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Sample records for hippocampal lesion model

  1. Visual performance of pigeons following hippocampal lesions.

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    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.

  2. Antipsychotic potential of quinazoline ErbB1 inhibitors in a schizophrenia model established with neonatal hippocampal lesioning.

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    Mizuno, Makoto; Iwakura, Yuriko; Shibuya, Masako; Zheng, Yingjun; Eda, Takeyoshi; Kato, Taisuke; Takasu, Yohei; Nawa, Hiroyuki

    2010-01-01

    Hyper-signaling of the epidermal growth factor receptor family (ErbB) is implicated in the pathophysiology of schizophrenia. Various quinazoline inhibitors targeting ErbB1 or ErbB2 - 4 have been developed as anti-cancer agents and might be useful for antipsychotic treatment. In the present study, we used an animal model of schizophrenia established by neonatal hippocampal lesioning and evaluated the neurobehavioral consequences of ErbB1-inhibitor treatment. Subchronic administration of the ErbB1 inhibitor ZD1839 to the cerebroventricle of rats receiving neonatal hippocampal lesioning ameliorated deficits in prepulse inhibition as well as those in the latent inhibition of tone-dependent fear learning. There were no apparent adverse effects on basal learning scores or locomotor activity, however. The administration of other ErbB1 inhibitors, PD153035 and OSI-774, similarly attenuated the prepulse inhibition impairment of this animal model. In parallel, there were decreases in ErbB1 phosphorylation in animals treated with ErbB1 inhibitors. These results indicate an antipsychotic potential of quinazoline ErbB1 inhibitors. ErbB receptor tyrosine kinases may be novel therapeutic targets for schizophrenia or its related psychotic symptoms.

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

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    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.

  4. Motivational responses to natural and drug rewards in rats with neonatal ventral hippocampal lesions: an animal model of dual diagnosis schizophrenia.

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    Chambers, R Andrew; Self, David W

    2002-12-01

    The high prevalence of substance use disorders in schizophrenia relative to the general population and other psychiatric diagnoses could result from developmental neuropathology in hippocampal and cortical structures that underlie schizophrenia. In this study, we tested the effects of neonatal ventral hippocampal lesions on instrumental behavior reinforced by sucrose pellets and intravenous cocaine injections. Lesioned rats acquired sucrose self-administration faster than sham-lesioned rats, but rates of extinction were not altered. Lesioned rats also responded at higher rates during acquisition of cocaine self-administration, and tended to acquire self-administration faster. Higher response rates reflected perseveration of responding during the post-injection "time-out" periods, and a greater incidence of binge-like cocaine intake, which persisted even after cocaine self-administration stabilized. In contrast to sucrose, extinction from cocaine self-administration was prolonged in lesioned rats, and reinstatement of cocaine seeking induced by cocaine priming increased compared with shams. These results suggest that neonatal ventral hippocampal lesions facilitate instrumental learning for both natural and drug rewards, and reduce inhibitory control over cocaine taking while promoting cocaine seeking and relapse after withdrawal. The findings are discussed in terms of possible developmental or direct effects of the lesions, and both positive reinforcement (substance use vulnerability as a primary disease symptom) and negative reinforcement (self-medication) theories of substance use comorbidity in schizophrenia.

  5. Impaired Odor Recognition Memory in Patients with Hippocampal Lesions

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    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…

  6. Calcified neurocysticercosis lesions and hippocampal sclerosis: potential dual pathology?

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    Rathore, Chaturbhuj; Thomas, Bejoy; Kesavadas, Chandrasekharan; Radhakrishnan, Kurupath

    2012-04-01

    In areas where cysticercosis is endemic, calcified neurocysticercosis lesion(s) (CNL) and hippocampal sclerosis (HS) commonly coexist in patients with localization-related epilepsies. To understand the pathogenesis of HS associated with CNL, we compared the characteristics of three groups of patients with antiepileptic drug-resistant epilepsies: CNL with HS, CNL without HS (CNL alone), and HS without CNL (HS alone). In comparison to patients with CNL alone, those with CNL with HS had CNL more frequently located in the ipsilateral temporal lobe. Those with CNL with HS had a lower incidence of febrile seizures, older age at initial precipitating injury and at onset of habitual complex partial seizures, and more frequent clustering of seizures and extratemporal/bitemporal interictal epileptiform discharges as compared to patients with HS alone. Our study illustrates that HS associated with CNL might have a different pathophysiologic basis as compared to classical HS. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

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

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    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…

  8. 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.

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

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    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.

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

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    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.

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

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    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.

  12. Medial Entorhinal Cortex Lesions Only Partially Disrupt Hippocampal Place Cells and Hippocampus-Dependent Place Memory

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    Jena B. Hales

    2014-11-01

    Full Text Available The entorhinal cortex provides the primary cortical projections to the hippocampus, a brain structure critical for memory. However, it remains unclear how the precise firing patterns of medial entorhinal cortex (MEC cells influence hippocampal physiology and hippocampus-dependent behavior. We found that complete bilateral lesions of the MEC resulted in a lower proportion of active hippocampal cells. The remaining active cells had place fields, but with decreased spatial precision and decreased long-term spatial stability. In addition, MEC rats were as impaired in the water maze as hippocampus rats, while rats with combined MEC and hippocampal lesions had an even greater deficit. However, MEC rats were not impaired on other hippocampus-dependent tasks, including those in which an object location or context was remembered. Thus, the MEC is not necessary for all types of spatial coding or for all types of hippocampus-dependent memory, but it is necessary for the normal acquisition of place memory.

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

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    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…

  14. Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions

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    Li-juan Ye

    2016-01-01

    Full Text Available Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 105 cells/μL were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

  15. Factors affecting graded and ungraded memory loss following hippocampal lesions.

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    Winocur, Gordon; Moscovitch, Morris; Sekeres, Melanie J

    2013-11-01

    This review evaluates three current theories--Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace-Transformation (Winocur, Moscovitch, & Bontempi, 2010)--in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Magnetic resonance imaging findings of mumps meningoencephalitis with bilateral hippocampal lesions without preceding acute parotitis: A case report

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    Woo, Ah Reum; Lee, Ha Young; Lim, Myung Kwan; Kang, Young Hye; Cho, Soon Gu; Choi, Seong Hye; Baek, Ji Hyeon [Inha University School of Medicine, Incheon (Korea, Republic of)

    2017-04-15

    Meningitis is a common central nervous system (CNS) complication of the mumps, a viral infection, but encephalitis and meningoencephalitis are less common in mumps. We describe magnetic resonance imaging findings of acute mumps meningoencephalitis in a 32-year-old male who showed bilateral hippocampal lesions without preceding parotitis. Although it is rare, hippocampal involvement should be considered a CNS complication of mumps infection.

  17. Stress-related factors in the emergence of transient global amnesia with hippocampal lesion

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    Juliane eDöhring

    2014-08-01

    Full Text Available The transient global amnesia (TGA is a rare amnesic syndrome that is characterized by an acute onset episode of an anterograde and retrograde amnesia. Its origin is still debated, but there is evidence for psychological factors involved in TGA. In neuroimaging, selective lesions in the CA1 fields of the hippocampus can be detected, a region that is particularly involved in the processing of memory, stress and emotion. The aim of this study was to assess the role of psychological stress in TGA by studying the prevalence of stress related precipitating events and individual stress-related personality profiles as well as coping strategies in patients. The hypothesis of a functional differentiation of the hippocampus in mnemonic and stress-related compartments was also evaluated. From all 113 patients, 18 % (n= 24 patients experienced emotional and psychological stress episodes directly before the TGA. In a cohort of 21 acute patients, TGA patients tend to cope with stress less efficiently and less constructively than controls. Patients who experienced a stress related precipitant event exhibited a higher level of anxiety in comparison to non-stress patients and controls. However, there was no difference between the general experience of stress and the number of stress inducing life events. The majority of patients (73% did show typical MRI lesions in the CA1 region of the hippocampal cornu ammonis. There was no clear association between stressful events, distribution of hippocampal CA1 lesions and behavioral patterns during the TGA. Disadvantageous coping strategies and an elevated anxiety level may increase the susceptibility to psychological stress which may facilitate the pathophysiological cascade in TGA. The findings suggest a role of emotional stress factors in the manifestation of TGA in a subgroup of patients. Stress may be one trigger involved in the emergence of transient lesions in the hippocampal CA1 region, which are thought to be the

  18. Increased synthesis of heparin affin regulatory peptide in the perforant path lesioned mouse hippocampal formation

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    Poulsen, F R; Lagord, C; Courty, J

    2000-01-01

    differentiation in vivo. Here we have investigated the expression of HARP mRNA and protein in the perforant path lesioned C57B1/6 mouse hippocampal formation from 1 to 35 days after surgery. This type of lesion induces a dense anterograde and terminal axonal degeneration, activation of glial cells, and reactive...... axonal sprouting within the perforant path zones of the fascia dentata and hippocampus as well as axotomy-induced retrograde neuronal degeneration in the entorhinal cortex. Analysis of sham- and unoperated control mice showed that HARP mRNA is expressed in neurons and white and gray matter glial cells...... as well as vascular and pial cells throughout the normal, adult brain. Lesioning induced high levels of HARP mRNA in astroglial-like cells in the denervated zones of fascia dentata and hippocampus as soon as day 2 postlesion. This expression reached maximum at day 4, and declined toward normal at day 7...

  19. Hippocampal N-methyl-d-aspartate and kainate binding in response to entorhinal cortex aspiration or 192 IgG-saporin lesions of the basal forebrain

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    Gallagher, M.; Gill, T.M.; Shivers, A.; Nicolle, M.M.

    1997-01-01

    Lesion models in the rat were used to examine the effects of removing innervation of the hippocampal formation on glutamate receptor binding in that system. Bilateral aspiration of the entorhinal cortex was used to remove the cortical innervation of the hippocampal formation and the dentate gyrus. The subcortical input to the hippocampus from cholinergic neurons of the basal forebrain was lesioned by microinjection of the immunotoxin 192 IgG-saporin into the medial septum and vertical limb of diagonal band. After a 30-day postlesion survival, the effects of these lesions on N-methyl-d-aspartate-displaceable [ 3 H]glutamate and [ 3 H]kainate binding in the hippocampus were quantified using in vitro autoradiography. The bilateral entorhinal lesion induced a sprouting response in the dentate gyrus, measured by an increase in the width of [ 3 H]kainate binding. It also induced an increase in the density of [ 3 H]kainate binding in CA3 stratum lucidum and an increase in N-methyl-d-aspartate binding throughout the hippocampus proper and the dentate gyrus. The selective lesion of cholinergic septal input did not have any effect on hippocampal [ 3 H]kainate binding and induced only a moderate decrease in N-methyl-d-aspartate binding that was not statistically reliable.The entorhinal and cholinergic lesions were used as in vivo models of the degeneration of hippocampal input that occurs in normal aging and Alzheimer's disease. The results from the present lesion study suggest that some, but not all, of the effects on hippocampal [ 3 H]kainate and N-methyl-d-aspartate binding induced by the lesions are consistent with the status of binding to these receptors in aging and Alzheimer's disease. Consistent with the effects of aging and Alzheimer's disease is an altered topography of [ 3 H]kainate binding after entorhinal cortex lesion and a modest decline in N-methyl-d-aspartate binding after lesions of the cholinergic septal input to the hippocampus. (Copyright (c) 1997

  20. Increased synthesis of heparin affin regulatory peptide in the perforant path lesioned mouse hippocampal formation

    DEFF Research Database (Denmark)

    Poulsen, F R; Lagord, C; Courty, J

    2000-01-01

    Heparin affin regulatory peptide (HARP), also known as pleiotrophin or heparin-binding growth-associated molecule, is a developmentally regulated extracellular matrix protein that induces cell proliferation and promotes neurite outgrowth in vitro as well as pre- and postsynaptic developmental...... differentiation in vivo. Here we have investigated the expression of HARP mRNA and protein in the perforant path lesioned C57B1/6 mouse hippocampal formation from 1 to 35 days after surgery. This type of lesion induces a dense anterograde and terminal axonal degeneration, activation of glial cells, and reactive...... axonal sprouting within the perforant path zones of the fascia dentata and hippocampus as well as axotomy-induced retrograde neuronal degeneration in the entorhinal cortex. Analysis of sham- and unoperated control mice showed that HARP mRNA is expressed in neurons and white and gray matter glial cells...

  1. Disrupted Co-activation of Interneurons and Hippocampal Network after Focal Kainate Lesion

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    Lim-Anna Sieu

    2017-11-01

    Full Text Available GABAergic interneurons are known to control activity balance in physiological conditions and to coordinate hippocampal networks during cognitive tasks. In temporal lobe epilepsy interneuron loss and consecutive network imbalance could favor pathological hypersynchronous epileptic discharges. We tested this hypothesis in mice by in vivo unilateral epileptogenic hippocampal kainate lesion followed by in vitro recording of extracellular potentials and patch-clamp from GFP-expressing interneurons in CA3, in an optimized recording chamber. Slices from lesioned mice displayed, in addition to control synchronous events, larger epileptiform discharges. Despite some ipsi/contralateral and layer variation, interneuron density tended to decrease, average soma size to increase. Their membrane resistance decreased, capacitance increased and contralateral interneuron required higher current intensity to fire action potentials. Examination of synchronous discharges of control and larger amplitudes, revealed that interneurons were biased to fire predominantly with the largest population discharges. Altogether, these observations suggest that the overall effect of reactive cell loss, hypertrophy and reduced contralateral excitability corresponds to interneuron activity tuning to fire with larger population discharges. Such cellular and network mechanisms may contribute to a runaway path toward epilepsy.

  2. Surgical treatment of patients with single and dual pathology: relevance of lesion and of hippocampal atrophy to seizure outcome.

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    Li, L M; Cendes, F; Watson, C; Andermann, F; Fish, D R; Dubeau, F; Free, S; Olivier, A; Harkness, W; Thomas, D G; Duncan, J S; Sander, J W; Shorvon, S D; Cook, M J; Arnold, D L

    1997-02-01

    Modern neuroimaging can disclose epileptogenic lesions in many patients with partial epilepsy and, at times, display the coexistence of hippocampal atrophy in addition to an extrahippocampal lesion (dual pathology). We studied the postoperative seizure outcome of 64 patients with lesional epilepsy (median follow-up, 30 months) and considered separately the surgical results in the 51 patients with a single lesion and in the 13 who had dual pathology. In patients with a single lesion, 85% were seizure free or significantly improved (Engel's class I-II) when the lesion was totally removed compared with only 40% when there was incomplete resection (p dual pathology who had both the lesion and the atrophic hippocampus removed became seizure free. In contrast, only 2 of the 10 patients with dual pathology undergoing surgery aimed at the lesion or at the hippocampus alone became seizure free (p dual pathology, surgery should, if possible, include resection of both the lesion and the atrophic hippocampus.

  3. [A surgical case of mesial temporal lobe epilepsy associated with hippocampal sclerosis and traumatic neocortical lesion].

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    Kitazawa, Yu; Jin, Kazutaka; Iwasaki, Masaki; Suzuki, Hiroyoshi; Tanaka, Fumiaki; Nakasato, Nobukazu

    2017-11-25

    A 26-year-old right-handed woman, with a history of left temporal lobe contusion caused by a fall at the age of 9 months, started to have complex partial seizures with oral automatism at the age of 7 years. The seizures occurred once or twice a month despite combination therapy with several antiepileptic agents. Her history and imaging studies suggested the diagnosis of epilepsy arising from traumatic neocortical temporal lesion. Comprehensive assessment including long-term video EEG monitoring, MRI, FDG-PET, MEG, and neuropsychological evaluation was performed at the age of 26 years. The diagnosis was left mesial temporal lobe epilepsy associated with hippocampal atrophy and traumatic temporal cortical lesion. The patient was readmitted for surgical treatment at the age of 27 years. Intracranial EEG monitoring showed that ictal discharges started in the left hippocampus and spread to the traumatic lesion in the left posterior superior temporal gyrus 10 seconds after the onset. This case could not be classified as dual pathology exactly, because the traumatic left temporal cortical lesion did not show independent epileptogenicity. However, the traumatic lesion was highly likely to be the source of the epileptogenicity, and she had right hemispheric dominance for language and functional deterioration in the whole temporal cortex. Therefore, left amygdalo-hippocampectomy and left temporal lobectomy including the traumatic lesion were performed according to the diagnosis of dual pathology. Subsequently, she remained seizure-free for 3 years. Comprehensive assessment of seizure semiology, neurophysiology, neuroradiology, and neuropsychology is important to determine the optimum therapeutic strategies for drug-resistant epilepsy.

  4. Why trace and delay conditioning are sometimes (but not always) hippocampal dependent: A computational model

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    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

  5. Motor skill learning and offline-changes in TGA patients with acute hippocampal CA1 lesions.

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    Döhring, Juliane; Stoldt, Anne; Witt, Karsten; Schönfeld, Robby; Deuschl, Günther; Born, Jan; Bartsch, Thorsten

    2017-04-01

    Learning and the formation of memory are reflected in various memory systems in the human brain such as the hippocampus based declarative memory system and the striatum-cortex based system involved in motor sequence learning. It is a matter of debate how both memory systems interact in humans during learning and consolidation and how this interaction is influenced by sleep. We studied the effect of an acute dysfunction of hippocampal CA1 neurons on the acquisition (on-line condition) and off-line changes of a motor skill in patients with a transient global amnesia (TGA). Sixteen patients (68 ± 4.4 yrs) were studied in the acute phase and during follow-up using a declarative and procedural test, and were compared to controls. Acute TGA patients displayed profound deficits in all declarative memory functions. During the acute amnestic phase, patients were able to acquire the motor skill task reflected by increasing finger tapping speed across the on-line condition, albeit to a lesser degree than during follow-up or compared to controls. Retrieval two days later indicated a greater off-line gain in motor speed in patients than controls. Moreover, this gain in motor skill performance was negatively correlated to the declarative learning deficit. Our results suggest a differential interaction between procedural and declarative memory systems during acquisition and consolidation of motor sequences in older humans. During acquisition, hippocampal dysfunction attenuates fast learning and thus unmasks the slow and rigid learning curve of striatum-based procedural learning. The stronger gains in the post-consolidation condition in motor skill in CA1 lesioned patients indicate a facilitated consolidation process probably occurring during sleep, and suggest a competitive interaction between the memory systems. These findings might be a reflection of network reorganization and plasticity in older humans and in the presence of CA1 hippocampal pathology. Copyright © 2016

  6. Intellectual impairment and brain MRI findings in myotonic dystrophy. With a special reference to hippocampal atrophy and white matter lesions

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    Kato, Etsuko; Takahashi, Satoshi; Yonezawa, Hisashi

    1995-01-01

    We performed a correlative study between intellectual impairment, CTG repeat expansion and magnetic resonance imaging (MRI) abnormalities, including hippocampal atrophy, white matter lesions and ventricular dilatation in 15 patients with myotonic dystrophy (MD). They included 4 males and 11 females aged from 20 to 66 years, averaging 43 years of age and 15 years of duration of illness. Nine patients had intellectual impairment (WAIS-R<80). Negative correlations were found between full scale IQ (FSIQ), duration of illness (p<0.05) and CTG repeat expansion (p<0.05). Compared with normal controls, the patients with MD showed a significant reduction in size of the hippocampal head (p<0.01), which was positively correlated to FSIQ, verbal IQ and performance IQ levels (p<0.05). Ten patients had white matter lesions. Severer white matter lesions tended to be recognized in patients with longer duration of illness and with decreased FSIQ level. These results suggest that hippocampal atrophy and white matter lesions are related to intellectual impairment in patients with MD. (author)

  7. 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.

  8. The hippocampus and appetitive Pavlovian conditioning: effects of excitotoxic hippocampal lesions on conditioned locomotor activity and autoshaping.

    Science.gov (United States)

    Ito, Rutsuko; Everitt, Barry J; Robbins, Trevor W

    2005-01-01

    The hippocampus (HPC) is known to be critically involved in the formation of associations between contextual/spatial stimuli and behaviorally significant events, playing a pivotal role in learning and memory. However, increasing evidence indicates that the HPC is also essential for more basic motivational processes. The amygdala, by contrast, is important for learning about the motivational significance of discrete cues. This study investigated the effects of excitotoxic lesions of the rat HPC and the basolateral amygdala (BLA) on the acquisition of a number of appetitive behaviors known to be dependent on the formation of Pavlovian associations between a reward (food) and discrete stimuli or contexts: (1) conditioned/anticipatory locomotor activity to food delivered in a specific context and (2) autoshaping, where rats learn to show conditioned discriminated approach to a discrete visual CS+. While BLA lesions had minimal effects on conditioned locomotor activity, hippocampal lesions facilitated the development of both conditioned activity to food and autoshaping behavior, suggesting that hippocampal lesions may have increased the incentive motivational properties of food and associated conditioned stimuli, consistent with the hypothesis that the HPC is involved in inhibitory processes in appetitive conditioning. (c) 2005 Wiley-Liss, Inc.

