appearance of neurological symptoms. This type of epilepsy is characterized by refractoriness to drug treatment, so to require surgical resection of mesial temporal regions involved in seizure onset. Even this last therapeutic approach may fail in giving relief to patients. Although prevention of hippocampal damage and epileptogenesis after a primary event could be a key innovative approach to TLE, the lack of clear data on the pathophysiological mechanisms leading to TLE does not allow any rational therapy. Here we address the current knowledge on mechanisms supposed to be involved in epileptogenesis, as well as on the possible innovative treatments that may lead to a preventive approach. Besides loss of principal neurons and of specific interneurons, network rearrangement caused by axonal sprouting and neurogenesis are well known phenomena that are integrated by changes in receptor and channel functioning and modifications in other cellular components. In particular, a growing body of evidence from the study of animal models suggests that disruption of vascular and astrocytic components of the blood-brain barrier takes place in injured brain regions such as the hippocampus and piriform cortex. These events may be counteracted by drugs able to prevent damage to the vascular component, as in the case of the growth hormone secretagogue ghrelin and its analogues. A thoroughly investigation on these new pharmacological tools may lead to design effective preventive therapies. PMID:24251566

  16. Cannabis-related hippocampal volumetric abnormalities specific to subregions in dependent users.

    Science.gov (United States)

    Chye, Yann; Suo, Chao; Yücel, Murat; den Ouden, Lauren; Solowij, Nadia; Lorenzetti, Valentina

    2017-07-01

    Cannabis use is associated with neuroanatomical alterations in the hippocampus. While the hippocampus is composed of multiple subregions, their differential vulnerability to cannabis dependence remains unknown. The objective of the study is to investigate gray matter alteration in each of the hippocampal subregions (presubiculum, subiculum, cornu ammonis (CA) subfields CA1-4, and dentate gyrus (DG)) as associated with cannabis use and dependence. A total of 35 healthy controls (HC), 22 non-dependent (CB-nondep), and 39 dependent (CB-dep) cannabis users were recruited. We investigated group differences in hippocampal subregion volumes between HC, CB-nondep, and CB-dep users. We further explored the association between CB use variables (age of onset of regular use, monthly use, lifetime use) and hippocampal subregions in CB-nondep and CB-dep users separately. The CA1, CA2/3, CA4/DG, as well as total hippocampal gray matter were reduced in volume in CB-dep but not in CB-nondep users, relative to HC. The right CA2/3 and CA4/DG volumes were also negatively associated with lifetime cannabis use in CB-dep users. Our results suggest a regionally and dependence-specific influence of cannabis use on the hippocampus. Hippocampal alteration in cannabis users was specific to the CA and DG regions and confined to dependent users.

  17. Initiation of sleep-dependent cortical-hippocampal correlations at wakefulness-sleep transition.

    Science.gov (United States)

    Haggerty, Daniel C; Ji, Daoyun

    2014-10-01

    Sleep is involved in memory consolidation. Current theories propose that sleep-dependent memory consolidation requires active communication between the hippocampus and neocortex. Indeed, it is known that neuronal activities in the hippocampus and various neocortical areas are correlated during slow-wave sleep. However, transitioning from wakefulness to slow-wave sleep is a gradual process. How the hippocampal-cortical correlation is established during the wakefulness-sleep transition is unknown. By examining local field potentials and multiunit activities in the rat hippocampus and visual cortex, we show that the wakefulness-sleep transition is characterized by sharp-wave ripple events in the hippocampus and high-voltage spike-wave events in the cortex, both of which are accompanied by highly synchronized multiunit activities in the corresponding area. Hippocampal ripple events occur earlier than the cortical high-voltage spike-wave events, and hippocampal ripple incidence is attenuated by the onset of cortical high-voltage spike waves. This attenuation leads to a temporary weak correlation in the hippocampal-cortical multiunit activities, which eventually evolves to a strong correlation as the brain enters slow-wave sleep. The results suggest that the hippocampal-cortical correlation is established through a concerted, two-step state change that first synchronizes the neuronal firing within each brain area and then couples the synchronized activities between the two regions. Copyright © 2014 the American Physiological Society.

  18. Inter-relationships among diet, obesity and hippocampal-dependent cognitive function.

    Science.gov (United States)

    Davidson, T L; Hargrave, S L; Swithers, S E; Sample, C H; Fu, X; Kinzig, K P; Zheng, W

    2013-12-03

    Intake of a Western diet (WD), which is high in saturated fat and sugar, is associated with deficits in hippocampal-dependent learning and memory processes as well as with markers of hippocampal pathology. In the present study, rats were trained to asymptote on hippocampal-dependent serial feature negative (FN) and hippocampal-independent simple discrimination problems. Performance was then assessed following 7 days on ad libitum chow and after 10, 24, 40, 60, and 90 days of maintenance on WD, on ketogenic (KETO) diet, which is high in saturated fat and low in sugar and other carbohydrates, or continued maintenance on chow (CHOW). Confirming and extending previous findings, diet-induced obese (DIO) rats fed WD showed impaired FN performance, increased blood-brain barrier (BBB) permeability, and increased fasting blood glucose levels compared to CHOW controls and to diet-resistant (DR) rats that did not become obese when maintained on WD. For rats fed the KETO diet, FN performance and BBB integrity were more closely associated with level of circulating ketone bodies than with obesity phenotype (DR or DIO), with higher levels of ketones appearing to provide a protective effect. The evidence also indicated that FN deficits preceded and predicted increased body weight and adiposity. This research (a) further substantiates previous findings of WD-induced deficits in hippocampal-dependent FN discriminations, (b) suggests that ketones may be protective against diet-induced cognitive impairment, and (c) provides evidence that diet-induced cognitive impairment precedes weight gain and obesity. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Porencephaly in dogs and cats: relationships between magnetic resonance imaging (MRI) features and hippocampal atrophy.

    Science.gov (United States)

    Hori, Ai; Hanazono, Kiwamu; Miyoshi, Kenjirou; Nakade, Tetsuya

    2015-07-01

    Porencephaly is the congenital cerebral defect and a rare malformation and described few MRI reports in veterinary medicine. MRI features of porencephaly are recognized the coexistence with the unilateral/bilateral hippocampal atrophy, caused by the seizure symptoms in human medicine. We studied 2 dogs and 1 cat with congenital porencephaly to characterize the clinical signs and MRI, and to discuss the associated MRI with hippocampal atrophy. The main clinical sign was the seizure symptoms, and all had hippocampal atrophy at the lesion side or the larger defect side. There is association between hippocampal atrophy or the cyst volume and the severe of clinical signs, and it is suggested that porencephaly coexists with hippocampal atrophy as well as humans in this study.

  20. Hippocampal declarative memory supports gesture production: Evidence from amnesia.

    Science.gov (United States)

    Hilverman, Caitlin; Cook, Susan Wagner; Duff, Melissa C

    2016-12-01

    Spontaneous co-speech hand gestures provide a visuospatial representation of what is being communicated in spoken language. Although it is clear that gestures emerge from representations in memory for what is being communicated (De Ruiter, 1998; Wesp, Hesse, Keutmann, & Wheaton, 2001), the mechanism supporting the relationship between gesture and memory is unknown. Current theories of gesture production posit that action - supported by motor areas of the brain - is key in determining whether gestures are produced. We propose that when and how gestures are produced is determined in part by hippocampally-mediated declarative memory. We examined the speech and gesture of healthy older adults and of memory-impaired patients with hippocampal amnesia during four discourse tasks that required accessing episodes and information from the remote past. Consistent with previous reports of impoverished spoken language in patients with hippocampal amnesia, we predicted that these patients, who have difficulty generating multifaceted declarative memory representations, may in turn have impoverished gesture production. We found that patients gestured less overall relative to healthy comparison participants, and that this was particularly evident in tasks that may rely more heavily on declarative memory. Thus, gestures do not just emerge from the motor representation activated for speaking, but are also sensitive to the representation available in hippocampal declarative memory, suggesting a direct link between memory and gesture production. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. 17β Estradiol increases resilience and improves hippocampal synaptic function in helpless ovariectomized rats

    Science.gov (United States)

    Bredemann, Teruko M.; McMahon, Lori L.

    2014-01-01

    Summary Memory impairment is the most commonly reported cognitive symptom associated with major depressive disorder. Decreased hippocampal volume and neurogenesis in depression link hippocampal dysfunction with deficits in memory. Stress decreases hippocampal dendritic spine density and long-term potentiation (LTP) at glutamate synapses, a cellular correlate of learning and memory. However, elevated plasma levels of 17β estradiol (E2) during proestrus increase hippocampal structure and function, directly opposing the negative consequences of stress. In women, significant fluctuations in ovarian hormones likely increase vulnerability of hippocampal circuits to stress, potentially contributing to the greater incidence of depression compared to men. Using the learned helplessness model of depression and ovariectomized female rats, we investigated whether acquisition of helplessness and hippocampal synaptic dysfunction is differentially impacted by the presence or absence of plasma E2. We find that inescapable shock induces a greater incidence of helplessness in vehicle- versus E2-treated OVX rats. In the vehicle-treated group, LTP was absent at CA3-CA1 synapses in slices only from helpless rats, and CA1 spine density was decreased compared to resilient rats. In contrast, significant LTP was observed in slices from E2-treated helpless rats; importantly, spine density was not different between E2-treated helpless and resilient rats, dissociating spine density from the LTP magnitude. We also find that E2 replacement can reverse previously established helpless behavior. Thus, our results show that E2 replacement in OVX rats increases resilience and improves hippocampal plasticity, suggesting that E2 therapy may increase resilience to stress and preserve hippocampal function in women experiencing large fluctuations in plasma estrogen levels. PMID:24636504

  2. Hippocampal effects of neuronostatin on memory, anxiety-like behavior and food intake in rats.

    Science.gov (United States)

    Carlini, V P; Ghersi, M; Gabach, L; Schiöth, H B; Pérez, M F; Ramirez, O A; Fiol de Cuneo, M; de Barioglio, S R

    2011-12-01

    A 13-amino acid peptide named neuronostatin (NST) encoded in the somatostatin pro-hormone has been recently reported. It is produced throughout the body, particularly in brain areas that have significant actions over the metabolic and autonomic regulation. The present study was performed in order to elucidate the functional role of NST on memory, anxiety-like behavior and food intake and the hippocampal participation in these effects. When the peptide was intra-hippocampally administered at 3.0 nmol/μl, it impaired memory retention in both, object recognition and step-down test. Also, this dose blocked the hippocampal long-term potentiation (LTP) generation. When NST was intra-hippocampally administered at 0.3 nmol/μl and 3.0 nmol/μl, anxiolytic effects were observed. Also, the administration in the third ventricle at the higher dose (3.0 nmol/μl) induced similar effects, and both doses reduced food intake. The main result of the present study is the relevance of the hippocampal formation in the behavioral effects induced by NST, and these effects could be associated to a reduced hippocampal synaptic plasticity. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Inhibition of NKCC1 attenuated hippocampal LTP formation and inhibitory avoidance in rat.

    Directory of Open Access Journals (Sweden)

    Meng Chang Ko

    Full Text Available The loop diuretic bumetanide (Bumex is thought to have antiepileptic properties via modulate GABAA mediated signaling through their antagonism of cation-chloride cotransporters. Given that loop diuretics may act as antiepileptic drugs that modulate GABAergic signaling, we sought to investigate whether they also affect hippocampal function. The current study was performed to evaluate the possible role of NKCC1 on the hippocampal function. Brain slice extracellular recording, inhibitory avoidance, and western blot were applied in this study. Results showed that hippocampal Long-term potentiation was attenuated by suprafusion of NKCC1 inhibitor bumetanide, in a dose dependent manner. Sequent experiment result showed that Intravenous injection of bumetanide (15.2 mg/kg 30 min prior to the training session blocked inhibitory avoidance learning significantly. Subsequent control experiment's results excluded the possible non-specific effect of bumetanide on avoidance learning. We also found the phosphorylation of hippocampal MAPK was attenuated after bumetanide administration. These results suggested that hippocampal NKCC1 may via MAPK signaling cascade to possess its function.

  4. Epigenetic control of hippocampal stem cells: modulation by hyperactivation, glucocorticoids and aging

    NARCIS (Netherlands)

    Schouten, M.

    2015-01-01

    The adult brain has the ability to structurally and functionally adapt to changes in its environment. Examples of these adaptations are the addition of new neurons to neurogenic regions such as the hippocampal dentate gyrus, termed adult hippocampal neurogenesis, and alterations in neuronal

  5. Assessment of PET & ASL metabolism in the hippocampal subfields of MCI and AD using simultaneous PET-MR

    Energy Technology Data Exchange (ETDEWEB)

    Goubran, Maged; Douglas, David; Chao, Steven; Quon, Andrew; Tripathi, Pragya; Holley, Dawn; Vasanawala, Minal; Zaharchuk, Greg; Zeineh, Michael [Stanford University (United States)

    2015-05-18

    Alzheimer’s disease (AD) has been reported to show decreased metabolic activity in the hippocampus using FDG PET-MR. Histological data suggests that the hippocampal subfields are selectively affected in AD. Given the simultaneous imaging nature of integrated PET-MR scanners and the multimodal capabilities of PET-MR, our purpose here is to assess FDG activity, as well as ASL perfusion in the subfields of MCI and AD patients. 10 consecutive subjects were recruited for this study 3 MCI, 3 AD patients and 4 age-matched controls. The scanning was performed on a simultaneous 3T PET/MR scanner. To delineate the hippocampal subfields, automatic segmentation of hippocampal subfields (ASHS) was employed. Static FDG-PET series were reconstructed for analysis at 45-75 min for all subjects. All imaging sequences were automatically registered to the oblique coronal T2-weighted images (segmentation space). PET standardized uptake values (SUV) in the hippocampal subfields were normalized by the pons. FDG PET metabolism was reduced significantly in AD, as well as MCI patients as compared to controls, with the highest effect demonstrated in the CA3/DG and CA1/2 (p = 0.047, subfields. Patients (MCI and AD combined) had decreased metabolism as compared to controls in CA1/2 and significantly smaller volumes the Subiculum. When assessing CBF across groups, a significant decrease in CBF was found in the Subiculum. Our preliminary results demonstrate that PET-MRI may potentially be a sensitive biomarker and tool for early diagnosis of AD. They also confirm the importance of assessing metabolic and structural changes of neurodegenerative diseases at the subfield level.

  6. Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study.

    Science.gov (United States)

    Lee, Katrina; Lenards, Nishele; Holson, Janice

    2016-01-01

    The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient׳s neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to the hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient׳s data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain. Copyright © 2016 American Association of Medical Dosimetrists. Published by Elsevier Inc. All rights reserved.

  7. Focal CA3 hippocampal subfield atrophy following LGI1 VGKC-complex antibody limbic encephalitis

    OpenAIRE

    Miller, T; Chong, T; Aimola Davies, A; Ng, T; Johnson, M; Irani, S; Vincent, A; Husain, M; Jacob, S; Maddison, P; Kennard, C; Gowland, P; Rosenthal, C

    2017-01-01

    Magnetic resonance imaging has linked chronic voltage-gated potassium channel (VGKC) complex antibody-mediated limbic encephalitis with generalized hippocampal atrophy. However, autoantibodies bind to specific rodent hippocampal subfields. Here, human hippocampal subfield (subiculum, cornu ammonis 1-3, and dentate gyrus) targets of immunomodulation-treated LGI1 VGKC-complex antibody-mediated limbic encephalitis were investigated using in vivo ultra-high resolution (0.39 × 0....

  8. Failure of hippocampal deactivation during loss events in treatment-resistant depression.

    Science.gov (United States)

    Johnston, Blair A; Tolomeo, Serenella; Gradin, Victoria; Christmas, David; Matthews, Keith; Steele, J Douglas

    2015-09-01

    Major depressive disorder is characterized by anhedonia, cognitive biases, ruminations, hopelessness and increased anxiety. Blunted responses to rewards have been reported in a number of recent neuroimaging and behavioural studies of major depressive disorder. In contrast, neural responses to aversive events remain an under-studied area. While selective serotonergic reuptake inhibitors are often effective in treating major depressive disorder, their mechanism of action remains unclear. Following a series of animal model investigations of depressive illness and serotonergic function, Deakin and Graeff predicted that brain activity in patients with major depressive disorder is associated with an overactive dorsal raphe nucleus with overactive projections to the amygdala, periaqueductal grey and striatum, and an underactive median raphe nucleus with underactive projections to the hippocampus. Here we describe an instrumental loss-avoidance and win-gain reinforcement learning functional magnetic resonance imaging study with 40 patients with highly treatment-resistant major depressive disorder and never-depressed controls. The dorsal raphe nucleus/ periaqueductal grey region of the midbrain and hippocampus were found to be overactive in major depressive disorder during unsuccessful loss-avoidance although the median raphe nucleus was not found to be underactive. Hippocampal overactivity was due to a failure to deactivate during loss events in comparison to controls, and hippocampal over-activity correlated with depression severity, self-report 'hopelessness' and anxiety. Deakin and Graeff argued that the median raphe nucleus normally acts to inhibit consolidation of aversive memories via the hippocampus and this system is underactive in major depressive disorder, facilitating the development of ruminations, while the dorsal raphe nucleus system is engaged by distal cues predictive of threats and is overactive in major depressive disorder. During win events the striatum

  9. Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear.

    Science.gov (United States)

    Tronson, Natalie C; Schrick, Christina; Guzman, Yomayra F; Huh, Kyu Hwan; Srivastava, Deepak P; Penzes, Peter; Guedea, Anita L; Gao, Can; Radulovic, Jelena

    2009-03-18

    Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos(+) and pErk(+) cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos(+) hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum.

  10. Autopsy-confirmed hippocampal-sparing Alzheimer's disease with delusional jealousy as initial manifestation.

    Science.gov (United States)

    Fujishiro, Hiroshige; Iritani, Shuji; Hattori, Miho; Sekiguchi, Hirotaka; Matsunaga, Shinji; Habuchi, Chikako; Torii, Youta; Umeda, Kentaro; Ozaki, Norio; Yoshida, Mari; Fujita, Kiyoshi

    2015-09-01

    Alzheimer's disease (AD) is clinically characterized by gradual onset over years with worsening of cognition. The initial and most prominent cognitive deficit is commonly memory dysfunction. However, a subset of AD cases has less hippocampal atrophy than would be expected relative to the predominance of cortical atrophy. These hippocampal-sparing cases have distinctive clinical features, including the presence of focal cortical clinical syndromes. Given that previous studies have indicated that severe hippocampal atrophy corresponds to prominent loss of episodic memory, it is likely that memory impairment is initially absent in hippocampal-sparing AD cases. Here, we report on a patient with an 8-year history of delusional jealousy with insidious onset who was clinically diagnosed as possible AD and pathologically confirmed to have AD with relatively preserved neurons in the hippocampus. This patient had delusional jealousy with a long pre-dementia stage, which initially was characterized by lack of memory impairment. Head magnetic resonance imaging findings showed preserved hippocampal volume with bilateral enlarged ventricles and mild-to-moderate cortical atrophy. Head single-photon emission computed tomography revealed severely decreased regional cerebral blood flow in the right temporal lobe. The resolution of the delusion was attributed to pharmacotherapy by an acetylcholinesterase inhibitor, suggesting that the occurrence of delusional jealousy was due to the disease process of AD. Although the neural basis of delusional jealousy remains unclear, this hippocampal-sparing AD case may be classified as an atypical presentation of AD. © 2015 The Authors. Psychogeriatrics © 2015 Japanese Psychogeriatric Society.

  11. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

    Directory of Open Access Journals (Sweden)

    Melanie Laßek

    2016-04-01

    Full Text Available The hallmarks of Alzheimer's disease (AD are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.

  12. Evidence for holistic episodic recollection via hippocampal pattern completion.

    Science.gov (United States)

    Horner, Aidan J; Bisby, James A; Bush, Daniel; Lin, Wen-Jing; Burgess, Neil

    2015-07-02

    Recollection is thought to be the hallmark of episodic memory. Here we provide evidence that the hippocampus binds together the diverse elements forming an event, allowing holistic recollection via pattern completion of all elements. Participants learn complex 'events' from multiple overlapping pairs of elements, and are tested on all pairwise associations. At encoding, element 'types' (locations, people and objects/animals) produce activation in distinct neocortical regions, while hippocampal activity predicts memory performance for all within-event pairs. When retrieving a pairwise association, neocortical activity corresponding to all event elements is reinstated, including those incidental to the task. Participant's degree of incidental reinstatement correlates with their hippocampal activity. Our results suggest that event elements, represented in distinct neocortical regions, are bound into coherent 'event engrams' in the hippocampus that enable episodic recollection--the re-experiencing or holistic retrieval of all aspects of an event--via a process of hippocampal pattern completion and neocortical reinstatement.

  13. Hippocampal development at gestation weeks 23 to 36. An ultrasound study on preterm neonates

    Energy Technology Data Exchange (ETDEWEB)

    Bajic, Dragan; Raininko, Raili [Uppsala University, Department of Radiology, University Hospital, Uppsala (Sweden); Ewald, Uwe [Uppsala University, Department of Women' s and Children' s Health, Uppsala (Sweden)

    2010-06-15

    During fetal development, the hippocampal structures fold around the hippocampal sulcus into the temporal lobe. According to the literature, this inversion should be completed at gestation week (GW) 21. Thereafter, the hippocampal shape should resemble the adult shape. However, incomplete hippocampal inversion (IHI) is found in 19% of the common population. The aim of this study was to study fetal hippocampal development by examining neonates born preterm. We analyzed cranial ultrasound examinations, performed as a part of the routine assessment of all preterm infants, over a 3-year period and excluded the infants with brain pathology. The final material consisted of 158 children born <35 GW. A rounded form (the ratio between the horizontal and vertical diameters of the hippocampal body {<=}1) in coronal slices was considered the sign of IHI. The age at examination was 23-24 GW in 24 neonates, 25-28 GW in 70 neonates, and 29-36 GW in 64 neonates. IHI was found in 50%, 24%, and 14%, respectively. The difference between the neonates <25 GW and {>=}25 GW was statistically highly significant (p < 0.001). The frequency of bilateral IHI was highest in the youngest age group. In the other groups, the left-sided IHI was the most common. In about 50% of the neonates, hippocampal inversion is not completed up to GW 24; but from 25 GW onwards, the frequency and laterality of IHI is similar to that in the adult population. (orig.)

  14. CB1 receptor antagonism increases hippocampal acetylcholine release: site and mechanism of action.

    Science.gov (United States)

    Degroot, Aldemar; Köfalvi, Attila; Wade, Mark R; Davis, Richard J; Rodrigues, Ricardo J; Rebola, Nelson; Cunha, Rodrigo A; Nomikos, George G

    2006-10-01

    Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR-141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB1Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct

  15. Neuroprotective effects of curcumin on endothelin-1 mediated cell death in hippocampal neurons.

    Science.gov (United States)

    Stankowska, Dorota L; Krishnamoorthy, Vignesh R; Ellis, Dorette Z; Krishnamoorthy, Raghu R

    2017-06-01

    Alzheimer's disease is a progressive neurodegenerative disease characterized by loss of hippocampal neurons leading to memory deficits and cognitive decline. Studies suggest that levels of the vasoactive peptide endothelin-1 (ET-1) are increased in the brain tissue of Alzheimer's patients. Curcumin, the main ingredient of the spice turmeric, has been shown to have anti-inflammatory, anti-cancer, and neuroprotective effects. However, the mechanisms underlying some of these beneficial effects are not completely understood. The objective of this study was to determine if curcumin could protect hippocampal neurons from ET-1 mediated cell death and examine the involvement of c-Jun in this pathway. Primary hippocampal neurons from rat pups were isolated using a previously published protocol. Viability of the cells was measured by the live/dead assay. Immunoblot and immunohistochemical analyses were performed to analyze c-Jun levels in hippocampal neurons treated with either ET-1 or a combination of ET-1 and curcumin. Apoptotic changes were evaluated by immunoblot detection of cleaved caspase-3, cleaved fodrin, and a caspase 3/7 activation assay. ET-1 treatment produced a 2-fold increase in the levels of c-Jun as determined by an immunoblot analysis in hippocampal neurons. Co-treatment with curcumin significantly attenuated the ET-1 mediated increase in c-Jun levels. ET-1 caused increased neuronal cell death of hippocampal neurons indicated by elevation of cleaved caspase-3, cleaved fodrin and an increased activity of caspases 3 and 7 which was attenuated by co-treatment with curcumin. Blockade of JNK, an upstream effector of c-Jun by specific inhibitor SP600125 did not fully protect from ET-1 mediated activation of pro-apoptotic enzymes in primary hippocampal cells. Our data suggests that one mechanism by which curcumin protects against ET-1-mediated cell death is through blocking an increase in c-Jun levels. Other possible mechanisms include decreasing pro

  16. Effects of low-level sarin and cyclosarin exposure on hippocampal microstructure in Gulf War Veterans.

    Science.gov (United States)

    Chao, Linda L; Zhang, Yu

    2018-05-04

    In early March 1991, shortly after the end of the Gulf War (GW), a munitions dump was destroyed at Khamisiyah, Iraq. Later, in 1996, the dump was found to have contained the organophosphorus (OP) nerve agents sarin and cyclosarin. We previously reported evidence of smaller hippocampal volumes in GW veterans with predicted exposure to the Khamisiyah plume compared to unexposed GW veterans. To investigate whether these macroscopic hippocampal volume changes are accompanied by microstructural alterations in the hippocampus, the current study acquired diffusion-tensor imaging (DTI), T1-, and T2-weighted images from 170 GW veterans (mean age: 53 ± 7 years), 81 of whom had predicted exposure to the Khamisiyah plume according to Department of Defense (DOD) plume modeling. We examined fractional anisotropy (FA), mean diffusivity (MD), and grey matter (GM) density from a hippocampal region of interest (ROI). Results indicate that, even after accounting for total hippocampal GM density (or hippocampal volume), age, sex, apolipoprotein ε4 genotype, and potential confounding OP pesticide exposures, hippocampal MD significantly predicted Khamisiyah exposure status (model p = 0.005, R 2  = 0.215, standardized coefficient β = 0.26, t = 2.85). Hippocampal MD was also inversely correlated with verbal memory learning performance in the entire study sample (p = 0.001). There were no differences in hippocampal FA or GM density; however, veterans with predicted Khamisiyah exposure had smaller hippocampal volumes compared to unexposed veterans. Because MD is sensitive to general microstructural disruptions that lead to increased extracellular spaces due to neuronal death, inflammation and gliosis, and/or to axonal loss or demyelination, these findings suggest that low-level exposure to the Khamisiyah plume has a detrimental, lasting effects on both macro- and micro-structure of the hippocampus. Copyright © 2018. Published by Elsevier Inc.