  9. 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.

  10. 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.

  11. Learning tasks as a possible treatment for DNA lesions induced by oxidative stress in hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    DragoCrneci; Radu Silaghi-Dumitrescu

    2013-01-01

    Reactive oxygen species have been implicated in conditions ranging from cardiovascular dysfunc-tion, arthritis, cancer, to aging and age-related disorders. The organism developed several path-ways to counteract these effects, with base excision repair being responsible for repairing one of the major base lesions (8-oxoG) in al organisms. Epidemiological evidence suggests that cognitive stimulation makes the brain more resilient to damage or degeneration. Recent studies have linked enriched environment to reduction of oxidative stressin neurons of mice with Alzheimer’s dis-ease-like disease, but given its complexity it is not clear what specific aspect of enriched environ-ment has therapeutic effects. Studies from molecular biology have shown that the protein p300, which is a transcription co-activator required for consolidation of memories during specific learning tasks, is at the same time involved in DNA replication and repair, playing a central role in the long-patch pathway of base excision repair. Based on the evidence, we propose that learning tasks such as novel object recognition could be tested as possible methods of base excision repair faci-litation, hence inducing DNA repair in the hippocampal neurons. If this method proves to be effective, it could be the start for designing similar tasks for humans, as a behavioral therapeutic complement to the classical drug-based therapy in treating neurodegenerative disorders. This review presents the current status of therapeutic methods used in treating neurodegenerative diseases induced by reactive oxygen species and proposes a new approach based on existing data.

  12. A comparison of the effects of temporary hippocampal lesions on single and dual context versions of the olfactory sequence memory task.

    Science.gov (United States)

    Sill, Orriana C; Smith, David M

    2012-08-01

    In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the "where" component of episodic memory. In the present study, we added a contextual component to the odor sequence memory task by training rats to choose the earlier odor in one context and the later odor in another context and we compared the effects of temporary hippocampal lesions on performance of the original single context task and the new dual context task. Temporary lesions significantly impaired the single context task, although performance remained significantly above chance levels. In contrast, performance dropped all the way to chance when temporary lesions were used in the dual context task. These results demonstrate that rats can learn a dual context version of the odor sequence learning task that requires the use of contextual information along with the requirement to remember the "what" and "when" components of the odor sequence. Moreover, the addition of the contextual component made the task fully dependent on the hippocampus.

  13. 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

  14. Hippocampal lesions impair performance on a conditional delayed matching and non-matching to position task in the rat.

    Science.gov (United States)

    Sloan, Hazel L; Döbrössy, Màtè; Dunnett, Stephen B

    2006-08-10

    The hippocampus is thought to be involved in a range of cognitive processes, from the ability to acquire new memories, to the ability to learn about spatial relationships. Humans and monkeys with damage to the hippocampus are typically impaired on delayed matching to sample tasks, of which the operant delayed matching to position task (DMTP) is a rat analogue. The reported effects of hippocampal damage on DMTP vary, ranging from delay-dependent deficits to no deficit whatsoever. The present study investigates a novel memory task; the conditional delayed matching/non-matching to position task (CDM/NMTP) in the Skinner box. CDM/NMTP uses the presence of specific stimulus cues to signify whether a particular trial is matching or non-matching in nature. Thus, it incorporates both the task contingencies within one session, and supplements the requirement for remembering the side of the lever in the sample phase with attending to the stimulus and remembering the conditional discrimination for the rule. Rats were trained preoperatively and the effects of bilateral excitotoxic lesions of the hippocampus were examined on postoperative retention of the task. Rats with lesions of the hippocampus incurred a significant impairment on the task that was manifest at all delays intervals. Despite a bias towards matching during training, trials of either type were performed with equivalent accuracy and neither rule was affected differentially by the lesion. This task may prove useful in determining the cognitive roles of a range of brain areas.

  15. Modelling vesicular release at hippocampal synapses.

    Directory of Open Access Journals (Sweden)

    Suhita Nadkarni

    2010-11-01

    Full Text Available We study local calcium dynamics leading to a vesicle fusion in a stochastic, and spatially explicit, biophysical model of the CA3-CA1 presynaptic bouton. The kinetic model for vesicle release has two calcium sensors, a sensor for fast synchronous release that lasts a few tens of milliseconds and a separate sensor for slow asynchronous release that lasts a few hundred milliseconds. A wide range of data can be accounted for consistently only when a refractory period lasting a few milliseconds between releases is included. The inclusion of a second sensor for asynchronous release with a slow unbinding site, and thereby a long memory, affects short-term plasticity by facilitating release. Our simulations also reveal a third time scale of vesicle release that is correlated with the stimulus and is distinct from the fast and the slow releases. In these detailed Monte Carlo simulations all three time scales of vesicle release are insensitive to the spatial details of the synaptic ultrastructure. Furthermore, our simulations allow us to identify features of synaptic transmission that are universal and those that are modulated by structure.

  16. Perforant path lesioning induces sprouting of CA3-associated fibre systems in mouse hippocampal formation

    DEFF Research Database (Denmark)

    Drøjdahl, Nina; Hegelund, Iørn V; Poulsen, Frantz R

    2002-01-01

    mice. We found that lesioning led to translaminar sprouting of Timm stained regio inferior hippocampus (CA3)-associated fibre systems into the denervated termination zones of the CA3 and dentate gyrus, from the adjacent non-denervated stratum radiatum of CA3. Differences were seen in the Timm staining...... pattern of the two strains of mice, while the response to lesioning appeared similar albeit less pronounced than that observed in the rat. We also observed an intensified acetylcholine esterase staining reflective of cholinergic sprouting in the denervated perforant path termination zones, which...... was particularly prominent in areas with sprouting of Timm stained CA3-associated fibres. Finally, we showed that some of the sprouting fibres within the CA3 were myelinated, due to an increased density of silver impregnated myelinated fibres in this region after lesioning. These results show that the basic...

  17. Implicit transitive inference and the human hippocampus: does intravenous midazolam function as a reversible hippocampal lesion?

    Directory of Open Access Journals (Sweden)

    Greene Anthony J

    2007-09-01

    Full Text Available Abstract Recent advances have led to an understanding that the hippocampus is involved more broadly than explicit or declarative memory alone. Tasks which involve the acquisition of complex associations involve the hippocampus whether the learning is explicit or implicit. One hippocampal-dependent implicit task is transitive inference (TI. Recently it was suggested that implicit transitive inference does not depend upon the hippocampus (Frank, M. J., O'Reilly, R. C., & Curran, T. 2006. When memory fails, intuition reigns: midazolam enhances implicit inference in humans. Psychological Science, 17, 700–707. The authors demonstrated that intravenous midazolam, which is thought to inactivate the hippocampus, may enhance TI performance. Three critical assumptions are required but not met: 1 that deactivations of other regions could not account for the effect 2 that intravenous midazolam does indeed deactivate the hippocampus and 3 that midazolam influences explicit but not implicit memory. Each of these assumptions is seriously flawed. Consequently, the suggestion that implicit TI does not depend upon the hippocampus is unfounded.

  18. Integrating incremental learning and episodic memory models of the hippocampal region.

    NARCIS (Netherlands)

    Meeter, M.; Myers, C.E; Gluck, M.A.

    2005-01-01

    By integrating previous computational models of corticohippocampal function, the authors develop and test a unified theory of the neural substrates of familiarity, recollection, and classical conditioning. This approach integrates models from 2 traditions of hippocampal modeling, those of episodic

  19. Long term exposure to combination paradigm of environmental enrichment, physical exercise and diet reverses the spatial memory deficits and restores hippocampal neurogenesis in ventral subicular lesioned rats.

    Science.gov (United States)

    Kapgal, Vijayakumar; Prem, Neethi; Hegde, Preethi; Laxmi, T R; Kutty, Bindu M

    2016-04-01

    Subiculum is an important structure of the hippocampal formation and plays an imperative role in spatial learning and memory functions. We have demonstrated earlier the cognitive impairment following bilateral ventral subicular lesion (VSL) in rats. We found that short term exposure to enriched environment (EE) did not help to reverse the spatial memory deficits in water maze task suggesting the need for an appropriate enriched paradigm towards the recovery of spatial memory. In the present study, the efficacy of long term exposure of VSL rats to combination paradigm of environmental enrichment (EE), physical exercise and 18 C.W. diet (Combination Therapy - CT) in reversing the spatial memory deficits in Morris water maze task has been studied. Ibotenate lesioning of ventral subiculum produced significant impairment of performance in the Morris water maze and reduced the hippocampal neurogenesis in rats. Post lesion exposure to C.T. restored the hippocampal neurogenesis and improved the spatial memory functions in VSL rats. Our study supports the hypothesis that the combination paradigm is critical towards the development of an enhanced behavioral and cognitive experience especially in conditions of CNS insults and the associated cognitive dysfunctions. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. 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.

  1. Multiple-lesion track-structure model

    International Nuclear Information System (INIS)

    Wilson, J.W.; Cucinotta, F.A.; Shinn, J.L.

    1992-03-01

    A multilesion cell kinetic model is derived, and radiation kinetic coefficients are related to the Katz track structure model. The repair-related coefficients are determined from the delayed plating experiments of Yang et al. for the C3H10T1/2 cell system. The model agrees well with the x ray and heavy ion experiments of Yang et al. for the immediate plating, delaying plating, and fractionated exposure protocols employed by Yang. A study is made of the effects of target fragments in energetic proton exposures and of the repair-deficient target-fragment-induced lesions

  2. Development of antipsychotic medications with novel mechanisms of action based on computational modeling of hippocampal neuropathology.

    Directory of Open Access Journals (Sweden)

    Peter J Siekmeier

    Full Text Available A large number of cellular level abnormalities have been identified in the hippocampus of schizophrenic subjects. Nonetheless, it remains uncertain how these pathologies interact at a system level to create clinical symptoms, and this has hindered the development of more effective antipsychotic medications. Using a 72-processor supercomputer, we created a tissue level hippocampal simulation, featuring multicompartmental neuron models with multiple ion channel subtypes and synaptic channels with realistic temporal dynamics. As an index of the schizophrenic phenotype, we used the specific inability of the model to attune to 40 Hz (gamma band stimulation, a well-characterized abnormality in schizophrenia. We examined several possible combinations of putatively schizophrenogenic cellular lesions by systematically varying model parameters representing NMDA channel function, dendritic spine density, and GABA system integrity, conducting 910 trials in total. Two discrete "clusters" of neuropathological changes were identified. The most robust was characterized by co-occurring modest reductions in NMDA system function (-30% and dendritic spine density (-30%. Another set of lesions had greater NMDA hypofunction along with low level GABA system dysregulation. To the schizophrenic model, we applied the effects of 1,500 virtual medications, which were implemented by varying five model parameters, independently, in a graded manner; the effects of known drugs were also applied. The simulation accurately distinguished agents that are known to lack clinical efficacy, and identified novel mechanisms (e.g., decrease in AMPA conductance decay time constant, increase in projection strength of calretinin-positive interneurons and combinations of mechanisms that could re-equilibrate model behavior. These findings shed light on the mechanistic links between schizophrenic neuropathology and the gamma band oscillatory abnormalities observed in the illness. As such, they

  3. 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.

  4. New Perspectives on the Brain Lesion Approach - Implications for Theoretical Models of Human Memory.

    Science.gov (United States)

    Irish, Muireann; van Kesteren, Marlieke T R

    2018-03-15

    Human lesion studies represent the cornerstone of modern day neuropsychology and provide an important adjunct to functional neuroimaging methods. The study of human lesion groups with damage to distinct regions of the brain permits the identification of underlying mechanisms and structures not only associated with, but essential for, complex cognitive processes. Here, we consider a recent review by McCormick et al., 2018 in which the power of the lesion model approach is elegantly presented with respect to a host of sophisticated cognitive endeavors, including autobiographical memory, future thinking, spatial navigation, and decision-making. By comparing profiles of loss and sparing in hippocampal (HC) and ventromedial prefrontal cortex (vmPFC) lesion groups, the authors provide new insights into the underlying neuroarchitecture of these diverse cognitive functions. Building on this framework, we consider how vmPFC and HC degeneration, in the context of large-scale network dysfunction in dementia, impacts discrete facets of memory and social cognition. Notably, we find remarkable concordance between the available evidence in dementia and that of the HC and vmPFC lesion literature. We further assess the role of the prefrontal cortex in modulating aspects of spatial navigation and discuss the role of schema-related processing in the service of memory more broadly. Far from being obsolete, we contend that human lesion work occupies a crucial position in cognitive neuroscience and offers an array of exciting areas for future study within this field. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals

    Science.gov (United States)

    Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard. J.; Myers, Catherine E.

    2012-01-01

    Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning. PMID:23164732

  6. 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.

  7. Development of a Modelling to Correlate Site and Diameter of Brain Metastases with Hippocampal Sparing Using Volumetric Modulated Arc Therapy

    Directory of Open Access Journals (Sweden)

    Silvia Chiesa

    2013-01-01

    Full Text Available Purpose. To correlate site and diameter of brain metastases with hippocampal sparing in patients treated by RapidArc (RA technique on whole brain with simultaneously integrated boost (SIB. Methods and Materials. An RA plan was calculated for brain metastases of 1-2-3 cm of diameter. The whole brain dose was 32.25 Gy (15 fractions, and SIB doses to brain metastases were 63 Gy (2 and 3 cm or 70.8 Gy (1 cm. Plans were optimized and evaluated for conformity, target coverage, prescription isodose to target volume, homogeneity index, and hippocampal sparing. Results. Fifteen brain lesions and RA plan were generated. Hippocampal volume was 4.09 cm3, and hippocampal avoidance volume was 17.50 cm3. Related to site of metastases, the mean hippocampal dose was 9.68 Gy2 for occipital lobe, 10.56 Gy2 for frontal lobe, 10.56 Gy2 for parietal lobe, 10.94 Gy2 for deep brain structures, and 40.44 Gy2 for temporal lobe. The mean hippocampal dose was 9.45 Gy2, 10.15 Gy2, and 11.70 Gy2 for diameter’s metastases of 1.2 and 3 cm, respectively, excluding results relative to temporal brain lesions. Conclusions. Location more than size of metastases can adversely influence the hippocampus sparing. Further investigation is necessary to meet definitive considerations.

  8. Surgical pathology of epilepsy-associated non-neoplastic cerebral lesions: a brief introduction with special reference to hippocampal sclerosis and focal cortical dysplasia

    Science.gov (United States)

    Miyata, Hajime; Hori, Tomokatsu; Vinters, Harry V.

    2014-01-01

    Among epilepsy-associated non-neoplastic lesions, mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE-HS) and malformation of cortical development (MCD) including focal cortical dysplasia (FCD), are the two most frequent causes of drug-resistant focal epilepsies constituting about 50% of all surgical pathology of epilepsy. Several distinct histological patterns have been historically recognized in both HS and FCD, and several studies have tried to perform clinicopathological correlation; results, however, have been controversial, particularly in terms of postsurgical seizure outcome. Recently, the International League Against Epilepsy constituted a Task Forces of Neuropathology and FCD within the Commission on Diagnostic Methods, to establish an international consensus of histological classification of HS and FCD, respectively, based on agreement with the recognition of the importance of defining a histopathological classification system that reliably has some clinicopathological correlation. Such consensus classifications are likely to facilitate future clinicopathological study. Meanwhile, we reviewed neuropathology of 41 surgical cases of mTLE, and confirmed three type/patterns of HS along with no HS, based on the qualitative evaluation of the distribution and severity of neuronal loss and gliosis within hippocampal formation; i.e., HS type 1 (61%) equivalent to ‘classical’ Ammon’s horn sclerosis, HS type 2 (2%) representing CA1 sclerosis, HS type 3 (17%) equivalent to end folium sclerosis, and no HS (19%). Furthermore we performed a neuropathological comparative study on mTLE-HS and dementia associated HS (d-HS) in elderly, and confirmed that neuropathological features differ between mTLE-HS and d-HS in the distribution of hippocampal neuronal loss and gliosis, morphology of reactive astrocytes and their protein expression, and presence of concomitant neurodegenerative changes particularly Alzheimer type and TDP-43 pathologies. These

  9. Computational Model of a Positive BDNF Feedback Loop in Hippocampal Neurons Following Inhibitory Avoidance Training

    Science.gov (United States)

    Zhang, Yili; Smolen, Paul; Alberini, Cristina M.; Baxter, Douglas A.; Byrne, John H.

    2016-01-01

    Inhibitory avoidance (IA) training in rodents initiates a molecular cascade within hippocampal neurons. This cascade contributes to the transition of short- to long-term memory (i.e., consolidation). Here, a differential equation-based model was developed to describe a positive feedback loop within this molecular cascade. The feedback loop begins…

  10. Generalization through the Recurrent Interaction of Episodic Memories: A Model of the Hippocampal System

    Science.gov (United States)

    Kumaran, Dharshan; McClelland, James L.

    2012-01-01

    In this article, we present a perspective on the role of the hippocampal system in generalization, instantiated in a computational model called REMERGE (recurrency and episodic memory results in generalization). We expose a fundamental, but neglected, tension between prevailing computational theories that emphasize the function of the hippocampus…

  11. [Establishment of oxygen and glucose deprive model of in vitro cultured hippocampal neuron and effect of ligustrazine on intracellular Ca+ level in model neurons].

    Science.gov (United States)

    Wan, Hai-tong; Wang, Yu; Yang, Jie-hong

    2007-03-01

    To establish the oxygen and glucose deprive (OGD) model in cultured hippocampal neuron and study the effect of ligustrazine on intracellular Ca2+ level in the model neurons. The OGD model was established in cultured hippocampal neuron, and the intracellular Ca2+ level in it was detected by laser scanning confocal microscope (LSCM). The OGD model was successfully established in cultured hippocampal neurons; the intracellular Ca2+ level in the OGD model group was significantly higher than that in the blank control group (P neuron, which could be antagonized by ligustrazine, indicating that ligustrazine has a protective effect on hippocampal neuron from hypoxic-ischemic injury.

  12. Hippocampal oscillations in the rodent model of schizophrenia induced by amygdala GABA receptor blockade

    Directory of Open Access Journals (Sweden)

    Tope eLanre-Amos

    2010-09-01

    Full Text Available Brain oscillations are critical for cognitive processes, and their alterations in schizophrenia have been proposed to contribute to cognitive impairments. Network oscillations rely upon GABAergic interneurons, which also show characteristic changes in schizophrenia. The aim of this study was to examine the capability of hippocampal networks to generate oscillations in a rat model previously shown to reproduce the stereotypic structural alterations of the hippocampal interneuron circuit seen in schizophrenic patients. This model uses injection of GABA-A receptor antagonist picrotoxin into the basolateral amygdala which causes cell-type specific disruption of interneuron signaling in the hippocampus. We found that after such treatment, hippocampal theta rhythm was still present during REM sleep, locomotion, and exploration of novel environment and could be elicited under urethane anesthesia. Subtle changes in theta and gamma parameters were observed in both preparations; specifically in the stimulus intensity—theta frequency relationship under urethane and in divergent reactions of oscillations at the two major theta dipoles in freely moving rats. Thus, theta power in the CA1 region was generally enhanced as compared with deep theta dipole which decreased or did not change. The results indicate that pathologic reorganization of interneurons that follows the over-activation of the amygdala-hippocampal pathway, as shown for this model of schizophrenia, does not lead to destruction of the oscillatory circuit but changes the normal balance of rhythmic activity in its various compartments.

  13. Optimized Model of Cerebral Ischemia In situ for the Long-Lasting Assessment of Hippocampal Cell Death

    Directory of Open Access Journals (Sweden)

    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.

  14. Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

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    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.

  15. Average spectral power changes at the hippocampal electroencephalogram in schizophrenia model induced by ketamine.

    Science.gov (United States)

    Sampaio, Luis Rafael L; Borges, Lucas T N; Silva, Joyse M F; de Andrade, Francisca Roselin O; Barbosa, Talita M; Oliveira, Tatiana Q; Macedo, Danielle; Lima, Ricardo F; Dantas, Leonardo P; Patrocinio, Manoel Cláudio A; do Vale, Otoni C; Vasconcelos, Silvânia M M

    2018-02-01

    The use of ketamine (Ket) as a pharmacological model of schizophrenia is an important tool for understanding the main mechanisms of glutamatergic regulated neural oscillations. Thus, the aim of the current study was to evaluate Ket-induced changes in the average spectral power using the hippocampal quantitative electroencephalography (QEEG). To this end, male Wistar rats were submitted to a stereotactic surgery for the implantation of an electrode in the right hippocampus. After three days, the animals were divided into four groups that were treated for 10 consecutive days with Ket (10, 50, or 100 mg/kg). Brainwaves were captured on the 1st or 10th day, respectively, to acute or repeated treatments. The administration of Ket (10, 50, or 100 mg/kg), compared with controls, induced changes in the hippocampal average spectral power of delta, theta, alpha, gamma low or high waves, after acute or repeated treatments. Therefore, based on the alterations in the average spectral power of hippocampal waves induced by Ket, our findings might provide a basis for the use of hippocampal QEEG in animal models of schizophrenia. © 2017 Société Française de Pharmacologie et de Thérapeutique.

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

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    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

  17. Altered neuronal excitability underlies impaired hippocampal function in an animal model of psychosis

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    Thomas eGrüter

    2015-05-01

    Full Text Available Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signalling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR results in similar molecular, cellular, cognitive and behavioural changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A, and increase in GABA(B-receptor-expression in PFC, along with a significant increase of GABA(B- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry.

  18. Breast lesion characterization using whole-lesion histogram analysis with stretched-exponential diffusion model.

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    Liu, Chunling; Wang, Kun; Li, Xiaodan; Zhang, Jine; Ding, Jie; Spuhler, Karl; Duong, Timothy; Liang, Changhong; Huang, Chuan

    2018-06-01

    Diffusion-weighted imaging (DWI) has been studied in breast imaging and can provide more information about diffusion, perfusion and other physiological interests than standard pulse sequences. The stretched-exponential model has previously been shown to be more reliable than conventional DWI techniques, but different diagnostic sensitivities were found from study to study. This work investigated the characteristics of whole-lesion histogram parameters derived from the stretched-exponential diffusion model for benign and malignant breast lesions, compared them with conventional apparent diffusion coefficient (ADC), and further determined which histogram metrics can be best used to differentiate malignant from benign lesions. This was a prospective study. Seventy females were included in the study. Multi-b value DWI was performed on a 1.5T scanner. Histogram parameters of whole lesions for distributed diffusion coefficient (DDC), heterogeneity index (α), and ADC were calculated by two radiologists and compared among benign lesions, ductal carcinoma in situ (DCIS), and invasive carcinoma confirmed by pathology. Nonparametric tests were performed for comparisons among invasive carcinoma, DCIS, and benign lesions. Comparisons of receiver operating characteristic (ROC) curves were performed to show the ability to discriminate malignant from benign lesions. The majority of histogram parameters (mean/min/max, skewness/kurtosis, 10-90 th percentile values) from DDC, α, and ADC were significantly different among invasive carcinoma, DCIS, and benign lesions. DDC 10% (area under curve [AUC] = 0.931), ADC 10% (AUC = 0.893), and α mean (AUC = 0.787) were found to be the best metrics in differentiating benign from malignant tumors among all histogram parameters derived from ADC and α, respectively. The combination of DDC 10% and α mean , using logistic regression, yielded the highest sensitivity (90.2%) and specificity (95.5%). DDC 10% and α mean derived from

  19. Crossmodal object recognition in rats with and without multimodal object pre-exposure: no effect of hippocampal lesions.

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    Reid, James M; Jacklin, Derek L; Winters, Boyer D

    2012-10-01

    The neural mechanisms and brain circuitry involved in the formation, storage, and utilization of multisensory object representations are poorly understood. We have recently introduced a crossmodal object recognition (CMOR) task that enables the study of such questions in rats. Our previous research has indicated that the perirhinal and posterior parietal cortices functionally interact to mediate spontaneous (tactile-to-visual) CMOR performance in rats; however, it remains to be seen whether other brain regions, particularly those receiving polymodal sensory inputs, contribute to this cognitive function. In the current study, we assessed the potential contribution of one such polymodal region, the hippocampus (HPC), to crossmodal object recognition memory. Rats with bilateral excitotoxic HPC lesions were tested in two versions of crossmodal object recognition: (1) the original CMOR task, which requires rats to compare between a stored tactile object representation and visually-presented objects to discriminate the novel and familiar stimuli; and (2) a novel 'multimodal pre-exposure' version of the CMOR task (PE/CMOR), in which simultaneous exploration of the tactile and visual sensory features of an object 24 h prior to the sample phase enhances CMOR performance across longer retention delays. Hippocampus-lesioned rats performed normally on both crossmodal object recognition tasks, but were impaired on a radial arm maze test of spatial memory, demonstrating the functional effectiveness of the lesions. These results strongly suggest that the HPC, despite its polymodal anatomical connections, is not critically involved in tactile-to-visual crossmodal object recognition memory. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Hippocampal P3-like auditory event-related potentials are disrupted in a rat model of cholinergic degeneration in Alzheimer's disease: reversal by donepezil treatment.

    Science.gov (United States)

    Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe; Bastlund, Jesper Frank

    2014-01-01

    P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related to several psychiatric and neurological diseases, e.g., Alzheimer's disease (AD). However, only a very limited number of rodent studies have addressed the back-translational validity of the P3-like ERPs as suitable markers of cognition. Thus, the potential of rodent P3-like ERPs to predict pro-cognitive effects in humans remains to be fully validated. The current study characterizes P3-like ERPs in the 192-IgG-SAP (SAP) rat model of the cholinergic degeneration associated with AD. Following training in a combined auditory oddball and lever-press setup, rats were subjected to bilateral intracerebroventricular infusion of 1.25 μg SAP or PBS (sham lesion) and recording electrodes were implanted in hippocampal CA1. Relative to sham-lesioned rats, SAP-lesioned rats had significantly reduced amplitude of P3-like ERPs. P3 amplitude was significantly increased in SAP-treated rats following pre-treatment with 1 mg/kg donepezil. Infusion of SAP reduced the hippocampal choline acetyltransferase activity by 75%. Behaviorally defined cognitive performance was comparable between treatment groups. The present study suggests that AD-like deficits in P3-like ERPs may be mimicked by the basal forebrain cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup.

  1. 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.

  2. 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.

  3. Cortical and hippocampal correlates of deliberation during model-based decisions for rewards in humans.

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    Aaron M Bornstein

    Full Text Available How do we use our memories of the past to guide decisions we've never had to make before? Although extensive work describes how the brain learns to repeat rewarded actions, decisions can also be influenced by associations between stimuli or events not directly involving reward - such as when planning routes using a cognitive map or chess moves using predicted countermoves - and these sorts of associations are critical when deciding among novel options. This process is known as model-based decision making. While the learning of environmental relations that might support model-based decisions is well studied, and separately this sort of information has been inferred to impact decisions, there is little evidence concerning the full cycle by which such associations are acquired and drive choices. Of particular interest is whether decisions are directly supported by the same mnemonic systems characterized for relational learning more generally, or instead rely on other, specialized representations. Here, building on our previous work, which isolated dual representations underlying sequential predictive learning, we directly demonstrate that one such representation, encoded by the hippocampal memory system and adjacent cortical structures, supports goal-directed decisions. Using interleaved learning and decision tasks, we monitor predictive learning directly and also trace its influence on decisions for reward. We quantitatively compare the learning processes underlying multiple behavioral and fMRI observables using computational model fits. Across both tasks, a quantitatively consistent learning process explains reaction times, choices, and both expectation- and surprise-related neural activity. The same hippocampal and ventral stream regions engaged in anticipating stimuli during learning are also engaged in proportion to the difficulty of decisions. These results support a role for predictive associations learned by the hippocampal memory system to

  4. The patient had a normal magnetic resonance imaging and temporal lobe epilepsy secondary to a porencephalic cyst but showed structural lesions (hippocampal sclerosis)☆

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    Matsubara, Teppei; Ayuzawa, Satoshi; Aoki, Tsukasa; Fujiomto, Ayataka; Osuka, Satoru; Matsumura, Akira

    2013-01-01

    Patients with a porencephalic cyst frequently develop intractable temporal lobe epilepsy (TLE). We report a surgically-treated male patient with intractable mesial TLE (mTLE) secondary to a porencephalic cyst. Although magnetic resonance imaging showed no hippocampal abnormalities, long-term video-electrocorticography revealed seizure onset discharges in the hippocampus. Temporal lobectomy brought an end to the patient's seizures. Hippocampal sclerosis was histopathologically confirmed (dual pathology). Careful evaluation of hippocampal epileptogenicity is required, and temporal lobectomy, which is less invasive than hemispherectomy, can be a treatment of choice for patients with mTLE secondary to a porencephalic cyst. PMID:25667851

  5. Dampened hippocampal oscillations and enhanced spindle activity in an asymptomatic model of developmental cortical malformations

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    Elena eCid

    2014-04-01

    Full Text Available Developmental cortical malformations comprise a large spectrum of histopathological brain abnormalities and syndromes. Their genetic, developmental and clinical complexity suggests they should be better understood in terms of the complementary action of independently timed perturbations (i.e. the multiple-hit hypothesis. However, understanding the underlying biological processes remains puzzling. Here we induced developmental cortical malformations in offspring, after intraventricular injection of methylazoxymethanol (MAM in utero in mice. We combined extensive histological and electrophysiological studies to characterize the model. We found that MAM injections at E14 and E15 induced a range of cortical and hippocampal malformations resembling histological alterations of specific genetic mutations and transplacental mitotoxic agent injections. However, in contrast to most of these models, intraventricularly MAM-injected mice remained asymptomatic and showed no clear epilepsy-related phenotype as tested in long-term chronic recordings and with pharmacological manipulations. Instead, they exhibited a non-specific reduction of hippocampal-related brain oscillations (mostly in CA1; including theta, gamma and HFOs; and enhanced thalamocortical spindle activity during non-REM sleep. These data suggest that developmental cortical malformations do not necessarily correlate with epileptiform activity. We propose that the intraventricular in utero MAM approach exhibiting a range of rhythmopathies is a suitable model for multiple-hit studies of associated neurological disorders.

  6. Impairment of adolescent hippocampal plasticity in a mouse model for Alzheimer's disease precedes disease phenotype.

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    Daniela Hartl

    Full Text Available The amyloid precursor protein (APP was assumed to be an important neuron-morphoregulatory protein and plays a central role in Alzheimer's disease (AD pathology. In the study presented here, we analyzed the APP-transgenic mouse model APP23 using 2-dimensional gel electrophoresis technology in combination with DIGE and mass spectrometry. We investigated cortex and hippocampus of transgenic and wildtype mice at 1, 2, 7 and 15 months of age. Furthermore, cortices of 16 days old embryos were analyzed. When comparing the protein patterns of APP23 with wildtype mice, we detected a relatively large number of altered protein spots at all age stages and brain regions examined which largely preceded the occurrence of amyloid plaques. Interestingly, in hippocampus of adolescent, two-month old mice, a considerable peak in the number of protein changes was observed. Moreover, when protein patterns were compared longitudinally between age stages, we found that a large number of proteins were altered in wildtype mice. Those alterations were largely absent in hippocampus of APP23 mice at two months of age although not in other stages compared. Apparently, the large difference in the hippocampal protein patterns between two-month old APP23 and wildtype mice was caused by the absence of distinct developmental changes in the hippocampal proteome of APP23 mice. In summary, the absence of developmental proteome alterations as well as a down-regulation of proteins related to plasticity suggest the disturption of a normally occurring peak of hippocampal plasticity during adolescence in APP23 mice. Our findings are in line with the observation that AD is preceded by a clinically silent period of several years to decades. We also demonstrate that it is of utmost importance to analyze different brain regions and different age stages to obtain information about disease-causing mechanisms.

  7. Pine needle extract prevents hippocampal memory impairment in acute restraint stress mouse model.

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    Lee, Jin-Seok; Kim, Hyeong-Geug; Lee, Hye-Won; Kim, Won-Yong; Ahn, Yo-Chan; Son, Chang-Gue

    2017-07-31

    The Pinus densiflora leaf has been traditionally used to treat mental health disorders as a traditional Chinese medicine. Here we examined the ethnopharmacological relevance of pine needle on memory impairment caused by stress. To elucidate the possible modulatory actions of 30% ethanolic pine needle extract (PNE) on stress-induced hippocampal excitotoxicity, we adopted an acute restraint stress mouse model. Mice were orally administered with PNE (25, 50, or 100mg/kg) or ascorbic acid (100mg/kg) for 9 days, and were then subjected to restraint stress (6h/day) for 3 days (from experimental day 7-9). To evaluate spatial cognitive and memory function, the Morris water maze was performed during experimental days 5-9. Restraint stress induced the memory impairment (the prolonged escape latency and cumulative path-length, and reduced time spent in the target quadrant), and these effects were significantly prevented by PNE treatment. The levels of corticosterone and its receptor in the sera/hippocampus were increased by restraint stress, which was normalized by PNE treatment. Restraint stress elicited the hippocampal excitotoxicity, the inflammatory response and oxidative injury as demonstrated by the increased glutamate levels, altered levels of tumor necrosis factor (TNF)-α and imbalanced oxidant-antioxidant balance biomarkers. Two immunohistochemistry activities against glial fibrillary acidic protein (GFAP)-positive astrocytes and neuronal nuclei (NeuN)-positive neurons supported the finding of excitotoxicity especially in the cornu ammonis (CA)3 region of the hippocampus. Those alterations were notably attenuated by administration of PNE. The above findings showed that PNE has pharmacological properties that modulate the hippocampal excitotoxicity-derived memory impairment under severe stress conditions. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

  8. Rosiglitazone Suppresses In Vitro Seizures in Hippocampal Slice by Inhibiting Presynaptic Glutamate Release in a Model of Temporal Lobe Epilepsy.

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    Shi-Bing Wong

    Full Text Available Peroxisomal proliferator-activated receptor gamma (PPARγ is a nuclear hormone receptor whose agonist, rosiglitazone has a neuroprotective effect to hippocampal neurons in pilocarpine-induced seizures. Hippocampal slice preparations treated in Mg2+ free medium can induce ictal and interictal-like epileptiform discharges, which is regarded as an in vitro model of N-methyl-D-aspartate (NMDA receptor-mediated temporal lobe epilepsy (TLE. We applied rosiglitazone in hippocampal slices treated in Mg2+ free medium. The effects of rosiglitazone on hippocampal CA1-Schaffer collateral synaptic transmission were tested. We also examined the neuroprotective effect of rosiglitazone toward NMDA excitotoxicity on cultured hippocampal slices. Application of 10 μM rosiglitazone significantly suppressed amplitude and frequency of epileptiform discharges in CA1 neurons. Pretreatment with the PPARγ antagonist GW9662 did not block the effect of rosiglitazone on suppressing discharge frequency, but reverse the effect on suppressing discharge amplitude. Application of rosiglitazone suppressed synaptic transmission in the CA1-Schaffer collateral pathway. By miniature excitatory-potential synaptic current (mEPSC analysis, rosiglitazone significantly suppressed presynaptic neurotransmitter release. This phenomenon can be reversed by pretreating PPARγ antagonist GW9662. Also, rosiglitazone protected cultured hippocampal slices from NMDA-induced excitotoxicity. The protective effect of 10 μM rosiglitazone was partially antagonized by concomitant high dose GW9662 treatment, indicating that this effect is partially mediated by PPARγ receptors. In conclusion, rosiglitazone suppressed NMDA receptor-mediated epileptiform discharges by inhibition of presynaptic neurotransmitter release. Rosiglitazone protected hippocampal slice from NMDA excitotoxicity partially by PPARγ activation. We suggest that rosiglitazone could be a potential agent to treat patients with TLE.

  9. Hippocampal closed-loop modeling and implications for seizure stimulation design

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    Sandler, Roman A.; Song, Dong; Hampson, Robert E.; Deadwyler, Sam A.; Berger, Theodore W.; Marmarelis, Vasilis Z.

    2015-10-01

    Objective. Traditional hippocampal modeling has focused on the series of feedforward synapses known as the trisynaptic pathway. However, feedback connections from CA1 back to the hippocampus through the entorhinal cortex (EC) actually make the hippocampus a closed-loop system. By constructing a functional closed-loop model of the hippocampus, one may learn how both physiological and epileptic oscillations emerge and design efficient neurostimulation patterns to abate such oscillations. Approach. Point process input-output models where estimated from recorded rodent hippocampal data to describe the nonlinear dynamical transformation from CA3 → CA1, via the schaffer-collateral synapse, and CA1 → CA3 via the EC. Each Volterra-like subsystem was composed of linear dynamics (principal dynamic modes) followed by static nonlinearities. The two subsystems were then wired together to produce the full closed-loop model of the hippocampus. Main results. Closed-loop connectivity was found to be necessary for the emergence of theta resonances as seen in recorded data, thus validating the model. The model was then used to identify frequency parameters for the design of neurostimulation patterns to abate seizures. Significance. Deep-brain stimulation (DBS) is a new and promising therapy for intractable seizures. Currently, there is no efficient way to determine optimal frequency parameters for DBS, or even whether periodic or broadband stimuli are optimal. Data-based computational models have the potential to be used as a testbed for designing optimal DBS patterns for individual patients. However, in order for these models to be successful they must incorporate the complex closed-loop structure of the seizure focus. This study serves as a proof-of-concept of using such models to design efficient personalized DBS patterns for epilepsy.

  10. Specific Disruption of Hippocampal Mossy Fiber Synapses in a Mouse Model of Familial Alzheimer's Disease

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    Wilke, Scott A.; Raam, Tara; Antonios, Joseph K.; Bushong, Eric A.; Koo, Edward H.; Ellisman, Mark H.; Ghosh, Anirvan

    2014-01-01

    The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control – they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease. PMID:24454724

  11. Stroke Lesions in a Large Upper Limb Rehabilitation Trial Cohort Rarely Match Lesions in Common Preclinical Models

    Science.gov (United States)

    Edwardson, Matthew A.; Wang, Ximing; Liu, Brent; Ding, Li; Lane, Christianne J.; Park, Caron; Nelsen, Monica A.; Jones, Theresa A; Wolf, Steven L; Winstein, Carolee J; Dromerick, Alexander W.

    2017-01-01

    Background Stroke patients with mild-moderate upper extremity (UE) motor impairments and minimal sensory and cognitive deficits provide a useful model to study recovery and improve rehabilitation. Laboratory-based investigators use lesioning techniques for similar goals. Objective Determine whether stroke lesions in an UE rehabilitation trial cohort match lesions from the preclinical stroke recovery models used to drive translational research. Methods Clinical neuroimages from 297 participants enrolled in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study were reviewed. Images were characterized based on lesion type (ischemic or hemorrhagic), volume, vascular territory, depth (cortical gray matter, cortical white matter, subcortical), old strokes, and leukoaraiosis. Lesions were compared with those of preclinical stroke models commonly used to study upper limb recovery. Results Among the ischemic stroke participants, median infarct volume was 1.8 mL, with most lesions confined to subcortical structures (61%) including the anterior choroidal artery territory (30%) and the pons (23%). Of ICARE participants, stroke patients, but they represent a clinically and scientifically important subgroup. Compared to lesions in general stroke populations and widely-studied animal models of recovery, ICARE participants had smaller, more subcortically-based strokes. Improved preclinical-clinical translational efforts may require better alignment of lesions between preclinical and human stroke recovery models. PMID:28337932

  12. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome.

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    Benjamin, Joel S; Pilarowski, Genay O; Carosso, Giovanni A; Zhang, Li; Huso, David L; Goff, Loyal A; Vernon, Hilary J; Hansen, Kasper D; Bjornsson, Hans T

    2017-01-03

    Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d +/βGeo ). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d +/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d +/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

  13. Mathematical and numerical modeling of early atherosclerotic lesions***

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    Raoult Annie

    2010-12-01

    Full Text Available This article is devoted to the construction of a mathematical model describing the early formation of atherosclerotic lesions. The early stage of atherosclerosis is an inflammatory process that starts with the penetration of low density lipoproteins in the intima and with their oxidation. This phenomenon is closely linked to the local blood flow dynamics. Extending a previous work [5] that was mainly restricted to a one-dimensional setting, we couple a simple lesion growth model relying on the biomolecular process that takes place in the intima with blood flow dynamics and mass transfer. We perform numerical simulations on a two-dimensional geometry taken from [6,7] that mimicks a carotid artery deformed by a perivascular cast and we compare the numerical results with experimental data.

  14. Diffusion-weighted MRI and quantitative biophysical modeling of hippocampal neurite loss in chronic stress.

    Directory of Open Access Journals (Sweden)

    Peter Vestergaard-Poulsen

    Full Text Available Chronic stress has detrimental effects on physiology, learning and memory and is involved in the development of anxiety and depressive disorders. Besides changes in synaptic formation and neurogenesis, chronic stress also induces dendritic remodeling in the hippocampus, amygdala and the prefrontal cortex. Investigations of dendritic remodeling during development and treatment of stress are currently limited by the invasive nature of histological and stereological methods. Here we show that high field diffusion-weighted MRI combined with quantitative biophysical modeling of the hippocampal dendritic loss in 21 day restraint stressed rats highly correlates with former histological findings. Our study strongly indicates that diffusion-weighted MRI is sensitive to regional dendritic loss and thus a promising candidate for non-invasive studies of dendritic plasticity in chronic stress and stress-related disorders.