  17. Age-dependent loss of cholinergic neurons in learning and memory-related brain regions and impaired learning in SAMP8 mice with trigeminal nerve damage

    Institute of Scientific and Technical Information of China (English)

    Yifan He; Jihong Zhu; Fang Huang; Liu Qin; Wenguo Fan; Hongwen He

    2014-01-01

    The tooth belongs to the trigeminal sensory pathway. Dental damage has been associated with impairments in the central nervous system that may be mediated by injury to the trigeminal nerve. In the present study, we investigated the effects of damage to the inferior alveolar nerve, an important peripheral nerve in the trigeminal sensory pathway, on learning and memory be-haviors and structural changes in related brain regions, in a mouse model of Alzheimer’s disease. Inferior alveolar nerve transection or sham surgery was performed in middle-aged (4-month-old) or elderly (7-month-old) senescence-accelerated mouse prone 8 (SAMP8) mice. When the middle-aged mice reached 8 months (middle-aged group 1) or 11 months (middle-aged group 2), and the elderly group reached 11 months, step-down passive avoidance and Y-maze tests of learn-ing and memory were performed, and the cholinergic system was examined in the hippocampus (Nissl staining and acetylcholinesterase histochemistry) and basal forebrain (choline acetyltrans-ferase immunohistochemistry). In the elderly group, animals that underwent nerve transection had fewer pyramidal neurons in the hippocampal CA1 and CA3 regions, fewer cholinergic ifbers in the CA1 and dentate gyrus, and fewer cholinergic neurons in the medial septal nucleus and vertical limb of the diagonal band, compared with sham-operated animals, as well as showing impairments in learning and memory. Conversely, no signiifcant differences in histology or be-havior were observed between middle-aged group 1 or group 2 transected mice and age-matched sham-operated mice. The present ifndings suggest that trigeminal nerve damage in old age, but not middle age, can induce degeneration of the septal-hippocampal cholinergic system and loss of hippocampal pyramidal neurons, and ultimately impair learning ability. Our results highlight the importance of active treatment of trigeminal nerve damage in elderly patients and those with Alzheimer’s disease, and

  18. Tuning afferent synapses of hippocampal interneurons by neuropeptide Y

    DEFF Research Database (Denmark)

    Ledri, Marco; Sørensen, Andreas Toft; Erdelyi, Ferenc

    2011-01-01

    Cholecystokinin (CCK)-expressing basket cells encompass a subclass of inhibitory GABAergic interneurons that regulate memory-forming oscillatory network activity of the hippocampal formation in accordance to the emotional and motivational state of the animal, conveyed onto these cells by respective...... are modulated by neuropeptide Y (NPY), one of the major local neuropeptides that strongly inhibits hippocampal excitability and has significant effect on its memory function. Here, using GAD65-GFP transgenic mice for prospective identification of CCK basket cells and whole-cell patch-clamp recordings, we show...

  19. The neuroprotective action of pyrroloquinoline quinone against glutamate-induced apoptosis in hippocampal neurons is mediated through the activation of PI3K/Akt pathway

    International Nuclear Information System (INIS)

    Zhang Qi; Shen Mi; Ding Mei; Shen Dingding; Ding Fei

    2011-01-01

    Pyrroloquinoline quinone (PQQ), a cofactor in several enzyme-catalyzed redox reactions, possesses a potential capability of scavenging reactive oxygen species (ROS) and inhibiting cell apoptosis. In this study, we investigated the effects of PQQ on glutamate-induced cell death in primary cultured hippocampal neurons and the possible underlying mechanisms. We found that glutamate-induced apoptosis in cultured hippocampal neurons was significantly attenuated by the ensuing PQQ treatment, which also inhibited the glutamate-induced increase in Ca2+ influx, caspase-3 activity, and ROS production, and reversed the glutamate-induced decrease in Bcl-2/Bax ratio. The examination of signaling pathways revealed that PQQ treatment activated the phosphorylation of Akt and suppressed the glutamate-induced phosphorylation of c-Jun N-terminal protein kinase (JNK). And inhibition of phosphatidylinositol-3-kinase (PI3K)/Akt cascade by LY294002 and wortmannin significantly blocked the protective effects of PQQ, and alleviated the increase in Bcl-2/Bax ratio. Taken together, our results indicated that PQQ could protect primary cultured hippocampal neurons against glutamate-induced cell damage by scavenging ROS, reducing Ca2+ influx, and caspase-3 activity, and suggested that PQQ-activated PI3K/Akt signaling might be responsible for its neuroprotective action through modulation of glutamate-induced imbalance between Bcl-2 and Bax. - Research Highlights: →PQQ attenuated glutamate-induced cell apoptosis of cultured hippocampal neurons. →PQQ inhibited glutamate-induced Ca 2+ influx and caspase-3 activity. →PQQ reduced glutamate-induced increase in ROS production. →PQQ affected phosphorylation of Akt and JNK signalings after glutamate injury. →PI3K/Akt was required for neuroprotection of PQQ by modulating Bcl-2/Bax ratio.

  20. Anticonvulsant Effects of Memantine and MK-801 in Guinea Pig Hippocampal Neurons.

    Science.gov (United States)

    investigation we compared the anticonvulsant properties of Mem to those of MK-801 in guinea pig hippocampal slices. Extracellular recordings were...obtained from area CA1 of guinea pig hippocampal slices in a total submersion chamber at 32 deg C in normal oxygenated artificial cerebrospinal fluid (ACSF

  1. Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.

    Science.gov (United States)

    Pressly, Jeffrey D; Mustafa, Suni M; Adibi, Ammaar H; Alghamdi, Sahar; Pandey, Pankaj; Roy, Kuldeep K; Doerksen, Robert J; Moore, Bob M; Park, Frank

    2018-02-01

    Ischemia-reperfusion injury (IRI) is a common cause of acute kidney injury (AKI), which is an increasing problem in the clinic and has been associated with elevated rates of mortality. Therapies to treat AKI are currently not available, so identification of new targets that can be modulated to ameliorate renal damage upon diagnosis of AKI is essential. In this study, a novel cannabinoid receptor 2 (CB2) agonist, SMM-295 [3'-methyl-4-(2-(thiophen-2-yl)propan-2-yl)biphenyl-2,6-diol], was designed, synthesized, and tested in vitro and in silico. Molecular docking of SMM-295 into a CB2 active-state homology model showed that SMM-295 interacts well with key amino acids to stabilize the active state. In human embryonic kidney 293 cells, SMM-295 was capable of reducing cAMP production with 66-fold selectivity for CB2 versus cannabinoid receptor 1 and dose-dependently increased mitogen-activated protein kinase and Akt phosphorylation. In vivo testing of the CB2 agonist was performed using a mouse model of bilateral IRI, which is a common model to mimic human AKI, where SMM-295 was immediately administered upon reperfusion of the kidneys after the ischemia episode. Histologic damage assessment 48 hours after reperfusion demonstrated reduced tubular damage in the presence of SMM-295. This was consistent with reduced plasma markers of renal dysfunction (i.e., creatinine and neutrophil gelatinase-associated lipocalin) in SMM-295-treated mice. Mechanistically, kidneys treated with SMM-295 were shown to have elevated activation of Akt with reduced terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling (TUNEL)-positive cells compared with vehicle-treated kidneys after IRI. These data suggest that selective CB2 receptor activation could be a potential therapeutic target in the treatment of AKI. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

  2. High dose tetrabromobisphenol A impairs hippocampal neurogenesis and memory retention.

    Science.gov (United States)

    Kim, Ah Hyun; Chun, Hye Jeong; Lee, Seulah; Kim, Hyung Sik; Lee, Jaewon

    2017-08-01

    Tetrabromobisphenol A (TBBPA) is a brominated flame retardant that is commonly used in commercial and household products, such as, computers, televisions, mobile phones, and electronic boards. TBBPA can accumulate in human body fluids, and it has been reported that TBBPA possesses endocrine disruptive activity. However, the neurotoxic effect of TBBPA on hippocampal neurogenesis has not yet been investigated. Accordingly, the present study was undertaken to evaluate the effect of TBBPA on adult hippocampal neurogenesis and cognitive function. Male C57BL/6 mice were orally administrated vehicle or TBBPA (20 mg/kg, 100 mg/kg, or 500 mg/kg daily) for two weeks. TBBPA was observed to significantly and dose-dependently reduce the survival of newly generated cells in the hippocampus but not to affect the proliferation of newly generated cells. Numbers of hippocampal BrdU and NeuN positive cells were dose-dependently reduced by TBBPA, indicating impaired neurogenesis in the hippocampus. Interestingly, glial activation without neuronal death was observed in hippocampi exposed to TBBPA. Furthermore, memory retention was found to be adversely affected by TBBPA exposure by a mechanism involving suppression of the BDNF-CREB signaling pathway. The study suggests high dose TBBPA disrupts hippocampal neurogenesis and induces associated memory deficits. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. Kindled seizures selectively reduce a subpopulation of [3H]quinuclidinyl benzilate binding sites in rat dentate gyrus

    International Nuclear Information System (INIS)

    Savage, D.D.; McNamara, J.O.

    1982-01-01

    Amygdala-kindled seizures reduced significantly the total number of [ 3 H]quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis

  4. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue

    2009-01-01

    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

  5. Cholinergic denervation of the hippocampal formation does not produce long-term changes in glucose metabolism

    International Nuclear Information System (INIS)

    Harrell, L.E.; Davis, J.N.

    1984-01-01

    Decreased glucose metabolism is found in Alzheimer's disease associated with a loss of cholinergic neurons. The relationship between the chronic cholinergic denervation produced by medial septal lesions and glucose metabolism was studied using 2-deoxy-D-[ 3 H]glucose in the rat hippocampal formation. Hippocampal glucose metabolism was increased 1 week after medial septal lesions. Three weeks after lesions, glucose metabolism was profoundly suppressed in all regions. By 3 months, intraregional hippocampal glucose metabolism had returned to control values. Our results demonstrate that chronic cholinergic denervation of the hippocampal formation does not result in permanent alterations of metabolic activity

  6. Hippocampal volume in relation to clinical and cognitive outcome after electroconvulsive therapy in depression.

    Science.gov (United States)

    Nordanskog, P; Larsson, M R; Larsson, E-M; Johanson, A

    2014-04-01

    In a previous magnetic resonance imaging (MRI) study, we found a significant increase in hippocampal volume immediately after electroconvulsive therapy (ECT) in patients with depression. The aim of this study was to evaluate hippocampal volume up to 1 year after ECT and investigate its possible relation to clinical and cognitive outcome. Clinical and cognitive outcome in 12 in-patients with depression receiving antidepressive pharmacological treatment referred for ECT were investigated with the Montgomery-Asberg Depression Rating Scale (MADRS) and a broad neuropsychological test battery within 1 week before and after ECT. The assessments were repeated 6 and 12 months after baseline in 10 and seven of these patients, respectively. Hippocampal volumes were measured on all four occasions with 3 Tesla MRI. Hippocampal volume returned to baseline during the follow-up period of 6 months. Neither the significant antidepressant effect nor the significant transient decrease in executive and verbal episodic memory tests after ECT could be related to changes in hippocampal volume. No persistent cognitive side effects were observed 1 year after ECT. The immediate increase in hippocampal volume after ECT is reversible and is not related to clinical or cognitive outcome. © 2013 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.

  7. Hippocampal volume reduction in congenital central hypoventilation syndrome.

    Directory of Open Access Journals (Sweden)

    Paul M Macey

    Full Text Available Children with congenital central hypoventilation syndrome (CCHS, a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2 sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female and 32 healthy control (age 15.2+/-2.4 years; 14 female children, and traced hippocampi on 1 mm(3 resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS.

  8. Cytokines effects on radio-induced apoptosis in cortical and hippocampal rat cells in culture

    International Nuclear Information System (INIS)

    Coffigny, H.; Briot, D.; Le Nin, I.

    2000-01-01

    In the central nervous system in development the radio-induced cell death occurs mainly by apoptosis. The effects of modulating factors like cytokines were studied on this kind of death. To handle more easily parameters implicated in nerve cell apoptosis, we studied the effects of radiation with a in vitro system. Cells were isolated from rat foetal cortex and hippocampus, two of the major structures implicated in human mental retardation observed after exposition in utero at Hiroshima and Nagasaki. Cortical or hippocampal cells were isolated from 17 day-old rat foetuses by enzymatic and mechanical treatments and irradiated with 0.50 or 1 Gy. The cells from both structures were cultured 1 or 3 days in serum free medium. Cytokines like βNGF, NT3, EGF, βTGF, α and βFGF, IGF I and II, interleukines like Il 1β, Il 2 and IL 6 were added to the medium. In 3 days cortical cell culture, only βFGF increased cell survival with as little as 10 ng/ml. This effect was dose dependent. In hippocampal cell culture, no significant increase of cell survival occurred with 10 ng/ml of any cytokines. In the same system culture with 1 Gy irradiation, the positive or negative effect of the association of βFGF with another cytokine was tested on cell survival. Only the association with EGF induced higher cell survival in cortical cell culture. In hippocampal cell culture where βFGF alone had no effect, the cell survival was not modified by the association. In the same system, the triple association of βFGF-EGF with another cytokine was tested on hippocampal and cortical cell cultures. No significant effect was observed in both cultures but cell survival trented to decrease with βTGF. In order to avoid the mitotic effect of cytokines in the 3 day-old culture, experiments were carried out on 20 hours cell culture, before the end of the first round of the cell cycle, with the selected cytokines (βFGF or βFGF-EGF). Without irradiation, the percentage of cortical cell survival

  9. FG7142, yohimbine, and βCCE produce anxiogenic-like effects in the elevated plus-maze but do not affect brainstem activated hippocampal theta.

    Science.gov (United States)

    Yeung, Michelle; Lu, Lily; Hughes, Adam M; Treit, Dallas; Dickson, Clayton T

    2013-12-01

    The neurobiological underpinnings of anxiety are of paramount importance to selective and efficacious pharmaceutical intervention. Hippocampal theta frequency in urethane anaesthetized rats is suppressed by all known (and some previously unknown) anti-anxiety (anxiolytic) drugs. Although these findings support the predictive validity of this assay, its construct validity (i.e., whether theta frequency actually indexes anxiety per se) has not been a subject of systematic investigation. We reasoned that if anxiolytic drugs suppress hippocampal theta frequency, then drugs that increase anxiety (i.e., anxiogenic agents) should increase theta frequency, thus providing evidence of construct validity. We used three proven anxiogenic drugs--two benzodiazepine receptor inverse agonists, N-methyl-β-carboline-3-carboxamide (FG7142) and β-carboline-3-carboxylate ethyl ester (βCCE), and one α2 noradrenergic receptor antagonist, 17α-hydroxy-yohimban-16α-carboxylic acid methyl ester (yohimbine) as pharmacological probes to assess the construct validity of the theta model. Although all three anxiogenic drugs significantly increased behavioural measures of anxiety in the elevated plus-maze, none of the three increased the frequency of hippocampal theta oscillations in the neurophysiological model. As a positive control, we demonstrated that diazepam, a proven anxiolytic drug, decreased the frequency of hippocampal theta, as in all other studies using this model. Given this discrepancy between the significant effects of anxiogenic drugs in the behavioural model and the null effects of these drugs in the neurophysiological model, we conclude that the construct validity of the hippocampal theta model of anxiety is questionable. Copyright © 2013 Elsevier Ltd. All rights reserved.

  10. Hippocampal atrophy in people with memory deficits: results from the population-based IPREA study.

    Science.gov (United States)

    Ferrarini, Luca; van Lew, Baldur; Reiber, Johan H C; Gandin, Claudia; Galluzzo, Lucia; Scafato, Emanuele; Frisoni, Giovanni B; Milles, Julien; Pievani, Michela

    2014-07-01

    Clinical studies have shown that hippocampal atrophy is present before dementia in people with memory deficits and can predict dementia development. The question remains whether this association holds in the general population. This is of interest for the possible use of hippocampal atrophy to screen population for preventive interventions. The aim of this study was to assess hippocampal volume and shape abnormalities in elderly adults with memory deficits in a cross-sectional population-based study. We included individuals participating in the Italian Project on the Epidemiology of Alzheimer Disease (IPREA) study: 75 cognitively normal individuals (HC), 31 individuals with memory deficits (MEM), and 31 individuals with memory deficits not otherwise specified (MEMnos). Hippocampal volumes and shape were extracted through manual tracing and the growing and adaptive meshes (GAMEs) shape-modeling algorithm. We investigated between-group differences in hippocampal volume and shape, and correlations with memory deficits. In MEM participants, hippocampal volumes were significantly smaller than in HC and were mildly associated with worse memory scores. Memory-associated shape changes mapped to the anterior hippocampus. Shape-based analysis detected no significant difference between MEM and HC, while MEMnos showed shape changes in the posterior hippocampus compared with HC and MEM groups. These findings support the discriminant validity of hippocampal volumetry as a biomarker of memory impairment in the general population. The detection of shape changes in MEMnos but not in MEM participants suggests that shape-based biomarkers might lack sensitivity to detect Alzheimer's-like pathology in the general population.

  11. The developmental expression of fluorescent proteins in organotypic hippocampal slice cultures from transgenic mice and its use in the determination of excitotoxic neurodegeneration

    DEFF Research Database (Denmark)

    Noraberg, Jens; Jensen, Carsten V; Bonde, Christian

    2007-01-01

    Transgenic mice, expressing fluorescent proteins in neurons and glia, provide new opportunities for real-time microscopic monitoring of degenerative and regenerative structural changes. We have previously validated and compared a number of quantifiable markers for neuronal damage and cell death...... changes, as well as the opportunity to monitor reversible changes or long-term effects in the event of minor damage. As a first step, we present: a) the developmental expression in organotypic hippocampal brain slice cultures of transgenic fluorescent proteins, useful for the visualisation of neuronal...... transgenic mouse strains which express fluorescent proteins in their neurons and/or astroglial cells. From the time of explantation, and subsequently for up to nine weeks in culture, the transgenic neuronal fluorescence displayed the expected characteristics of a developmental, in vivo-like increase...

  12. Perceived Stress Is Differentially Related to Hippocampal Subfield Volumes among Older Adults.

    Directory of Open Access Journals (Sweden)

    Molly E Zimmerman

    Full Text Available Chronic exposure to stress has been shown to impact a wide range of health-related outcomes in older adults. Despite extensive animal literature revealing deleterious effects of biological markers of stress on the dentate gyrus subfield of the hippocampus, links between hippocampal subfields and psychological stress have not been studied in humans. This study examined the relationship between perceived stress and hippocampal subfield volumes among racially/ethnically diverse older adults.Between July 2011 and March 2014, 116 nondemented participants were consecutively drawn from the Einstein Aging Study, an ongoing community-based sample of individuals over the age of 70 residing in Bronx, New York. All participants completed the Perceived Stress Scale, Geriatric Depression Scale, and underwent 3.0 T MRI. FreeSurfer was used to derive total hippocampal volume, hippocampal subfield volumes (CA1, CA2/CA3, CA4/Dentate Gyrus (CA4/DG, and subiculum, entorhinal cortex volume, whole brain volume, and total intracranial volume.Linear regression analyses revealed that higher levels of perceived stress were associated with smaller total hippocampal volume (β = -0.20, t = -2.40, p = 0.02, smaller CA2/CA3 volumes (β = -0.18, t = -2.24, p = 0.03 and smaller CA4/DG volumes (β = -0.19, t = -2.28, p = 0.03 after controlling for total intracranial volume, age, gender, and race. These findings remained unchanged after removal of individuals with clinically significant symptoms of depression.Our findings provide evidence of a relationship between a direct indicator of psychological stress and specific hippocampal subfield volumes in elderly individuals. These results highlight the importance of clinical screening for chronic stress in otherwise healthy older adults.

  13. Estradiol-induced increase in novel object recognition requires hippocampal NR2B-containing NMDA receptors.

    Science.gov (United States)

    Vedder, Lindsey C; Smith, Caroline C; Flannigan, Alaina E; McMahon, Lori L

    2013-01-01

    17β-estradiol (E2), at high circulating levels, enhances learning and memory in many women, making it a clinical treatment for hormone-related cognitive decline in aging. However, the mechanisms stimulated by E2, which are responsible for its cognitive enhancing effects, remain incompletely defined. Using an ovariectomized rat model, we previously reported that increasing plasma E2 enhances the magnitude of long-term potentiation (LTP) at hippocampal CA3-CA1 synapses, which is caused by a selective increase in current mediated by NR2B-containing NMDARs, leading to an increase in the NMDAR/AMPAR ratio. Whether the increase in NR2B current is causally related to the ability of E2 to enhance hippocampal dependent learning and memory has yet to be tested. Here, we find that E2 enhances performance in the novel object recognition (NOR) task with the same time course we previously showed E2 enhances the LTP magnitude, temporally linking the increase in LTP to enhanced learning and memory. Furthermore, using the selective NR2B subunit antagonist Ro25-6981, we find that the E2-enhanced NOR, like the enhanced LTP, requires hippocampal NR2B-containing NMDARs, specifically in area CA1. Finally, using whole-cell recordings and the phosphatase inhibitor orthovanadate, we investigated whether the E2-induced increase in NMDAR current is caused by an increase in the density of synaptic NMDARs and/or an increase in NMDAR subunit phosphorylation. We find that both mechanisms are responsible for the enhanced NMDAR current in E2-treated rats. Our results show that the E2-enhanced NOR requires a functional increase in NR2B-containing NMDARs, a requirement shared with the E2-enhanced LTP magnitude at CA3-CA1 synapses, supporting the hypothesis that the increase in LTP likely contributes to the enhanced learning and memory following an increase in plasma E2 levels. Copyright © 2012 Wiley Periodicals, Inc.

  14. Basic fibroblast growth factor enhances cell proliferation in the dentate gyrus of neonatal rats following hypoxic-ischemic brain damage.

    Science.gov (United States)

    Zhu, Huan; Qiao, Lixing; Sun, Yao; Yin, Liping; Huang, Li; Jiang, Li; Li, Jiaqing

    2018-04-23

    Perinatal hypoxic-ischemic insult is considered a major contributor to child mortality and morbidity and leads to neurological deficits in newborn infants. There has been a lack of promising neurotherapeutic interventions for hypoxic-ischemic brain damage (HIBD) for clinical application in infants. The present study aimed to investigate the correlation between neurogenesis and basic fibroblast growth factor (bFGF) in the hippocampal dentate gyrus (DG) region in neonatal rats following HIBD. Cell proliferation was examined by detecting BrdU signals, and the role of bFGF in cell proliferation in the DG region following neonatal HIBD was investigated. Cell proliferation was induced by HIBD in the hippocampal DG of neonatal rats. Furthermore, bFGF gene expression was upregulated in the hippocampus in neonatal rats, particularly between 7 and 14 days after HIBD. Moreover, intraperitoneal injection of exogenous bFGF enhanced cell proliferation in the hippocampal DG following neonatal HIBD. Taken together, these data indicate that cell proliferation in the DG could be induced by neonatal HIBD, and bFGF promotes proliferation following neonatal HIBD. Copyright © 2018 Elsevier B.V. All rights reserved.

  15. Hypothalamic-pituitary-adrenal axis tonus is associated with hippocampal microstructural asymmetry

    DEFF Research Database (Denmark)

    Madsen, Kathrine Skak; Jernigan, Terry L; Iversen, Pernille

    2012-01-01

    It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since there is gr......It is well-established that prolonged high levels of cortisol have adverse effects on hippocampal neurons and glial cells. Morphometric studies linking hippocampus volume to basal HPA-axis activity, however, have yielded less consistent results. Asymmetry may also be considered, since....... Observed associations raise a number of possibilities, among them an asymmetric role of the hippocampus on HPA-axis regulation, or conversely, that individual variations in secreted cortisol, perhaps associated with stress, may have lateralized effects on hippocampal microstructure. Our results point...

  16. Unpacking the cognitive map: the parallel map theory of hippocampal function.

    Science.gov (United States)

    Jacobs, Lucia F; Schenk, Françoise

    2003-04-01

    In the parallel map theory, the hippocampus encodes space with 2 mapping systems. The bearing map is constructed primarily in the dentate gyrus from directional cues such as stimulus gradients. The sketch map is constructed within the hippocampus proper from positional cues. The integrated map emerges when data from the bearing and sketch maps are combined. Because the component maps work in parallel, the impairment of one can reveal residual learning by the other. Such parallel function may explain paradoxes of spatial learning, such as learning after partial hippocampal lesions, taxonomic and sex differences in spatial learning, and the function of hippocampal neurogenesis. By integrating evidence from physiology to phylogeny, the parallel map theory offers a unified explanation for hippocampal function.