  15. Candidate hippocampal biomarkers of susceptibility and resilience to stress in a rat model of depression

    DEFF Research Database (Denmark)

    Henningsen, Kim; Palmfeldt, Johan; Christiansen, Sofie Friis

    2012-01-01

    -scale proteomics was used to map hippocampal protein alterations in different stress states. Membrane proteins were successfully captured by two-phase separation and peptide based proteomics. Using iTRAQ labeling coupled with mass spectrometry, more than 2000 proteins were quantified and 73 proteins were found......Susceptibility to stress plays a crucial role in the development of psychiatric disorders such as unipolar depression and post-traumatic stress disorder. In the present study the chronic mild stress rat model of depression was used to reveal stress-susceptible and stress-resilient rats. Large...... to be differentially expressed. Stress susceptibility was associated with increased expression of a sodium-channel protein (SCN9A) currently investigated as a potential antidepressant target. Differential protein profiling also indicated stress susceptibility to be associated with deficits in synaptic vesicle release...

  16. Distinctive hippocampal zinc distribution patterns following stress exposure in an animal model of PTSD.

    Science.gov (United States)

    Sela, Hagit; Cohen, Hagit; Karpas, Zeev; Zeiri, Yehuda

    2017-03-22

    Emerging evidence suggests that zinc (Zn) deficiency is associated with depression and anxiety in both human and animal studies. The present study sought to assess whether there is an association between the magnitude of behavioral responses to stress and patterns of Zn distribution. The work has focused on one case study, the association between an animal model of posttraumatic stress disorder (PTSD) and the Zn distribution in the rat hippocampus. Behaviors were assessed with the elevated plus-maze and acoustic startle response tests 7 days later. Preset cut-off criteria classified exposed animals according to their individual behavioral responses. To further characterize the distribution of Zn that occurs in the hippocampus 8 days after the exposure, laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) imaging was used. It has been found that Zn distribution in the dentate gyrus (DG) sub-region in the hippocampus is clearly more widely spread for rats that belong to the extreme behavioral response (EBR) group as compared to the control group. Comparison of the Zn concentration changes in the cornu ammonis 1 (CA1) and the DG sub-regions of the hippocampus shows that the concentration changes are statistically significantly higher in the EBR rats compared to the rats in the control and minimal behavioral response (MBR) groups. In order to understand the mechanism of stress-induced hippocampal Zn dyshomeostasis, relative quantitative analyses of metallothionein (MT), B-cell lymphoma 2 (Bcl-2) and caspase 3 immunoreactivity were performed. Significant differences in the number of caspase-ir and Bcl-2 cells were found in the hippocampal DG sub-region between the EBR group and the control and MBR groups. The results of this study demonstrate a statistically significant association between the degree of behavioral disruption resulting from stress exposure and the patterns of Zn distribution and concentration changes in the various hippocampal regions

  17. Background based Gaussian mixture model lesion segmentation in PET

    Energy Technology Data Exchange (ETDEWEB)

    Soffientini, Chiara Dolores, E-mail: chiaradolores.soffientini@polimi.it; Baselli, Giuseppe [DEIB, Department of Electronics, Information, and Bioengineering, Politecnico di Milano, Piazza Leonardo da Vinci 32, Milan 20133 (Italy); De Bernardi, Elisabetta [Department of Medicine and Surgery, Tecnomed Foundation, University of Milano—Bicocca, Monza 20900 (Italy); Zito, Felicia; Castellani, Massimo [Nuclear Medicine Department, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, via Francesco Sforza 35, Milan 20122 (Italy)

    2016-05-15

    Purpose: Quantitative {sup 18}F-fluorodeoxyglucose positron emission tomography is limited by the uncertainty in lesion delineation due to poor SNR, low resolution, and partial volume effects, subsequently impacting oncological assessment, treatment planning, and follow-up. The present work develops and validates a segmentation algorithm based on statistical clustering. The introduction of constraints based on background features and contiguity priors is expected to improve robustness vs clinical image characteristics such as lesion dimension, noise, and contrast level. Methods: An eight-class Gaussian mixture model (GMM) clustering algorithm was modified by constraining the mean and variance parameters of four background classes according to the previous analysis of a lesion-free background volume of interest (background modeling). Hence, expectation maximization operated only on the four classes dedicated to lesion detection. To favor the segmentation of connected objects, a further variant was introduced by inserting priors relevant to the classification of neighbors. The algorithm was applied to simulated datasets and acquired phantom data. Feasibility and robustness toward initialization were assessed on a clinical dataset manually contoured by two expert clinicians. Comparisons were performed with respect to a standard eight-class GMM algorithm and to four different state-of-the-art methods in terms of volume error (VE), Dice index, classification error (CE), and Hausdorff distance (HD). Results: The proposed GMM segmentation with background modeling outperformed standard GMM and all the other tested methods. Medians of accuracy indexes were VE <3%, Dice >0.88, CE <0.25, and HD <1.2 in simulations; VE <23%, Dice >0.74, CE <0.43, and HD <1.77 in phantom data. Robustness toward image statistic changes (±15%) was shown by the low index changes: <26% for VE, <17% for Dice, and <15% for CE. Finally, robustness toward the user-dependent volume initialization was

  18. CCL2-ethanol interactions and hippocampal synaptic protein expression in a transgenic mouse model

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    Donna eGruol

    2014-04-01

    Full Text Available Chronic exposure to ethanol produces a number of detrimental effects on behavior. Neuroadaptive changes in brain structure or function underlie these behavioral changes and may be transient or persistent in nature. Central to the functional changes are alterations in the biology of neuronal and glial cells of the brain. Recent data show that ethanol induces glial cells of the brain to produce elevated levels of neuroimmune factors including CCL2, a key innate immune chemokine. Depending on the conditions of ethanol exposure, the upregulated levels of CCL2 can be transient or persistent and outlast the period of ethanol exposure. Importantly, results indicate that the upregulated levels of CCL2 may lead to CCL2-ethanol interactions that mediate or regulate the effects of ethanol on the brain. Glial cells are in close association with neurons and regulate many neuronal functions. Therefore, effects of ethanol on glial cells may underlie some of the effects of ethanol on neurons. To investigate this possibility, we are studying the effects of chronic ethanol on hippocampal synaptic function in a transgenic mouse model that expresses elevated levels of CCL2 in the brain through enhanced glial expression, a situation know to occur in alcoholics. Both CCL2 and ethanol have been reported to alter synaptic function in the hippocampus. In the current study, we determined if interactions are evident between CCL2 and ethanol at level of hippocampal synaptic proteins. Two ethanol exposure paradigms were used; the first involved ethanol exposure by drinking and the second involved ethanol exposure in a paradigm that combines drinking plus ethanol vapor. The first paradigm does not produce dependence on ethanol, whereas the second paradigm is commonly used to produce ethanol dependence. Results show modest effects of both ethanol exposure paradigms on the level of synaptic proteins in the hippocampus of CCL2 transgenic mice compared with their non

  19. Prepubertal Ovariectomy Exaggerates Adult Affective Behaviors and Alters the Hippocampal Transcriptome in a Genetic Rat Model of Depression

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    Neha S. Raghavan

    2018-01-01

    Full Text Available Major depressive disorder (MDD is a debilitating illness that affects twice as many women than men postpuberty. This female bias is thought to be caused by greater heritability of MDD in women and increased vulnerability induced by female sex hormones. We tested this hypothesis by removing the ovaries from prepubertal Wistar Kyoto (WKY more immobile (WMI females, a genetic animal model of depression, and its genetically close control, the WKY less immobile (WLI. In adulthood, prepubertally ovariectomized (PrePubOVX animals and their Sham-operated controls were tested for depression- and anxiety-like behaviors, using the routinely employed forced swim and open field tests, respectively, and RNA-sequencing was performed on their hippocampal RNA. Our results confirmed that the behavioral and hippocampal expression changes that occur after prepubertal ovariectomy are the consequences of an interaction between genetic predisposition to depressive behavior and ovarian hormone-regulated processes. Lack of ovarian hormones during and after puberty in the WLIs led to increased depression-like behavior. In WMIs, both depression- and anxiety-like behaviors worsened by prepubertal ovariectomy. The unbiased exploration of the hippocampal transcriptome identified sets of differentially expressed genes (DEGs between the strains and treatment groups. The relatively small number of hippocampal DEGs resulting from the genetic differences between the strains confirmed the genetic relatedness of these strains. Nevertheless, the differences in DEGs between the strains in response to prepubertal ovariectomy identified different molecular processes, including the importance of glucocorticoid receptor-mediated mechanisms, that may be causative of the increased depression-like behavior in the presence or absence of genetic predisposition. This study contributes to the understanding of hormonal maturation-induced changes in affective behaviors and the hippocampal

  20. Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development.

    Science.gov (United States)

    Schachtschneider, Kyle M; Liu, Yingkai; Rund, Laurie A; Madsen, Ole; Johnson, Rodney W; Groenen, Martien A M; Schook, Lawrence B

    2016-11-03

    Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene expression and function. DNA methylation is an epigenetic mark involved in gene regulation and altered by environmental factors. In this study, hippocampal DNA methylation and gene expression were assessed via reduced representation bisulfite sequencing and RNA-seq on samples from a previous study reporting reduced hippocampal-based learning and memory in a porcine biomedical model of neonatal iron deficiency. In total 192 differentially expressed genes (DEGs) were identified between the iron deficient and control groups. GO term and pathway enrichment analysis identified DEGs associated with hypoxia, angiogenesis, increased blood brain barrier (BBB) permeability, and altered neurodevelopment and function. Of particular interest are genes previously implicated in cognitive deficits and behavioral disorders in humans and mice, including HTR2A, HTR2C, PAK3, PRSS12, and NETO1. Altered genome-wide DNA methylation was observed across 0.5 million CpG and 2.4 million non-CpG sites. In total 853 differentially methylated (DM) CpG and 99 DM non-CpG sites were identified between groups. Samples clustered by group when comparing DM non-CpG sites, suggesting high conservation of non-CpG methylation in response to neonatal environment. In total 12 DM sites were associated with 9 DEGs, including genes involved in angiogenesis, neurodevelopment, and neuronal function. Neonatal iron deficiency leads to altered hippocampal DNA methylation and gene regulation involved in hypoxia, angiogenesis, increased BBB permeability, and altered neurodevelopment and function. Together, these results provide new insights into the mechanisms through which neonatal iron deficiency results in long lasting reductions in cognitive

  1. Shaofu Zhuyu Decoction Regresses Endometriotic Lesions in a Rat Model

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    Guanghui Zhu

    2018-01-01

    Full Text Available The current therapies for endometriosis are restricted by various side effects and treatment outcome has been less than satisfactory. Shaofu Zhuyu Decoction (SZD, a classic traditional Chinese medicinal (TCM prescription for dysmenorrhea, has been widely used in clinical practice by TCM doctors to relieve symptoms of endometriosis. The present study aimed to investigate the effects of SZD on a rat model of endometriosis. Forty-eight female Sprague-Dawley rats with regular estrous cycles went through autotransplantation operation to establish endometriosis model. Then 38 rats with successful ectopic implants were randomized into two groups: vehicle- and SZD-treated groups. The latter were administered SZD through oral gavage for 4 weeks. By the end of the treatment period, the volume of the endometriotic lesions was measured, the histopathological properties of the ectopic endometrium were evaluated, and levels of proliferating cell nuclear antigen (PCNA, CD34, and hypoxia inducible factor- (HIF- 1α in the ectopic endometrium were detected with immunohistochemistry. Furthermore, apoptosis was assessed using the terminal deoxynucleotidyl transferase (TdT deoxyuridine 5′-triphosphate (dUTP nick-end labeling (TUNEL assay. In this study, SZD significantly reduced the size of ectopic lesions in rats with endometriosis, inhibited cell proliferation, increased cell apoptosis, and reduced microvessel density and HIF-1α expression. It suggested that SZD could be an effective therapy for the treatment and prevention of endometriosis recurrence.

  2. 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.)

  3. Cavernous angioma associated with ipsilateral hippocampal sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  4. Detecting hippocampal shape changes in Alzheimer's disease using statistical shape models

    Science.gov (United States)

    Shen, Kaikai; Bourgeat, Pierrick; Fripp, Jurgen; Meriaudeau, Fabrice; Salvado, Olivier

    2011-03-01

    The hippocampus is affected at an early stage in the development of Alzheimer's disease (AD). Using brain Magnetic Resonance (MR) images, we can investigate the effect of AD on the morphology of the hippocampus. Statistical shape models (SSM) are usually used to describe and model the hippocampal shape variations among the population. We use the shape variation from SSM as features to classify AD from normal control cases (NC). Conventional SSM uses principal component analysis (PCA) to compute the modes of variations among the population. Although these modes are representative of variations within the training data, they are not necessarily discriminant on labelled data. In this study, a Hotelling's T 2 test is used to qualify the landmarks which can be used for PCA. The resulting variation modes are used as predictors of AD from NC. The discrimination ability of these predictors is evaluated in terms of their classification performances using support vector machines (SVM). Using only landmarks statistically discriminant between AD and NC in SSM showed a better separation between AD and NC. These predictors also showed better correlation to the cognitive scores such as mini-mental state examination (MMSE) and Alzheimer's disease assessment scale (ADAS).

  5. Cytoskeleton of hippocampal neurons as a target for valproic acid in an experimental model of depression.

    Science.gov (United States)

    Ferrero, Alejandro J; Cereseto, Marina; Sifonios, Laura L; Reinés, Analía; Peixoto, Estanislao; Rubio, Modesto C; Wikinski, Silvia

    2007-10-01

    Atrophy of pyramidal hippocampal neurons and of the entire hippocampus has been reported in experimental models of depression and in depressive patients respectively. We investigated the efficacy of valproic acid (VPA) for reversing a depressive-like behaviour and a cytoskeletal alteration in the hippocampus, the loss of the light neurofilament subunit (NF-L). Depressive-like behaviour was induced by inescapable stress. Animals were divided into four groups: two to assess the response to 21 days of treatment with 200 mg/kg (I.P.) of valproic acid, and two in which the treatment was interrupted and the effects of VPA were evaluated 90 days later. Depressive-like behaviour was evaluated by the quantification of escape movements in a swimming test. NF-L was quantified by immunohistochemistry in dentate gyrus and CA3 of hippocampus. VPA corrected the depressive-like behaviour and reversed the diminution of NF-L in the hippocampus. Ninety days after the end of the treatment, and in contrast to the results previously obtained with fluoxetine, no recurrence of the depressive-like behaviour was observed. Despite interruption of the treatment, a long-lasting effect of VPA was observed. A possible relationship between the effect on NF-L and the prevention of depressive-like behaviour recurrence could be suggested.

  6. Developmental hippocampal neuroplasticity in a model of nicotine replacement therapy during pregnancy and breastfeeding.

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    Ian Mahar

    Full Text Available The influence of developmental nicotine exposure on the brain represents an important health topic in light of the popularity of nicotine replacement therapy (NRT as a smoking cessation method during pregnancy.In this study, we used a model of NRT during pregnancy and breastfeeding to explore the consequences of chronic developmental nicotine exposure on cerebral neuroplasticity in the offspring. We focused on two dynamic lifelong phenomena in the dentate gyrus (DG of the hippocampus that are highly sensitive to the environment: granule cell neurogenesis and long-term potentiation (LTP.Pregnant rats were implanted with osmotic mini-pumps delivering either nicotine or saline solutions. Plasma nicotine and metabolite levels were measured in dams and offspring. Corticosterone levels, DG neurogenesis (cell proliferation, survival and differentiation and glutamatergic electrophysiological activity were measured in pups.Juvenile (P15 and adolescent (P41 offspring exposed to nicotine throughout prenatal and postnatal development displayed no significant alteration in DG neurogenesis compared to control offspring. However, NRT-like nicotine exposure significantly increased LTP in the DG of juvenile offspring as measured in vitro from hippocampal slices, suggesting that the mechanisms underlying nicotine-induced LTP enhancement previously described in adult rats are already functional in pups.These results indicate that synaptic plasticity is disrupted in offspring breastfed by dams passively exposed to nicotine in an NRT-like fashion.

  7. Ginsenoside Rg1 ameliorates hippocampal long-term potentiation and memory in an Alzheimer's disease model.

    Science.gov (United States)

    Li, Fengling; Wu, Xiqing; Li, Jing; Niu, Qingliang

    2016-06-01

    The complex etiopathogenesis of Alzheimer's disease (AD) has limited progression in the identification of effective therapeutic agents. Amyloid precursor protein (APP) and presenilin‑1 (PS1) are always overexpressed in AD, and are considered to be the initiators of the formation of β‑amyloid plaques and the symptoms of AD. In the present study, a transgenic AD model, constructed via the overexpression of APP and PS1, was used to verify the protective effects of ginsenoside Rg1 on memory performance and synaptic plasticity. AD mice (6‑month‑old) were treated via intraperitoneal injection of 0.1‑10 mg/kg ginsenoside Rg1. Long‑term memory, synaptic plasticity, and the levels of AD‑associated and synaptic plasticity‑associated proteins were measured following treatment. Memory was measured using a fear conditioning task and protein expression levels were investigated using western blotting. All the data was analyzed by one-way analysis of variance or t‑test. Following 30 days of consecutive treatment, memory in the AD mouse model was ameliorated in the 10 mg/kg ginsenoside Rg1 treatment group. As demonstrated by biochemical experiments, ginsenoside Rg1 treatment reduced the accumulations of β‑amyloid 1‑42 and phosphorylated (p)‑Tau in the AD model. Additionally, brain-derived neurotrophic factor (BDNF) and p‑TrkB synaptic plasticity‑associated proteins were upregulated following ginsenoside Rg1 application. Correspondingly, long‑term potentiation (LTP) was restored following ginsenoside Rg1 application in the AD mice model. Taken together, ginsenoside Rg1 repaired hippocampal LTP and memory, likely through facilitating the clearance of AD‑associated proteins and through activation of the BDNF‑TrkB pathway. Therefore, ginsenoside Rg1 may be a candidate drug for the treatment of AD.

  8. Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Anna Papazoglou

    2016-01-01

    Full Text Available Alzheimer’s disease (AD is a multifactorial disorder leading to progressive memory loss and eventually death. In this study an APPswePS1dE9 AD mouse model has been analyzed using implantable video-EEG radiotelemetry to perform long-term EEG recordings from the primary motor cortex M1 and the hippocampal CA1 region in both genders. Besides motor activity, EEG recordings were analyzed for electroencephalographic seizure activity and frequency characteristics using a Fast Fourier Transformation (FFT based approach. Automatic seizure detection revealed severe electroencephalographic seizure activity in both M1 and CA1 deflection in APPswePS1dE9 mice with gender-specific characteristics. Frequency analysis of both surface and deep EEG recordings elicited complex age, gender, and activity dependent alterations in the theta and gamma range. Females displayed an antithetic decrease in theta (θ and increase in gamma (γ power at 18-19 weeks of age whereas related changes in males occurred earlier at 14 weeks of age. In females, theta (θ and gamma (γ power alterations predominated in the inactive state suggesting a reduction in atropine-sensitive type II theta in APPswePS1dE9 animals. Gender-specific central dysrhythmia and network alterations in APPswePS1dE9 point to a functional role in behavioral and cognitive deficits and might serve as early biomarkers for AD in the future.

  9. 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.

  10. Long-lasting hippocampal synaptic protein loss in a mouse model of posttraumatic stress disorder.

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    Leonie Herrmann

    Full Text Available Despite intensive research efforts, the molecular pathogenesis of posttraumatic stress disorder (PTSD and especially of the hippocampal volume loss found in the majority of patients suffering from this anxiety disease still remains elusive. We demonstrated before that trauma-induced hippocampal shrinkage can also be observed in mice exhibiting a PTSD-like syndrome. Aiming to decipher the molecular correlates of these trans-species posttraumatic hippocampal alterations, we compared the expression levels of a set of neurostructural marker proteins between traumatized and control mice at different time points after their subjection to either an electric footshock or mock treatment which was followed by stressful re-exposure in several experimental groups. To our knowledge, this is the first systematic in vivo study analyzing the long-term neuromolecular sequelae of acute traumatic stress combined with re-exposure. We show here that a PTSD-like syndrome in mice is accompanied by a long-lasting reduction of hippocampal synaptic proteins which interestingly correlates with the strength of the generalized and conditioned fear response but not with the intensity of hyperarousal symptoms. Furthermore, we demonstrate that treatment with the serotonin reuptake inhibitor (SSRI fluoxetine is able to counteract both the PTSD-like syndrome and the posttraumatic synaptic protein loss. Taken together, this study demonstrates for the first time that a loss of hippocampal synaptic proteins is associated with a PTSD-like syndrome in mice. Further studies will have to reveal whether these findings are transferable to PTSD patients.

  11. Statistical models for quantifying diagnostic accuracy with multiple lesions per patient

    NARCIS (Netherlands)

    Zwinderman, Aeilko H.; Glas, Afina S.; Bossuyt, Patrick M.; Florie, Jasper; Bipat, Shandra; Stoker, Jaap

    2008-01-01

    We propose random-effects models to summarize and quantify the accuracy of the diagnosis of multiple lesions on a single image without assuming independence between lesions. The number of false-positive lesions was assumed to be distributed as a Poisson mixture, and the proportion of true-positive

  12. Exogenous galanin attenuates spatial memory impairment and decreases hippocampal β-amyloid levels in rat model of Alzheimer's disease.

    Science.gov (United States)

    Li, Lei; Yu, Liling; Kong, Qingxia

    2013-11-01

    One of the major pathological characteristics of Alzheimer's disease (AD) is the presence of enhanced deposits of beta-amyloid peptide (Aβ). The neuropeptide galanin (GAL) and its receptors are overexpressed in degenerating brain regions in AD. The functional consequences of galaninergic systems plasticity in AD are unclear. The objective of the present study was to investigate whether exogenous galanin could attenuate spatial memory impairment and hippocampal Aβ aggregation in rat model of AD. The effects of Aβ, galanin, galanin receptor 1 agonist M617 and galanin receptor 2 agonist AR-M1896 on spatial memory were tested by Morris water maze. The effects of Aβ, galanin, M617 and AR-M1896 on hippocampal Aβ protein expression were evaluated by western blot assay. The expression of galanin, galanin receptors 1 and 2 in rats' hippocampus were detected by real time PCR and western blot assay. The results showed that (1) Galanin administration was effective in improving the spatial memory and decreasing hippocampal Aβ levels after intracerebroventricular injection of Aβ; (2) AR-M1896 rather than M617 could imitate these effects of galanin; (3) GAL and GALR2 mRNA and protein levels increased significantly in hippocampus after Aβ administration, while GALR1 mRNA and protein levels did not change; (4) GAL, AR-M1896 and M617 administration did not show significant effect on GAL, GalR1 and GalR2 mRNA and protein levels in hippocampus after Aβ administration. These results implied that galanin receptor 2, but not receptor 1 was involved in the protective effects against spatial memory impairment and hippocampal Aβ aggregation.

  13. Dipeptide Piracetam Analogue Noopept Improves Viability of Hippocampal HT-22 Neurons in the Glutamate Toxicity Model.

    Science.gov (United States)

    Antipova, T A; Nikolaev, S V; Ostrovskaya, P U; Gudasheva, T A; Seredenin, S B

    2016-05-01

    Effect of noopept (N-phenylacetyl-prolylglycine ethyl ester) on viability of neurons exposed to neurotoxic action of glutamic acid (5 mM) was studied in vitro in immortalized mouse hippocampal HT-22 neurons. Noopept added to the medium before or after glutamic acid improved neuronal survival in a concentration range of 10-11-10-5 M. Comparison of the effective noopept concentrations determined in previous studies on cultured cortical and cerebellar neurons showed that hippocampal neurons are more sensitive to the protective effect of noopept.

  14. Increased hippocampal excitability in the 3xTgAD mouse model for Alzheimer's disease in vivo.

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    Katherine E Davis

    Full Text Available Mouse Alzheimer's disease (AD models develop age- and region-specific pathology throughout the hippocampal formation. One recently established pathological correlate is an increase in hippocampal excitability in vivo. Hippocampal pathology also produces episodic memory decline in human AD and we have shown a similar episodic deficit in 3xTg AD model mice aged 3-6 months. Here, we tested whether hippocampal synaptic dysfunction accompanies this cognitive deficit by probing dorsal CA1 and DG synaptic responses in anaesthetized, 4-6 month-old 3xTgAD mice. As our previous reports highlighted a decline in episodic performance in aged control mice, we included aged cohorts for comparison. CA1 and DG responses to low-frequency perforant path stimulation were comparable between 3xTgAD and controls at both age ranges. As expected, DG recordings in controls showed paired-pulse depression; however, paired-pulse facilitation was observed in DG and CA1 of young and old 3xTgAD mice. During stimulus trains both short-latency (presumably monosynaptic: 'direct' and long-latency (presumably polysynaptic: 're-entrant' responses were observed. Facilitation of direct responses was modest in 3xTgAD animals. However, re-entrant responses in DG and CA1 of young 3xTgAD mice developed earlier in the stimulus train and with larger amplitude when compared to controls. Old mice showed less DG paired-pulse depression and no evidence for re-entrance. In summary, DG and CA1 responses to low-frequency stimulation in all groups were comparable, suggesting no loss of synaptic connectivity in 3xTgAD mice. However, higher-frequency activation revealed complex change in synaptic excitability in DG and CA1 of 3xTgAD mice. In particular, short-term plasticity in DG and CA1 was facilitated in 3xTgAD mice, most evidently in younger animals. In addition, re-entrance was facilitated in young 3xTgAD mice. Overall, these data suggest that the episodic-like memory deficit in 3xTgAD mice

  15. Sex differences in depressive, anxious behaviors and hippocampal transcript levels in a genetic rat model.

    Science.gov (United States)

    Mehta, N S; Wang, L; Redei, E E

    2013-10-01

    Major depressive disorder (MDD) is a common, debilitating illness with high prevalence of comorbid anxiety. The incidence of depression and of comorbid anxiety is much higher in women than in men. These gender biases appear after puberty and their etiology is mostly unknown. Selective breeding of the Wistar Kyoto (WKY) rat strain, an accepted model of adult and adolescent depression, resulted in two fully inbred substrains. Adult WKY more immobile (WMI) rats of both sexes consistently show increased depression-like behavior in the forced swim test when compared with the control WKY less immobile (WLI) strain. In contrast, here we show that while adult female WMIs and WLIs both display high anxiety-like behaviors, only WLI males, but not WMI males, show this behavior. Moreover, the behavioral profile of WMI males is consistent from early adolescence to adulthood, but the high depression- and anxiety-like behaviors of the female WMIs appear only in adulthood. These sex-specific behavioral patterns are paralleled by marked sex differences in hippocampal gene expression differences established by genome-wide transcriptional analyses of 13th generation WMIs and WLIs. Moreover, sex- and age-specific differences in transcript levels of selected genes are present in the hippocampus of the current, fully inbred WMIs and WLIs. Thus, the contribution of specific genes and/or the influence of the gonadal hormonal environment to depression- and anxiety-like behaviors may differ between male and female WMIs, resulting in their distinct behavioral and transcriptomic profiles despite shared sequences of the somatic chromosomes. © 2013 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

  16. Inhibitory neuron and hippocampal circuit dysfunction in an aged mouse model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Anupam Hazra

    Full Text Available In Alzheimer's disease (AD, a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12-16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.

  17. Detecting global and local hippocampal shape changes in Alzheimer's disease using statistical shape models

    NARCIS (Netherlands)

    Shen, Kai-kai; Fripp, Jurgen; Mériaudeau, Fabrice; Chételat, Gaël; Salvado, Olivier; Bourgeat, Pierrick; Saradha, A.; Abdi, Hervé; Abdulkadir, Ahmed; Acharya, Deepa; Achuthan, Anusha; Adluru, Nagesh; Aghajanian, Jania; Agrusti, Antonella; Agyemang, Alex; Ahdidan, Jamila; Ahmad, Duaa; Ahmed, Shiek; Aisen, Paul; Akhondi-Asl, Alireza; Aksu, Yaman; Alberca, Roman; Alcauter, Sarael; Alexander, Daniel; Alin, Aylin; Almeida, Fabio; Alvarez-Lineara, Juan; Amlien, Inge; Anand, Shyam; Anderson, Dallas; Ang, Amma; Angersbach, Steve; Ansarian, Reza; Aoyama, Eiji; Appannah, Arti; Arfanakis, Konstantinos; Armor, Tom; Arrighi, Michael; Arumughababu, S. Vethanayaki; Arunagiri, Vidhya; Ashe-McNalley, Cody; Ashford, Wes; Le Page, Aurelie; Avants, Brian; Aviv, Richard; Awasthi, Sukrati; Ayache, Nicholas; Chen, Wei; Richard, Edo; Schmand, Ben

    2012-01-01

    The hippocampus is affected at an early stage in the development of Alzheimer's disease (AD). With the use of structural magnetic resonance (MR) imaging, we can investigate the effect of AD on the morphology of the hippocampus. The hippocampal shape variations among a population can be usually

  18. Hippocampal Ripple Oscillations and Inhibition-First Network Models: Frequency Dynamics and Response to GABA Modulators.

    Science.gov (United States)

    Donoso, José R; Schmitz, Dietmar; Maier, Nikolaus; Kempter, Richard

    2018-03-21

    Hippocampal ripples are involved in memory consolidation, but the mechanisms underlying their generation remain unclear. Models relying on interneuron networks in the CA1 region disagree on the predominant source of excitation to interneurons: either "direct," via the Schaffer collaterals that provide feedforward input from CA3 to CA1, or "indirect," via the local pyramidal cells in CA1, which are embedded in a recurrent excitatory-inhibitory network. Here, we used physiologically constrained computational models of basket-cell networks to investigate how they respond to different conditions of transient, noisy excitation. We found that direct excitation of interneurons could evoke ripples (140-220 Hz) that exhibited intraripple frequency accommodation and were frequency-insensitive to GABA modulators, as previously shown in in vitro experiments. In addition, the indirect excitation of the basket-cell network enabled the expression of intraripple frequency accommodation in the fast-gamma range (90-140 Hz), as in vivo In our model, intraripple frequency accommodation results from a hysteresis phenomenon in which the frequency responds differentially to the rising and descending phases of the transient excitation. Such a phenomenon predicts a maximum oscillation frequency occurring several milliseconds before the peak of excitation. We confirmed this prediction for ripples in brain slices from male mice. These results suggest that ripple and fast-gamma episodes are produced by the same interneuron network that is recruited via different excitatory input pathways, which could be supported by the previously reported intralaminar connectivity bias between basket cells and functionally distinct subpopulations of pyramidal cells in CA1. Together, our findings unify competing inhibition-first models of rhythm generation in the hippocampus. SIGNIFICANCE STATEMENT The hippocampus is a part of the brain of humans and other mammals that is critical for the acquisition and

  19. Hippocampal-dependent spatial memory in the water maze is preserved in an experimental model of temporal lobe epilepsy in rats.

    Directory of Open Access Journals (Sweden)

    Marion Inostroza

    Full Text Available Cognitive impairment is a major concern in temporal lobe epilepsy (TLE. While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA from two different rat strains (Wistar and Sprague-Dawley using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se.

  20. The flexible use of multiple cue relationships in spatial navigation : A comparison of water maze performance following hippocampal, medial septal, prefrontal cortex, or posterior parietal cortex lesions

    NARCIS (Netherlands)

    Compton, DM; Griffith, HR; McDaniel, WF; Foster, RA; Davis, BK

    Rats prepared with lesions of the prefrontal cortex, posterior parietal cortex, hippocampus, or medial septal area were tested for acquisition of a number of variations of the open-field water maze using a version of place learning assessment described by Eichenbaum, Stewart, and Morris (1991).

  1. Associative recognition and the hippocampus: differential effects of hippocampal lesions on object-place, object-context and object-place-context memory.

    Science.gov (United States)

    Langston, Rosamund F; Wood, Emma R

    2010-10-01

    The hippocampus is thought to be required for the associative recognition of objects together with the spatial or temporal contexts in which they occur. However, recent data showing that rats with fornix lesions perform as well as controls in an object-place task, while being impaired on an object-place-context task (Eacott and Norman (2004) J Neurosci 24:1948-1953), suggest that not all forms of context-dependent associative recognition depend on the integrity of the hippocampus. To examine the role of the hippocampus in context-dependent recognition directly, the present study tested the effects of large, selective, bilateral hippocampus lesions in rats on performance of a series of spontaneous recognition memory tasks: object recognition, object-place recognition, object-context recognition and object-place-context recognition. Consistent with the effects of fornix lesions, animals with hippocampus lesions were impaired only on the object-place-context task. These data confirm that not all forms of context-dependent associative recognition are mediated by the hippocampus. Subsequent experiments suggested that the object-place task does not require an allocentric representation of space, which could account for the lack of impairment following hippocampus lesions. Importantly, as the object-place-context task has similar spatial requirements, the selective deficit in object-place-context recognition suggests that this task requires hippocampus-dependent neural processes distinct from those required for allocentric spatial memory, or for object memory, object-place memory or object-context memory. Two possibilities are that object, place, and context information converge only in the hippocampus, or that recognition of integrated object-place-context information requires a hippocampus-dependent mode of retrieval, such as recollection. © 2009 Wiley-Liss, Inc.

  2. 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.)

  3. PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of posttraumatic epilepsy

    OpenAIRE

    Berdichevsky, Yevgeny; Dryer, Alexandra M.; Saponjian, Yero; Mahoney, Mark M.; Pimentel, Corrin A.; Lucini, Corrina A.; Usenovic, Marija; Staley, Kevin J.

    2013-01-01

    mTOR is activated in epilepsy, but the mechanisms of mTOR activation in post-traumatic epileptogenesis are unknown. It is also not clear whether mTOR inhibition has an antiepileptogenic, or merely anti-convulsive effect. The rat hippocampal organotypic culture model of post-traumatic epilepsy was used to study the effects of long term (four weeks) inhibition of signaling pathways that interact with mTOR. Ictal activity was quantified by measurement of lactate production and electrical recordi...

  4. Generation of connectivity-preserving surface models of multiple sclerosis lesions.

    Science.gov (United States)

    Meruvia-Pastor, Oscar; Xiao, Mei; Soh, Jung; Sensen, Christoph W

    2011-01-01

    Progression of multiple sclerosis (MS) results in brain lesions caused by white matter inflammation. MS lesions have various shapes, sizes and locations, affecting cognitive abilities of patients to different extents. To facilitate the visualization of the brain lesion distribution, we have developed a software tool to build 3D surface models of MS lesions. This tool allows users to create 3D models of lesions quickly and to visualize the lesions and brain tissues using various visual attributes and configurations. The software package is based on breadth-first search based 3D connected component analysis and a 3D flood-fill based region growing algorithm to generate 3D models from binary or non-binary segmented medical image stacks.

  5. Postoperative intermittent fasting prevents hippocampal oxidative stress and memory deficits in a rat model of chronic cerebral hypoperfusion.

    Science.gov (United States)

    Hu, Yuan; Zhang, Miao; Chen, Yunyun; Yang, Ying; Zhang, Jun-Jian

    2018-01-11

    Whether intermittent fasting (IF) treatment after stroke can prevent its long-term detrimental effects remains unknown. Here, we investigate the effects of postoperative IF on cognitive deficits and its underlying mechanisms in a permanent two-vessel occlusion (2VO) vascular dementia rat model. Rats were subjected to either IF or ad libitum feeding 1 week after 2VO surgery. The cognition of rats was assessed using the novel object recognition (NOR) task and Morris water maze (MWM) 8 weeks after surgery. After behavioral testing, hippocampal malondialdehyde (MDA) and glutathione (GSH) concentrations, superoxide dismutase (SOD) activity, gene expression of antioxidative enzymes, inflammatory protein levels, and microglia density were determined. Postoperative IF significantly ameliorated the cognitive performance of 2VO rats in the NOR and MWM tests. Cognitive enhancement paralleled preservation of the PSD95 and BDNF levels in the 2VO rat hippocampus. Mechanistically, postoperative IF mitigated hippocampal oxidative stress in 2VO rats, as indicated by the reduced MDA concentration and mRNA and the protein levels of the reactive oxygen species-generating enzyme nicotinamide adenine dinucleotide phosphate oxidase 1. IF treatment also preserved the GSH level and SOD activity, as well as the levels of their upstream regulating enzymes, resulting in preserved antioxidative capability. In addition, postoperative IF prevented hippocampal microglial activation and elevation of sphingosine 1-phosphate receptor 1 and inflammatory cytokines in 2VO rats. Our results suggest that postoperative IF suppresses neuroinflammation and oxidative stress induced by chronic cerebral ischemia, thereby preserving cognitive function in a vascular dementia rat model.

  6. Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

    Science.gov (United States)

    2014-01-01

    Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

  7. Enhancement of information transmission with stochastic resonance in hippocampal CA1 neuron models: effects of noise input location.

    Science.gov (United States)

    Kawaguchi, Minato; Mino, Hiroyuki; Durand, Dominique M

    2007-01-01

    Stochastic resonance (SR) has been shown to enhance the signal to noise ratio or detection of signals in neurons. It is not yet clear how this effect of SR on the signal to noise ratio affects signal processing in neural networks. In this paper, we investigate the effects of the location of background noise input on information transmission in a hippocampal CA1 neuron model. In the computer simulation, random sub-threshold spike trains (signal) generated by a filtered homogeneous Poisson process were presented repeatedly to the middle point of the main apical branch, while the homogeneous Poisson shot noise (background noise) was applied to a location of the dendrite in the hippocampal CA1 model consisting of the soma with a sodium, a calcium, and five potassium channels. The location of the background noise input was varied along the dendrites to investigate the effects of background noise input location on information transmission. The computer simulation results show that the information rate reached a maximum value for an optimal amplitude of the background noise amplitude. It is also shown that this optimal amplitude of the background noise is independent of the distance between the soma and the noise input location. The results also show that the location of the background noise input does not significantly affect the maximum values of the information rates generated by stochastic resonance.

  8. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

    KAUST Repository

    Giralt, Albert; Brito, Veronica; Chevy, Quentin; Simonnet, Clé mence; Otsu, Yo; Cifuentes-Dí az, Carmen; Pins, Benoit de; Coura, Renata; Alberch, Jordi; Giné s, Sí lvia; Poncer, Jean-Christophe; Girault, Jean-Antoine

    2017-01-01

    The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington’s disease cognitive impairments.

  9. Persistent deficits in hippocampal synaptic plasticity accompany losses of hippocampus-dependent memory in a rodent model of psychosis

    Directory of Open Access Journals (Sweden)

    Valentina eWiescholleck

    2013-03-01

    Full Text Available Irreversible N-methyl-D-aspartate receptor (NMDAR antagonism is known to provoke symptoms of psychosis and schizophrenia in healthy humans. NMDAR hypofunction is believed to play a central role in the pathophysiology of both disorders and in an animal model of psychosis, that is based on irreversible antagonism of NMDARs, pronounced deficits in hippocampal synaptic plasticity have been reported shortly after antagonist treatment. Here, we examined the long-term consequences for long-term potentiation (LTP of a single acute treatment with an irreversible antagonist and investigated whether deficits are associated with memory impairments.The ability to express long-term potentiation (LTP at the perforant pathway – dentate gyrus synapse, as well as object recognition memory was assessed 1, 2, 3 and 4 weeks after a single -treatment of the antagonist, MK801. Here, LTP in freely behaving rats was significantly impaired at all time-points compared to control LTP before treatment. Object recognition memory was also significantly poorer in MK801-treated compared to vehicle-treated animals for several weeks after treatment. Histological analysis revealed no changes in brain tissue.Taken together, these data support that acute treatment with an irreversible NMDAR antagonist persistently impairs hippocampal functioning on behavioral, as well as synaptic levels. The long-term deficits in synaptic plasticity may underlie the cognitive impairments that are associated with schizophrenia-spectrum disorders.

  10. Using the Change Manager Model for the Hippocampal System to Predict Connectivity and Neurophysiological Parameters in the Perirhinal Cortex

    Science.gov (United States)

    Coward, L. Andrew; Gedeon, Tamas D.

    2016-01-01

    Theoretical arguments demonstrate that practical considerations, including the needs to limit physiological resources and to learn without interference with prior learning, severely constrain the anatomical architecture of the brain. These arguments identify the hippocampal system as the change manager for the cortex, with the role of selecting the most appropriate locations for cortical receptive field changes at each point in time and driving those changes. This role results in the hippocampal system recording the identities of groups of cortical receptive fields that changed at the same time. These types of records can also be used to reactivate the receptive fields active during individual unique past events, providing mechanisms for episodic memory retrieval. Our theoretical arguments identify the perirhinal cortex as one important focal point both for driving changes and for recording and retrieving episodic memories. The retrieval of episodic memories must not drive unnecessary receptive field changes, and this consideration places strong constraints on neuron properties and connectivity within and between the perirhinal cortex and regular cortex. Hence the model predicts a number of such properties and connectivity. Experimental test of these falsifiable predictions would clarify how change is managed in the cortex and how episodic memories are retrieved. PMID:26819594

  11. Pyk2 modulates hippocampal excitatory synapses and contributes to cognitive deficits in a Huntington’s disease model

    KAUST Repository

    Giralt, Albert

    2017-05-30

    The structure and function of spines and excitatory synapses are under the dynamic control of multiple signalling networks. Although tyrosine phosphorylation is involved, its regulation and importance are not well understood. Here we study the role of Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase highly expressed in the hippocampus. Hippocampal-related learning and CA1 long-term potentiation are severely impaired in Pyk2-deficient mice and are associated with alterations in NMDA receptors, PSD-95 and dendritic spines. In cultured hippocampal neurons, Pyk2 has autophosphorylation-dependent and -independent roles in determining PSD-95 enrichment and spines density. Pyk2 levels are decreased in the hippocampus of individuals with Huntington and in the R6/1 mouse model of the disease. Normalizing Pyk2 levels in the hippocampus of R6/1 mice rescues memory deficits, spines pathology and PSD-95 localization. Our results reveal a role for Pyk2 in spine structure and synaptic function, and suggest that its deficit contributes to Huntington’s disease cognitive impairments.