  17. β-Adrenoceptor activation depresses brain inflammation and is neuroprotective in lipopolysaccharide-induced sensitization to oxygen-glucose deprivation in organotypic hippocampal slices

    Directory of Open Access Journals (Sweden)

    Cilio Corrado

    2010-12-01

    Full Text Available Abstract Background Inflammation acting in synergy with brain ischemia aggravates perinatal ischemic brain damage. The sensitizing effect of pro-inflammatory exposure prior to hypoxia is dependent on signaling by TNF-α through TNF receptor (TNFR 1. Adrenoceptor (AR activation is known to modulate the immune response and synaptic transmission. The possible protective effect of α˜ and β˜AR activation against neuronal damage caused by tissue ischemia and inflammation, acting in concert, was evaluated in murine hippocampal organotypic slices treated with lipopolysaccharide (LPS and subsequently subjected to oxygen-glucose deprivation (OGD. Method Hippocampal slices from mice were obtained at P6, and were grown in vitro for 9 days on nitrocellulose membranes. Slices were treated with β1(dobutamine-, β2(terbutaline-, α1(phenylephrine- and α2(clonidine-AR agonists (5 and 50 μM, respectively during LPS (1 μg/mL, 24 h -exposure followed by exposure to OGD (15 min in a hypoxic chamber. Cell death in the slice CA1 region was assessed by propidium iodide staining of dead cells. Results Exposure to LPS + OGD caused extensive cell death from 4 up to 48 h after reoxygenation. Co-incubation with β1-agonist (50 μM during LPS exposure before OGD conferred complete protection from cell death (P -/- and TNFR2-/- slices exposed to LPS followed by OGD. Conclusions Our data demonstrate that activation of both β1- and β2-receptors is neuroprotective and may offer mechanistic insights valuable for development of neuro-protective strategies in neonates.

  18. Neuropsychology, Autobiographical Memory, and Hippocampal Volume in “Younger” and “Older” Patients with Chronic Schizophrenia

    Science.gov (United States)

    Herold, Christina Josefa; Lässer, Marc Montgomery; Schmid, Lena Anna; Seidl, Ulrich; Kong, Li; Fellhauer, Iven; Thomann, Philipp Arthur; Essig, Marco; Schröder, Johannes

    2015-01-01

    Despite a wide range of studies on neuropsychology in schizophrenia, autobiographical memory (AM) has been scarcely investigated in these patients. Hence, less is known about AM in older patients and hippocampal contribution to autobiographical memories of varying remoteness. Therefore, we investigated hippocampal volume and AM along with important neuropsychological domains in patients with chronic schizophrenia and the respective relationships between these parameters. We compared 25 older patients with chronic schizophrenia to 23 younger patients and an older healthy control group (N = 21) with respect to AM, additional neuropsychological parameters, and hippocampal volume. Personal episodic and semantic memory was investigated using a semi-structured interview. Additional neuropsychological parameters were assessed by using a battery of standard neuropsychological tests. Structural magnetic resonance imaging data were analyzed with an automated region-of-interest procedure. While hippocampal volume reduction and neuropsychological impairment were more pronounced in the older than in the younger patients, both groups showed equivalent reduced AM performance for recent personal episodes. In the patient group, significant correlations between left hippocampal volume and recent autobiographical episodes as well as personal semantic memories arose. Verbal memory and working memory were significantly correlated with right hippocampal volume; executive functions, however, were associated with bilateral hippocampal volumes. These findings underline the complexity of AM and its impairments in the course of schizophrenia in comparison to rather progressive neuropsychological deficits and address the importance of hippocampal contribution. PMID:25954208

  19. Neogenin, a regulator of adult hippocampal neurogenesis, prevents depressive-like behavior.

    Science.gov (United States)

    Sun, Dong; Sun, Xiang-Dong; Zhao, Lu; Lee, Dae-Hoon; Hu, Jin-Xia; Tang, Fu-Lei; Pan, Jin-Xiu; Mei, Lin; Zhu, Xiao-Juan; Xiong, Wen-Cheng

    2018-01-08

    Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

  20. Five-year retrospective changes in hippocampal atrophy and cognitive screening test performances in very mild Alzheimer's disease: the Tajiri Project

    Energy Technology Data Exchange (ETDEWEB)

    Yamaguchi, S.; Meguro, K.; Shimada, M.; Ishizaki, J.; Yamadori, A. [Division of Neuropsychology, Department of Disability Medicine, Tohoku University Graduate School of Medicine, Sendai (Japan); Sekita, Y. [Tohoku University Graduate School of Economics, Sendai (Japan)

    2002-01-01

    The medial temporal lobe, especially the hippocampus, is important for normal cognitive function, especially for memory, and is the region with the earliest and most extensive pathological changes in Alzheimer's disease (AD). We investigated the atrophic changes of the hippocampus over a 5-year period and its relation to cognitive screening test performances in normal elderly subjects, those with very mild AD, and patients with AD. Fifty-seven elderly subjects without a moderate or greater degree of cerebrovascular disease as shown by MRI were randomly selected from the town of Tajiri. Thirty-three subjects with a clinical dementia rating (CDR) of 0 (normal), 18 CDR-0.5 (very mild AD) subjects, and six CDR-1 and 2 (AD) subjects underwent MRI and the Mini Mental State Examination (MMSE) twice during the period. Retrospective changes in the hippocampal width and the MMSE scores were evaluated. There were significant CDR group effects for the changes in the mean bilateral hippocampal widths and the MMSE scores. Normal subjects did not show cognitive decline, although there was a slight tendency for hippocampal atrophy. A significant and meaningful Spearman's correlation was noted between left hippocampal atrophy and the MMSE scores over the 5-year period for the CDR-0.5 group. These CDR-0.5 subjects met the MCI (mild cognitive impairment) criteria as proposed by the consensus paper. Findings suggested that normal elderly subjects maintain a high level of cognitive functions for at least 5 years, although hippocampal atrophy might occur. Atrophic change of the left hippocampus might be a good marker of the very early stage of AD. (orig.)

  1. Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Farah Chamaa

    2018-05-01

    Full Text Available The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O is an N-methyl-D-aspartic acid (NMDA antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2. Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.

  2. Hippocampal activation during face-name associative memory encoding: blocked versus permuted design

    International Nuclear Information System (INIS)

    De Vogelaere, Frederick; Vingerhoets, Guy; Santens, Patrick; Boon, Paul; Achten, Erik

    2010-01-01

    The contribution of the hippocampal subregions to episodic memory through the formation of new associations between previously unrelated items such as faces and names is established but remains under discussion. Block design studies in this area of research generally tend to show posterior hippocampal activation during encoding of novel associational material while event-related studies emphasize anterior hippocampal involvement. We used functional magnetic resonance imaging to assess the involvement of anterior and posterior hippocampus in the encoding of novel associational material compared to the viewing of previously seen associational material. We used two different experimental designs, a block design and a permuted block design, and applied it to the same associative memory task to perform valid statistical comparisons. Our results indicate that the permuted design was able to capture more anterior hippocampal activation compared to the block design, which emphasized more posterior hippocampal involvement. These differences were further investigated and attributed to a combination of the polymodal stimuli we used and the experimental design. Activation patterns during encoding in both designs occurred along the entire longitudinal axis of the hippocampus, but with different centers of gravity. The maximal activated voxel in the block design was situated in the posterior half of the hippocampus while in the permuted design this was located in the anterior half. (orig.)

  3. Hippocampal activation during face-name associative memory encoding: blocked versus permuted design

    Energy Technology Data Exchange (ETDEWEB)

    De Vogelaere, Frederick; Vingerhoets, Guy [Ghent University, Laboratory for Neuropsychology, Department of Neurology, Ghent (Belgium); Santens, Patrick; Boon, Paul [Ghent University Hospital, Department of Neurology, Ghent (Belgium); Achten, Erik [Ghent University Hospital, Department of Radiology, Ghent (Belgium)

    2010-01-15

    The contribution of the hippocampal subregions to episodic memory through the formation of new associations between previously unrelated items such as faces and names is established but remains under discussion. Block design studies in this area of research generally tend to show posterior hippocampal activation during encoding of novel associational material while event-related studies emphasize anterior hippocampal involvement. We used functional magnetic resonance imaging to assess the involvement of anterior and posterior hippocampus in the encoding of novel associational material compared to the viewing of previously seen associational material. We used two different experimental designs, a block design and a permuted block design, and applied it to the same associative memory task to perform valid statistical comparisons. Our results indicate that the permuted design was able to capture more anterior hippocampal activation compared to the block design, which emphasized more posterior hippocampal involvement. These differences were further investigated and attributed to a combination of the polymodal stimuli we used and the experimental design. Activation patterns during encoding in both designs occurred along the entire longitudinal axis of the hippocampus, but with different centers of gravity. The maximal activated voxel in the block design was situated in the posterior half of the hippocampus while in the permuted design this was located in the anterior half. (orig.)

  4. Neuroprotective mechanism of Kai Xin San: upregulation of hippocampal insulin-degrading enzyme protein expression and acceleration of amyloid-beta degradation

    Directory of Open Access Journals (Sweden)

    Na Wang

    2017-01-01

    Full Text Available Kai Xin San is a Chinese herbal formula composed of Radix Ginseng , Poria , Radix Polygalae and Acorus Tatarinowii Rhizome . It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β (Aβ-induced cognitive dysfunction and is neuroprotective in vivo , but its precise mechanism remains unclear. Expression of insulin-degrading enzyme (IDE, which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42 (200 μM, 5 μL into the hippocampus and subsequently administered Kai Xin San (0.54 or 1.08 g/kg/d intragastrically for 21 consecutive days. Hematoxylin-eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme-linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not mRNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.

  5. Kindled seizures selectively reduce a subpopulation of (/sup 3/H)quinuclidinyl benzilate binding sites in rat dentate gyrus

    Energy Technology Data Exchange (ETDEWEB)

    Savage, D.D.; McNamara, J.O.

    1982-09-01

    Amygdala-kindled seizures reduced significantly the total number of (/sup 3/H)quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis.

  6. Effects of Estradiol on Learned Helplessness and Associated Remodeling of Hippocampal Spine Synapses in Female Rats

    Science.gov (United States)

    Hajszan, Tibor; Szigeti-Buck, Klara; Sallam, Nermin L; Bober, Jeremy; Parducz, Arpad; MacLusky, Neil J; Leranth, Csaba; Duman, Ronald S

    2009-01-01

    Background Despite the fact that women are twice as likely to develop depression as men, our understanding of depression neurobiology in females is limited. We have recently reported in male rats that development of helpless behavior is associated with a severe loss of hippocampal spine synapses, which is reversed by treatment with the antidepressant, desipramine. Considering the fact that estradiol has a hippocampal synaptogenic effect similar to those of antidepressants, the presence of estradiol during the female reproductive life may influence behavioral and synaptic responses to stress and depression. Methods Using electron microscopic stereology, we analyzed hippocampal spine synapses in association with helpless behavior in ovariectomized female rats (n=70), under different conditions of estradiol exposure. Results Stress induced an acute and persistent loss of hippocampal spine synapses, while subchronic treatment with desipramine reversed the stress-induced synaptic loss. Estradiol supplementation given either prior to stress or prior to escape testing of nonstressed animals both increased the number of hippocampal spine synapses. Correlation analysis demonstrated a statistically significant negative correlation between the severity of helpless behavior and hippocampal spine synapse numbers. Conclusions These findings suggest that hippocampal spine synapse remodeling may be a critical factor underlying learned helplessness and, possibly, the neurobiology of depression. PMID:19811775

  7. Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight.

    Science.gov (United States)

    Coplan, Jeremy D; Fathy, Hassan M; Abdallah, Chadi G; Ragab, Sherif A; Kral, John G; Mao, Xiangling; Shungu, Dikoma C; Mathew, Sanjay J

    2014-01-01

    We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis - a form of neuroplasticity - and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging ((1)H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted.

  8. Reduced hippocampal N-acetyl-aspartate (NAA) as a biomarker for overweight☆

    Science.gov (United States)

    Coplan, Jeremy D.; Fathy, Hassan M.; Abdallah, Chadi G.; Ragab, Sherif A.; Kral, John G.; Mao, Xiangling; Shungu, Dikoma C.; Mathew, Sanjay J.

    2014-01-01

    Objective We previously demonstrated an inverse relationship between both dentate gyrus neurogenesis – a form of neuroplasticity – and expression of the antiapoptotic gene marker, BCL-2 and adult macaque body weight. We therefore explored whether a similar inverse correlation existed in humans between body mass index (BMI) and hippocampal N-acetyl-aspartate (NAA), a marker of neuronal integrity and putatively, neuroplasticity. We also studied the relationship of a potentially neurotoxic process, worry, to hippocampal NAA in patients with generalized anxiety disorder (GAD) and control subjects (CS). Methods We combined two previously studied cohorts of GAD and control subjects. Using proton magnetic resonance spectroscopy imaging (1H MRSI) in medication-free patients with GAD (n = 29) and a matched healthy control group (n = 22), we determined hippocampal concentrations of (1) NAA (2) choline containing compounds (CHO), and (3) Creatine + phosphocreatine (CR). Data were combined from 1.5 T and 3 T scans by converting values from each cohort to z-scores. Overweight and GAD diagnosis were used as categorical variables while the Penn State Worry Questionnaire (PSWQ) and Anxiety Sensitivity Index (ASI) were used as dependent variables. Results Overweight subjects (BMI ≥ 25) exhibited lower NAA levels in the hippocampus than normal-weight subjects (BMI NAA and BMI. High scores on the PSWQ predicted low hippocampal NAA and CR. Both BMI and worry were independent inverse predictors of hippocampal NAA. Conclusion Overweight was associated with reduced NAA concentrations in the hippocampus with a strong effect size. Future mechanistic studies are warranted. PMID:24501701

  9. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

    Science.gov (United States)

    Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

    2018-02-15

    The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. Hippocampal structure and function are maintained despite severe innate peripheral inflammation.

    Science.gov (United States)

    Süß, Patrick; Kalinichenko, Liubov; Baum, Wolfgang; Reichel, Martin; Kornhuber, Johannes; Loskarn, Sandra; Ettle, Benjamin; Distler, Jörg H W; Schett, Georg; Winkler, Jürgen; Müller, Christian P; Schlachetzki, Johannes C M

    2015-10-01

    Chronic peripheral inflammation mediated by cytokines such as TNFα, IL-1β, and IL-6 is associated with psychiatric disorders like depression and anxiety. However, it remains elusive which distinct type of peripheral inflammation triggers neuroinflammation and affects hippocampal plasticity resulting in depressive-like behavior. We hypothesized that chronic peripheral inflammation in the human TNF-α transgenic (TNFtg) mouse model of rheumatoid arthritis spreads into the central nervous system and induces depressive state manifested in specific behavioral pattern and impaired adult hippocampal neurogenesis. TNFtg mice showed severe erosive arthritis with increased IL-1β and IL-6 expression in tarsal joints with highly elevated human TNF-α levels in the serum. Intriguingly, IL-1β and IL-6 mRNA levels were not altered in the hippocampus of TNFtg mice. In contrast to the pronounced monocytosis in joints and spleen of TNFtg mice, signs of hippocampal microgliosis or astrocytosis were lacking. Furthermore, locomotion was impaired, but there was no locomotion-independent depressive behavior in TNFtg mice. Proliferation and maturation of hippocampal neural precursor cells as well as survival of newly generated neurons were preserved in the dentate gyrus of TNFtg mice despite reduced motor activity and peripheral inflammatory signature. We conclude that peripheral inflammation in TNFtg mice is mediated by chronic activation of the innate immune system. However, severe peripheral inflammation, though impairing locomotor activity, does not elicit depressive-like behavior. These structural and functional findings indicate the maintenance of hippocampal immunity, cellular plasticity, and behavior despite peripheral innate inflammation. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Gradient COUP-TFI Expression Is Required for Functional Organization of the Hippocampal Septo-Temporal Longitudinal Axis.

    Science.gov (United States)

    Flore, Gemma; Di Ruberto, Giuseppina; Parisot, Joséphine; Sannino, Sara; Russo, Fabio; Illingworth, Elizabeth A; Studer, Michèle; De Leonibus, Elvira

    2017-02-01

    The hippocampus (HP), a medial cortical structure, is subdivided into a distinct dorsal (septal) and ventral (temporal) portion, which is separated by an intermediate region lying on a longitudinal curvature. While the dorsal portion is more dedicated to spatial navigation and memory, the most ventral part processes emotional information. Genetic factors expressed in gradient during development seem to control the size and correct positioning of the HP along its longitudinal axis; however, their roles in regulating differential growth and in supporting its anatomical and functional dissociation remain unexplored. Here, we challenge the in vivo function of the nuclear receptor COUP-TFI (chicken ovalbumin upstream promoter transcription factor 1) in controlling the hippocampal, anatomical, and functional properties along its longitudinal axis. Loss of cortical COUP-TFI function results in a dysmorphic HP with altered shape, volume, and connectivity, particularly in its dorsal and intermediate regions. Notably, topographic inputs from the entorhinal cortex are strongly impaired in the dorsal portion of COUP-TFI mutants. These severe morphological changes are associated with selective spatial learning and memory impairment. These findings identify a novel transcriptional regulator required in the functional organization along the hippocampal septo-temporal axis supporting a genetic basis of the hippocampal volumetric growth with its final shape, circuit, and type of memory function. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    Directory of Open Access Journals (Sweden)

    Eleni Paizanis

    2007-01-01

    Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

  13. Relationships between hippocampal activity and breathing patterns

    DEFF Research Database (Denmark)

    Harper, R M; Poe, G R; Rector, D M

    1998-01-01

    Single cell discharge, EEG activity, and optical changes accompanying alterations in breathing patterns, as well as the knowledge that respiratory musculature is heavily involved in movement and other behavioral acts, implicate hippocampal regions in some aspects of breathing control. The control...... is unlikely to reside in oscillatory breathing movements, because such patterns emerge in preparations retaining only the medulla (and perhaps only the spinal cord). However, momentary changes in breathing patterns induced by affect, startle, whole-body movement changes, or compensatory ventilatory changes...... of hippocampal contributions to breathing control should be viewed in the context that significant interactions exist between blood pressure changes and ventilation, and that modest breathing challenges, such as exposure to hypercapnia or to increased resistive loads, bring into action a vast array of brain...

  14. MDMA enhances hippocampal-dependent learning and memory under restrictive conditions, and modifies hippocampal spine density.

    Science.gov (United States)

    Abad, Sònia; Fole, Alberto; del Olmo, Nuria; Pubill, David; Pallàs, Mercè; Junyent, Fèlix; Camarasa, Jorge; Camins, Antonio; Escubedo, Elena

    2014-03-01

    Addictive drugs produce forms of structural plasticity in the nucleus accumbens and prefrontal cortex. The aim of this study was to investigate the impact of chronic MDMA exposure on pyramidal neurons in the CA1 region of hippocampus and drug-related spatial learning and memory changes. Adolescent rats were exposed to saline or MDMA in a regime that mimicked chronic administration. One week later, when acquisition or reference memory was evaluated in a standard Morris water maze (MWM), no differences were obtained between groups. However, MDMA-exposed animals performed better when the MWM was implemented under more difficult conditions. Animals of MDMA group were less anxious and were more prepared to take risks, as in the open field test they ventured more frequently into the central area. We have demonstrated that MDMA caused an increase in brain-derived neurotrophic factor (BDNF) expression. When spine density was evaluated, MDMA-treated rats presented a reduced density when compared with saline, but overall, training increased the total number of spines, concluding that in MDMA-group, training prevented a reduction in spine density or induced its recovery. This study provides support for the conclusion that binge administration of MDMA, known to be associated to neurotoxic damage of hippocampal serotonergic terminals, increases BDNF expression and stimulates synaptic plasticity when associated with training. In these conditions, adolescent rats perform better in a more difficult water maze task under restricted conditions of learning and memory. The effect on this task could be modulated by other behavioural changes provoked by MDMA.

  15. Taxonomic separation of hippocampal networks: principal cell populations and adult neurogenesis

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    Roelof Maarten evan Dijk

    2016-03-01

    Full Text Available While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non

  16. Neuroprotective effects of oxysophocarpine on neonatal rat primary cultured hippocampal neurons injured by oxygen-glucose deprivation and reperfusion.

    Science.gov (United States)

    Zhu, Qing-Luan; Li, Yu-Xiang; Zhou, Ru; Ma, Ning-Tian; Chang, Ren-Yuan; Wang, Teng-Fei; Zhang, Yi; Chen, Xiao-Ping; Hao, Yin-Ju; Jin, Shao-Ju; Ma, Lin; Du, Juan; Sun, Tao; Yu, Jian-Qiang

    2014-08-01

    Oxysophocarpine (OSC), a quinolizidine alkaloid extracted from leguminous plants of the genus Robinia, is traditionally used for various diseases including neuronal disorders. This study investigated the protective effects of OSC on neonatal rat primary-cultured hippocampal neurons were injured by oxygen-glucose deprivation and reperfusion (OGD/RP). Cultured hippocampal neurons were exposed to OGD for 2 h followed by a 24 h RP. OSC (1, 2, and 5 μmol/L) and nimodipine (Nim) (12 μmol/L) were added to the culture after OGD but before RP. The cultures of the control group were not exposed to OGD/RP. MTT and LDH assay were used to evaluate the protective effects of OSC. The concentration of intracellular-free calcium [Ca(2+)]i and mitochondrial membrane potential (MMP) were determined to evaluate the degree of neuronal damage. Morphologic changes of neurons following OGD/RP were observed with a microscope. The expression of caspase-3 and caspase-12 mRNA was examined by real-time quantitative PCR. The IC50 of OSC was found to be 100 μmol/L. Treatment with OSC (1, 2, and 5 μmol/L) attenuated neuronal damage (p < 0.001), with evidence of increased cell viability (p < 0.001) and decreased cell morphologic impairment. Furthermore, OSC increased MMP (p < 0.001), but it inhibited [Ca(2+)]i (p < 0.001) elevation in a dose-dependent manner at OGD/RP. OSC (5 μmol/L) also decreased the expression of caspase-3 (p < 0.05) and caspase-12 (p < 0.05). The results suggested that OSC has significant neuroprotective effects that can be attributed to inhibiting endoplasmic reticulum (ER) stress-induced apoptosis.

  17. Memory Dysfunction in Type 2 Diabetes Mellitus Correlates with Reduced Hippocampal CA1 and Subiculum Volumes

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    Yan-Wei Zhang

    2015-01-01

    Full Text Available Background: Little attention has been paid to the role of subcortical deep gray matter (SDGM structures in type 2 diabetes mellitus (T2DM-induced cognitive impairment, especially hippocampal subfields. Our aims were to assess the in vivo volumes of SDGM structures and hippocampal subfields using magnetic resonance imaging (MRI and to test their associations with cognitive performance in T2DM. Methods: A total of 80 T2DM patients and 80 neurologically unimpaired healthy controls matched by age, sex and education level was enrolled in this study. We assessed the volumes of the SDGM structures and seven hippocampal subfields on MRI using a novel technique that enabled automated volumetry. We used Mini-Mental State Examination and Montreal Cognitive Assessment (MoCA scores as measures of cognitive performance. The association of glycosylated hemoglobin (HbA1c with SDGM structures and neuropsychological tests and correlations between hippocampal subfields and neuropsychological tests were assessed by partial correlation analysis in T2DM. Results: Bilaterally, the hippocampal volumes were smaller in T2DM patients, mainly in the CA1 and subiculum subfields. Partial correlation analysis showed that the MoCA scores, particularly those regarding delayed memory, were significantly positively correlated with reduced hippocampal CA1 and subiculum volumes in T2DM patients. Additionally, higher HbA1c levels were significantly associated with poor memory performance and hippocampal atrophy among T2DM patients. Conclusions: These data indicate that the hippocampus might be the main affected region among the SDGM structures in T2DM. These structural changes in the hippocampal CA1 and subiculum areas might be at the core of underlying neurobiological mechanisms of hippocampal dysfunction, suggesting that degeneration in these regions could be responsible for memory impairments in T2DM patients.

  18. Salvianolic Acids Attenuate Rat Hippocampal Injury after Acute CO Poisoning by Improving Blood Flow Properties

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    Li Guan

    2015-01-01

    Full Text Available Carbon monoxide (CO poisoning causes the major injury and death due to poisoning worldwide. The most severe damage via CO poisoning is brain injury and mortality. Delayed encephalopathy after acute CO poisoning (DEACMP occurs in forty percent of the survivors of acute CO exposure. But the pathological cause for DEACMP is not well understood. And the corresponding therapy is not well developed. In order to investigate the effects of salvianolic acid (SA on brain injury caused by CO exposure from the view point of hemorheology, we employed a rat model and studied the dynamic of blood changes in the hemorheological and coagulative properties over acute CO exposure. Compared with the groups of CO and 20% mannitol + CO treatments, the severe hippocampal injury caused by acute CO exposure was prevented by SA treatment. These protective effects were associated with the retaining level of hematocrit (Hct, plasma viscosity, fibrinogen, whole blood viscosities and malondialdehyde (MDA levels in red blood cells (RBCs. These results indicated that SA treatment could significantly improve the deformation of erythrocytes and prevent the damage caused by CO poisoning. Meanwhile, hemorheological indexes are good indicators for monitoring the pathological dynamic after acute CO poisoning.