  12. Correlation between model observer and human observer performance in CT imaging when lesion location is uncertain

    Energy Technology Data Exchange (ETDEWEB)

    Leng, Shuai; Yu, Lifeng; Zhang, Yi; McCollough, Cynthia H. [Department of Radiology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (United States); Carter, Rickey [Department of Biostatistics, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (United States); Toledano, Alicia Y. [Biostatistics Consulting, LLC, 10606 Wheatley Street, Kensington, Maryland 20895 (United States)

    2013-08-15

    Purpose: The purpose of this study was to investigate the correlation between model observer and human observer performance in CT imaging for the task of lesion detection and localization when the lesion location is uncertain.Methods: Two cylindrical rods (3-mm and 5-mm diameters) were placed in a 35 × 26 cm torso-shaped water phantom to simulate lesions with −15 HU contrast at 120 kV. The phantom was scanned 100 times on a 128-slice CT scanner at each of four dose levels (CTDIvol = 5.7, 11.4, 17.1, and 22.8 mGy). Regions of interest (ROIs) around each lesion were extracted to generate images with signal-present, with each ROI containing 128 × 128 pixels. Corresponding ROIs of signal-absent images were generated from images without lesion mimicking rods. The location of the lesion (rod) in each ROI was randomly distributed by moving the ROIs around each lesion. Human observer studies were performed by having three trained observers identify the presence or absence of lesions, indicating the lesion location in each image and scoring confidence for the detection task on a 6-point scale. The same image data were analyzed using a channelized Hotelling model observer (CHO) with Gabor channels. Internal noise was added to the decision variables for the model observer study. Area under the curve (AUC) of ROC and localization ROC (LROC) curves were calculated using a nonparametric approach. The Spearman's rank order correlation between the average performance of the human observers and the model observer performance was calculated for the AUC of both ROC and LROC curves for both the 3- and 5-mm diameter lesions.Results: In both ROC and LROC analyses, AUC values for the model observer agreed well with the average values across the three human observers. The Spearman's rank order correlation values for both ROC and LROC analyses for both the 3- and 5-mm diameter lesions were all 1.0, indicating perfect rank ordering agreement of the figures of merit (AUC

  13. Disrupted hippocampal sharp‐wave ripple‐associated spike dynamics in a transgenic mouse model of dementia

    Science.gov (United States)

    Witton, Jonathan; Staniaszek, Lydia E.; Bartsch, Ullrich; Randall, Andrew D.; Jones, Matthew W.

    2015-01-01

    Key points High frequency (100–250 Hz) neuronal oscillations in the hippocampus, known as sharp‐wave ripples (SWRs), synchronise the firing behaviour of groups of neurons and play a key role in memory consolidation.Learning and memory are severely compromised in dementias such as Alzheimer's disease; however, the effects of dementia‐related pathology on SWRs are unknown.The frequency and temporal structure of SWRs was disrupted in a transgenic mouse model of tauopathy (one of the major hallmarks of several dementias).Excitatory pyramidal neurons were more likely to fire action potentials in a phase‐locked manner during SWRs in the mouse model of tauopathy; conversely, inhibitory interneurons were less likely to fire phase‐locked spikes during SWRs.These findings indicate there is reduced inhibitory control of hippocampal network events and point to a novel mechanism which may underlie the cognitive impairments in this model of dementia. Abstract Neurons within the CA1 region of the hippocampus are co‐activated during high frequency (100–250 Hz) sharp‐wave ripple (SWR) activity in a manner that probably drives synaptic plasticity and promotes memory consolidation. In this study we have used a transgenic mouse model of dementia (rTg4510 mice), which overexpresses a mutant form of tau protein, to examine the effects of tauopathy on hippocampal SWRs and associated neuronal firing. Tetrodes were used to record simultaneous extracellular action potentials and local field potentials from the dorsal CA1 pyramidal cell layer of 7‐ to 8‐month‐old wild‐type and rTg4510 mice at rest in their home cage. At this age point these mice exhibit neurofibrillary tangles, neurodegeneration and cognitive deficits. Epochs of sleep or quiet restfulness were characterised by minimal locomotor activity and a low theta/delta ratio in the local field potential power spectrum. SWRs detected off‐line were significantly lower in amplitude and had an altered temporal

  14. Cytomorphometric changes in hippocampal CA1 neurons exposed to simulated microgravity using rats as model

    Directory of Open Access Journals (Sweden)

    Amit eRanjan

    2014-05-01

    Full Text Available Microgravity and sleep loss lead to cognitive and learning deficits. These behavioral alterations are likely to be associated with cytomorphological changes and loss of neurons. To understand the phenomenon, we exposed rats (225-275g to 14 days simulated microgravity (SMg and compared its effects on CA1 hippocampal neuronal plasticity, with that of normal cage control rats. We observed that the mean area, perimeter, synaptic cleft and length of active zone of CA1 hippocampal neurons significantly decreased while dendritic arborization and number of spines significantly increased in SMg group as compared with controls. The mean thickness of the post synaptic density and total dendritic length remained unaltered. The changes may be a compensatory effect induced by exposure to microgravity; however, the effects may be transient or permanent, which need further study. These findings may be useful for designing effective prevention for those, including the astronauts, exposed to microgravity. Further, subject to confirmation we propose that SMg exposure might be useful for recovery of stroke patients.

  15. PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of posttraumatic epilepsy

    Science.gov (United States)

    Berdichevsky, Yevgeny; Dryer, Alexandra M.; Saponjian, Yero; Mahoney, Mark M.; Pimentel, Corrin A.; Lucini, Corrina A.; Usenovic, Marija; Staley, Kevin J.

    2013-01-01

    mTOR is activated in epilepsy, but the mechanisms of mTOR activation in post-traumatic epileptogenesis are unknown. It is also not clear whether mTOR inhibition has an antiepileptogenic, or merely anti-convulsive effect. The rat hippocampal organotypic culture model of post-traumatic epilepsy was used to study the effects of long term (four weeks) inhibition of signaling pathways that interact with mTOR. Ictal activity was quantified by measurement of lactate production and electrical recordings, and cell death was quantified with LDH release measurements and Nissl-stained neuron counts. Lactate and LDH measurements were well-correlated with electrographic activity and neuron counts, respectively. Inhibition of PI3K and Akt prevented activation of mTOR, and was as effective as inhibition of mTOR in reducing ictal activity and cell death. A dual inhibitor of PI3K and mTOR, NVP-BEZ235, was also effective. Inhibition of mTOR with rapamycin reduced axon sprouting. Late start of rapamycin treatment was effective in reducing epileptic activity and cell death, while early termination of rapamycin treatment did not result in increased epileptic activity or cell death. The conclusions of the study are: (1), the organotypic hippocampal culture model of posttraumatic epilepsy comprises a rapid assay of antiepileptogenic and neuroprotective activities and, in this model (2), mTOR activation depends on PI3K-Akt signaling, and (3) transient inhibition of mTOR has sustained effects on epilepsy. PMID:23699517

  16. Lateralized hippocampal effects of vasoactive intestinal peptide on learning and memory in rats in a model of depression.

    Science.gov (United States)

    Ivanova, Margarita; Belcheva, Stiliana; Belcheva, Iren; Negrev, Negrin; Tashev, Roman

    2012-06-01

    Findings of pharmacological studies revealed that vasoactive intestinal peptide (VIP) plays a modulatory role in learning and memory. A role of the peptide in the neurobiological mechanisms of affective disorders was also suggested. The objectives are to study the involvement of VIP in learning and memory processes after unilateral and bilateral local application into hippocampal CA1 area in rats with a model of depression (bilateral olfactory bulbectomy--OBX) and to test whether VIP receptors could affect cognition. VIP (50 ng) and combination (VIP(6-28) 10 ng + VIP 50 ng) microinjected bilaterally or into the right CA1 area improved the learning and memory of OBX rats in shuttle-box and step-through behavioral tests as compared to the saline-treated OBX controls. Left-side VIP microinjections did not affect the number of avoidances (shuttle box) and learning criteria (step through) as compared to the left-side saline-treated OBX controls. The administration of the combination into left CA1 influenced positively the performance in the step-through task. VIP antagonist (VIP(6-28), 10 ng) did not affect learning and memory of OBX rats. These findings suggest asymmetric effect of VIP on cognitive processes in hippocampus of rats with OBX model of depression. Our results point to a lateralized modulatory effect of VIP injected in the hippocampal CA1 area on the avoidance deficits in OBX rats. The right CA1 area was predominantly involved in the positive effect of VIP on learning and memory. A possible role of the PAC1 receptors is suggested.

  17. Impact of neonatal iron deficiency on hippocampal DNA methylation and gene transcription in a porcine biomedical model of cognitive development

    NARCIS (Netherlands)

    Schachtschneider, Kyle M.; Liu, Yingkai; Rund, Laurie A.; Madsen, Ole; Johnson, Rodney W.; Groenen, Martien A.M.; Schook, Lawrence B.

    2016-01-01


    Background

    Iron deficiency is a common childhood micronutrient deficiency that results in altered hippocampal function and cognitive disorders. However, little is known about the mechanisms through which neonatal iron deficiency results in long lasting alterations in hippocampal gene

  18. Learning Discloses Abnormal Structural and Functional Plasticity at Hippocampal Synapses in the APP23 Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    Middei, Silvia; Roberto, Anna; Berretta, Nicola; Panico, Maria Beatrice; Lista, Simone; Bernardi, Giorgio; Mercuri, Nicola B.; Ammassari-Teule, Martine; Nistico, Robert

    2010-01-01

    B6-Tg/Thy1APP23Sdz (APP23) mutant mice exhibit neurohistological hallmarks of Alzheimer's disease but show intact basal hippocampal neurotransmission and synaptic plasticity. Here, we examine whether spatial learning differently modifies the structural and electrophysiological properties of hippocampal synapses in APP23 and wild-type mice. While…

  19. Simultaneous Whole-Brain Segmentation and White Matter Lesion Detection Using Contrast-Adaptive Probabilistic Models

    DEFF Research Database (Denmark)

    Puonti, Oula; Van Leemput, Koen

    2016-01-01

    In this paper we propose a new generative model for simultaneous brain parcellation and white matter lesion segmentation from multi-contrast magnetic resonance images. The method combines an existing whole-brain segmentation technique with a novel spatial lesion model based on a convolutional...... restricted Boltzmann machine. Unlike current state-of-the-art lesion detection techniques based on discriminative modeling, the proposed method is not tuned to one specific scanner or imaging protocol, and simultaneously segments dozens of neuroanatomical structures. Experiments on a public benchmark dataset...... in multiple sclerosis indicate that the method’s lesion segmentation accuracy compares well to that of the current state-of-the-art in the field, while additionally providing robust whole-brain segmentations....

  20. Fish biomarkers for environmental monitoring: An integrated model supporting enzyme activity and histopathological lesions

    Science.gov (United States)

    Neta, Raimunda Nonata Fortes Carvalho; Torres Junior, Audalio Rebelo

    2014-10-01

    We present a mathematical model describing the association between glutathione-S-transferase activity and brachial lesions in the catfish, Sciades herzbergii (Ariidae) from a polluted port. The catfish were sampled from a port known to be contaminated with heavy metals and organic compounds and from a natural reserve in São Marcos Bay, Brazil. Two biomarkers, hepatic glutathione S-transferase (GST) activity and histopathological lesions, in gills tissue were measured. The values for GST activity were modeled with the occurrence of branchial lesions by fitting a third order polynomial. Results from the mathematical model indicate that GST activity has a strong polynomial relationship with the occurrence of branchial lesions in both the wet and the dry seasons, but only at the polluted port site. The model developed in this study indicates that branchial and hepatic lesions are initiated when GST activity reaches 2.15 μmol min-1 mg protein-1. Beyond this limit, GST activity decreased to very low levels and irreversible histopathological lesions occurred. This mathematical model provides a realistic approach to analyze predictive biomarkers of environmental health status.

  1. Development of a unilaterally-lesioned 6-OHDA mouse model of Parkinson's disease.

    Science.gov (United States)

    Thiele, Sherri L; Warre, Ruth; Nash, Joanne E

    2012-02-14

    The unilaterally lesioned 6-hyroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) has proved to be invaluable in advancing our understanding of the mechanisms underlying parkinsonian symptoms, since it recapitulates the changes in basal ganglia circuitry and pharmacology observed in parkinsonian patients(1-4). However, the precise cellular and molecular changes occurring at cortico-striatal synapses of the output pathways within the striatum, which is the major input region of the basal ganglia remain elusive, and this is believed to be site where pathological abnormalities underlying parkinsonian symptoms arise(3,5). In PD, understanding the mechanisms underlying changes in basal ganglia circuitry following degeneration of the nigro-striatal pathway has been greatly advanced by the development of bacterial artificial chromosome (BAC) mice over-expressing green fluorescent proteins driven by promoters specific for the two striatal output pathways (direct pathway: eGFP-D1; indirect pathway: eGFP-D2 and eGFP-A2a)(8), allowing them to be studied in isolation. For example, recent studies have suggested that there are pathological changes in synaptic plasticity in parkinsonian mice(9,10). However, these studies utilised juvenile mice and acute models of parkinsonism. It is unclear whether the changes described in adult rats with stable 6-OHDA lesions also occur in these models. Other groups have attempted to generate a stable unilaterally-lesioned 6-OHDA adult mouse model of PD by lesioning the medial forebrain bundle (MFB), unfortunately, the mortality rate in this study was extremely high, with only 14% surviving the surgery for 21 days or longer(11). More recent studies have generated intra-nigral lesions with both a low mortality rate >80% loss of dopaminergic neurons, however expression of L-DOPA induced dyskinesia(11,12,13,14) was variable in these studies. Another well established mouse model of PD is the MPTP-lesioned mouse(15). Whilst this

  2. Conversion of Synthetic Aβ to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model.

    Science.gov (United States)

    Novotny, Renata; Langer, Franziska; Mahler, Jasmin; Skodras, Angelos; Vlachos, Andreas; Wegenast-Braun, Bettina M; Kaeser, Stephan A; Neher, Jonas J; Eisele, Yvonne S; Pietrowski, Marie J; Nilsson, K Peter R; Deller, Thomas; Staufenbiel, Matthias; Heimrich, Bernd; Jucker, Mathias

    2016-05-04

    The aggregation of amyloid-β peptide (Aβ) in brain is an early event and hallmark of Alzheimer's disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral β-amyloidosis by establishing a long-term hippocampal slice culture (HSC) model. While no Aβ deposition was noted in untreated HSCs of postnatal Aβ precursor protein transgenic (APP tg) mice, Aβ deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic Aβ. Seeded Aβ deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic Aβ species determined the conformational characteristics of HSC Aβ deposition. HSC Aβ deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic Aβ, homogenates of Aβ deposits containing HSCs induced cerebral β-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic Aβ into a potent in vivo seeding-active form. In this study, we report the seeded induction of Aβ aggregation and deposition in long-term hippocampal slice cultures. Remarkably, we find that the biological activities of the largely synthetic Aβ aggregates in the culture are very similar to those observed in vivo This observation is the first to show that potent in vivo seeding-active Aβ aggregates can be obtained by seeded conversion of synthetic Aβ in a living (wild-type) cellular environment. Copyright © 2016 the authors 0270-6474/16/365084-10$15.00/0.

  3. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder.

    Science.gov (United States)

    Roth, Tania L; Zoladz, Phillip R; Sweatt, J David; Diamond, David M

    2011-07-01

    Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed Bdnf DNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased Bdnf DNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in Bdnf DNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of Bdnf mRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnf gene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal Bdnf DNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD. Copyright © 2011 Elsevier Ltd. All rights reserved.

  4. Propofol prevents electroconvulsive-shock-induced memory impairment through regulation of hippocampal synaptic plasticity in a rat model of depression

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    Luo J

    2014-09-01

    Full Text Available Jie Luo, Su Min, Ke Wei, Jun Cao, Bin Wang, Ping Li, Jun Dong, Yuanyuan Liu Department of Anesthesiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China Background: Although a rapid and efficient psychiatric treatment, electroconvulsive therapy (ECT induces memory impairment. Modified ECT requires anesthesia for safety purposes. Although traditionally found to exert amnesic effects in general anesthesia, which is an inherent part of modified ECT, some anesthetics have been found to protect against ECT-induced cognitive impairment. However, the mechanisms remain unclear. We investigated the effects of propofol (2,6-diisopropylphenol on memory in depressed rats undergoing electroconvulsive shock (ECS, the analog of ECT in animals, under anesthesia as well as its mechanisms.Methods: Chronic unpredictable mild stresses were adopted to reproduce depression in a rodent model. Rats underwent ECS (or sham ECS with anesthesia with propofol or normal saline. Behavior was assessed in sucrose preference, open field and Morris water maze tests. Hippocampal long-term potentiation (LTP was measured using electrophysiological techniques. PSD-95, CREB, and p-CREB protein expression was assayed with western blotting.Results: Depression induced memory damage, and downregulated LTP, PSD-95, CREB, and p-CREB; these effects were exacerbated in depressed rats by ECS; propofol did not reverse the depression-induced changes, but when administered in modified ECS, propofol improved memory and reversed the downregulation of LTP and the proteins. Conclusion: These findings suggest that propofol prevents ECS-induced memory impairment, and modified ECS under anesthesia with propofol improves memory in depressed rats, possibly by reversing the excessive changes in hippocampal synaptic plasticity. These observations provide a novel insight into potential targets for optimizing the clinical use of ECT for psychiatric

  5. A Comparison of the Effects of Temporary Hippocampal Lesions on Single and Dual Context Versions of the Olfactory Sequence Memory Task

    OpenAIRE

    Sill, Orriana C.; Smith, David M.

    2012-01-01

    In recent years, many animal models of memory have focused on one or more of the various components of episodic memory. For example, the odor sequence memory task requires subjects to remember individual items and events (the odors) and the temporal aspects of the experience (the sequence of odor presentation). The well-known spatial context coding function of the hippocampus, as exemplified by place cell firing, may reflect the ‘where’ component of episodic memory. In the present study, we a...

  6. Cylindrical SUV distribution model for detecting skin lesions in body trunk FDG-PET/CT images

    International Nuclear Information System (INIS)

    Nemoto, Mitsutaka; Nomura, Yukihiro; Masutani, Yoshitaka; Yoshikawa, Takeharu; Hayashi, Naoto; Yoshioka, Naoki; Ohtomo, Kuni; Hanaoka, Shouhei

    2010-01-01

    We have been developing a computerized detection method for skin lesions in body trunk fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT images. Spots on the skin with a high standard uptake value (SUV) are due not only to glucose metabolism in skin lesions but also to the physiological metabolism of organs near the skin. The distribution pattern of regional SUV on the skin is important information for the differential diagnosis of such high-SUV spots. In this study, we have developed a new skin lesion detection method based on a cylindrical SUV distribution model of the skin. The shape of the SUV distribution model is an approximation of the body trunk, and the SUV distribution model includes standard values for regional skin SUV. Classifier ensembles based on CT image features, SUV features, and subtraction features between the SUVs in FDG-PET images and the values in the SUV distribution model are used to extract and classify candidate regions for skin lesions. In a study of skin lesion detection using FDG-PET/CT images in 36 clinical cases, the true-positive rate was 61.7%, with 11.7 false-positive regions per case. The training results of the classifier ensemble for extracting and classifying candidate regions showed the effective features for detecting skin lesions in the study. (author)

  7. 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

  8. Learning and memory alterations are associated with hippocampal N-acetylaspartate in a rat model of depression as measured by 1H-MRS.

    Directory of Open Access Journals (Sweden)

    Guangjun Xi

    Full Text Available It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS, to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI and magnetic resonance spectroscopy (MRS. Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

  9. 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.

  10. Hippocampal atrophy and memory dysfunction associated with physical inactivity in community-dwelling elderly subjects: The Sefuri study.