  19. Maturation- and sex-sensitive depression of hippocampal excitatory transmission in a rat schizophrenia model.

    Science.gov (United States)

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Schizophrenia is associated with behavioral and brain structural abnormalities, of which the hippocampus appears to be one of the most consistent region affected. Previous studies performed on the poly I:C model of schizophrenia suggest that alterations in hippocampal synaptic transmission and plasticity take place in the offspring. However, these investigations yielded conflicting results and the neurophysiological alterations responsible for these deficits are still unclear. Here we performed for the first time a longitudinal study examining the impact of prenatal poly I:C treatment and of gender on hippocampal excitatory neurotransmission. In addition, we examined the potential preventive/curative effects of risperidone (RIS) treatment during the peri-adolescence period. Excitatory synaptic transmission was determined by stimulating Schaffer collaterals and monitoring fiber volley amplitude and slope of field-EPSP (fEPSP) in CA1 pyramidal neurons in male and female offspring hippocampal slices from postnatal days (PNDs) 18-20, 34, 70 and 90. Depression of hippocampal excitatory transmission appeared at juvenile age in male offspring of the poly I:C group, while it expressed with a delay in female, manifesting at adulthood. In addition, a reduced hippocampal size was found in both adult male and female offspring of poly I:C treated dams. Treatment with RIS at the peri-adolescence period fully restored in males but partly repaired in females these deficiencies. A maturation- and sex-dependent decrease in hippocampal excitatory transmission occurs in the offspring of poly I:C treated pregnant mothers. Pharmacological intervention with RIS during peri-adolescence can cure in a gender-sensitive fashion early occurring hippocampal synaptic deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement.

    Directory of Open Access Journals (Sweden)

    Giuseppe Esposito

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPARγ has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD. Cannabidiol (CBD, a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.

  1. Neuroprotective effects of oleuropein against cognitive dysfunction induced by colchicine in hippocampal CA1 area in rats.

    Science.gov (United States)

    Pourkhodadad, Soheila; Alirezaei, Masoud; Moghaddasi, Mehrnoush; Ahmadvand, Hassan; Karami, Manizheh; Delfan, Bahram; Khanipour, Zahra

    2016-09-01

    Alzheimer's disease is a progressive neurodegenerative disorder with decline in memory. The role of oxidative stress is well known in the pathogenesis of the disease. The purpose of this study was to evaluate pretreatment effects of oleuropein on oxidative status and cognitive dysfunction induced by colchicine in the hippocampal CA1 area. Male Wistar rats were pretreated orally once daily for 10 days with oleuropein at doses of 10, 15 and 20 mg/kg. Thereafter, colchicine (15 μg/rat) was administered into the CA1 area of the hippocampus to induce cognitive dysfunction. The Morris water maze was used to assess learning and memory. Biochemical parameters such as glutathione peroxidase and catalase activities, nitric oxide and malondialdehyde concentrations were measured to evaluate the antioxidant status in the rat hippocampus. Our results indicated that colchicine significantly impaired spatial memory and induced oxidative stress; in contrast, oleuropein pretreatment significantly improved learning and memory retention, and attenuated the oxidative damage. The results clearly indicate that oleuropein has neuroprotective effects against colchicine-induced cognitive dysfunction and oxidative damage in rats.

  2. Protective effects of hydroponic Teucrium polium on hippocampal neurodegeneration in ovariectomized rats.

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    Simonyan, K V; Chavushyan, V A

    2016-10-24

    The hippocampus is a target of ovarian hormones, and is necessary for memory. Ovarian hormone loss is associated with a progressive reduction in synaptic strength and dendritic spine. Teucrium polium has beneficial effects on learning and memory. However, it remains unknown whether Teucrium polium ameliorates hippocampal cells spike activity and morphological impairments induced by estrogen deficiency. In the present study, we investigated the effects of hydroponic Teucrium polium on hippocampal neuronal activity and morpho-histochemistry of bilateral ovariectomized (OVX) rats. Tetanic potentiation or depression with posttetanic potentiation and depression was recorded extracellularly in response to ipsilateral entorhinal cortex high frequency stimulation. In morpho-histochemical study revealing of the activity of Ca 2+ -dependent acid phosphatase was observed. In all groups (sham-operated, sham + Teucrium polium, OVX, OVX + Teucrium polium), most recorded hippocampal neurons at HFS of entorhinal cortex showed TD-PTP responses. After 8 weeks in OVX group an anomalous evoked spike activity was detected (a high percentage of typical areactive units). In OVX + Teucrium polium group a synaptic activity was revealed, indicating prevention OVX-induced degenerative alterations: balance of types of responses was close to norm and areactive units were not recorded. All recorded neurons in sham + Teucrium polium group were characterized by the highest mean frequency background and poststimulus activity. In OVX+ Teucrium polium group the hippocampal cells had recovered their size and shape in CA1 and CA3 field compared with OVX group where hippocampal cells were characterized by a sharp drop in phosphatase activity and there was a complete lack of processes reaction. Thus, Teucrium polium reduced OVX-induce neurodegenerative alterations in entorhinal cortex-hippocamp circuitry and facilitated neuronal survival by modulating activity of neurotransmitters and

  3. A proteomics study of hyperhomocysteinemia injury of the hippocampal neurons using iTRAQ.

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    Fang, Min; Wang, Jing; Yan, Han; Zhao, Yan-Xin; Liu, Xue-Yuan

    2014-11-01

    High levels of homocysteine, caused by abnormal methionine metabolism, can induce degeneration of mouse hippocampal neurons. iTRAQ™ technology has been widely used in the field of proteomics research and through employing this technology, the present study identified that hyperhomocysteinemia induced the downregulation of 52 proteins and upregulation of 44 proteins in the mouse hippocampus. Through gene ontology and pathway analysis, the upregulation of components of the cytoskeleton, actin, regulators of focal adhesion, calcium signaling pathways, tight junctions, ErbB and gonadotrophin‑releasing hormone signaling, leukocyte, transendothelial migration, propanoate and pyruvate metabolism, valine, leucine and isoleucine biosynthesis, synthesis and degradation of ketone bodies and benzoate degradation via CoA ligation pathway, was identified. It was additionally verified that tau protein was highly expressed in the hyperhomocysteinemic neurons. Further analysis revealed that tau network proteins played functional roles in homocysteine‑induced neuronal damage.

  4. Estradiol and luteinizing hormone regulate recognition memory following subchronic phencyclidine: Evidence for hippocampal GABA action.

    Science.gov (United States)

    Riordan, Alexander J; Schaler, Ari W; Fried, Jenny; Paine, Tracie A; Thornton, Janice E

    2018-05-01

    The cognitive symptoms of schizophrenia are poorly understood and difficult to treat. Estrogens may mitigate these symptoms via unknown mechanisms. To examine these mechanisms, we tested whether increasing estradiol (E) or decreasing luteinizing hormone (LH) could mitigate short-term episodic memory loss in a phencyclidine (PCP) model of schizophrenia. We then assessed whether changes in cortical or hippocampal GABA may underlie these effects. Female rats were ovariectomized and injected subchronically with PCP. To modulate E and LH, animals received estradiol capsules or Antide injections. Short-term episodic memory was assessed using the novel object recognition task (NORT). Brain expression of GAD67 was analyzed via western blot, and parvalbumin-containing cells were counted using immunohistochemistry. Some rats received hippocampal infusions of a GABA A agonist, GABA A antagonist, or GAD inhibitor before behavioral testing. We found that PCP reduced hippocampal GAD67 and abolished recognition memory. Antide restored hippocampal GAD67 and rescued recognition memory in PCP-treated animals. Estradiol prevented PCP's amnesic effect in NORT but failed to restore hippocampal GAD67. PCP did not cause significant differences in number of parvalbumin-expressing cells or cortical expression of GAD67. Hippocampal infusions of a GABA A agonist restored recognition memory in PCP-treated rats. Blocking hippocampal GAD or GABA A receptors in ovx animals reproduced recognition memory loss similar to PCP and inhibited estradiol's protection of recognition memory in PCP-treated animals. In summary, decreasing LH or increasing E can lessen short-term episodic memory loss, as measured by novel object recognition, in a PCP model of schizophrenia. Alterations in hippocampal GABA may contribute to both PCP's effects on recognition memory and the hormones' ability to prevent or reverse them. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Membrane protein damage and repair: selective loss of a quinone-protein function in chloroplast membranes

    International Nuclear Information System (INIS)

    Kyle, D.J.; Ohad, I.; Arntzen, C.J.

    1984-01-01

    A loss of electron transport capacity in chloroplast membranes was induced by high-light intensities (photoinhibition). The primary site of inhibition was at the reducing side of photosystem II (PSII) with little damage to the oxidizing side or to the reaction center core of PSII. Addition of herbicides (atrazine or diuron) partially protected the membrane from photoinhibition; these compounds displace the bound plastoquinone (designated as Q/sub B/), which functions as the secondary electron acceptor on the reducing side of PSII. Loss of function of the 32-kilodalton Q/sub B/ apoprotein was demonstrated by a loss of binding sites for [ 14 C]atraazine. We suggest that quinone anions, which may interact with molecular oxygen to produce an oxygen radical, selectively damage the apoprotein of the secondary acceptor of PSII, thus rendering it inactive and thereby blocking photosynthetic electron flow under conditions of high photon flux densities. 21 references, 4 figures, 2 tables

  6. Susceptibility to hippocampal kindling seizures is increased in aging C57 black mice

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    Kurt R. Stover

    2017-12-01

    Full Text Available The incidence of seizures increases with old age. Stroke, dementia and brain tumors are recognized risk factors for new-onset seizures in the aging populations and the incidence of these conditions also increased with age. Whether aging is associated with higher seizure susceptibility in the absence of the above pathologies remains unclear. We used classic kindling to explore this issue as the kindling model is highly reproducible and allows close monitoring of electrographic and motor seizure activities in individual animals. We kindled male young and aging mice (C57BL/6 strain, 2–3 and 18–22 months of age via daily hippocampal CA3 stimulation and monitored seizure activity via video and electroencephalographic recordings. The aging mice needed fewer stimuli to evoke stage-5 motor seizures and exhibited longer hippocampal afterdischarges and more frequent hippocampal spikes relative to the young mice, but afterdischarge thresholds and cumulative afterdischarge durations to stage 5 motor seizures were not different between the two age groups. While hippocampal injury and structural alterations at cellular and micro-circuitry levels remain to be examined in the kindled mice, our present observations suggest that susceptibility to hippocampal CA3 kindling seizures is increased with aging in male C57 black mice.

  7. Prevention of Severe Hypoglycemia-Induced Brain Damage and Cognitive Impairment with Verapamil.

    Science.gov (United States)

    Jackson, David A; Michael, Trevin; Vieira de Abreu, Adriana; Agrawal, Rahul; Bortolato, Marco; Fisher, Simon J

    2018-05-03

    People with insulin-treated diabetes are uniquely at risk for severe hypoglycemia-induced brain damage. Since calcium influx may mediate brain damage, we tested the hypothesis that the calcium channel blocker, verapamil, would significantly reduce brain damage and cognitive impairment caused by severe hypoglycemia. Ten-week-old Sprague-Dawley rats were randomly assigned to one of three treatments; 1) control hyperinsulinemic (200 mU.kg -1 min -1 ) euglycemic (80-100mg/dl) clamps (n=14), 2) hyperinsulinemic hypoglycemic (10-15mg/dl) clamps (n=16), or 3) hyperinsulinemic hypoglycemic clamps followed by a single treatment with verapamil (20mg/kg) (n=11). As compared to euglycemic controls, hypoglycemia markedly increased dead/dying neurons in the hippocampus and cortex, by 16-fold and 14-fold, respectively. Verapamil treatment strikingly decreased hypoglycemia-induced hippocampal and cortical damage, by 87% and 94%, respectively. Morris Water Maze probe trial results demonstrated that hypoglycemia induced a retention, but not encoding, memory deficit (noted by both abolished target quadrant preference and reduced target quadrant time). Verapamil treatment significantly rescued spatial memory as noted by restoration of target quadrant preference and target quadrant time. In summary, a one-time treatment with verapamil following severe hypoglycemia prevented neural damage and memory impairment caused by severe hypoglycemia. For people with insulin treated diabetes, verapamil may be a useful drug to prevent hypoglycemia-induced brain damage. © 2018 by the American Diabetes Association.

  8. Hippocampal CA1 transcriptional profile of sleep deprivation: relation to aging and stress.

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    Nada M Porter

    Full Text Available Many aging changes seem similar to those elicited by sleep-deprivation and psychosocial stress. Further, sleep architecture changes with age suggest an age-related loss of sleep. Here, we hypothesized that sleep deprivation in young subjects would elicit both stress and aging-like transcriptional responses.F344 rats were divided into control and sleep deprivation groups. Body weight, adrenal weight, corticosterone level and hippocampal CA1 transcriptional profiles were measured. A second group of animals was exposed to novel environment stress (NES, and their hippocampal transcriptional profiles measured. A third cohort exposed to control or SD was used to validate transcriptional results with Western blots. Microarray results were statistically contrasted with prior transcriptional studies. Microarray results pointed to sleep pressure signaling and macromolecular synthesis disruptions in the hippocampal CA1 region. Animals exposed to NES recapitulated nearly one third of the SD transcriptional profile. However, the SD-aging relationship was more complex. Compared to aging, SD profiles influenced a significant subset of genes. mRNA associated with neurogenesis and energy pathways showed agreement between aging and SD, while immune, glial, and macromolecular synthesis pathways showed SD profiles that opposed those seen in aging.We conclude that although NES and SD exert similar transcriptional changes, selective presynaptic release machinery and Homer1 expression changes are seen in SD. Among other changes, the marked decrease in Homer1 expression with age may represent an important divergence between young and aged brain response to SD. Based on this, it seems reasonable to conclude that therapeutic strategies designed to promote sleep in young subjects may have off-target effects in the aged. Finally, this work identifies presynaptic vesicular release and intercellular adhesion molecular signatures as novel therapeutic targets to counter

  9. Inhibitory effects of caffeine on hippocampal neurogenesis and function.

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    Han, Myoung-Eun; Park, Kyu-Hyun; Baek, Sun-Yong; Kim, Bong-Seon; Kim, Jae-Bong; Kim, Hak-Jin; Oh, Sae-Ock

    2007-05-18

    Caffeine is one of the most extensively consumed psychostimulants in the world. However, compared to short-term effects of caffeine, the long-term effects of caffeine consumption on learning and memory are poorly characterized. The present study found that long-term consumption of low dose caffeine (0.3 g/L) slowed hippocampus-dependent learning and impaired long-term memory. Caffeine consumption for 4 weeks also significantly reduced hippocampal neurogenesis compared to controls. From these results, we concluded that long-term consumption of caffeine could inhibit hippocampus-dependent learning and memory partially through inhibition of hippocampal neurogenesis.

  10. Hippocampal insulin resistance and cognitive dysfunction

    NARCIS (Netherlands)

    Biessels, Geert Jan; Reagan, Lawrence P.

    2015-01-01

    Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as

  11. Influence of parental care on offspring hippocampal volume in young adults varies as a function of overprotection.

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    Wang, Yinan; Song, Yiying; Li, Xueting; Zhang, Lin; Liu, Jia

    2017-04-12

    Parental care results in increased hippocampal volumes through adaptive stress responses in developing animals. However, human studies have not yet provided consistent findings analogous to the animal literature, possibly because parental care in humans is likely intermingled with parental overprotection, as suggested by the optimal parenting theory. Here, we tested the hypothesis that the effect of parental care on offspring hippocampal volume varies as a function of parental overprotection with a large cohort of young adult participants (N = 257). Consistent with some previous human studies, we found that parental care in childhood alone had little association with the hippocampal volume in adulthood. However, when parental overprotection was low, parental care was positively correlated with offspring hippocampal volume, whereas there was no association between parental care and offspring hippocampal volume when parental overprotection was high. Thus, an interaction exists between parental care and overprotection in human's hippocampal development, which contributes to the elucidation of the complex relationship between brain structure and environmental factors.

  12. Neuroprotective function for ramified microglia in hippocampal excitotoxicity

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    Vinet Jonathan

    2012-01-01

    Full Text Available Abstract Background Most of the known functions of microglia, including neurotoxic and neuroprotective properties, are attributed to morphologically-activated microglia. Resting, ramified microglia are suggested to primarily monitor their environment including synapses. Here, we show an active protective role of ramified microglia in excitotoxicity-induced neurodegeneration. Methods Mouse organotypic hippocampal slice cultures were treated with N-methyl-D-aspartic acid (NMDA to induce excitotoxic neuronal cell death. This procedure was performed in slices containing resting microglia or slices that were chemically or genetically depleted of their endogenous microglia. Results Treatment of mouse organotypic hippocampal slice cultures with 10-50 μM N-methyl-D-aspartic acid (NMDA induced region-specific excitotoxic neuronal cell death with CA1 neurons being most vulnerable, whereas CA3 and DG neurons were affected less. Ablation of ramified microglia severely enhanced NMDA-induced neuronal cell death in the CA3 and DG region rendering them almost as sensitive as CA1 neurons. Replenishment of microglia-free slices with microglia restored the original resistance of CA3 and DG neurons towards NMDA. Conclusions Our data strongly suggest that ramified microglia not only screen their microenvironment but additionally protect hippocampal neurons under pathological conditions. Morphological activation of ramified microglia is thus not required to influence neuronal survival.

  13. Past, present, and future in hippocampal formation and memory research.

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    Muñoz-López, Mónica

    2015-06-01

    Over 100 years of research on the hippocampal formation has led us understand the consequences of lesions in humans, the functional networks, anatomical pathways, neuronal types and their local circuitry, receptors, molecules, intracellular cascades, and some of the physiological mechanisms underlying long-term spatial and episodic memory. In addition, complex computational models allow us to formulate sophisticated hypotheses; many of them testable with techniques recently developed unthinkable in the past. Although the neurobiology of the cognitive map is starting to be revealed today, we still face a future with many unresolved questions. The aim of this commentary is twofold. First is to point out some of the critical findings in hippocampal formation research and new challenges. Second, to briefly summarize what the anatomy of memory can tell us about how highly processed sensory information from distant cortical areas communicate with different subareas of the entorhinal cortex, dentate gyrus, and hippocampal subfields to integrate and consolidate unique episodic memory traces. © 2015 Wiley Periodicals, Inc.

  14. Evidence of Hippocampal Structural Alterations in Gulf War Veterans With Predicted Exposure to the Khamisiyah Plume.

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    Chao, Linda L; Raymond, Morgan R; Leo, Cynthia K; Abadjian, Linda R

    2017-10-01

    To replicate and expand our previous findings of smaller hippocampal volumes in Gulf War (GW) veterans with predicted exposure to the Khamisiyah plume. Total hippocampal and hippocampal subfield volumes were quantified from 3 Tesla magnetic resonance images in 113 GW veterans, 62 of whom had predicted exposure as per the Department of Defense exposure models. Veterans with predicted exposure had smaller total hippocampal and CA3/dentate gyrus volumes compared with unexposed veterans, even after accounting for potentially confounding genetic and clinical variables. Among veterans with predicted exposure, memory performance was positively correlated with hippocampal volume and negatively correlated with estimated exposure levels and self-reported memory difficulties. These results replicate and extend our previous finding that low-level exposure to chemical nerve agents from the Khamisiyah pit demolition has detrimental, lasting effects on brain structure and function.

  15. Optimized Model of Cerebral Ischemia In situ for the Long-Lasting Assessment of Hippocampal Cell Death

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    Oksana Rybachuk

    2017-07-01

    Full Text Available Among all the brain, the hippocampus is the most susceptible region to ischemic lesion, with the highest vulnerability of CA1 pyramidal neurons to ischemic damage. This damage may cause either prompt neuronal death (within hours or with a delayed appearance (over days, providing a window for applying potential therapies to reduce or prevent ischemic impairments. However, the time course when ischemic damage turns to neuronal death strictly depends on experimental modeling of cerebral ischemia and, up to now, studies were predominantly focused on a short time-window—from hours to up to a few days post-lesion. Using different schemes of oxygen-glucose deprivation (OGD, the conditions taking place upon cerebral ischemia, we optimized a model of mimicking ischemic conditions in organotypical hippocampal slices for the long-lasting assessment of CA1 neuronal death (at least 3 weeks. By combining morphology and electrophysiology, we show that prolonged (30-min duration OGD results in a massive neuronal death and overwhelmed astrogliosis within a week post-OGD whereas OGD of a shorter duration (10-min triggered programmed CA1 neuronal death with a significant delay—within 2 weeks—accompanied with drastically impaired CA1 neuron functions. Our results provide a rationale toward optimized modeling of cerebral ischemia for reliable examination of potential treatments for brain neuroprotection, neuro-regeneration, or testing neuroprotective compounds in situ.

  16. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

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    Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

    2011-03-23

    Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

  17. Hippocampal leptin signaling reduces food intake and modulates food-related memory processing.

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    Kanoski, Scott E; Hayes, Matthew R; Greenwald, Holly S; Fortin, Samantha M; Gianessi, Carol A; Gilbert, Jennifer R; Grill, Harvey J

    2011-08-01

    The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 μg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 μg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.

  18. Differential gene expression in dentate granule cells in mesial temporal lobe epilepsy with and without hippocampal sclerosis.

    Science.gov (United States)

    Griffin, Nicole G; Wang, Yu; Hulette, Christine M; Halvorsen, Matt; Cronin, Kenneth D; Walley, Nicole M; Haglund, Michael M; Radtke, Rodney A; Skene, J H Pate; Sinha, Saurabh R; Heinzen, Erin L

    2016-03-01

    Hippocampal sclerosis is the most common neuropathologic finding in cases of medically intractable mesial temporal lobe epilepsy. In this study, we analyzed the gene expression profiles of dentate granule cells of patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis to show that next-generation sequencing methods can produce interpretable genomic data from RNA collected from small homogenous cell populations, and to shed light on the transcriptional changes associated with hippocampal sclerosis. RNA was extracted, and complementary DNA (cDNA) was prepared and amplified from dentate granule cells that had been harvested by laser capture microdissection from surgically resected hippocampi from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis. Sequencing libraries were sequenced, and the resulting sequencing reads were aligned to the reference genome. Differential expression analysis was used to ascertain expression differences between patients with and without hippocampal sclerosis. Greater than 90% of the RNA-Seq reads aligned to the reference. There was high concordance between transcriptional profiles obtained for duplicate samples. Principal component analysis revealed that the presence or absence of hippocampal sclerosis was the main determinant of the variance within the data. Among the genes up-regulated in the hippocampal sclerosis samples, there was significant enrichment for genes involved in oxidative phosphorylation. By analyzing the gene expression profiles of dentate granule cells from surgically resected hippocampal specimens from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis, we have demonstrated the utility of next-generation sequencing methods for producing biologically relevant results from small populations of homogeneous cells, and have provided insight on the transcriptional changes associated with this pathology. Wiley Periodicals, Inc. © 2016

  19. Brain Tissues Oxidative Damage as a Possible Mechanism of Deleterious Effects of Propylthiouracil- Induced Hypothyroidism on Learning and Memory in Neonatal and Juvenile Growth in Rats

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    Esmeil Farrokhi

    2014-11-01

    randomly selected and tested in the Morris water maze (MWM. Then, samples of blood were collected to measure thyroxine. Finally, the brains were removed and total thiol groups and molondialdehyde (MDA concentrations were determined. Results: Compared to the control group’s offspring, serum thyroxine levels in the PTU group’s off spring were significantly low (P<0.001. In MWM, the escape latency and traveled path in the PTU group were significantly higher than that in the control group (P<0.01- P<0.001. In PTU group, the total thiol concentrations in both cortical and hippocampal tissues were significantly lower and MDA concentrations were higher than control group (P<0.001. Discussion: It seems that deleterious effect of hypothyroidism during neonatal and juvenile growth on learning and memory is at least in part due to brain tissues oxidative damage.

  20. Smaller hippocampal volume as a vulnerability factor for the persistence of post-traumatic stress disorder.

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    van Rooij, S J H; Kennis, M; Sjouwerman, R; van den Heuvel, M P; Kahn, R S; Geuze, E

    2015-10-01

    Smaller hippocampal volume has often been observed in patients with post-traumatic stress disorder (PTSD). However, there is no consensus whether this is a result of stress/trauma exposure, or constitutes a vulnerability factor for the development of PTSD. Second, it is unclear whether hippocampal volume normalizes with successful treatment of PTSD, or whether a smaller hippocampus is a risk factor for the persistence of PTSD. Magnetic resonance imaging (MRI) scans and clinical interviews were collected from 47 war veterans with PTSD, 25 healthy war veterans (combat controls) and 25 healthy non-military controls. All veterans were scanned a second time with a 6- to 8-month interval, during which PTSD patients received trauma-focused therapy. Based on post-treatment PTSD symptoms, patients were divided into a PTSD group who was in remission (n = 22) and a group in whom PTSD symptoms persisted (n = 22). MRI data were analysed with Freesurfer. Smaller left hippocampal volume was observed in PTSD patients compared with both control groups. Hippocampal volume of the combat controls did not differ from healthy controls. Second, pre- and post-treatment analyses of the PTSD patients and combat controls revealed reduced (left) hippocampal volume only in the persistent patients at both time points. Importantly, hippocampal volume did not change with treatment. Our findings suggest that a smaller (left) hippocampus is not the result of stress/trauma exposure. Furthermore, hippocampal volume does not increase with successful treatment. Instead, we demonstrate for the first time that a smaller (left) hippocampus constitutes a risk factor for the persistence of PTSD.

  1. Nicotinamide mononucleotide inhibits post-ischemic NAD(+) degradation and dramatically ameliorates brain damage following global cerebral ischemia.

    Science.gov (United States)

    Park, Ji H; Long, Aaron; Owens, Katrina; Kristian, Tibor

    2016-11-01

    Nicotinamide adenine dinucleotide (NAD(+)) is an essential cofactor for multiple cellular metabolic reactions and has a central role in energy production. Brain ischemia depletes NAD(+) pools leading to bioenergetics failure and cell death. Nicotinamide mononucleotide (NMN) is utilized by the NAD(+) salvage pathway enzyme, nicotinamide adenylyltransferase (Nmnat) to generate NAD(+). Therefore, we examined whether NMN could protect against ischemic brain damage. Mice were subjected to transient forebrain ischemia and treated with NMN or vehicle at the start of reperfusion or 30min after the ischemic insult. At 2, 4, and 24h of recovery, the proteins poly-ADP-ribosylation (PAR), hippocampal NAD(+) levels, and expression levels of NAD(+) salvage pathway enzymes were determined. Furthermore, animal's neurologic outcome and hippocampal CA1 neuronal death was assessed after six days of reperfusion. NMN (62.5mg/kg) dramatically ameliorated the hippocampal CA1 injury and significantly improved the neurological outcome. Additionally, the post-ischemic NMN treatment prevented the increase in PAR formation and NAD(+) catabolism. Since the NMN administration did not affect animal's temperature, blood gases or regional cerebral blood flow during recovery, the protective effect was not a result of altered reperfusion conditions. These data suggest that administration of NMN at a proper dosage has a strong protective effect against ischemic brain injury. Published by Elsevier Inc.

  2. Functional α7β2 nicotinic acetylcholine receptors expressed in hippocampal interneurons exhibit high sensitivity to pathological level of amyloid β peptides

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    Liu Qiang

    2012-12-01

    Full Text Available Abstract Background β-amyloid (Aβ accumulation is described as a hallmark of Alzheimer’s disease (AD. Aβ perturbs a number of synaptic components including nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs, which are abundantly expressed in the hippocampus and found on GABAergic interneurons. We have previously demonstrated the existence of a novel, heteromeric α7β2-nAChR in basal forebrain cholinergic neurons that exhibits high sensitivity to acute Aβ exposure. To extend our previous work, we evaluated the expression and pharmacology of α7β2-nAChRs in hippocampal interneurons and their sensitivity to Aβ. Results GABAergic interneurons in the CA1 subregion of the hippocampus expressed functional α7β2-nAChRs, which were characterized by relatively slow whole-cell current kinetics, pharmacological sensitivity to dihydro-β-erythroidine (DHβE, a nAChR β2* subunit selective blocker, and α7 and β2 subunit interaction using immunoprecipitation assay. In addition, α7β2-nAChRs were sensitive to 1 nM oligomeric Aβ. Similar effects were observed in identified hippocampal interneurons prepared from GFP-GAD mice. Conclusion These findings suggest that Aβ modulation of cholinergic signaling in hippocampal GABAergic interneurons via α7β2-nAChRs could be an early and critical event in Aβ-induced functional abnormalities of hippocampal function, which may be relevant to learning and memory deficits in AD.

  3. TNF-α from hippocampal microglia induces working memory deficits by acute stress in mice.

    Science.gov (United States)

    Ohgidani, Masahiro; Kato, Takahiro A; Sagata, Noriaki; Hayakawa, Kohei; Shimokawa, Norihiro; Sato-Kasai, Mina; Kanba, Shigenobu

    2016-07-01

    The role of microglia in stress responses has recently been highlighted, yet the underlying mechanisms of action remain unresolved. The present study examined disruption in working memory due to acute stress using the water-immersion resistant stress (WIRS) test in mice. Mice were subjected to acute WIRS, and biochemical, immunohistochemical, and behavioral assessments were conducted. Spontaneous alternations (working memory) significantly decreased after exposure to acute WIRS for 2h. We employed a 3D morphological analysis and site- and microglia-specific gene analysis techniques to detect microglial activity. Morphological changes in hippocampal microglia were not observed after acute stress, even when assessing ramification ratios and cell somata volumes. Interestingly, hippocampal tumor necrosis factor (TNF)-α levels were significantly elevated after acute stress, and acute stress-induced TNF-α was produced by hippocampal-ramified microglia. Conversely, plasma concentrations of TNF-α were not elevated after acute stress. Etanercept (TNF-α inhibitor) recovered working memory deficits in accordance with hippocampal TNF-α reductions. Overall, results suggest that TNF-α from hippocampal microglia is a key contributor to early-stage stress-to-mental responses. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Efficacy of the fluid attenuated inversion recovery (FLAIR) sequence of MRI as a preoperative diagnosis of hippocampal sclerosis

    International Nuclear Information System (INIS)

    Morioka, Takato; Nishio, Shunji; Mihara, Futoshi; Muraishi, Mitsuteru; Hisada, Kei; Hasuo, Kanehiro; Fukui, Masashi

    1998-01-01

    A newly advanced MRI pulse sequence, the FLAIR (fluid attenuated inversion recovery) imaging, in which a long TE spin echo sequence is used with suppression of the CSF with an inversion pulse, displays the CSF space as a no-signal intensity area. There have been only a few reports on the FLAIR pulse sequence of temporal lobe epilepsy (TLE) as yet. We examined 9 cases of intractable TLE by FLAIR images and analyzed the advantages and disadvantages of the FLAIR pulse sequence for decision making on temporal lobectomy. All patients underwent anterior temporal lobectomy with hippocampectomy, and the diagnoses were confirmed histologically after surgery. Abnormally high T2 signals (HT2S) were more conspicuous with the FLAIR sequence than with any of the conventional sequences. Tilted axial plane, orientated along to the long axis of the hippocampal body, clearly demonstrated hippocampal atrophy (HA). Selection of a FLAIR sequence into the routine MR examination of patients with TLE is recommended. (author)

  5. Abrogation of Early Apoptosis Does Not Alter Late Inhibition of Hippocampal Neurogenesis After Irradiation

    International Nuclear Information System (INIS)

    Li Yuqing; Aubert, Isabelle; Wong, C. Shun

    2010-01-01

    Purpose: Irradiation of the adult brain results in acute apoptosis of neural progenitors and vascular endothelial cells, as well as late dysfunction of neural progenitors and inhibition of neurogenesis. We sought to determine whether the early apoptotic response has a causative role in late inhibition of neurogenesis after cranial irradiation. Methods and Materials: Using a genetic approach with p53 and smpd1 transgenic mice and a pharmacologic approach with basic fibroblast growth factor (bFGF) to abrogate the early apoptotic response, we evaluated the late inhibition of neurogenesis in the hippocampal dentate gyrus after cranial irradiation. Results: In dentate gyrus, subgranular neural progenitors underwent p53-dependent apoptosis within 24 h after irradiation. Despite a near abrogation of neural progenitor apoptosis in p53-/- mice, the reduction in newborn neurons in dentate gyrus at 9 weeks after irradiation in p53-/- mice was not different from that observed in wildtype controls. Endothelial cell apoptosis after radiation is mediated by membrane damage initiated by activation of acid sphingomyelinase (ASMase). Deletion of the smpd1 gene (which encodes ASMase) attenuated the apoptotic response of endothelial cells. At 9 weeks after irradiation, the inhibition of hippocampal neurogenesis was not rescued by ASMase deficiency. Intravenous administration of bFGF protected both endothelial cells and neural progenitors against radiation-induced apoptosis. There was no protection against inhibition of neurogenesis at 9 weeks after irradiation in bFGF-treated mice. Conclusion: Early apoptotic death of neural progenitors, endothelial cells, or both does not have a causative association with late inhibition of neurogenesis after irradiation.

  6. The Impacts of Swimming Exercise on Hippocampal Expression of Neurotrophic Factors in Rats Exposed to Chronic Unpredictable Mild Stress

    Directory of Open Access Journals (Sweden)

    Pei Jiang

    2014-01-01

    Full Text Available Depression is associated with stress-induced neural atrophy in limbic brain regions, whereas exercise has antidepressant effects as well as increasing hippocampal synaptic plasticity by strengthening neurogenesis, metabolism, and vascular function. A key mechanism mediating these broad benefits of exercise on the brain is induction of neurotrophic factors, which instruct downstream structural and functional changes. To systematically evaluate the potential neurotrophic factors that were involved in the antidepressive effects of exercise, in this study, we assessed the effects of swimming exercise on hippocampal mRNA expression of several classes of the growth factors (BDNF, GDNF, NGF, NT-3, FGF2, VEGF, and IGF-1 and peptides (VGF and NPY in rats exposed to chronic unpredictable mild stress (CUMS. Our study demonstrated that the swimming training paradigm significantly induced the expression of BDNF and BDNF-regulated peptides (VGF and NPY and restored their stress-induced downregulation. Additionally, the exercise protocol also increased the antiapoptotic Bcl-xl expression and normalized the CUMS mediated induction of proapoptotic Bax mRNA level. Overall, our data suggest that swimming exercise has antidepressant effects, increasing the resistance to the neural damage caused by CUMS, and both BDNF and its downstream neurotrophic peptides may exert a major function in the exercise related adaptive processes to CUMS.

  7. Effects of acetylpuerarin on hippocampal neurons and intracellular free calcium subjected to oxygen-glucose deprivation/reperfusion in primary culture.

    Science.gov (United States)

    Liu, Rui; Wei, Xin-bing; Zhang, Xiu-Mei

    2007-05-25

    This study was undertaken to find out the effects of acetylpuerarin on hippocampal neurons and intracellular free calcium in primary culture subjected to oxygen-glucose deprivation/reperfusion. According to different reperfusion time (1 h, 6 h, 12 h, 24 h), three concentrations (1.6 micromol l(-1), 0.4 micromol l(-1), 0.1 micromol l(-1)) of acetylpuerarin, and MK-801 (10 micromol l(-1)), a positive control drug, neurons were randomly divided into 21 groups. Each group was observed by inverted phase contrast microscope; neuron viability was measured by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); intracellular Ca(2+) was observed by Fura-2/AM ester through fluorospectrophotometer. The injured neurons were protected and degeneration and necrosis were alleviated in treatment groups of acetylpuerarin and MK-801. Acetylpuerarin increased the neuron viability at high, middle and low concentrations. Fluorescence detection results showed that the calcium concentration in the group treated with acetylpuerarin and MK-801 was lowered in each reperfusion time. Our results demonstrated that acetylpuerarin could protect the hippocampal neurons from ischemia-reperfusion injury in rats by alleviating the morphological damage, increasing neuron viability and decreasing calcium concentration in neuron.

  8. Nuclear receptor TLX stimulates hippocampal neurogenesis and enhances learning and memory in a transgenic mouse model.

    Science.gov (United States)

    Murai, Kiyohito; Qu, Qiuhao; Sun, GuoQiang; Ye, Peng; Li, Wendong; Asuelime, Grace; Sun, Emily; Tsai, Guochuan E; Shi, Yanhong

    2014-06-24

    The role of the nuclear receptor TLX in hippocampal neurogenesis and cognition has just begun to be explored. In this study, we generated a transgenic mouse model that expresses TLX under the control of the promoter of nestin, a neural precursor marker. Transgenic TLX expression led to mice with enlarged brains with an elongated hippocampal dentate gyrus and increased numbers of newborn neurons. Specific expression of TLX in adult hippocampal dentate gyrus via lentiviral transduction increased the numbers of BrdU(+) cells and BrdU(+)NeuN(+) neurons. Furthermore, the neural precursor-specific expression of the TLX transgene substantially rescued the neurogenic defects of TLX-null mice. Consistent with increased neurogenesis in the hippocampus, the TLX transgenic mice exhibited enhanced cognition with increased learning and memory. These results suggest a strong association between hippocampal neurogenesis and cognition, as well as significant contributions of TLX to hippocampal neurogenesis, learning, and memory.

  9. Virtual Environmental Enrichment through Video Games Improves Hippocampal-Associated Memory

    Science.gov (United States)

    Clemenson, Gregory D.

    2015-01-01

    The positive effects of environmental enrichment and their neural bases have been studied extensively in the rodent (van Praag et al., 2000). For example, simply modifying an animal's living environment to promote sensory stimulation can lead to (but is not limited to) enhancements in hippocampal cognition and neuroplasticity and can alleviate hippocampal cognitive deficits associated with neurodegenerative diseases and aging. We are interested in whether these manipulations that successfully enhance cognition (or mitigate cognitive decline) have similar influences on humans. Although there are many “enriching” aspects to daily life, we are constantly adapting to new experiences and situations within our own environment on a daily basis. Here, we hypothesize that the exploration of the vast and visually stimulating virtual environments within video games is a human correlate of environmental enrichment. We show that video gamers who specifically favor complex 3D video games performed better on a demanding recognition memory task that assesses participants' ability to discriminate highly similar lure items from repeated items. In addition, after 2 weeks of training on the 3D video game Super Mario 3D World, naive video gamers showed improved mnemonic discrimination ability and improvements on a virtual water maze task. Two control conditions (passive and training in a 2D game, Angry Birds), showed no such improvements. Furthermore, individual performance in both hippocampal-associated behaviors correlated with performance in Super Mario but not Angry Birds, suggesting that how individuals explored the virtual environment may influence hippocampal behavior. SIGNIFICANCE STATEMENT The hippocampus has long been associated with episodic memory and is commonly thought to rely on neuroplasticity to adapt to the ever-changing environment. In animals, it is well understood that exposing animals to a more stimulating environment, known as environmental enrichment, can

  10. Virtual Environmental Enrichment through Video Games Improves Hippocampal-Associated Memory.

    Science.gov (United States)

    Clemenson, Gregory D; Stark, Craig E L

    2015-12-09

    The positive effects of environmental enrichment and their neural bases have been studied extensively in the rodent (van Praag et al., 2000). For example, simply modifying an animal's living environment to promote sensory stimulation can lead to (but is not limited to) enhancements in hippocampal cognition and neuroplasticity and can alleviate hippocampal cognitive deficits associated with neurodegenerative diseases and aging. We are interested in whether these manipulations that successfully enhance cognition (or mitigate cognitive decline) have similar influences on humans. Although there are many "enriching" aspects to daily life, we are constantly adapting to new experiences and situations within our own environment on a daily basis. Here, we hypothesize that the exploration of the vast and visually stimulating virtual environments within video games is a human correlate of environmental enrichment. We show that video gamers who specifically favor complex 3D video games performed better on a demanding recognition memory task that assesses participants' ability to discriminate highly similar lure items from repeated items. In addition, after 2 weeks of training on the 3D video game Super Mario 3D World, naive video gamers showed improved mnemonic discrimination ability and improvements on a virtual water maze task. Two control conditions (passive and training in a 2D game, Angry Birds), showed no such improvements. Furthermore, individual performance in both hippocampal-associated behaviors correlated with performance in Super Mario but not Angry Birds, suggesting that how individuals explored the virtual environment may influence hippocampal behavior. The hippocampus has long been associated with episodic memory and is commonly thought to rely on neuroplasticity to adapt to the ever-changing environment. In animals, it is well understood that exposing animals to a more stimulating environment, known as environmental enrichment, can stimulate neuroplasticity and

  11. Training labels for hippocampal segmentation based on the EADC-ADNI harmonized hippocampal protocol.

    Science.gov (United States)

    Boccardi, Marina; Bocchetta, Martina; Morency, Félix C; Collins, D Louis; Nishikawa, Masami; Ganzola, Rossana; Grothe, Michel J; Wolf, Dominik; Redolfi, Alberto; Pievani, Michela; Antelmi, Luigi; Fellgiebel, Andreas; Matsuda, Hiroshi; Teipel, Stefan; Duchesne, Simon; Jack, Clifford R; Frisoni, Giovanni B

    2015-02-01

    The European Alzheimer's Disease Consortium and Alzheimer's Disease Neuroimaging Initiative (ADNI) Harmonized Protocol (HarP) is a Delphi definition of manual hippocampal segmentation from magnetic resonance imaging (MRI) that can be used as the standard of truth to train new tracers, and to validate automated segmentation algorithms. Training requires large and representative data sets of segmented hippocampi. This work aims to produce a set of HarP labels for the proper training and certification of tracers and algorithms. Sixty-eight 1.5 T and 67 3 T volumetric structural ADNI scans from different subjects, balanced by age, medial temporal atrophy, and scanner manufacturer, were segmented by five qualified HarP tracers whose absolute interrater intraclass correlation coefficients were 0.953 and 0.975 (left and right). Labels were validated as HarP compliant through centralized quality check and correction. Hippocampal volumes (mm(3)) were as follows: controls: left = 3060 (standard deviation [SD], 502), right = 3120 (SD, 897); mild cognitive impairment (MCI): left = 2596 (SD, 447), right = 2686 (SD, 473); and Alzheimer's disease (AD): left = 2301 (SD, 492), right = 2445 (SD, 525). Volumes significantly correlated with atrophy severity at Scheltens' scale (Spearman's ρ = segmentation algorithms. The publicly released labels will allow the widespread implementation of the standard segmentation protocol. Copyright © 2015 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  12. Effects of lamotrigine on hippocampal activation in corticosteroid-treated patients.

    Science.gov (United States)

    Brown, E Sherwood; Zaidel, Liam; Allen, Greg; McColl, Roderick; Vazquez, Miguel; Ringe, Wendy K

    2010-11-01

    An extensive animal literature suggests that stress or excessive corticosteroid exposure is associated with changes in hippocampal function and memory. These findings are pertinent to psychiatric disorders with elevated cortisol, Cushing's disease and the millions of patients receiving prescription corticosteroids. In animals, agents that decrease glutamate release attenuate the effects of corticosteroids on the hippocampus. Minimal data are available on preventing or reversing the effects of corticosteroids on the human hippocampus. We previously reported improvement in memory in corticosteroid-treated patients given lamotrigine. In this report, we examined the impact of lamotrigine on task-related hippocampal activation in patients taking prescription corticosteroids. A total of 28 outpatients taking long-term oral prednisone for medical conditions, such as renal transplant rejection, were randomized to lamotrigine or placebo for 24 weeks. Hippocampal activation in response to a visual memory task was assessed with blood oxygenation level dependent (BOLD) functional magnetic resonance imaging (fMRI). Consistent with a reduction in glutamate release, the right posterior hippocampus showed a significant decrease in task-related activation in the lamotrigine group as compared to the placebo group. The modest sample size and an assessment period of only 24 weeks are study limitations. Between-group differences in hippocampal activation were observed. The results suggest that an agent that modulates glutamate may modify the effects of long-term corticosteroid exposure on the human hippocampus. Copyright © 2010 Elsevier B.V. All rights reserved.

  13. Hippocampal development in youth with a history of childhood maltreatment.

    Science.gov (United States)

    Paquola, Casey; Bennett, Maxwell R; Hatton, Sean N; Hermens, Daniel F; Groote, Inge; Lagopoulos, Jim

    2017-08-01

    Childhood maltreatment (CM) is associated with enhanced risk of psychiatric illness and reduced subcortical grey matter in adulthood. The hippocampus and amygdala, due to their involvement in stress and emotion circuitries, have been subject to extensive investigations regarding the effect of CM. However, the complex relationship between CM, subcortical grey matter and mental illness remains poorly understood partially due to a lack of longitudinal studies. Here we used segmentation and linear mixed effect modelling to examine the impact of CM on hippocampal and amygdala development in young people with emerging mental illness. A total of 215 structural magnetic resonance imaging (MRI) scans were acquired from 123 individuals (age: 14-28 years, 79 female), 52 of whom were scanned twice or more. Hippocampal and amygdala volumes increased linearly with age, and their developmental trajectories were not moderated by symptom severity. However, exposure to CM was associated with significantly stunted right hippocampal growth. This finding bridges the gap between child and adult research in the field and provides novel evidence that CM is associated with disrupted hippocampal development in youth. Although CM was associated with worse symptom severity, we did not find evidence that CM-induced structural abnormalities directly underpin psychopathology. This study has important implications for the psychiatric treatment of individuals with CM since they are clinically and neurobiologically distinct from their peers who were not maltreated. Copyright © 2017 Elsevier Ltd. All rights reserved.

  14. Attention promotes episodic encoding by stabilizing hippocampal representations

    Science.gov (United States)

    Aly, Mariam; Turk-Browne, Nicholas B.

    2016-01-01

    Attention influences what is later remembered, but little is known about how this occurs in the brain. We hypothesized that behavioral goals modulate the attentional state of the hippocampus to prioritize goal-relevant aspects of experience for encoding. Participants viewed rooms with paintings, attending to room layouts or painting styles on different trials during high-resolution functional MRI. We identified template activity patterns in each hippocampal subfield that corresponded to the attentional state induced by each task. Participants then incidentally encoded new rooms with art while attending to the layout or painting style, and memory was subsequently tested. We found that when task-relevant information was better remembered, the hippocampus was more likely to have been in the correct attentional state during encoding. This effect was specific to the hippocampus, and not found in medial temporal lobe cortex, category-selective areas of the visual system, or elsewhere in the brain. These findings provide mechanistic insight into how attention transforms percepts into memories. PMID:26755611

  15. Hippocampal sclerosis dementia: An amnesic variant of frontotemporal degeneration

    Directory of Open Access Journals (Sweden)

    Chiadi U. Onyike

    Full Text Available ABSTRACT Objective: To describe characteristics of hippocampal sclerosis dementia. Methods: Convenience sample of Hippocampal sclerosis dementia (HSD recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. Results: The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2% had amnesia at illness onset, and many (54.2% showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD was uncommon (seen in 8%. Conclusion: HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant.

  16. Hippocampal sclerosis dementia: an amnesic variant of frontotemporal degeneration

    Science.gov (United States)

    Onyike, Chiadi U.; Pletnikova, Olga; Sloane, Kelly L.; Sullivan, Campbell; Troncoso, Juan C.; Rabins, Peter V.

    2013-01-01

    OBJECTIVE To describe characteristics of hippocampal sclerosis dementia. METHODS Convenience sample of Hippocampal sclerosis dementia (HSD) recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. RESULTS The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2%) had amnesia at illness onset, and many (54.2%) showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD) was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD) was uncommon (seen in 8%). CONCLUSION HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant. PMID:24363834

  17. Contribution of cerebellar sensorimotor adaptation to hippocampal spatial memory.

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Passot

    Full Text Available Complementing its primary role in motor control, cerebellar learning has also a bottom-up influence on cognitive functions, where high-level representations build up from elementary sensorimotor memories. In this paper we examine the cerebellar contribution to both procedural and declarative components of spatial cognition. To do so, we model a functional interplay between the cerebellum and the hippocampal formation during goal-oriented navigation. We reinterpret and complete existing genetic behavioural observations by means of quantitative accounts that cross-link synaptic plasticity mechanisms, single cell and population coding properties, and behavioural responses. In contrast to earlier hypotheses positing only a purely procedural impact of cerebellar adaptation deficits, our results suggest a cerebellar involvement in high-level aspects of behaviour. In particular, we propose that cerebellar learning mechanisms may influence hippocampal place fields, by contributing to the path integration process. Our simulations predict differences in place-cell discharge properties between normal mice and L7-PKCI mutant mice lacking long-term depression at cerebellar parallel fibre-Purkinje cell synapses. On the behavioural level, these results suggest that, by influencing the accuracy of hippocampal spatial codes, cerebellar deficits may impact the exploration-exploitation balance during spatial navigation.

  18. Relationship between hippocampal subfield volumes and memory deficits in patients with thalamus infarction.

    Science.gov (United States)

    Chen, Li; Luo, Tianyou; Lv, Fajin; Shi, Dandan; Qiu, Jiang; Li, Qi; Fang, Weidong; Peng, Juan; Li, Yongmei; Zhang, Zhiwei; Li, Yang

    2016-09-01

    Clinical studies have shown that thalamus infarction (TI) affects memory function. The thalamic nucleus is directly or indirectly connected to the hippocampal system in animal models. However, this connection has not been investigated using structural magnetic resonance imaging (MRI) in humans. From the pathological perspective, TI patients may serve as valid models for revealing the interaction between the thalamus and hippocampus in memory function. In this study, we aim to assess different hippocampal subfield volumes in TI patients and control subjects using MRI and test their associations with memory function. A total of 37 TI patients (TI group), 38 matched healthy control subjects (HC group), and 22 control patients with other stroke location (SC group) underwent 3.0-T MRI scans and clinical memory examinations. Hippocampal subfield volumes were measured and compared by using FreeSurfer software. We examined the correlation between hippocampal subfield volumes and memory scores. Smaller ipsilesional presubiculum and subiculum volumes were observed, and former was related to graphics recall in both left and right TI patients. The left subiculum volume was correlated with short-delayed recall in left TI patients. The right presubiculum volume was correlated with short- and long-delayed recall in right TI patients. TI was found to result in hippocampal abnormality and memory deficits, and its neural mechanisms might be related with and interaction between the thalamus and hippocampus.

  19. MRI volumetric measurement of hippocampal formation based on statistic parametric mapping

    International Nuclear Information System (INIS)

    Hua Jianming; Jiang Biao; Zhou Jiong; Zhang Weimin

    2010-01-01

    Objective: To study MRI volumetric measurement of hippocampal formation using statistic parametric mapping (SPM) software and to discuss the value of the method applied to Alzheimer's disease (AD). Methods: The SPM software was used to divide the three-dimensional MRI brain image into gray matter, white matter and CSF separately. The bilateral hippocampal formations in both AD group and normal control group were delineated and the volumes were measured. The SPM method was compared with conventional method based on region of interest (ROI), which was the gold standard of volume measurement. The time used in measuring the volume by these two methods were respectively recorded and compared by two independent samples't test. Moreover, 7 physicians measured the left hippocampal formation of one same control with both of the two methods. The frequency distribution and dispersion of data acquired with the two methods were evaluated using standard deviation coefficient. Results (1) The volume of the bilateral hippocampal formations with SPM method was (1.88 ± 0.07) cm 3 and (1.93 ± 0.08) cm 3 respectively in the AD group, while was (2.99 ± 0.07) cm 3 and (3.02 ± 0.06) cm 3 in the control group. The volume of bilateral hippocampal formations measured by ROI method was (1.87 ± 0.06) cm 3 and (1.91 ± 0.09) cm 3 in the AD group, while was (2.97 ± 0.08) cm 3 and (3.00 ± 0.05) cm 3 in the control group. There was no significant difference between SPM method and conventional ROI method in the AD group and the control group (t=1.500, 1.617, 1.095, 1.889, P>0.05). However, the time used for delineation and volume measurement was significantly different. The time used in SPM measurement was (38.1 ± 2.0) min, while that in ROI measurement was (55.4 ± 2.4) min (t=-25.918, P 3 respectively. The frequency distribution of hippocampal formation volume measured by SPM method and ROI method was different. The CV SPM was 7% and the CV ROI was 19%. Conclusions: The borders of

  20. Intracerebroventricular Administration of Amyloid β-protein Oligomers Selectively Increases Dorsal Hippocampal Dialysate Glutamate Levels in the Awake Rat

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    Sean D. O’Shea

    2008-11-01

    Full Text Available Extensive evidence supports an important role for soluble oligomers of the amyloid β-protein (Aβ in Alzheimer’s Disease pathogenesis. In the present study we combined intracerebroventricular (icv injections with brain microdialysis technology in the fully conscious rat to assess the effects of icv administered SDS-stable low-n Aβ oligomers (principally dimers and trimers on excitatory and inhibitory amino acid transmission in the ipsilateral dorsal hippocampus. Microdialysis was employed to assess the effect of icv administration of Aβ monomers and Aβ oligomers on dialysate glutamate, aspartate and GABA levels in the dorsal hippocampus. Administration of Aβ oligomers was associated with a +183% increase (p<0.0001 vs. Aβ monomer-injected control in dorsal hippocampal glutamate levels which was still increasing at the end of the experiment (260 min, whereas aspartate and GABA levels were unaffected throughout. These findings demonstrate that icv administration and microdialysis technology can be successfully combined in the awake rat and suggests that altered dorsal hippocampal glutamate transmission may be a useful target for pharmacological intervention in Alzheimer’s Disease.