    Science.gov (United States)

    Hashimoto, Manabu; Araki, Yuko; Takashima, Yuki; Nogami, Kohjiro; Uchino, Akira; Yuzuriha, Takefumi; Yao, Hiroshi

    2017-02-01

    Physical inactivity is one of the modifiable risk factors for hippocampal atrophy and Alzheimer's disease. We investigated the relationship between physical activity, hippocampal atrophy, and memory using structural equation modeling (SEM). We examined 213 community-dwelling elderly subjects (99 men and 114 women with a mean age of 68.9 years) without dementia or clinically apparent depression. All participants underwent Mini-Mental State Examination (MMSE) and Rivermead Behavioral Memory Test (RBMT). Physical activities were assessed with a structured questionnaire. We evaluated the degree of hippocampal atrophy (z-score-referred to as ZAdvance hereafter), using a free software program-the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) based on statistical parametric mapping 8 plus Diffeomorphic Anatomical Registration Through an Exponentiated Lie algebra. Routine magnetic resonance imaging findings were as follows: silent brain infarction, n  = 24 (11.3%); deep white matter lesions, n  = 72 (33.8%); periventricular hyperintensities, n  = 35 (16.4%); and cerebral microbleeds, n  = 14 (6.6%). Path analysis based on SEM indicated that the direct paths from leisure-time activity to hippocampal atrophy (β = -.18, p  physical inactivity, and hippocampal atrophy appeared to cause memory dysfunction, although we are unable to infer a causal or temporal association between hippocampal atrophy and memory dysfunction from the present observational study.

  11. Decreased Hippocampal Neuroplasticity and Behavioral Impairment in an Animal Model of Inhalant Abuse

    Directory of Open Access Journals (Sweden)

    Hanaa Malloul

    2018-02-01

    Full Text Available Thinners are highly toxic chemicals widely employed as organic solvents in industrial and domestic use. They have psychoactive properties when inhaled, and their chronic abuse as inhalants is associated with severe long-term health effects, including brain damage and cognitive-behavioral alterations. Yet, the sites and mechanisms of action of these compounds on the brain are far from being fully understood. Here, we investigated the consequences of paint thinner inhalation in adult male mice. Depression-like behaviors and an anxiolytic effect were found following repeated exposure in chronic treatments lasting 12 weeks. Both subchronic (6 weeks and chronic treatments impaired learning and memory functions, while no changes were observed after acute treatment. To investigate possible molecular/structural alterations underlying such behavioral changes, we focused on the hippocampus. Notably, prolonged, but not acute thinner inhalation strongly affected adult neurogenesis in the dentate gyrus (DG, reducing progenitor cell proliferation after chronic treatments and impairing the survival of newborn neurons following both chronic and subchronic treatments. Furthermore, a down-regulation in the expression of BDNF and NMDA receptor subunits as well as a reduction in CREB expression/phosphorylation were found in the hippocampi of chronically treated mice. Our findings demonstrate for the first time significant structural and molecular changes in the adult hippocampus after prolonged paint thinner inhalation, indicating reduced hippocampal neuroplasticity and strongly supporting its implication in the behavioral dysfunctions associated to inhalant abuse.

  12. Dynamic causal modeling of hippocampal links within the human default mode network: Lateralization and computational stability of effective connections

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    Vadim Leonidovich Ushakov

    2016-10-01

    Full Text Available The purpose of this paper was to study causal relationships between left and right hippocampal regions (LHIP and RHIP, respectively within the default mode network (DMN as represented by its key structures: the medial prefrontal cortex (MPFC, posterior cingulate cortex (PCC and the inferior parietal cortex of left (LIPC and right (RIPC hemispheres. Furthermore, we were interested in testing the stability of the connectivity patterns when adding or deleting regions of interest. The functional magnetic resonance imaging (fMRI data from a group of 30 healthy right-handed subjects in the resting state were collected and a connectivity analysis was performed. To model the effective connectivity, we used the spectral Dynamic Causal Modeling (DCM. Three DCM analyses were completed. Two of them modeled interaction between five nodes that included four DMN key structures in addition to either LHIP or RHIP. The last DCM analysis modeled interactions between four nodes whereby one of the main DMN structures, PCC, was excluded from the analysis. The results of all DCM analyses indicated a high level of stability in the computational method: those parts of the winning models that included the key DMN structures demonstrated causal relations known from recent research. However, we discovered new results as well. First of all, we found a pronounced asymmetry in LHIP and RHIP connections. LHIP demonstrated a high involvement of DMN activity with preponderant information outflow to all other DMN regions. Causal interactions of LHIP were bidirectional only in the case of LIPC. On the contrary, RHIP was primarily affected by inputs from LIPC, RIPC and LHIP without influencing these or other DMN key structures. For the first time, an inhibitory link was found from MPFC to LIPC, which may indicate the subjects’ effort to maintain a resting state. Functional connectivity data echoed these results, though they also showed links not reflected in the patterns of

  13. A computational simulation of long-term synaptic potentiation inducing protocol processes with model of CA3 hippocampal microcircuit.

    Science.gov (United States)

    Świetlik, D; Białowąs, J; Kusiak, A; Cichońska, D

    2018-01-01

    An experimental study of computational model of the CA3 region presents cog-nitive and behavioural functions the hippocampus. The main property of the CA3 region is plastic recurrent connectivity, where the connections allow it to behave as an auto-associative memory. The computer simulations showed that CA3 model performs efficient long-term synaptic potentiation (LTP) induction and high rate of sub-millisecond coincidence detection. Average frequency of the CA3 pyramidal cells model was substantially higher in simulations with LTP induction protocol than without the LTP. The entropy of pyramidal cells with LTP seemed to be significantly higher than without LTP induction protocol (p = 0.0001). There was depression of entropy, which was caused by an increase of forgetting coefficient in pyramidal cells simulations without LTP (R = -0.88, p = 0.0008), whereas such correlation did not appear in LTP simulation (p = 0.4458). Our model of CA3 hippocampal formation microcircuit biologically inspired lets you understand neurophysiologic data. (Folia Morphol 2018; 77, 2: 210-220).

  14. [Effects of electroacupuncture on hippocampal nNOS expression in rats of post-traumatic stress disorder model].

    Science.gov (United States)

    Hou, Liang-Qin; Liu, Song; Xiong, Ke-Ren

    2013-07-01

    To explore the mechanism of electroacupuncture (EA) in the treatment of post-traumatic stress disorder (PTSD). Thirty male Sprague-Dawley rats were randomly divided into a normal group, a model group and an electroacupuncture group. The single prolonged stress (SPS) method was used to set up the PTSD models in latter two groups. After SPS Stimulation, EA group was treated with 2Hz electroacupuncture at Baihui (GV 20) and Zusanli (ST 36) for 30 min, once a day for a week. Reverse transcriptase polymerase chain reaction (RT-PCR) and immuno-histochemistry were used to detect the mRNA and protein expression of nNOS in the hippocampus of rats in the each group. (1) The nNOS mRNA expression in hippocampus in model group was higher than that in normal group (P electroacupuncture treatment, its expression in EA group was lower significantly than that in model group (P Electroacupuncture play a down-regulation effects in the hippocampal nNOS expression, which may be one mechanism of electroacupuncture for treatment of PTSD.

  15. Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome.

    Science.gov (United States)

    Stagni, Fiorenza; Giacomini, Andrea; Emili, Marco; Trazzi, Stefania; Guidi, Sandra; Sassi, Martina; Ciani, Elisabetta; Rimondini, Roberto; Bartesaghi, Renata

    2016-10-01

    Cognitive disability is an unavoidable feature of Down syndrome (DS), a genetic disorder due to the triplication of human chromosome 21. DS is associated with alterations of neurogenesis, neuron maturation and connectivity that are already present at prenatal life stages. Recent evidence shows that pharmacotherapies can have a large impact on the trisomic brain provided that they are administered perinatally. Epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, performs many actions in the brain, including inhibition of DYRK1A, a kinase that is over-expressed in the DS brain and contributes to the DS phenotype. Young adults with DS treated with EGCG exhibit some cognitive benefits, although these effects disappear with time. We deemed it extremely important, however, to establish whether treatment with EGCG at the initial stages of brain development leads to plastic changes that outlast treatment cessation. In the current study, we exploited the Ts65Dn mouse model of DS in order to establish whether pharmacotherapy with EGCG during peak of neurogenesis in the hippocampal dentate gyrus (DG) enduringly restores hippocampal development and memory performance. Euploid and Ts65Dn mice were treated with EGCG from postnatal day 3 (P3) to P15. The effects of treatment were examined at its cessation (at P15) or after one month (at P45). We found that at P15 treated trisomic pups exhibited restoration of neurogenesis, total hippocampal granule cell number and levels of pre- and postsynaptic proteins in the DG, hippocampus and neocortex. However, at P45 none of these effects were still present, nor did treated Ts65Dn mice exhibit any improvement in hippocampus-dependent tasks. These findings show that treatment with EGCG carried out in the neonatal period rescues numerous trisomy-linked brain alterations. However, even during this, the most critical time window for hippocampal development, EGCG does not elicit enduring effects on the hippocampal physiology

  16. Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: A potential model of geriatric depression

    Science.gov (United States)

    Mitschelen, Matthew; Yan, Han; Farley, Julie A.; Warrington, Junie P.; Han, Song; Hereñú, Claudia B.; Csiszar, Anna; Ungvari, Zoltan; Bailey-Downs, Lora C.; Bass, Caroline E.; Sonntag, William E.

    2011-01-01

    Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression. PMID:21524689

  17. detecting multiple sclerosis lesions with a fully bioinspired visual attention model

    Science.gov (United States)

    Villalon-Reina, Julio; Gutierrez-Carvajal, Ricardo; Thompson, Paul M.; Romero-Castro, Eduardo

    2013-11-01

    The detection, segmentation and quantification of multiple sclerosis (MS) lesions on magnetic resonance images (MRI) has been a very active field for the last two decades because of the urge to correlate these measures with the effectiveness of pharmacological treatment. A myriad of methods has been developed and most of these are non specific for the type of lesions and segment the lesions in their acute and chronic phases together. On the other hand, radiologists are able to distinguish between several stages of the disease on different types of MRI images. The main motivation of the work presented here is to computationally emulate the visual perception of the radiologist by using modeling principles of the neuronal centers along the visual system. By using this approach we are able to detect the lesions in the majority of the images in our population sample. This type of approach also allows us to study and improve the analysis of brain networks by introducing a priori information.

  18. Computational modelling and analysis of hippocampal-prefrontal information coding during a spatial decision-making task

    Directory of Open Access Journals (Sweden)

    Thomas eJahans-Price

    2014-03-01

    Full Text Available We introduce a computational model describing rat behaviour and the interactions of neural populations processing spatial and mnemonic information during a maze-based, decision-making task. The model integrates sensory input and implements a working memory to inform decisions at a choice point, reproducing rat behavioural data and predicting the occurrence of turn- and memory-dependent activity in neuronal networks supporting task performance. We tested these model predictions using a new software toolbox (Maze Query Language, MQL to analyse activity of medial prefrontal cortical (mPFC and dorsal hippocampal (dCA1 neurons recorded from 6 adult rats during task performance. The firing rates of dCA1 neurons discriminated context (i.e. the direction of the previous turn, whilst a subset of mPFC neurons was selective for current turn direction or context, with some conjunctively encoding both. mPFC turn-selective neurons displayed a ramping of activity on approach to the decision turn and turn-selectivity in mPFC was significantly reduced during error trials. These analyses complement data from neurophysiological recordings in non-human primates indicating that firing rates of cortical neurons correlate with integration of sensory evidence used to inform decision-making.

  19. Repair of model compounds of photoinduced lesions in DNA. Electrochemical approaches; Reparation de modeles de lesions photoinduites de l'ADN. Approches electrochimiques

    Energy Technology Data Exchange (ETDEWEB)

    Boussicault, F

    2006-09-15

    The goal of this work is to better understand the repair mechanism of photoinduced lesions in DNA (cyclobutane dimers and pyrimidine (6-4) pyrimidone adducts) by photolyase redox enzymes, using tools and concepts of molecular electrochemistry. Thanks to the study of model compounds of cyclobutane lesions by cyclic voltametry, we have been able to mimic the key step of the enzymatic repair (dissociative electron transfer) and to monitor the repair of model compounds by Escherichia coli DNA photolyase. From these results, we have discussed the repair mechanism, especially the stepwise or concerted character of the process. Repair mechanism of (6-4) adducts is not known now, but a possible pathway implies an electron transfer coupled to the cleavage of two bonds in the closed form of the lesions (oxetanes). Voltammetric study of reduction and oxidation of model oxetanes and their repair by E. coli DNA photolyase gave some experimental evidence confirming the proposed mechanism and allowing a better understanding of it. (author)

  20. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    Energy Technology Data Exchange (ETDEWEB)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y [University of Michigan, Ann Arbor, MI (United States)

    2014-06-15

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  1. TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

    International Nuclear Information System (INIS)

    Farjam, R; Pramanik, P; Srinivasan, A; Chapman, C; Tsien, C; Lawrence, T; Cao, Y

    2014-01-01

    Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans were performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular

  2. Rosiglitazone reverses memory decline and hippocampal glucocorticoid receptor down-regulation in an Alzheimer's disease mouse model

    International Nuclear Information System (INIS)

    Escribano, Luis; Simon, Ana-Maria; Perez-Mediavilla, Alberto; Salazar-Colocho, Pablo; Rio, Joaquin Del; Frechilla, Diana

    2009-01-01

    Clinical trials with rosiglitazone, a potent agonist at peroxisome proliferator-activated receptor gamma (PPARγ) suggest an improvement of cognitive function in Alzheimer's disease (AD) patients. The mechanisms mediating this potential beneficial effect remain to be fully elucidated. In mice overexpressing mutant human amyloid precursor protein (hAPP), a model of AD, we found that memory impairment in the object recognition test was prevented and also reversed by chronic rosiglitazone treatment. Given the possible involvement of glucocorticoid receptors (GR) in the actions of PPARγ-ligands, we studied the effect of chronic rosiglitazone treatment on GR levels in the hippocampus of hAPP mice. An early down-regulation of GR, not related to elevated plasma corticosterone levels, was found in different hippocampal subfields of the transgenic mice and this decrease was prevented by rosiglitazone. In parallel with behavioural studies, rosiglitazone also normalized GR levels in older animals. This effect may contribute to explain the attenuation of memory decline by PPARγ activation in an AD mouse model.

  3. Past, present, and future in hippocampal formation and memory research.

    Science.gov (United States)

    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.

  4. Quantification of gut lesions in a subclinical necrotic enteritis model

    DEFF Research Database (Denmark)

    Gholamiandehkordi, Ahmad R.; Timbermont, Leen; Lanckriet, Anouk

    2007-01-01

    Currently Clostridium perfringens-induced necrotic enteritis is a major problem in broiler flocks. In the present study, broilers were inoculated with a combination of Eimeria maxima or overdose coccidial vaccine (one inoculation) with C. perfringens (repeated inoculations). Single C. perfringens...... in combination with multiple oral C. perfringens inoculations is a suitable model for necrotic enteritis without inducing mortality of the animals. C. perfringens and Eimeria act synergistically in inducing grossly visible gut damage....

  5. Bio-Spectroscopic Imaging Provides Evidence of Hippocampal Zn Deficiency and Decreased Lipid Unsaturation in an Accelerated Ageing Mouse Model.

    Science.gov (United States)

    Fimognari, Nicholas; Hollings, Ashley; Lam, Virginie; Tidy, Rebecca J; Kewish, Cameron M; Albrecht, Matthew A; Takechi, Ryu; Mamo, John C L; Hackett, Mark J

    2018-06-14

    Western society is facing a health epidemic due to the increasing incidence of dementia in ageing populations, and there are still few effective diagnostic methods, minimal treatment options, and no cure. Ageing is the greatest risk factor for memory loss that occurs during the natural ageing process, as well as being the greatest risk factor for neurodegenerative disease such as Alzheimer's disease. Therefore, greater understanding of the biochemical pathways that drive a healthy ageing brain towards dementia (pathological ageing or Alzheimer's disease), is required to accelerate the development of improved diagnostics and therapies. Unfortunately, many animal models of dementia model chronic amyloid precursor protein over-expression, which although highly relevant to mechanisms of amyloidosis and familial Alzheimer's disease, does not model well dementia during the natural ageing process. A promising animal model reported to model mechanisms of accelerated natural ageing and memory impairments, is the senescence accelerated murine prone strain 8 (SAMP8), which has been adopted by many research group to study the biochemical transitions that occur during brain ageing. A limitation to traditional methods of biochemical characterisation is that many important biochemical and elemental markers (lipid saturation, lactate, transition metals) cannot be imaged at meso- or micro-spatial resolution. Therefore, in this investigation we report the first multi-modal biospectroscopic characterisation of the SAMP8 model, and have identified important biochemical and elemental alterations, and co-localisations, between 4 month old SAMP8 mice and the relevant control (SAMR1) mice. Specifically, we demonstrate direct evidence of altered metabolism and disturbed lipid homeostasis within corpus callosum white matter, in addition to localised hippocampal metal deficiencies, in the accelerated ageing phenotype. Such findings have important implication for future research aimed at

  6. Standardization of a spinal cord lesion model and neurologic evaluation using mice

    Science.gov (United States)

    Borges, Paulo Alvim; Cristante, Alexandre Fogaça; de Barros-Filho, Tarcísio Eloy Pessoa; Natalino, Renato Jose Mendonça; dos Santos, Gustavo Bispo; Marcon, Raphael Marcus

    2018-01-01

    OBJECTIVE: To standardize a spinal cord lesion mouse model. METHODS: Thirty BALB/c mice were divided into five groups: four experimental groups and one control group (sham). The experimental groups were subjected to spinal cord lesion by a weight drop from different heights after laminectomy whereas the sham group only underwent laminectomy. Mice were observed for six weeks, and functional behavior scales were applied. The mice were then euthanized, and histological investigations were performed to confirm and score spinal cord lesion. The findings were evaluated to prove whether the method of administering spinal cord lesion was effective and different among the groups. Additionally, we correlated the results of the functional scales with the results from the histology evaluations to identify which scale is more reliable. RESULTS: One mouse presented autophagia, and six mice died during the experiment. Because four of the mice that died were in Group 5, Group 5 was excluded from the study. All the functional scales assessed proved to be significantly different from each other, and mice presented functional evolution during the experiment. Spinal cord lesion was confirmed by histology, and the results showed a high correlation between the Basso, Beattie, Bresnahan Locomotor Rating Scale and the Basso Mouse Scale. The mouse function scale showed a moderate to high correlation with the histological findings, and the horizontal ladder test had a high correlation with neurologic degeneration but no correlation with the other histological parameters evaluated. CONCLUSION: This spinal cord lesion mouse model proved to be effective and reliable with exception of lesions caused by a 10-g drop from 50 mm, which resulted in unacceptable mortality. The Basso, Beattie, Bresnahan Locomotor Rating Scale and Basso Mouse Scale are the most reliable functional assessments, and but the horizontal ladder test is not recommended. PMID:29561931

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

    Directory of Open Access Journals (Sweden)

    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

  8. [Mechanistic modelling allows to assess pathways of DNA lesion interactions underlying chromosome aberration formation].

    Science.gov (United States)

    Eĭdel'man, Iu A; Slanina, S V; Sal'nikov, I V; Andreev, S G

    2012-12-01

    The knowledge of radiation-induced chromosomal aberration (CA) mechanisms is required in many fields of radiation genetics, radiation biology, biodosimetry, etc. However, these mechanisms are yet to be quantitatively characterised. One of the reasons is that the relationships between primary lesions of DNA/chromatin/chromosomes and dose-response curves for CA are unknown because the pathways of lesion interactions in an interphase nucleus are currently inaccessible for direct experimental observation. This article aims for the comparative analysis of two principally different scenarios of formation of simple and complex interchromosomal exchange aberrations: by lesion interactions at chromosome territories' surface vs. in the whole space of the nucleus. The analysis was based on quantitative mechanistic modelling of different levels of structures and processes involved in CA formation: chromosome structure in an interphase nucleus, induction, repair and interactions of DNA lesions. It was shown that the restricted diffusion of chromosomal loci, predicted by computational modelling of chromosome organization, results in lesion interactions in the whole space of the nucleus being impossible. At the same time, predicted features of subchromosomal dynamics agrees well with in vivo observations and does not contradict the mechanism of CA formation at the surface of chromosome territories. On the other hand, the "surface mechanism" of CA formation, despite having certain qualities, proved to be insufficient to explain high frequency of complex exchange aberrations observed by mFISH technique. The alternative mechanism, CA formation on nuclear centres is expected to be sufficient to explain frequent complex exchanges.

  9. Adult hippocampal neurogenesis and cognitive aging

    Directory of Open Access Journals (Sweden)

    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.