  1. B-Raf and CRHR1 internalization mediate biphasic ERK1/2 activation by CRH in hippocampal HT22 Cells.

    Science.gov (United States)

    Bonfiglio, Juan J; Inda, Carolina; Senin, Sergio; Maccarrone, Giuseppina; Refojo, Damián; Giacomini, Damiana; Turck, Christoph W; Holsboer, Florian; Arzt, Eduardo; Silberstein, Susana

    2013-03-01

    CRH is a key regulator of neuroendocrine, autonomic, and behavioral response to stress. CRH-stimulated CRH receptor 1 (CRHR1) activates ERK1/2 depending on intracellular context. In a previous work, we demonstrated that CRH activates ERK1/2 in limbic areas of the mouse brain (hippocampus and basolateral amygdala). ERK1/2 is an essential mediator of hippocampal physiological processes including emotional behavior, synaptic plasticity, learning, and memory. To elucidate the molecular mechanisms by which CRH activates ERK1/2 in hippocampal neurons, we used the mouse hippocampal cell line HT22. We document for the first time that ERK1/2 activation in response to CRH is biphasic, involving a first cAMP- and B-Raf-dependent early phase and a second phase that critically depends on CRHR1 internalization and β-arrestin2. By means of mass-spectrometry-based screening, we identified B-Raf-associated proteins that coimmunoprecipitate with endogenous B-Raf after CRHR1 activation. Using molecular and pharmacological tools, the functional impact of selected B-Raf partners in CRH-dependent ERK1/2 activation was dissected. These results indicate that 14-3-3 proteins, protein kinase A, and Rap1, are essential for early CRH-induced ERK1/2 activation, whereas dynamin and vimentin are required for the CRHR1 internalization-dependent phase. Both phases of ERK1/2 activation depend on calcium influx and are affected by calcium/calmodulin-dependent protein kinase II inactivation. Thus, this report describes the dynamics and biphasic nature of ERK1/2 activation downstream neuronal CRHR1 and identifies several new critical components of the CRHR1 signaling machinery that selectively controls the early and late phases of ERK1/2 activation, thus providing new potential therapeutic targets for stress-related disorders.

  2. A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation.

    Science.gov (United States)

    Ma, Ting Martin; Grimm, Jimm; McIntyre, Riley; Anderson-Keightly, Heather; Kleinberg, Lawrence R; Hales, Russell K; Moore, Joseph; Vannorsdall, Tracy; Redmond, Kristin J

    2017-11-01

    To prospectively evaluate hippocampal radiation dose volume effects and memory decline following cranial irradiation. Effects of hippocampal radiation over a wide range of doses were investigated by combining data from three prospective studies. In one, adults with small cell lung cancer received hippocampal-avoidance prophylactic cranial irradiation. In the other two, adults with glioblastoma multiforme received neural progenitor cell sparing radiation or no sparing with extra dose delivered to subventricular zone. Memory was measured by the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 6 months after radiation. Dose-volume histograms were generated and dose-response data were fitted to a nonlinear model. Of 60 patients enrolled, 30 were analyzable based on HVLT-R DR testing completion status, baseline HVLT-R DR and intracranial metastasis/recurrence or prior hippocampal resection status. We observed a dose-response of radiation to the hippocampus with regard to decline in HVLT-R DR. D50% of the bilateral hippocampi of 22.1 Gy is associated with 20% risk of decline. This prospective study demonstrates an association between hippocampal dose volume effects and memory decline measured by HVLT-R DR over a wide dose range. These data support a potential benefit of hippocampal sparing and encourage continued trial enrollment. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Potential hippocampal region atrophy in diabetes mellitus type 2. A voxel-based morphometry VSRAD study

    International Nuclear Information System (INIS)

    Kamiyama, Kazutoshi; Sugihara, Masaki; Wada, Akihiko

    2010-01-01

    Among diabetes mellitus type 2 (DM2) patients, the frequency of cognitive dysfunction is higher and the relative risk of Alzheimer's disease (AD) is approximately twice that of nondiabetics. Cognitive impairment symptoms of AD are induced by limbic system dysfunction, and an early-stage AD brain without dementia has the potential for atrophy in the hippocampal region. In this study, we estimated potential hippocampal region atrophy in DM2 and pursued the association between DM2 and cognitive impairment/AD. Voxel-based morphometry analysis was performed in 28 diabetics (14 men, 14 women; ages 59-79 years, mean 70.7 years) and 28 sex- and age- matched (±1 year) nondiabetics. Severity of gray matter loss in the hippocampal region and whole brain were investigated. Group analysis was performed using two-tailed unpaired t-test; significance was assumed with less than 1% (P<0.01) of the critical rate. There was a significant difference between diabetics and nondiabetics regarding the severity of hippocampal region atrophy and whole-brain atrophy. Only diabetics showed a positive correlation for severity of hippocampal region atrophy and whole-brain atrophy (rs=0.69, P<0.0001). Aged DM2 patients have the potential for hippocampal region atrophy, and its dysfunction can be related to the expression of a cognitive impairment that resembles AD. (author)

  4. Remote infarct of the temporal lobe with coexistent hippocampal sclerosis in mesial temporal lobe epilepsy.

    Science.gov (United States)

    Gales, Jordan M; Prayson, Richard A

    2016-02-01

    In patients undergoing surgery for temporal lobe epilepsy, hippocampal sclerosis remains the most commonly observed pathology. In addition to hippocampal sclerosis, 5% to 30% of these resections on magnetic resonance imaging contain a second independently epileptogenic lesion, commonly referred to as dual pathology. A second etiology of seizure activity, as seen in dual pathology, may serve as an important cause of treatment failure in striving for post-operative seizure control. Dual pathology, consisting of hippocampal sclerosis and a remote infarct of the adjacent cortex, has been rarely reported. Cases of pathologically confirmed hippocampal sclerosis diagnosed between January 2000 and December 2012 (n = 349) were reviewed, and 7 cases of coexistent infarct (2%) formed the study group. Seven individuals (mean age, 29years; range, 5-47 years) with a mean epilepsy duration of 12.5years (3.3-25 years) and a mean pre-surgery frequency of 15 seizures per week (range, 0.5-56 seizures/week) were followed up postoperatively for a mean duration of 64months (range, 3-137 months). Pathologically, the most common form of hippocampal sclerosis observed was International League against Epilepsy type Ib or severe variant (n = 4). Four of the six individuals with post-surgery follow-up were seizure free at last encounter. The reported incidence of dual pathology, including hippocampal sclerosis and remote infarct, is low (2% in the present study) but may indicate a slightly increased risk of developing hippocampal sclerosis in the setting of a remote infarct. Surgical intervention for such cases anecdotally appears effective in achieving seizure control. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. COMT Val158Met polymorphism moderates the association between PTSD symptom severity and hippocampal volume.

    Science.gov (United States)

    Hayes, Jasmeet P; Logue, Mark W; Reagan, Andrew; Salat, David; Wolf, Erika J; Sadeh, Naomi; Spielberg, Jeffrey M; Sperbeck, Emily; Hayes, Scott M; McGlinchey, Regina E; Milberg, William P; Verfaellie, Mieke; Stone, Annjanette; Schichman, Steven A; Miller, Mark W

    2017-03-01

    Memory-based alterations are among the hallmark symptoms of posttraumatic stress disorder (PTSD) and may be associated with the integrity of the hippocampus. However, neuroimaging studies of hippocampal volume in individuals with PTSD have yielded inconsistent results, raising the possibility that various moderators, such as genetic factors, may influence this association. We examined whether the catechol-O-methyltransferase (COMT) Val158Met polymorphism, which has previously been shown to be associated with hippocampal volume in healthy individuals, moderates the association between PTSD and hippocampal volume. Recent war veterans underwent structural MRI on a 3 T scanner. We extracted volumes of the right and left hippocampus using FreeSurfer and adjusted them for individual differences in intracranial volume. We assessed PTSD severity using the Clinician-Administered PTSD Scale. Hierarchical linear regression was used to model the genotype (Val158Met polymorphism) × PTSD severity interaction and its association with hippocampal volume. We included 146 white, non-Hispanic recent war veterans (90% male, 53% with diagnosed PTSD) in our analyses. A significant genotype × PTSD symptom severity interaction emerged such that individuals with greater current PTSD symptom severity who were homozygous for the Val allele showed significant reductions in left hippocampal volume. The direction of proposed effects is unknown, thus precluding definitive assessment of whether differences in hippocampal volume reflect a consequence of PTSD, a pre-existing characteristic, or both. Our findings suggest that the COMT polymorphism moderates the association between PTSD and hippocampal volume. These results highlight the role that the dopaminergic system has in brain structure and suggest a possible mechanism for memory disturbance in individuals with PTSD.

  6. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism.

    Science.gov (United States)

    Shiraki, Ayako; Saito, Fumiyo; Akane, Hirotoshi; Akahori, Yumi; Imatanaka, Nobuya; Itahashi, Megu; Yoshida, Toshinori; Shibutani, Makoto

    2016-01-01

    We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects. Copyright © 2015 John Wiley & Sons, Ltd.

  7. Hippocampal gamma oscillations increase with memory load

    NARCIS (Netherlands)

    Van Vugt, Marieke K.; Schulze-Bonhage, Andreas; Litt, Brian; Brandt, Armin; Kahana, Michael J.

    2010-01-01

    Although the hippocampus plays a crucial role in encoding and retrieval of contextually mediated episodic memories, considerable controversy surrounds the role of the hippocampus in short-term or working memory. To examine both hippocampal and neocortical contributions to working memory function, we

  8. Impaired neuronal maturation of hippocampal neural progenitor cells in mice lacking CRAF.

    Science.gov (United States)

    Pfeiffer, Verena; Götz, Rudolf; Camarero, Guadelupe; Heinsen, Helmut; Blum, Robert; Rapp, Ulf Rüdiger

    2018-01-01

    RAF kinases are major constituents of the mitogen activated signaling pathway, regulating cell proliferation, differentiation and cell survival of many cell types, including neurons. In mammals, the family of RAF proteins consists of three members, ARAF, BRAF, and CRAF. Ablation of CRAF kinase in inbred mouse strains causes major developmental defects during fetal growth and embryonic or perinatal lethality. Heterozygous germline mutations in CRAF result in Noonan syndrome, which is characterized by neurocognitive impairment that may involve hippocampal physiology. The role of CRAF signaling during hippocampal development and generation of new postnatal hippocampal granule neurons has not been examined and may provide novel insight into the cause of hippocampal dysfunction in Noonan syndrome. In this study, by crossing CRAF-deficiency to CD-1 outbred mice, a CRAF mouse model was established which enabled us to investigate the interplay of neural progenitor proliferation and postmitotic differentiation during adult neurogenesis in the hippocampus. Albeit the general morphology of the hippocampus was unchanged, CRAF-deficient mice displayed smaller granule cell layer (GCL) volume at postnatal day 30 (P30). In CRAF-deficient mice a substantial number of abnormal, chromophilic, fast dividing cells were found in the subgranular zone (SGZ) and hilus of the dentate gyrus (DG), indicating that CRAF signaling contributes to hippocampal neural progenitor proliferation. CRAF-deficient neural progenitor cells showed an increased cell death rate and reduced neuronal maturation. These results indicate that CRAF function affects postmitotic neural cell differentiation and points to a critical role of CRAF-dependent growth factor signaling pathway in the postmitotic development of adult-born neurons.

  9. Role of medial cortical, hippocampal and striatal interactions during cognitive set-shifting.

    Science.gov (United States)

    Graham, Steven; Phua, Elaine; Soon, Chun Siong; Oh, Tomasina; Au, Chris; Shuter, Borys; Wang, Shih-Chang; Yeh, Ing Berne

    2009-05-01

    To date, few studies have examined the functional connectivity of brain regions involved in complex executive function tasks, such as cognitive set-shifting. In this study, eighteen healthy volunteers performed a cognitive set-shifting task modified from the Wisconsin card sort test while undergoing functional magnetic resonance imaging. These modifications allowed better disambiguation between cognitive processes and revealed several novel findings: 1) peak activation in the caudate nuclei in the first instance of negative feedback signaling a shift in rule, 2) lowest caudate activation once the rule had been identified, 3) peak hippocampal activation once the identity of the rule had been established, and 4) decreased hippocampal activation during the generation of new rule candidates. This pattern of activation across cognitive set-shifting events suggests that the caudate nuclei play a role in response generation when the identity of the new rule is unknown. In contrast, the reciprocal pattern of hippocampal activation suggests that the hippocampi help consolidate knowledge about the correct stimulus-stimulus associations, associations that become inappropriate once the rule has changed. Functional connectivity analysis using Granger Causality Mapping revealed that caudate and hippocampal regions interacted indirectly via a circuit involving the medial orbitofrontal and posterior cingulate regions, which are known to bias attention towards stimuli based on expectations built up from task-related feedback. Taken together, the evidence suggests that these medial regions may mediate striato-hippocampal interactions and hence affect goal-directed attentional transitions from a response strategy based on stimulus-reward heuristics (caudate-dependent) to one based on stimulus-stimulus associations (hippocampus-dependent).

  10. Dehydroepiandrosterone impacts working memory by shaping cortico-hippocampal structural covariance during development.

    Science.gov (United States)

    Nguyen, Tuong-Vi; Wu, Mia; Lew, Jimin; Albaugh, Matthew D; Botteron, Kelly N; Hudziak, James J; Fonov, Vladimir S; Collins, D Louis; Campbell, Benjamin C; Booij, Linda; Herba, Catherine; Monnier, Patricia; Ducharme, Simon; McCracken, James T

    2017-12-01

    Existing studies suggest that dehydroepiandrosterone (DHEA) may be important for human brain development and cognition. For example, molecular studies have hinted at the critical role of DHEA in enhancing brain plasticity. Studies of human brain development also support the notion that DHEA is involved in preserving cortical plasticity. Further, some, though not all, studies show that DHEA administration may lead to improvements in working memory in adults. Yet these findings remain limited by an incomplete understanding of the specific neuroanatomical mechanisms through which DHEA may impact the CNS during development. Here we examined associations between DHEA, cortico-hippocampal structural covariance, and working memory (216 participants [female=123], age range 6-22 years old, mean age: 13.6 +/-3.6 years, each followed for a maximum of 3 visits over the course of 4 years). In addition to administering performance-based, spatial working memory tests to these children, we also collected ecological, parent ratings of working memory in everyday situations. We found that increasingly higher DHEA levels were associated with a shift toward positive insular-hippocampal and occipito-hippocampal structural covariance. In turn, DHEA-related insular-hippocampal covariance was associated with lower spatial working memory but higher overall working memory as measured by the ecological parent ratings. Taken together with previous research, these results support the hypothesis that DHEA may optimize cortical functions related to general attentional and working memory processes, but impair the development of bottom-up, hippocampal-to-cortical connections, resulting in impaired encoding of spatial cues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Beyond dizziness: virtual navigation, spatial anxiety and hippocampal volume in bilateral vestibulopathy

    Directory of Open Access Journals (Sweden)

    Olympia eKremmyda

    2016-03-01

    Full Text Available Bilateral vestibulopathy (BVP is defined as the impairment or loss of function of either the labyrinths or the eighth nerves. Patients with total BVP due to bilateral vestibular nerve section exhibit difficulties in spatial memory and navigation and show a loss of hippocampal volume. In clinical practice, most patients do not have a complete loss of function but rather an asymmetrical residual functioning of the vestibular system. The purpose of the current study was to investigate navigational ability and hippocampal atrophy in BVP patients with residual vestibular function. Fifteen patients with BVP and a group of age- and gender- matched healthy controls were examined. Self-reported questionnaires on spatial anxiety and wayfinding were used to assess the applied strategy of wayfinding and quality of life. Spatial memory and navigation were tested directly using a virtual Morris Water Maze Task. The hippocampal volume of these two groups was evaluated by voxel-based morphometry. In the patients, the questionnaire showed a higher spatial anxiety and the Morris Water Maze Task a delayed spatial learning performance. MRI revealed a significant decrease in the gray matter mid-hippocampal volume (Left: p = 0.006, Z = 4.58, Right: p < 0.001, Z = 3.63 and posterior parahippocampal volume (Right: p = 0.005, Z = 4.65, Left: p < 0.001, Z = 3.87 compared to those of healthy controls. In addition, a decrease in hippocampal formation volume correlated with a more dominant route-finding strategy. Our current findings demonstrate that even partial bilateral vestibular loss leads to anatomical and functional

  12. MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis.

    Science.gov (United States)

    Sun, Zu-Zhen; Lv, Zhan-Yun; Tian, Wen-Jing; Yang, Yan

    2017-09-01

    Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.

  13. Voluntary resistance running with short distance enhances spatial memory related to hippocampal BDNF signaling.

    Science.gov (United States)

    Lee, Min Chul; Okamoto, Masahiro; Liu, Yu Fan; Inoue, Koshiro; Matsui, Takashi; Nogami, Haruo; Soya, Hideaki

    2012-10-15

    Although voluntary running has beneficial effects on hippocampal cognitive functions if done abundantly, it is still uncertain whether resistance running would be the same. For this purpose, voluntary resistance wheel running (RWR) with a load is a suitable model, since it allows increased work levels and resultant muscular adaptation in fast-twitch muscle. Here, we examined whether RWR would have potential effects on hippocampal cognitive functions with enhanced hippocampal brain-derived neurotrophic factor (BDNF), as does wheel running without a load (WR). Ten-week-old male Wistar rats were assigned randomly to sedentary (Sed), WR, and RWR (to a maximum load of 30% of body weight) groups for 4 wk. We found that in RWR, work levels increased with load, but running distance decreased by about half, which elicited muscular adaptation for fast-twitch plantaris muscle without causing any negative stress effects. Both RWR and WR led to improved spatial learning and memory as well as gene expressions of hippocampal BDNF signaling-related molecules. RWR increased hippocampal BDNF, tyrosine-related kinase B (TrkB), and cAMP response element-binding (CREB) protein levels, whereas WR increased only BDNF. With both exercise groups, there were correlations between spatial memory and BDNF protein (r = 0.41), p-CREB protein (r = 0.44), and work levels (r = 0.77). These results suggest that RWR plays a beneficial role in hippocampus-related cognitive functions associated with hippocampal BDNF signaling, even with short distances, and that work levels rather than running distance are more determinant of exercise-induced beneficial effects in wheel running with and without a load.

  14. Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome.

    Science.gov (United States)

    Jardim, Anaclara Prada; Neves, Rafael Scarpa da Costa; Caboclo, Luís Otávio Sales Ferreira; Lancellotti, Carmen Lucia Penteado; Marinho, Murilo Martinez; Centeno, Ricardo Silva; Cavalheiro, Esper Abrão; Scorza, Carla Alessandra; Yacubian, Elza Márcia Targas

    2012-05-01

    To analyze retrospectively a series of patients with temporal lobe epilepsy (TLE) and mesial temporal sclerosis (MTS), and the association of patterns of hippocampal sclerosis with clinical data and surgical prognosis. Sixty-six patients with medically refractory TLE with unilateral MTS after anterior temporal lobectomy were included. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patient's clinical data and surgical outcome were reviewed. Occurrence of initial precipitating insult (IPI), as well as better postoperative seizure control (i.e. Engel class 1), were associated with classical and severe patterns of hippocampal sclerosis (MTS type 1a and 1b, respectively). Quantitative evaluation of hippocampal neuronal loss patterns predicts surgical outcome in patients with TLE-MTS.

  15. Participation of hippocampal nitric oxide synthase and soluble guanylate cyclase in the modulation of behavioral responses elicited by the rat forced swimming test.

    Science.gov (United States)

    Sales, Amanda J; Hiroaki-Sato, Vinícius A; Joca, Sâmia R L

    2017-02-01

    Systemic or hippocampal administration of nitric oxide (NO) synthase inhibitors induces antidepressant-like effects in animals, implicating increased hippocampal levels of NO in the neurobiology of depression. However, the role played by different NO synthase in this process has not been clearly defined. As stress is able to induce neuroinflammatory mechanisms and trigger the expression of inducible nitric oxide synthase (iNOS) in the brain, as well as upregulate neuronal nitric oxide synthase (nNOS) activity, the aim of the present study was to investigate the possible differential contribution of hippocampal iNOS and nNOS in the modulation of the consequences of stress elicited by the forced swimming test. Male Wistar rats received intrahippocampal injections, immediately after the pretest or 1 h before the forced swimming test, of selective inhibitors of nNOS (N-propyl-L-arginine), iNOS (1400W), or sGC (ODQ), the main pharmacological target for NO. Stress exposure increased nNOS and phospho-nNOS levels at all time points, whereas iNOS expression was increased only 24 h after the pretest. All drugs induced an antidepressant-like effect. However, whereas the nNOS inhibitor was equally effective when injected at different times, the iNOS inhibitor was more effective 24 h after the pretest. These results suggest that hippocampal nNOS and iNOS contribute to increase in NO levels in response to stress, although with a differential time course after stress exposure.

  16. SPATIAL MEMORY IMPAIRMENT AND HIPPOCAMPAL CELL LOSS INDUCED BY OKADAIC ACID (EXPERIMENTAL STUDY).

    Science.gov (United States)

    Chighladze, M; Dashniani, M; Beselia, G; Kruashvili, L; Naneishvili, T

    2016-01-01

    In the present study, we evaluated and compared effect of intracerebroventricular (ICV) and intrahippocampal bilateral microinjection of okadaic acid (OA) on spatial memory function assessed in one day water maze paradigm and hippocampal structure in rats. Rats were divided in following groups: Control(icv) - rats injected with ICV and aCSF; Control(hipp) - rats injected intrahippocampally with aCSF; OAicv - rats injected with ICV and OA; OAhipp - rats injected intrahippocampally with OA. Nissl staining of hippocampal sections showed that the pyramidal cell loss in OAhipp group is significantly higher than that in the OAicv. The results of behavioral experiments showed that ICV or intrahippocampal bilateral microinjection of OA did not affect learning process and short-term spatial memory but induced impairment in spatial long-term memory assessed in probe test performance 24 h after training. OA-induced spatial memory impairment may be attributed to the hippocampal cell death. Based on these results OA induced memory deficit and hippocampal cell loss in rat may be considered as a potential animal model for preclinical evaluation of antidementic drug activity.

  17. Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-03-01

    The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Western High-Fat Diet Consumption during Adolescence Increases Susceptibility to Traumatic Stress while Selectively Disrupting Hippocampal and Ventricular Volumes

    Science.gov (United States)

    Kalyan-Masih, Priya; Vega-Torres, Julio David; Haddad, Elizabeth; Rainsbury, Sabrina; Baghchechi, Mohsen

    2016-01-01

    Abstract Psychological trauma and obesity co-occur frequently and have been identified as major risk factors for psychiatric disorders. Surprisingly, preclinical studies examining how obesity disrupts the ability of the brain to cope with psychological trauma are lacking. The objective of this study was to determine whether an obesogenic Western-like high-fat diet (WD) predisposes rats to post-traumatic stress responsivity. Adolescent Lewis rats (postnatal day 28) were fed ad libitum for 8 weeks with either the experimental WD diet (41.4% kcal from fat) or the control diet (16.5% kcal from fat). We modeled psychological trauma by exposing young adult rats to a cat odor threat. The elevated plus maze and the open field test revealed increased psychological trauma-induced anxiety-like behaviors in the rats that consumed the WD when compared with control animals 1 week after undergoing traumatic stress (p < 0.05). Magnetic resonance imaging showed significant hippocampal atrophy (20% reduction) and lateral ventricular enlargement (50% increase) in the animals fed the WD when compared with controls. These volumetric abnormalities were associated with behavioral indices of anxiety, increased leptin and FK506-binding protein 51 (FKBP51) levels, and reduced hippocampal blood vessel density. We found asymmetric structural vulnerabilities to the WD, particularly the ventral and left hippocampus and lateral ventricle. This study highlights how WD consumption during adolescence impacts key substrates implicated in post-traumatic stress disorder. Understanding how consumption of a WD affects the developmental trajectories of the stress neurocircuitry is critical, as stress susceptibility imposes a marked vulnerability to neuropsychiatric disorders. PMID:27844058

  19. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling

    Directory of Open Access Journals (Sweden)

    Harish Babu

    2009-09-01

    Full Text Available Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potential (LTP-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a significant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ influx. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells. This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling.

  20. IGF-I Gene Therapy in Aging Rats Modulates Hippocampal Genes Relevant to Memory Function.

    Science.gov (United States)

    Pardo, Joaquín; Abba, Martin C; Lacunza, Ezequiel; Ogundele, Olalekan M; Paiva, Isabel; Morel, Gustavo R; Outeiro, Tiago F; Goya, Rodolfo G

    2018-03-14

    In rats, learning and memory performance decline during normal aging, which makes this rodent species a suitable model to evaluate therapeutic strategies. In aging rats, insulin-like growth factor-I (IGF-I), is known to significantly improve spatial memory accuracy as compared to control counterparts. A constellation of gene expression changes underlie the hippocampal phenotype of aging but no studies on the effects of IGF-I on the hippocampal transcriptome of old rodents have been documented. Here, we assessed the effects of IGF-I gene therapy on spatial memory performance in old female rats and compared them with changes in the hippocampal transcriptome. In the Barnes maze test, experimental rats showed a significantly higher exploratory frequency of the goal hole than controls. Hippocampal RNA-sequencing showed that 219 genes are differentially expressed in 28-month-old rats intracerebroventricularly injected with an adenovector expressing rat IGF-I as compared with placebo adenovector-injected counterparts. From the differentially expressed genes, 81 were down and 138 upregulated. From those genes, a list of functionally relevant genes, concerning hippocampal IGF-I expression, synaptic plasticity as well as neuronal function was identified. Our results provide an initial glimpse at the molecular mechanisms underlying the neuroprotective actions of IGF-I in the aging brain.

  1. Bihippocampal damage with emotional dysfunction: impaired auditory recognition of fear.

    Science.gov (United States)

    Ghika-Schmid, F; Ghika, J; Vuilleumier, P; Assal, G; Vuadens, P; Scherer, K; Maeder, P; Uske, A; Bogousslavsky, J

    1997-01-01

    A right-handed man developed a sudden transient, amnestic syndrome associated with bilateral hemorrhage of the hippocampi, probably due to Urbach-Wiethe disease. In the 3rd month, despite significant hippocampal structural damage on imaging, only a milder degree of retrograde and anterograde amnesia persisted on detailed neuropsychological examination. On systematic testing of recognition of facial and vocal expression of emotion, we found an impairment of the vocal perception of fear, but not that of other emotions, such as joy, sadness and anger. Such selective impairment of fear perception was not present in the recognition of facial expression of emotion. Thus emotional perception varies according to the different aspects of emotions and the different modality of presentation (faces versus voices). This is consistent with the idea that there may be multiple emotion systems. The study of emotional perception in this unique case of bilateral involvement of hippocampus suggests that this structure may play a critical role in the recognition of fear in vocal expression, possibly dissociated from that of other emotions and from that of fear in facial expression. In regard of recent data suggesting that the amygdala is playing a role in the recognition of fear in the auditory as well as in the visual modality this could suggest that the hippocampus may be part of the auditory pathway of fear recognition.

  2. Cognitive decline in temporal lobe epilepsy due to unilateral hippocampal sclerosis.

    Science.gov (United States)

    Marques, Carolina Mattos; Caboclo, Luís Otávio Sales Ferreira; da Silva, Tatiana Indelicato; Noffs, Maria Helena da Silva; Carrete, Henrique; Lin, Katia; Lin, Jaime; Sakamoto, Américo Ceiki; Yacubian, Elza Márcia Targas

    2007-05-01

    We assessed the cognitive performance of patients with temporal lobe epilepsy (TLE) caused by unilateral hippocampal sclerosis (HS), in comparison with that of matched, healthy controls. We report the relationship between cognitive measures and duration of epilepsy, correlating with hippocampal volumes, and the impact of educational level on cognitive decline. This study involved 61 outpatients (40 with 8 years of formal education) with unilateral HS and 61 controls. Volumetric MRI was performed on all patients and 10 controls. The results (mean, SD) of the neuropsychological tests of healthy subjects and patients were compared using the Student t and Mann-Whitney tests. Patients performed worse than controls in the neuropsychological evaluation. When adjusted z scores were used to calculate the impairment index, patients had a greater percentage of abnormal tests compared with controls. The cognitive decline, assessed through the impairment index, correlated with duration of epilepsy. Higher level of education did not protect against this decline, thus not supporting the hypothesis of cerebral reserve in this population. A significant correlation between hippocampal volumetric measures and duration of epilepsy was observed only in patients with left HS. Patients with TLE caused by HS present with cognitive morbidity that extends beyond memory deficits. Cognitive decline is associated with duration of epilepsy, and in patients with left-sided HS, duration may correlate with volumetric hippocampal loss.

  3. Estrogen Regulates Protein Synthesis and Actin Polymerization in Hippocampal Neurons through Different Molecular Mechanisms

    Science.gov (United States)

    Briz, Victor; Baudry, Michel

    2014-01-01

    Estrogen rapidly modulates hippocampal synaptic plasticity by activating selective membrane-associated receptors. Reorganization of the actin cytoskeleton and stimulation of mammalian target of rapamycin (mTOR)-mediated protein synthesis are two major events required for the consolidation of hippocampal long-term potentiation and memory. Estradiol regulates synaptic plasticity by interacting with both processes, but the underlying molecular mechanisms are not yet fully understood. Here, we used acute rat hippocampal slices to analyze the mechanisms underlying rapid changes in mTOR activity and actin polymerization elicited by estradiol. Estradiol-induced mTOR phosphorylation was preceded by rapid and transient activation of both extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) and by phosphatase and tensin homolog (PTEN) degradation. These effects were prevented by calpain and ERK inhibitors. Estradiol-induced mTOR stimulation did not require activation of classical estrogen receptors (ER), as specific ERα and ERβ agonists (PPT and DPN, respectively) failed to mimic this effect, and ER antagonists could not block it. Estradiol rapidly activated both RhoA and p21-activated kinase (PAK). Furthermore, a specific inhibitor of RhoA kinase (ROCK), H1152, and a potent and specific PAK inhibitor, PF-3758309, blocked estradiol-induced cofilin phosphorylation and actin polymerization. ER antagonists also blocked these effects of estrogen. Consistently, both PPT and DPN stimulated PAK and cofilin phosphorylation as well as actin polymerization. Finally, the effects of estradiol on actin polymerization were insensitive to protein synthesis inhibitors, but its stimulation of mTOR activity was impaired by latrunculin A, a drug that disrupts actin filaments. Taken together, our results indicate that estradiol regulates local protein synthesis and cytoskeletal reorganization via different molecular mechanisms and signaling pathways. PMID:24611062

  4. Impact of hippocampal subfield histopathology in episodic memory impairment in mesial temporal lobe epilepsy and hippocampal sclerosis.

    Science.gov (United States)

    Comper, Sandra Mara; Jardim, Anaclara Prada; Corso, Jeana Torres; Gaça, Larissa Botelho; Noffs, Maria Helena Silva; Lancellotti, Carmen Lúcia Penteado; Cavalheiro, Esper Abrão; Centeno, Ricardo Silva; Yacubian, Elza Márcia Targas

    2017-10-01

    The objective of the study was to analyze preoperative visual and verbal episodic memories in a homogeneous series of patients with mesial temporal lobe epilepsy (MTLE) and unilateral hippocampal sclerosis (HS) submitted to corticoamygdalohippocampectomy and its association with neuronal cell density of each hippocampal subfield. The hippocampi of 72 right-handed patients were collected and prepared for histopathological examination. Hippocampal sclerosis patterns were determined, and neuronal cell density was calculated. Preoperatively, two verbal and two visual memory tests (immediate and delayed recalls) were applied, and patients were divided into two groups, left and right MTLE (36/36). There were no statistical differences between groups regarding demographic and clinical data. Cornu Ammonis 4 (CA4) neuronal density was significantly lower in the right hippocampus compared with the left (p=0.048). The groups with HS presented different memory performance - the right HS were worse in visual memory test [Complex Rey Figure, immediate (p=0.001) and delayed (p=0.009)], but better in one verbal task [RAVLT delayed (p=0.005)]. Multiple regression analysis suggested that the verbal memory performance of the group with left HS was explained by CA1 neuronal density since both tasks were significantly influenced by CA1 [Logical Memory immediate recall (p=0.050) and Logical Memory and RAVLT delayed recalls (p=0.004 and p=0.001, respectively)]. For patients with right HS, both CA1 subfield integrity (p=0.006) and epilepsy duration (p=0.012) explained Complex Rey Figure immediate recall performance. Ultimately, epilepsy duration also explained the performance in the Complex Rey Figure delayed recall (pepilepsy duration were associated with visual memory performance in patients with right HS. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Optimizing hippocampal segmentation in infants utilizing MRI post-acquisition processing.

    Science.gov (United States)

    Thompson, Deanne K; Ahmadzai, Zohra M; Wood, Stephen J; Inder, Terrie E; Warfield, Simon K; Doyle, Lex W; Egan, Gary F

    2012-04-01

    This study aims to determine the most reliable method for infant hippocampal segmentation by comparing magnetic resonance (MR) imaging post-acquisition processing techniques: contrast to noise ratio (CNR) enhancement, or reformatting to standard orientation. MR scans were performed with a 1.5 T GE scanner to obtain dual echo T2 and proton density (PD) images at term equivalent (38-42 weeks' gestational age). 15 hippocampi were manually traced four times on ten infant images by 2 independent raters on the original T2 image, as well as images processed by: a) combining T2 and PD images (T2-PD) to enhance CNR; then b) reformatting T2-PD images perpendicular to the long axis of the left hippocampus. CNRs and intraclass correlation coefficients (ICC) were calculated. T2-PD images had 17% higher CNR (15.2) than T2 images (12.6). Original T2 volumes' ICC was 0.87 for rater 1 and 0.84 for rater 2, whereas T2-PD images' ICC was 0.95 for rater 1 and 0.87 for rater 2. Reliability of hippocampal segmentation on T2-PD images was not improved by reformatting images (rater 1 ICC = 0.88, rater 2 ICC = 0.66). Post-acquisition processing can improve CNR and hence reliability of hippocampal segmentation in neonate MR scans when tissue contrast is poor. These findings may be applied to enhance boundary definition in infant segmentation for various brain structures or in any volumetric study where image contrast is sub-optimal, enabling hippocampal structure-function relationships to be explored.

  6. Disruption of amygdala-entorhinal-hippocampal network in late-life depression.

    Science.gov (United States)

    Leal, Stephanie L; Noche, Jessica A; Murray, Elizabeth A; Yassa, Michael A

    2017-04-01

    Episodic memory deficits are evident in late-life depression (LLD) and are associated with subtle synaptic and neurochemical changes in the medial temporal lobes (MTL). However, the particular mechanisms by which memory impairment occurs in LLD are currently unknown. We tested older adults with (DS+) and without (DS-) depressive symptoms using high-resolution fMRI that is capable of discerning signals in hippocampal subfields and amygdala nuclei. Scanning was conducted during performance of an emotional discrimination task used previously to examine the relationship between depressive symptoms and amygdala-mediated emotional modulation of hippocampal pattern separation in young adults. We found that hippocampal dentate gyrus (DG)/CA3 activity was reduced during correct discrimination of negative stimuli and increased during correct discrimination of neutral items in DS+ compared to DS- adults. The extent of the latter increase was correlated with symptom severity. Furthermore, DG/CA3 and basolateral amygdala (BLA) activity predicted discrimination performance on negative trials, a relationship that depended on symptom severity. The impact of the BLA on depressive symptom severity was mediated by the DG/CA3 during discrimination of neutral items, and by the lateral entorhinal cortex (LEC) during false recognition of positive items. These results shed light on a novel mechanistic account for amygdala-hippocampal network changes and concurrent alterations in emotional episodic memory in LLD. The BLA-LEC-DG/CA3 network, which comprises a key pathway by which emotion modulates memory, is specifically implicated in LLD. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  7. Evaluating Alzheimer's disease progression using rate of regional hippocampal atrophy.

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    Edit Frankó

    Full Text Available Alzheimer's disease (AD is characterized by neurofibrillary tangle and neuropil thread deposition, which ultimately results in neuronal loss. A large number of magnetic resonance imaging studies have reported a smaller hippocampus in AD patients as compared to healthy elderlies. Even though this difference is often interpreted as atrophy, it is only an indirect measurement. A more direct way of measuring the atrophy is to use repeated MRIs within the same individual. Even though several groups have used this appropriate approach, the pattern of hippocampal atrophy still remains unclear and difficult to relate to underlying pathophysiology. Here, in this longitudinal study, we aimed to map hippocampal atrophy rates in patients with AD, mild cognitive impairment (MCI and elderly controls. Data consisted of two MRI scans for each subject. The symmetric deformation field between the first and the second MRI was computed and mapped onto the three-dimensional hippocampal surface. The pattern of atrophy rate was similar in all three groups, but the rate was significantly higher in patients with AD than in control subjects. We also found higher atrophy rates in progressive MCI patients as compared to stable MCI, particularly in the antero-lateral portion of the right hippocampus. Importantly, the regions showing the highest atrophy rate correspond to those that were described to have the highest burden of tau deposition. Our results show that local hippocampal atrophy rate is a reliable biomarker of disease stage and progression and could also be considered as a method to objectively evaluate treatment effects.

  8. Palmitoylethanolamide exerts neuroprotective effects in mixed neuroglial cultures and organotypic hippocampal slices via peroxisome proliferator-activated receptor-α

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    Scuderi Caterina

    2012-03-01

    Full Text Available Abstract Background In addition to cytotoxic mechanisms directly impacting neurons, β-amyloid (Aβ-induced glial activation also promotes release of proinflammatory molecules that may self-perpetuate reactive gliosis and damage neighbouring neurons, thus amplifying neuropathological lesions occurring in Alzheimer's disease (AD. Palmitoylethanolamide (PEA has been studied extensively for its anti-inflammatory, analgesic, antiepileptic and neuroprotective effects. PEA is a lipid messenger isolated from mammalian and vegetable tissues that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors. Some of its pharmacological properties are considered to be dependent on the expression of peroxisome proliferator-activated receptors-α (PPARα. Findings In the present study, we evaluated the effect of PEA on astrocyte activation and neuronal loss in models of Aβ neurotoxicity. To this purpose, primary rat mixed neuroglial co-cultures and organotypic hippocampal slices were challenged with Aβ1-42 and treated with PEA in the presence or absence of MK886 or GW9662, which are selective PPARα and PPARγ antagonists, respectively. The results indicate that PEA is able to blunt Aβ-induced astrocyte activation and, subsequently, to improve neuronal survival through selective PPARα activation. The data from organotypic cultures confirm that PEA anti-inflammatory properties implicate PPARα mediation and reveal that the reduction of reactive gliosis subsequently induces a marked rebound neuroprotective effect on neurons. Conclusions In line with our previous observations, the results of this study show that PEA treatment results in decreased numbers of infiltrating astrocytes during Aβ challenge, resulting in significant neuroprotection. PEA could thus represent a promising pharmacological tool because it is able to reduce Aβ-evoked neuroinflammation and attenuate its neurodegenerative consequences.

  9. Why trace and delay conditioning are sometimes (but not always) hippocampal dependent: A computational model

    Science.gov (United States)

    Moustafa, Ahmed A.; Wufong, Ella; Servatius, Richard J.; Pang, Kevin C. H.; Gluck, Mark A.; Myers, Catherine E.

    2013-01-01

    A recurrent-network model provides a unified account of the hippocampal region in mediating the representation of temporal information in classical eyeblink conditioning. Much empirical research is consistent with a general conclusion that delay conditioning (in which the conditioned stimulus CS and unconditioned stimulus US overlap and co-terminate) is independent of the hippocampal system, while trace conditioning (in which the CS terminates before US onset) depends on the hippocampus. However, recent studies show that, under some circumstances, delay conditioning can be hippocampal-dependent and trace conditioning can be spared following hippocampal lesion. Here, we present an extension of our prior trial-level models of hippocampal function and stimulus representation that can explain these findings within a unified framework. Specifically, the current model includes adaptive recurrent collateral connections that aid in the representation of intra-trial temporal information. With this model, as in our prior models, we argue that the hippocampus is not specialized for conditioned response timing, but rather is a general-purpose system that learns to predict the next state of all stimuli given the current state of variables encoded by activity in recurrent collaterals. As such, the model correctly predicts that hippocampal involvement in classical conditioning should be critical not only when there is an intervening trace interval, but also when there is a long delay between CS onset and US onset. Our model simulates empirical data from many variants of classical conditioning, including delay and trace paradigms in which the length of the CS, the inter-stimulus interval, or the trace interval is varied. Finally, we discuss model limitations, future directions, and several novel empirical predictions of this temporal processing model of hippocampal function and learning. PMID:23178699

  10. An association between human hippocampal volume and topographical memory in healthy young adults.

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    Tom eHartley

    2012-12-01

    Full Text Available The association between human hippocampal structure and topographical memory was investigated in healthy adults (N=30. Structural MR images were acquired, and voxel-based morphometry (VBM was used to estimate local gray matter volume throughout the brain. A complementary automated mesh-based segmentation approach was used to independently isolate and measure specified structures including the hippocampus. Topographical memory was assessed using a version of the Four Mountains Task, a short test designed to target hippocampal spatial function. Each item requires subjects to briefly study a landscape scene before recognizing the depicted place from a novel viewpoint and under altered non-spatial conditions when presented amongst similar alternative scenes. Positive correlations between topographical memory performance and hippocampal volume were observed in both VBM and segmentation-based analyses. Score on the topographical memory task was also correlated with the volume of some subcortical structures, extra-hippocampal gray matter and total brain volume, with the most robust and extensive covariation seen in circumscribed neocortical regions in the insula and anterior temporal lobes. Taken together with earlier findings, the results suggest that global variations in brain morphology affect the volume of the hippocampus and its specific contribution to topographical memory. We speculate that behavioral variation might arise directly through the impact of resource constraints on spatial representations in the hippocampal formation and its inputs, and perhaps indirectly through an increased reliance on non-allocentric strategies.

  11. Real-time changes in hippocampal energy demands during a spatial working memory task.

    Science.gov (United States)

    Kealy, John; Bennett, Rachel; Woods, Barbara; Lowry, John P

    2017-05-30

    Activity-dependent changes in hippocampal energy consumption have largely been determined using microdialysis. However, real-time recordings of brain energy consumption can be more accurately achieved using amperometric sensors, allowing for sensitive real-time monitoring of concentration changes. Here, we test the theory that systemic pre-treatment with glucose in rats prevents activity-dependent decreases in hippocampal glucose levels and thus enhances their performance in a spontaneous alternation task. Male Sprague Dawley rats were implanted into the hippocampus with either: 1) microdialysis probe; or 2) an oxygen sensor and glucose biosensor co-implanted together. Animals were pre-treated with either saline or glucose (250mg/kg) 30min prior to performing a single 20-min spontaneous alternation task in a +-maze. There were no significant differences found between either treatment group in terms of spontaneous alternation performance. Additionally, there was a significant difference found between treatment groups on hippocampal glucose levels measured using microdialysis (a decrease associated with glucose pre-treatment in control animals) but not amperometry. There were significant increases in hippocampal oxygen during +-maze exploration. Combining the findings from both methods, it appears that hippocampal activity in the spontaneous alternation task does not cause an increase in glucose consumption, despite an increase in regional cerebral blood flow (using oxygen supply as an index of blood flow) and, as such, pre-treatment with glucose does not enhance spontaneous alternation performance. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.

    Science.gov (United States)

    Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L; Szigeti-Buck, Klara; Sallam, Nermin L; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S

    2009-03-01

    Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects. These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.

  13. Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood.

    Science.gov (United States)

    Daugherty, Ana M; Flinn, Robert; Ofen, Noa

    2017-06-01

    Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8-25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood

    Science.gov (United States)

    Daugherty, Ana M.; Flinn, Robert; Ofen, Noa

    2017-01-01

    Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution proton density-weighted images in a sample of healthy participants (age 8–25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. PMID:28342999

  15. Effects of voluntary running on plasma levels of neurotrophins, hippocampal cell proliferation and learning and memory in stressed rats.

    Science.gov (United States)

    Yau, S-Y; Lau, B W-M; Zhang, E-D; Lee, J C-D; Li, A; Lee, T M C; Ching, Y-P; Xu, A-M; So, K-F

    2012-10-11

    Previous studies have shown that a 2-week treatment with 40 mg/kg corticosterone (CORT) in rats suppresses hippocampal neurogenesis and decreases hippocampal brain-derived neurotrophic factor (BDNF) levels and impairs spatial learning, all of which could be counteracted by voluntary wheel running. BDNF and insulin-like growth factor (IGF-1) have been suggested to mediate physical exercise-enhanced hippocampal neurogenesis and cognition. Here we examined whether such running-elicited benefits were accompanied by corresponding changes of peripheral BDNF and IGF-1 levels in a rat model of stress. We examined the effects of acute (5 days) and chronic (4 weeks) treatment with CORT and/or wheel running on (1) hippocampal cell proliferation, (2) spatial learning and memory and (3) plasma levels of BDNF and IGF-1. Acute CORT treatment improved spatial learning without altered cell proliferation compared to vehicle treatment. Acute CORT-treated non-runners showed an increased trend in plasma BDNF levels together with a significant increase in hippocampal BDNF levels. Acute running showed no effect on cognition, cell proliferation and peripheral BDNF and IGF-1 levels. Conversely, chronic CORT treatment in non-runners significantly impaired spatial learning and suppressed cell proliferation in association with a decreased trend in plasma BDNF level and a significant increase in hippocampal BDNF levels. Running counteracted cognitive deficit and restored hippocampal cell proliferation following chronic CORT treatment; but without corresponding changes in plasma BDNF and IGF-1 levels. The results suggest that the beneficial effects of acute stress on cognitive improvement may be mediated by BDNF-enhanced synaptic plasticity that is hippocampal cell proliferation-independent, whereas chronic stress may impair cognition by decreasing hippocampal cell proliferation and BDNF levels. Furthermore, the results indicate a trend in changes of plasma BDNF levels associated with a

  16. Transformation of a Spatial Map across the Hippocampal-Lateral Septal Circuit.

    Science.gov (United States)

    Tingley, David; Buzsáki, György

    2018-05-15

    The hippocampus constructs a map of the environment. How this "cognitive map" is utilized by other brain regions to guide behavior remains unexplored. To examine how neuronal firing patterns in the hippocampus are transmitted and transformed, we recorded neurons in its principal subcortical target, the lateral septum (LS). We observed that LS neurons carry reliable spatial information in the phase of action potentials, relative to hippocampal theta oscillations, while the firing rates of LS neurons remained uninformative. Furthermore, this spatial phase code had an anatomical microstructure within the LS and was bound to the hippocampal spatial code by synchronous gamma frequency cell assemblies. Using a data-driven model, we show that rate-independent spatial tuning arises through the dynamic weighting of CA1 and CA3 cell assemblies. Our findings demonstrate that transformation of the hippocampal spatial map depends on higher-order theta-dependent neuronal sequences. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

    Science.gov (United States)

    Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B; Hubbard, Dusten D; Hanka, Dakota C; Gonzalez, Paola V; Kuwajima, Masaaki; Mendenhall, John M; Parker, Patrick H; Abraham, Wickliffe C; Sejnowski, Terrence J; Harris, Kristen M

    2018-03-06

    An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

  18. The many tunes of perisomatic targeting interneurons in the hippocampal network

    Directory of Open Access Journals (Sweden)

    Tommas J Ellender

    2010-07-01

    Full Text Available The axonal targets of perisomatic targeting interneurons make them ideally suited to synchronise excitatory neurons. As such they have been implicated in rhythm generation of network activity in many brain regions including the hippocampus. However, several recent publications indicate that their roles extend beyond that of rhythm generation. Firstly, it has been shown that, in addition to rhythm generation, GABAergic perisomatic inhibition also serves as a current generator contributing significantly to hippocampal oscillatory EEG signals. Furthermore, GABAergic interneurons have a hitherto unexpected role in the initiation of hippocampal population bursts, both in the developing and adult hippocampus. In this review, we describe these new observations in detail and discuss the implications they have for our understanding of the mechanisms underlying physiological and pathological hippocampal network activities. This review is part of the Frontiers in Cellular Neuroscience's special topic entitled GABA signalling in health and disease based on the meeting at the CNCR Amsterdam.

  19. Encoding, Consolidation, and Retrieval of Contextual Memory: Differential Involvement of Dorsal CA3 and CA1 Hippocampal Subregions

    Science.gov (United States)

    Daumas, Stephanie; Halley, Helene; Frances, Bernard; Lassalle, Jean-Michel

    2005-01-01

    Studies on human and animals shed light on the unique hippocampus contributions to relational memory. However, the particular role of each hippocampal subregion in memory processing is still not clear. Hippocampal computational models and theories have emphasized a unique function in memory for each hippocampal subregion, with the CA3 area acting…

  20. Test-retest reliability and longitudinal analysis of automated hippocampal subregion volumes in healthy ageing and Alzheimer's disease populations.

    Science.gov (United States)

    Worker, Amanda; Dima, Danai; Combes, Anna; Crum, William R; Streffer, Johannes; Einstein, Steven; Mehta, Mitul A; Barker, Gareth J; C R Williams, Steve; O'daly, Owen

    2018-04-01

    The hippocampal formation is a complex brain structure that is important in cognitive processes such as memory, mood, reward processing and other executive functions. Histological and neuroimaging studies have implicated the hippocampal region in neuropsychiatric disorders as well as in neurodegenerative diseases. This highly plastic limbic region is made up of several subregions that are believed to have different functional roles. Therefore, there is a growing interest in imaging the subregions of the hippocampal formation rather than modelling the hippocampus as a homogenous structure, driving the development of new automated analysis tools. Consequently, there is a pressing need to understand the stability of the measures derived from these new techniques. In this study, an automated hippocampal subregion segmentation pipeline, released as a developmental version of Freesurfer (v6.0), was applied to T1-weighted magnetic resonance imaging (MRI) scans of 22 healthy older participants, scanned on 3 separate occasions and a separate longitudinal dataset of 40 Alzheimer's disease (AD) patients. Test-retest reliability of hippocampal subregion volumes was assessed using the intra-class correlation coefficient (ICC), percentage volume difference and percentage volume overlap (Dice). Sensitivity of the regional estimates to longitudinal change was estimated using linear mixed effects (LME) modelling. The results show that out of the 24 hippocampal subregions, 20 had ICC scores of 0.9 or higher in both samples; these regions include the molecular layer, granule cell layer of the dentate gyrus, CA1, CA3 and the subiculum (ICC > 0.9), whilst the hippocampal fissure and fimbria had lower ICC scores (0.73-0.88). Furthermore, LME analysis of the independent AD dataset demonstrated sensitivity to group and individual differences in the rate of volume change over time in several hippocampal subregions (CA1, molecular layer, CA3, hippocampal tail, fissure and presubiculum

  1. Hippocampal volume and serotonin transporter polymorphism in major depressive disorder

    DEFF Research Database (Denmark)

    Ahdidan, Jamila; Foldager, Leslie; Rosenberg, Raben

    2013-01-01

    Objective: The main aim of the present study was to replicate a previous finding in major depressive disorder (MDD) of association between reduced hippocampal volume and the long variant of the di- and triallelic serotonin transporter polymorphism in SLC6A4 on chromosome 17q11.2. Secondarily, we...... that we aimed to replicate, and no significant associations with the serotonin transporter polymorphism were found. Conclusions: The present quantitative and morphometric MRI study was not able to replicate the previous finding of association between reduced hippocampal volume in depressed patients...... and the serotonin transporter polymorphism....

  2. Hippocampal low-frequency stimulation inhibits afterdischarge and increases GABA (A) receptor expression in amygdala-kindled pharmacoresistant epileptic rats.

    Science.gov (United States)

    Wu, Guofeng; Wang, Likun; Hong, Zhen; Ren, Siying; Zhou, Feng

    2017-08-01

    The purpose of the present study was to observe the effects of hippocampal low-frequency stimulation (Hip-LFS) on amygdala afterdischarge and GABA (A) receptor expression in pharmacoresistant epileptic (PRE) rats. A total of 110 healthy adult male Wistar rats were used to generate a model of epilepsy by chronic stimulation of the amygdala. Sixteen PRE rats were selected from 70 amygdala-kindled rats by testing their response to Phenytoin and Phenobarbital, and they were randomly assigned to a pharmacoresistant stimulation group (PRS group, 8 rats) or a pharmacoresistant control group (PRC group, 8 rats). A stimulation electrode was implanted into the hippocampus of all of the rats. Hip-LFS was administered twice per day in the PRS group for two weeks. Simultaneously, amygdala stimulus-induced seizures and afterdischarge were recorded. After the hippocampal stimulation was terminated, the brain tissues were obtained to determine the GABA (A) receptors by a method of immumohistochemistry and a real-time polymerase chain reaction. The stages and duration of the amygdala stimulus-induced epileptic seizures were decreased in the PRS group. The afterdischarge threshold was increased and the duration as well as the afterdischarge frequency was decreased. Simultaneously, the GABA (A) expression was significantly increased in the PRS group. Hip-LFS may inhibit amygdala stimulus-induced epileptic seizures and up-regulate GABA (A) receptor expression in PRE rats. The antiepileptic effects of hippocampal stimulation may be partly achieved by increasing the GABA (A) receptor.

  3. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

    Science.gov (United States)

    Rayen, Ine; van den Hove, Daniël L; Prickaerts, Jos; Steinbusch, Harry W; Pawluski, Jodi L

    2011-01-01

    Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs) medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1 (P1). Adolescent male and female offspring were divided into 4 groups: 1) prenatal stress+fluoxetine exposure, 2) prenatal stress+vehicle, 3) fluoxetine exposure alone, and 4) vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

  4. Fluoxetine during development reverses the effects of prenatal stress on depressive-like behavior and hippocampal neurogenesis in adolescence.

    Directory of Open Access Journals (Sweden)

    Ine Rayen

    Full Text Available Depression during pregnancy and the postpartum period is a growing health problem, which affects up to 20% of women. Currently, selective serotonin reuptake inhibitor (SSRIs medications are commonly used for treatment of maternal depression. Unfortunately, there is very little research on the long-term effect of maternal depression and perinatal SSRI exposure on offspring development. Therefore, the aim of this study was to determine the role of exposure to fluoxetine during development on affective-like behaviors and hippocampal neurogenesis in adolescent offspring in a rodent model of maternal depression. To do this, gestationally stressed and non-stressed Sprague-Dawley rat dams were treated with either fluoxetine (5 mg/kg/day or vehicle beginning on postnatal day 1 (P1. Adolescent male and female offspring were divided into 4 groups: 1 prenatal stress+fluoxetine exposure, 2 prenatal stress+vehicle, 3 fluoxetine exposure alone, and 4 vehicle alone. Adolescent offspring were assessed for anxiety-like behavior using the Open Field Test and depressive-like behavior using the Forced Swim Test. Brains were analyzed for endogenous markers of hippocampal neurogenesis via immunohistochemistry. Results demonstrate that maternal fluoxetine exposure reverses the reduction in immobility evident in prenatally stressed adolescent offspring. In addition, maternal fluoxetine exposure reverses the decrease in hippocampal cell proliferation and neurogenesis in maternally stressed adolescent offspring. This research provides important evidence on the long-term effect of fluoxetine exposure during development in a model of maternal adversity.

  5. Temporal lobe epilepsy with mesial temporal sclerosis: hippocampal neuronal loss as a predictor of surgical outcome

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    Anaclara Prada Jardim

    2012-05-01

    Full Text Available OBJECTIVE: To analyze retrospectively a series of patients with temporal lobe epilepsy (TLE and mesial temporal sclerosis (MTS, and the association of patterns of hippocampal sclerosis with clinical data and surgical prognosis. METHOD: Sixty-six patients with medically refractory TLE with unilateral MTS after anterior temporal lobectomy were included. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patient's clinical data and surgical outcome were reviewed. RESULTS: Occurrence of initial precipitating insult (IPI, as well as better postoperative seizure control (i.e. Engel class 1, were associated with classical and severe patterns of hippocampal sclerosis (MTS type 1a and 1b, respectively. CONCLUSION: Quantitative evaluation of hippocampal neuronal loss patterns predicts surgical outcome in patients with TLE-MTS.

  6. Hippocampal atrophy and altered brain responses to pleasant tastes among obese compared with healthy weight children.

    Science.gov (United States)

    Mestre, Z L; Bischoff-Grethe, A; Eichen, D M; Wierenga, C E; Strong, D; Boutelle, K N

    2017-10-01

    The hippocampus is a key structure implicated in food motivation and intake. Research has shown that the hippocampus is vulnerable to the consumption of a western diet (i.e., high saturated fat and simple carbohydrates). Studies of patients with obesity (OB), compared with healthy weight (HW), show changes in hippocampal volume and response to food cues. Moreover, evidence suggests that OB children, relative to HW, have greater hippocampal response to taste. However, no study has examined the association of hippocampal volume with taste functioning in children. We hypothesized that OB children, relative to HW, would show a significant reduction in hippocampal volume and that decreased volume would be significantly associated with greater activation to taste. Finally, we explored whether hippocampal activation would be associated with measures on eating and eating habits. Twenty-five 8-12-year-old children (i.e., 13 HW, 12 OB) completed a magnetic resonance imaging scan while participating in a taste paradigm (i.e., 1 ml of 10% sucrose or ionic water delivered pseudorandomly every 20 s). Children with OB, relative to HW, showed reduced left hippocampal volume (t=1.994, P=0.03, 95% confidence interval (CI)=-40.23,  755.42), and greater response to taste in three clusters within the left hippocampus (z=3.3, P=0.001, 95% CI=-0.241, -0.041; z=3.3, P=0.001, 95% CI=-0.2711, -0.0469; z=2.7, P=0.007, 95% CI=-0.6032, -0.0268). Activation within the hippocampus was associated with eating in the absence of hunger (EAH%; t=2.408, P=0.025, 95% CI= 1.751708, 23.94109) and two subscales on a measure of eating behaviors (Food responsiveness, t=2.572, P=0.017, 95% CI= 0.9565195, 9.043440; Food enjoyment, t=2.298, P=0.032, 95% CI=0.2256749, 4.531298). As hypothesized, OB children, relative to HW, had significantly reduced hippocampal volume, and greater hippocampal activation to taste. Moreover, hippocampal activation was associated with measures of eating. These results

  7. Atorvastatin prevents Aβ oligomer-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting Tau cleavage

    Science.gov (United States)

    Sui, Hai-juan; Zhang, Ling-ling; Liu, Zhou; Jin, Ying

    2015-01-01

    Aim: The proteolytic cleavage of Tau is involved in Aβ-induced neuronal dysfunction and cell death. In this study, we investigated whether atorvastatin could prevent Tau cleavage and hence prevent Aβ1–42 oligomer (AβO)-induced neurotoxicity in cultured cortical neurons. Methods: Cultured rat hippocampal neurons were incubated in the presence of AβOs (1.25 μmol/L) with or without atorvastatin pretreatment. ATP content and LDH in the culture medium were measured to assess the neuronal viability. Caspase-3/7 and calpain protease activities were detected. The levels of phospho-Akt, phospho-Erk1/2, phospho-GSK3β, p35 and Tau proteins were measured using Western blotting. Results: Treatment of the neurons with AβO significantly decreased the neuronal viability, induced rapid activation of calpain and caspase-3/7 proteases, accompanied by Tau degradation and relatively stable fragments generated in the neurons. AβO also suppressed Akt and Erk1/2 kinase activity, while increased GSK3β and Cdk5 activity in the neurons. Pretreatment with atorvastatin (0.5, 1, 2.5 μmol/L) dose-dependently inhibited AβO-induced activation of calpain and caspase-3/7 proteases, and effectively diminished the generation of Tau fragments, attenuated synaptic damage and increased neuronal survival. Atorvastatin pretreatment also prevented AβO-induced decreases in Akt and Erk1/2 kinase activity and the increases in GSK3β and Cdk5 kinase activity. Conclusion: Atorvastatin prevents AβO-induced neurotoxicity in cultured rat hippocampal neurons by inhibiting calpain- and caspase-mediated Tau cleavage. PMID:25891085

  8. n-3 polyunsaturated fatty acids supplementation enhances hippocampal functionality in aged mice

    Directory of Open Access Journals (Sweden)

    Debora eCutuli

    2014-08-01

    Full Text Available As major components of neuronal membranes, omega-3 polyunsaturated acids (n-3 PUFA exhibit a wide range of regulatory functions, modulating from synaptic plasticity to neuroinflammation, from oxidative stress to neuroprotection. Recent human and animal studies indicated the n-3 PUFA neuroprotective properties in aging, with a clear negative correlation between n-3 PUFA levels and hippocampal deficits. The present multidimensional study was aimed at associating cognition, hippocampal neurogenesis, volume, neurodegeneration and metabolic correlates to verify n-3 PUFA neuroprotective effects in aging. To this aim 19 month-old mice were given n-3 PUFA mixture, or olive oil or no dietary supplement for 8 weeks during which hippocampal-dependent mnesic functions were tested. At the end of behavioral testing morphological and metabolic correlates were analyzed. n-3 PUFA supplemented aged mice exhibited better object recognition memory, spatial and localizatory memory, and aversive response retention, without modifications in anxiety levels in comparison to controls. These improved hippocampal cognitive functions occurred in the context of an enhanced cellular plasticity and a reduced neurodegeneration. In fact, n-3 PUFA supplementation increased hippocampal neurogenesis and dendritic arborization of newborn neurons, volume, neuronal density and microglial cell number, while it decreased apoptosis, astrocytosis and lipofuscin accumulation in the hippocampus. The increased levels of some metabolic correlates (blood Acetyl-L-Carnitine and brain n-3 PUFA concentrations found in n-3 PUFA supplemented mice also pointed towards an effective neuroprotection.On the basis of the present results n-3 PUFA supplementation appears to be a useful tool in health promotion and cognitive decline prevention during aging.

  9. Hippocampal Processing of Ambiguity Enhances Fear Memory.

    Science.gov (United States)

    Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V; Goosens, Ki A

    2017-02-01

    Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.

  10. A Compressed Sensing Perspective of Hippocampal Function

    Directory of Open Access Journals (Sweden)

    Panagiotis ePetrantonakis

    2014-08-01

    Full Text Available Hippocampus is one of the most important information processing units in the brain. Input from the cortex passes through convergent axon pathways to the downstream hippocampal subregions and, after being appropriately processed, is fanned out back to the cortex. Here, we review evidence of the hypothesis that information flow and processing in the hippocampus complies with the principles of Compressed Sensing (CS. The CS theory comprises a mathematical framework that describes how and under which conditions, restricted sampling of information (data set can lead to condensed, yet concise, forms of the initial, subsampled information entity (i.e. of the original data set. In this work, hippocampus related regions and their respective circuitry are presented as a CS-based system whose different components collaborate to realize efficient memory encoding and decoding processes. This proposition introduces a unifying mathematical framework for hippocampal function and opens new avenues for exploring coding and decoding strategies in the brain.

  11. Midlife managerial experience is linked to late life hippocampal morphology and function.

    Science.gov (United States)

    Suo, C; Gates, N; Fiatarone Singh, M; Saigal, N; Wilson, G C; Meiklejohn, J; Sachdev, P; Brodaty, H; Wen, W; Singh, N; Baune, B T; Baker, M; Foroughi, N; Wang, Y; Valenzuela, Michael J

    2017-04-01

    An active cognitive lifestyle has been suggested to have a protective role in the long-term maintenance of cognition. Amongst healthy older adults, more managerial or supervisory experiences in midlife are linked to a slower hippocampal atrophy rate in late life. Yet whether similar links exist in individuals with Mild Cognitive Impairment (MCI) is not known, nor whether these differences have any functional implications. 68 volunteers from the Sydney SMART Trial, diagnosed with non-amnestic MCI, were divided into high and low managerial experience (HME/LME) during their working life. All participants underwent neuropsychological testing, structural and resting-state functional MRI. Group comparisons were performed on hippocampal volume, morphology, hippocampal seed-based functional connectivity, memory and executive function and self-ratings of memory proficiency. HME was linked to better memory function (p = 0.024), mediated by larger hippocampal volume (p = 0.025). More specifically, deformation analysis found HME had relatively more volume in the CA1 sub-region of the hippocampus (p < 0.05). Paradoxically, this group rated their memory proficiency worse (p = 0.004), a result correlated with diminished functional connectivity between the right hippocampus and right prefrontal cortex (p < 0.001). Finally, hierarchical regression modelling substantiated this double dissociation.

  12. Neurosyphilis with dementia and bilateral hippocampal atrophy on brain magnetic resonance imaging

    International Nuclear Information System (INIS)

    Mehrabian, S.; Raycheva, M.; Traykova, M.; Stankova, T.; Penev, L.; Georgieva-Kozarova, G.; Grigorova, O.; Traykov, L.

    2012-01-01

    Full text: Background: This article reports a rare case of active neurosyphilis in a 33-years-old man with mild to moderate dementia and marked hippocampal atrophy, mimicking early onset Alzheimer's disease. Few number of cases described bilateral hippocampal atrophy mimicking Alzheimer's disease in neurosyphilis. Case presentation: The clinical feature is characterized by a progressive cognitive decline and behavioral changes for the last 18 months. Neuropsychological examination revealed mild to moderate dementia (MMSE=16) with impaired memory, attention and executive dysfunction. Pyramidal, extrapyramidal signs, dysarthria and impairment in coordination were documented. Brain magnetic resonance imaging showed cortical atrophy with marked bilateral hippocampal atrophy. The diagnosis of active neurosyphilis was based on positive results of Venereal Disease Research Laboratory test - Treponema Pallidum. Hemagglutination reactions in blood and cerebrospinal fluid samples. In addition, cerebrospinal fluid analysis showed pleocytosis and elevated protein levels. High dose intravenous penicillin therapy was administered. During the follow up examination at 6 month, the clinical signs, and neuropsychological examinations, and cerebrospinal fluid samples showed improvement. Conclusion: This case underlines the importance of early diagnosis of neurosyphilis. The results suggest that neurosyphilis should be considered when magnetic resonance imaging results indicate mesiotemporal abnormalities and hippocampal atrophy. Neurosyphilis is a treatable condition and needs early aggressive antibiotic therapy

  13. Hippocampal volume change measurement: quantitative assessment of the reproducibility of expert manual outlining and the automated methods FreeSurfer and FIRST.

    Science.gov (United States)

    Mulder, Emma R; de Jong, Remko A; Knol, Dirk L; van Schijndel, Ronald A; Cover, Keith S; Visser, Pieter J; Barkhof, Frederik; Vrenken, Hugo

    2014-05-15

    To measure hippocampal volume change in Alzheimer's disease (AD) or mild cognitive impairment (MCI), expert manual delineation is often used because of its supposed accuracy. It has been suggested that expert outlining yields poorer reproducibility as compared to automated methods, but this has not been investigated. To determine the reproducibilities of expert manual outlining and two common automated methods for measuring hippocampal atrophy rates in healthy aging, MCI and AD. From the Alzheimer's Disease Neuroimaging Initiative (ADNI), 80 subjects were selected: 20 patients with AD, 40 patients with mild cognitive impairment (MCI) and 20 healthy controls (HCs). Left and right hippocampal volume change between baseline and month-12 visit was assessed by using expert manual delineation, and by the automated software packages FreeSurfer (longitudinal processing stream) and FIRST. To assess reproducibility of the measured hippocampal volume change, both back-to-back (BTB) MPRAGE scans available for each visit were analyzed. Hippocampal volume change was expressed in μL, and as a percentage of baseline volume. Reproducibility of the 1-year hippocampal volume change was estimated from the BTB measurements by using linear mixed model to calculate the limits of agreement (LoA) of each method, reflecting its measurement uncertainty. Using the delta method, approximate p-values were calculated for the pairwise comparisons between methods. Statistical analyses were performed both with inclusion and exclusion of visibly incorrect segmentations. Visibly incorrect automated segmentation in either one or both scans of a longitudinal scan pair occurred in 7.5% of the hippocampi for FreeSurfer and in 6.9% of the hippocampi for FIRST. After excluding these failed cases, reproducibility analysis for 1-year percentage volume change yielded LoA of ±7.2% for FreeSurfer, ±9.7% for expert manual delineation, and ±10.0% for FIRST. Methods ranked the same for reproducibility of 1

  14. Hippocampal sclerosis and status epilepticus: cause or consequence? A MRI study

    International Nuclear Information System (INIS)

    Kuster, Gustavo Wruck; Braga-Neto, Pedro; Santos-Neto, Denizart; Santana, Maria Teresa Garcia; Barsottini, Orlando Graziani; Maia Junior, Antonio Carlos Martins

    2007-01-01

    Background: Transient imaging abnormalities, including changes on diffusion-weighted imaging (DWI), may be seen in status epilepticus. These abnormalities can be followed by hippocampal sclerosis. Case Report: We report a 15-year-old lady with focal non convulsive status epilepticus (NCSE) and focal slowing on EEG. DWI exhibited abnormal hyperintense signals in bilateral temporal and insular cortices. After 3 weeks, MRI performed a localized hippocampal atrophy. Conclusion: The MRI findings indicated vasogenic and cytotoxic edema during seizure activity and subsequent loss of brain parenchyma. (author)

  15. Hippocampal Abnormalities after Prolonged Febrile Convulsions

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2003-11-01

    Full Text Available Hippocampal volume and T2 relaxation times were determined in an MRI study of 14 children with prolonged febrile convulsions (PFC who were investigated, 1 within 5 days of a PFC, and 2 at follow-up 4-8 months after the acute study, at the Institute of Child Health, University College, and Great Ormond Street Hospital, London, UK.

  16. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Science.gov (United States)

    Pawluski, Jodi L.; van Donkelaar, Eva; Abrams, Zipporah; Steinbusch, Harry W. M.; Charlier, Thierry D.

    2014-01-01

    Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1) cookie and (2) osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL) at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat. PMID:24757568

  17. Fluoxetine Dose and Administration Method Differentially Affect Hippocampal Plasticity in Adult Female Rats

    Directory of Open Access Journals (Sweden)

    Jodi L. Pawluski

    2014-01-01

    Full Text Available Selective serotonin reuptake inhibitor medications are one of the most common treatments for mood disorders. In humans, these medications are taken orally, usually once per day. Unfortunately, administration of antidepressant medications in rodent models is often through injection, oral gavage, or minipump implant, all relatively stressful procedures. The aim of the present study was to investigate how administration of the commonly used SSRI, fluoxetine, via a wafer cookie, compares to fluoxetine administration using an osmotic minipump, with regards to serum drug levels and hippocampal plasticity. For this experiment, adult female Sprague-Dawley rats were divided over the two administration methods: (1 cookie and (2 osmotic minipump and three fluoxetine treatment doses: 0, 5, or 10 mg/kg/day. Results show that a fluoxetine dose of 5 mg/kg/day, but not 10 mg/kg/day, results in comparable serum levels of fluoxetine and its active metabolite norfluoxetine between the two administration methods. Furthermore, minipump administration of fluoxetine resulted in higher levels of cell proliferation in the granule cell layer (GCL at a 5 mg dose compared to a 10 mg dose. Synaptophysin expression in the GCL, but not CA3, was significantly lower after fluoxetine treatment, regardless of administration method. These data suggest that the administration method and dose of fluoxetine can differentially affect hippocampal plasticity in the adult female rat.

  18. Selective amygdalohippocampectomy via trans-superior temporal gyrus keyhole approach.

    Science.gov (United States)

    Mathon, Bertrand; Clemenceau, Stéphane

    2016-04-01

    Hippocampal sclerosis is the most common cause of drug-resistant epilepsy amenable for surgical treatment and seizure control. The rationale of the selective amygdalohippocampectomy is to spare cerebral tissue not included in the seizure generator. Describe the selective amygdalohippocampectomy through the trans-superior temporal gyrus keyhole approach. Selective amygdalohippocampectomy for temporal lobe epilepsy is performed when the data (semiology, neuroimaging, electroencephalography) point to the mesial temporal structures. The trans-superior temporal gyrus keyhole approach is a minimally invasive and safe technique that allows disconnection of the temporal stem and resection of temporomesial structures.

  19. Alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats.

    Science.gov (United States)

    Sun, Hongli; Su, Qian; Zhang, Huifang; Liu, Weimin; Zhang, Huiping; Ding, Ding; Zhu, Zhongliang; Li, Hui

    2015-06-01

    To clarify the alterations of proliferation and differentiation of hippocampal cells in prenatally stressed rats. We investigated the impact of prenatal restraint stress on the hipocampal cell proliferation in the progeny with 5-bromo-2'-deoxyuridine (BrdU), which is a marker of proliferating cells and their progeny. In addition, we observed the differentiation of neural stem cells (NSCs) with double labeling of BrdU/neurofilament (NF), BrdU/glial fibrillary acidic protein (GFAP) in the hipocampus. Prenatal stress (PS) increased cell proliferation in the dentate gyrus (DG) only in female and neuron differentiation of newly divided cells in the DG and CA4 in both male and female. Moreover, the NF and GFAP-positive cells, but not the BrdU-positive cells, BrdU/NF and BrdU/GFAP-positive cells, were found frequently in the CA3 and CA1 in the offspring of each group. These results possibly suggest a compensatory adaptive response to neuronal damage or loss in hippocampus induced by PS. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  20. [ERK activation effects on GABA secretion inhibition induced by SDF-1 in hippocampal neurons of rats].

    Science.gov (United States)

    Zhang, Zi-juan; Guo, Mei-xia; Xing, Ying

    2015-09-01

    To investigate the effect of extracellular regulating kinase (ERK) signaling pathway on the secretion of gamma-aminobutyric acid (GABA) in cultured rat hippocampal neurons induced by stromal cell derived factor-1 (SDF-1). The hippocampal neurons of newborn SD rats were cultured and identified in vitro; the phosphorylation level of ERK1/2 was examined by Western blot; ELISA was used to detect the effect of PD98059, a ERK1/2 specific blocker on GABA secretion of cultured hippocampal neurons and Western blot were adopted to measure the protein expression levels of glutamate decarboxylase (GAD65/67) and gamma aminobutyric acid transporter (GAT); after blocking ERK1/2 signaling pathway with PD98059; RT-PCR was used to detect the mRNA expression levels of GAT-1 and GAD65 after treated with PD98059. The levels of ERKl/2 phosphorylation were increased significantly by SDF1 acting on hippocampal neurons, and CX-CR4 receptor blocker AMD3100, could inhibit SDF-1 induced ERK1/2 activation; SDF-1 could inhibit the secretion of GABA in cultured hippocampal neurons, and ERK1/2 specific inhibitor PD98059, could partly reverse the inhibition of GABA secretion by SDF-1. The effects of SDF-1 on cultured hippocampal neurons was to decrease the mRNA genesis of glutamic acid decarboxylase GAD65 and GABA transporter GAT-1, besides, ERK inhibitor PD98059 could effectively flip the effect of SDF-1. The results of Western blot showed that SDF-1 could inhibit the protein expression of GAT-1 and GAD65/67 in hippocampal neurons and the inhibition of GAT-1 and GAD65/67 protein expression could be partially restored by ERK1/2 blocker. SDF-1 acts on the CXCR4 of hippocampal neurons in vitro, and inhibits the expression of GAD by activating the ERK1/2 signaling pathway, and this may represent one possible pathway of GABA secretion inhibition.