  10. A million-plus neuron model of the hippocampal dentate gyrus: Dependency of spatio-temporal network dynamics on topography.

    Science.gov (United States)

    Hendrickson, Phillip J; Yu, Gene J; Song, Dong; Berger, Theodore W

    2015-01-01

    This paper describes a million-plus granule cell compartmental model of the rat hippocampal dentate gyrus, including excitatory, perforant path input from the entorhinal cortex, and feedforward and feedback inhibitory input from dentate interneurons. The model includes experimentally determined morphological and biophysical properties of granule cells, together with glutamatergic AMPA-like EPSP and GABAergic GABAA-like IPSP synaptic excitatory and inhibitory inputs, respectively. Each granule cell was composed of approximately 200 compartments having passive and active conductances distributed throughout the somatic and dendritic regions. Modeling excitatory input from the entorhinal cortex was guided by axonal transport studies documenting the topographical organization of projections from subregions of the medial and lateral entorhinal cortex, plus other important details of the distribution of glutamatergic inputs to the dentate gyrus. Results showed that when medial and lateral entorhinal cortical neurons maintained Poisson random firing, dentate granule cells expressed, throughout the million-cell network, a robust, non-random pattern of spiking best described as spatiotemporal "clustering". To identify the network property or properties responsible for generating such firing "clusters", we progressively eliminated from the model key mechanisms such as feedforward and feedback inhibition, intrinsic membrane properties underlying rhythmic burst firing, and/or topographical organization of entorhinal afferents. Findings conclusively identified topographical organization of inputs as the key element responsible for generating a spatio-temporal distribution of clustered firing. These results uncover a functional organization of perforant path afferents to the dentate gyrus not previously recognized: topography-dependent clusters of granule cell activity as "functional units" that organize the processing of entorhinal signals.

  11. EFFECT OF FLUORIDE MOUTHRINSING ON CARIES LESION DEVELOPMENT IN SHARK ENAMEL - AN INSITU CARIES MODEL STUDY

    NARCIS (Netherlands)

    OGAARD, B; ROLLA, G; DIJKMAN, T; RUBEN, J; ARENDS, J

    1991-01-01

    Shark enamel consists of nearly pure fluorapatite and has been shown to demineralize in an in situ caries model. The present study was conducted to investigate whether additional fluoride supplementation in the form of mouthrinsing would inhibit lesion development in shark enamel. The study slabs of

  12. 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.).

  13. Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI.

    Science.gov (United States)

    Waddell, Jaylyn; Hanscom, Marie; Shalon Edwards, N; McKenna, Mary C; McCarthy, Margaret M

    2016-01-01

    Hypoxia-ischemia (HI) of the brain in near-term and term infants is a leading cause of infant mortality and lifelong disability but current therapeutic approaches remain limited. Males consistently display greater vulnerability to the deleterious consequences of HI in both humans and animal models. Neurogenesis increases after neonatal HI and offers a potential therapeutic target for recovery. The steroid hormone estradiol has been extensively explored as a neuroprotectant in adult models of stroke but with mixed results. Less consideration has been afforded to this naturally occurring agent in the developing brain, which has unique challenges from the adult. Using a model of term HI in the rat we have explored the impact of this insult on cell genesis in the hippocampus of males and females and the ability of estradiol treatment immediately after insult to restore function. Both short-term (3 days) and long-term (7 days) post-injury were assessed and revealed that only females had markedly increased cell genesis on the short-term but both sexes were increased long-term. A battery of behavioral tests revealed motor impairment in males and compromised episodic memory while both sexes were modestly impaired in spatial memory. Juvenile social play was also depressed in both sexes after HI. Estradiol therapy improved behavioral performance in both sexes but did not reverse a deficit in hippocampal volume ipsilateral to the insult. Thus the effects of estradiol do not appear to be via cell death or proliferation but rather involve other components of neural functioning. Published by Elsevier Inc.

  14. Sex differences in cell genesis, hippocampal volume and behavioral outcomes in a rat model of neonatal HI

    Science.gov (United States)

    Waddell, Jaylyn; Hanscom, Marie; Edwards, N. Shalon; McKenna, Mary C.; McCarthy, Margaret M.

    2015-01-01

    Hypoxia ischemia (HI) of the brain in near-term and term infants is a leading cause of infant mortality and lifelong disability but current therapeutic approaches remain limited. Males consistently display greater vulnerability to the deleterious consequences of HI in both humans and animal models. Neurogenesis increases after neonatal HI and offers a potential therapeutic target for recovery. The steroid hormone estradiol has been extensively explored as a neuroprotectant in adult models of stroke but with mixed results. Less consideration has been afforded to this naturally occurring agent in the developing brain, which has unique challenges from the adult. Using a model of term HI in the rat we have explored the impact of this insult on cell genesis in the hippocampus of males and females and the ability of estradiol treatment immediately after insult to restore function. Both short-term (3 days) and long-term (7 days) post-injury were assessed and revealed that only females had markedly increased cell genesis on the short-term but both sexes were increased long-term. A battery of behavioral tests revealed motor impairment in males and compromised episodic memory while both sexes were modestly impaired in spatial memory. Juvenile social play was also depressed in both sexes after HI. Estradiol therapy improved behavioral performance in both sexes but did not reverse a deficit in hippocampal volume ipsilateral to the insult. Thus the effects of estradiol do not appear to be via cell death or proliferation but rather involve other components of neural functioning. PMID:26376217

  15. The role of additive neurogenesis and synaptic plasticity in a hippocampal memory model with grid-cell like input.

    Directory of Open Access Journals (Sweden)

    Peter A Appleby

    Full Text Available Recently, we presented a study of adult neurogenesis in a simplified hippocampal memory model. The network was required to encode and decode memory patterns despite changing input statistics. We showed that additive neurogenesis was a more effective adaptation strategy compared to neuronal turnover and conventional synaptic plasticity as it allowed the network to respond to changes in the input statistics while preserving representations of earlier environments. Here we extend our model to include realistic, spatially driven input firing patterns in the form of grid cells in the entorhinal cortex. We compare network performance across a sequence of spatial environments using three distinct adaptation strategies: conventional synaptic plasticity, where the network is of fixed size but the connectivity is plastic; neuronal turnover, where the network is of fixed size but units in the network may die and be replaced; and additive neurogenesis, where the network starts out with fewer initial units but grows over time. We confirm that additive neurogenesis is a superior adaptation strategy when using realistic, spatially structured input patterns. We then show that a more biologically plausible neurogenesis rule that incorporates cell death and enhanced plasticity of new granule cells has an overall performance significantly better than any one of the three individual strategies operating alone. This adaptation rule can be tailored to maximise performance of the network when operating as either a short- or long-term memory store. We also examine the time course of adult neurogenesis over the lifetime of an animal raised under different hypothetical rearing conditions. These growth profiles have several distinct features that form a theoretical prediction that could be tested experimentally. Finally, we show that place cells can emerge and refine in a realistic manner in our model as a direct result of the sparsification performed by the dentate gyrus

  16. A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome

    Directory of Open Access Journals (Sweden)

    Sonal eGoswami

    2012-06-01

    Full Text Available Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e. that require the hippocampus or not the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze. Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma, PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.

  17. A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome.

    Science.gov (United States)

    Goswami, Sonal; Samuel, Sherin; Sierra, Olga R; Cascardi, Michele; Paré, Denis

    2012-01-01

    Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situation known to precipitate PTSD in humans. This study aimed to assess whether the hippocampus-associated deficits observed in the human syndrome are reproduced in this rodent model. Prior to predatory threat, different groups of rats were each tested on one of three object recognition memory tasks that varied in the types of contextual clues (i.e., that require the hippocampus or not) the rats could use to identify novel items. After task completion, the rats were subjected to predatory threat and, one week later, tested on the elevated plus maze (EPM). Based on their exploratory behavior in the plus maze, rats were then classified as resilient or PTSD-like and their performance on the pre-threat object recognition tasks compared. The performance of PTSD-like rats was inferior to that of resilient rats but only when subjects relied on an allocentric frame of reference to identify novel items, a process thought to be critically dependent on the hippocampus. Therefore, these results suggest that even prior to trauma PTSD-like rats show a deficit in hippocampal-dependent functions, as reported in twin studies of human PTSD.

  18. Effects of gypenosides on anxiety disorders in MPTP-lesioned mouse model of Parkinson's disease.

    Science.gov (United States)

    Shin, Keon Sung; Zhao, Ting Ting; Choi, Hyun Sook; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

    2014-06-03

    Ethanol extract (GP-EX) of Gynostemma pentaphyllum (GP) ameliorates chronic stress-induced anxiety in mice. The present study investigated the effects of gypenoside-enriched components (GPS), GP-EX and water extract of GP (GP-WX) on MPTP lesion-induced affective disorders in C57BL/6 mice. GPS (50mg/kg) and GP-EX (50mg/kg) for 21 day-treatment period improved the symptom of anxiety disorders in the MPTP-lesioned mouse model of PD with or without L-DOPA treatment, which was examined by the elevated plus-maze and marble burying tests. In these states, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) significantly increased the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. In addition, treatments with GPS (50mg/kg) and GP-EX (50mg/kg) showed protective effects on dopaminergic neurons in MPTP-lesioned mouse model of PD with or without L-DOPA treatment. In contrast, GPS (30 mg/kg) and GP-WX (50mg/kg) showed anxiolytic effects in the same animal models, but it was not significant. These results suggest that GPS (50mg/kg) and GP-EX (50mg/kg) showed anxiolytic effects on affective disorders and protective effects on dopaminergic neurons by modulating the brain levels of dopamine and serotonin in the MPTP-lesioned mouse model of PD with or without l-DOPA treatment. Clinical trials of GPS and GP-EX need to be conducted further so as to develop adjuvant therapeutic agents for PD patients. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. A Generative Probabilistic Model and Discriminative Extensions for Brain Lesion Segmentation - With Application to Tumor and Stroke

    DEFF Research Database (Denmark)

    Menze, Bjoern H.; Van Leemput, Koen; Lashkari, Danial

    2016-01-01

    jointly from the image data. It delineates lesion areas individually in each channel, allowing for differences in lesion appearance across modalities, an important feature of many brain tumor imaging sequences. We also propose discriminative model extensions to map the output of the generative model......), to estimate the label map for a new image. Our model augments the probabilistic atlas of the healthy tissues with a latent atlas of the lesion. We derive an estimation algorithm with closed-form EM update equations. The method extracts a latent atlas prior distribution and the lesion posterior distributions...

  20. Robust hippocampal responsivity during retrieval of consolidated associative memory.

    Science.gov (United States)

    Hattori, Shoai; Chen, Lillian; Weiss, Craig; Disterhoft, John F

    2015-05-01

    A contentious point in memory research is whether or not the hippocampus plays a time-limited role in the consolidation of declarative memories. A widely held view is that declarative memories are initially encoded in the hippocampus, then transferred to the neocortex for long-term storage. Alternate views argue instead that the hippocampus continues to play a role in remote memory recall. These competing theories are largely based on human amnesic and animal lesion/inactivation studies. However, in vivo electrophysiological evidence supporting these views is scarce. Given that other studies examining the role of the hippocampus in remote memory retrieval using lesion and imaging techniques in human and animal models have provided mixed results, it would be particularly useful to gain insight at the in vivo electrophysiological level. Here we report hippocampal single-neuron and theta activity recorded longitudinally during acquisition and remote retrieval of trace eyeblink conditioning. Results from conditioned rabbits were compared to those obtained from yoked pseudo-conditioned control rabbits. Results reveal continued learning-specific hippocampal activity one month after initial acquisition of the task. Our findings yield insight into the normal physiological responses of the hippocampus during memory processes and provide compelling in vivo electrophysiological evidence that the hippocampus is involved in both acquisition and retrieval of consolidated memories. © 2014 The Authors Hippocampus Published by Wiley Periodicals, Inc.

  1. The cytolethal distending toxin of Haemophilus ducreyi aggravates dermal lesions in a rabbit model of chancroid.

    Science.gov (United States)

    Wising, Catharina; Mölne, Lena; Jonsson, Ing-Marie; Ahlman, Karin; Lagergård, Teresa

    2005-05-01

    Haemophilus ducreyi, the etiologic agent of the sexually transmitted disease chancroid, produces a cytolethal distending toxin (HdCDT) that inhibits cultured cell proliferation, leading to cell death. A rabbit model of dermal infection was used to investigate the roles of H. ducreyi bacteria and HdCDT in the development, clinical appearance, and persistence of infection. A non-toxin producing H. ducreyi strain, and for comparison purposes a non-capsulated Haemophilus influenzae strain, were inoculated intradermally, with and without co-administration of purified HdCDT. Co-administration of HdCDT resulted in significant aggravation of H. ducreyi-induced inflammatory lesions, and development of ulcers in rabbit skin. Less pronounced inflammatory lesions and lack of epithelial eruption were observed after inoculation with H. influenzae. Histopathological sections of the H. ducreyi-induced lesions, in both the presence and absence of HdCDT, showed dense infiltrates of the same type inflammatory cells, with the exception of a prominent endothelial cell proliferation noted in sections from lesions caused by H. ducreyi and toxin. Signs of chronic inflammation with involvement of T cells, macrophages, eosinophils, and granuloma formation were observed after H. ducreyi inoculation both with and without toxin. In conclusion, H. ducreyi causes a pronounced, chronic inflammation with involvement of T cells and macrophages, and in combination with HdCDT production of ulcers in the rabbit model. These pathogenic mechanisms may promote the development and persistence of chancroid ulcers.

  2. Detection of oral early cancerous lesion by using polarization-sensitive optical coherence tomography: mice model

    Science.gov (United States)

    Lee, Hong-Yi; Chen, Ping-Hsien; Lee, Tzu-Han; Chang, Kuo-Wei; Kuo, Wen-Chuan

    2018-02-01

    Oral cancer is the 11th most common cancer worldwide, especially in a male adult. The median age of death in oral cancer was 55 years, 10-20 years earlier than other cancers. Presently, oral cancer is often found in late stage, because the lesion is often flat in early stage and is difficult to diagnose under traditional white light imaging. The only definitive method for determining cancer is an invasive biopsy and then using histology examination. How to detect precancerous lesions or early malignant lesions is an important issue for improving prognosis of oral cancer. Optical coherence tomography (OCT) is a new optical tool for diagnosing early malignant lesions in the skin or gastrointestinal tract recently. Here we report a new method for detecting precancerous or early malignant oral lesions by using swept source polarization-sensitive optical coherence tomography (PS-OCT) with center-wavelength 1310 nm, bandwidth 110 nm and 100 kHz swept rate. We used all single-mode fiber design to detect the change of birefringence information in the epithelium structure. This system has an advantage that enables measurement of backscattered intensity and birefringence simultaneously with only one A-scan per transverse location. In preliminary result, we computed the slope of the every A-scan signal in tissue part using a linear-curve fitting in backscattered intensity and birefringence on the enface. In this research, we used an oral cancer mice model for observing the change of structure and birefringence properties in different stages of oral cancer mice. We presented the parametric enface imaging that can detect the early oral malignant lesions.

  3. Application of radiosurgical techniques to produce a primate model of brain lesions

    Directory of Open Access Journals (Sweden)

    Jun eKunimatsu

    2015-04-01

    Full Text Available Behavioral analysis of subjects with discrete brain lesions provides important information about the mechanisms of various brain functions. However, it is generally difficult to experimentally produce discrete lesions in deep brain structures. Here we show that a radiosurgical technique, which is used as an alternative treatment for brain tumors and vascular malformations, is applicable to create non-invasive lesions in experimental animals for the research in systems neuroscience. We delivered highly focused radiation (130–150 Gy at ISO center to the frontal eye field of macaque monkeys using a clinical linear accelerator (LINAC. The effects of irradiation were assessed by analyzing oculomotor performance along with magnetic resonance (MR images before and up to 8 months following irradiation. In parallel with tissue edema indicated by MR images, deficits in saccadic and smooth pursuit eye movements were observed during several days following irradiation. Although initial signs of oculomotor deficits disappeared within a month, damage to the tissue and impaired eye movements gradually developed during the course of the subsequent 6 months. Postmortem histological examinations showed necrosis and hemorrhages within a large area of the white matter and, to a lesser extent, in the adjacent gray matter, which was centered at the irradiated target. These results indicated that the LINAC system was useful for making brain lesions in experimental animals, while the suitable radiation parameters to generate more focused lesions need to be further explored. We propose the use of a radiosurgical technique for establishing animal models of brain lesions, and discuss the possible uses of this technique for functional neurosurgical treatments in humans.

  4. The Stress Model of Chronic Pain: Evidence from Basal Cortisol and Hippocampal Structure and Function in Humans

    Science.gov (United States)

    Vachon-Presseau, Etienne; Roy, Mathieu; Martel, Marc-Olivier; Caron, Etienne; Marin, Marie-France; Chen, Jeni; Albouy, Genevieve; Plante, Isabelle; Sullivan, Michael J.; Lupien, Sonia J.; Rainville, Pierre

    2013-01-01

    Recent theories have suggested that chronic pain could be partly maintained by maladaptive physiological responses of the organism facing a recurrent stressor. The present study examined the associations between basal levels of cortisol collected over seven consecutive days, the hippocampal volumes and brain activation to thermal stimulations…

  5. Effect of sevoflurane on the ATPase activity of hippocampal neurons in a rat model of cerebral ischemia-reperfusion injury via the cAMP-PKA signaling pathway.

    Science.gov (United States)

    Liu, Tie-Jun; Zhang, Jin-Cun; Gao, Xiao-Zeng; Tan, Zhi-Bin; Wang, Jian-Jun; Zhang, Pan-Pan; Cheng, Ai-Bin; Zhang, Shu-Bo

    2018-01-01

    We aim to investigate the effects of sevoflurane on the ATPase activity of the hippocampal neurons in rats with cerebral ischemia-reperfusion injury (IRI) via the cyclic adenosine monophosphate (cAMP) and protein kinase A (PKA) signaling pathway. Sixty rats were assigned into the normal, model and sevoflurane groups (n = 20, the latter two groups were established as focal cerebral IRI models). The ATPase activity was detected using an ultramicro Na (+)-K (+)-ATP enzyme kit. Immunohistochemical staining was used to detect the positive protein expression of cAMP and PKA. The hippocampal neurons were assigned to the normal, IRI, IRI + sevoflurane, IRI + forskolin, IRI + H89 and IRI + sevoflurane + H89 groups. qRT-PCR and Western blotting were performed for the expressions of cAMP, PKA, cAMP-responsive element-binding protein (CREB) and brain derived neurotrophic factor (BDNF). The normal and sevoflurane groups exhibited a greater positive protein expression of cAMP and PKA than the model group. Compared with the normal group, the expressions of cAMP, PKA, CREB and BDNF all reduced in the IRI, model and IRI + H89 groups. The sevoflurane group showed higher cAMP, PKA, CREB and BDNF expressions than the model group. Compared with the IRI group, ATPase activity and expressions of cAMP, PKA, CREB and BDNF all increased in the normal, IRI + sevoflurane and IRI + forskolin groups but decreased in the IRI + H89 group. It suggests that sevoflurane could enhance ATPase activity in hippocampal neurons of cerebral IRI rats through activating cAMP-PKA signaling pathway. Copyright © 2017. Published by Elsevier Taiwan.

  6. A biophysical model of endocannabinoid-mediated short term depression in hippocampal inhibition.

    Directory of Open Access Journals (Sweden)

    Margarita Zachariou

    Full Text Available Memories are believed to be represented in the synaptic pathways of vastly interconnected networks of neurons. The plasticity of synapses, that is, their strengthening and weakening depending on neuronal activity, is believed to be the basis of learning and establishing memories. An increasing number of studies indicate that endocannabinoids have a widespread action on brain function through modulation of synaptic transmission and plasticity. Recent experimental studies have characterised the role of endocannabinoids in mediating both short- and long-term synaptic plasticity in various brain regions including the hippocampus, a brain region strongly associated with cognitive functions, such as learning and memory. Here, we present a biophysically plausible model of cannabinoid retrograde signalling at the synaptic level and investigate how this signalling mediates depolarisation induced suppression of inhibition (DSI, a prominent form of short-term synaptic depression in inhibitory transmission in hippocampus. The model successfully captures many of the key characteristics of DSI in the hippocampus, as observed experimentally, with a minimal yet sufficient mathematical description of the major signalling molecules and cascades involved. More specifically, this model serves as a framework to test hypotheses on the factors determining the variability of DSI and investigate under which conditions it can be evoked. The model reveals the frequency and duration bands in which the post-synaptic cell can be sufficiently stimulated to elicit DSI. Moreover, the model provides key insights on how the state of the inhibitory cell modulates DSI according to its firing rate and relative timing to the post-synaptic activation. Thus, it provides concrete suggestions to further investigate experimentally how DSI modulates and is modulated by neuronal activity in the brain. Importantly, this model serves as a stepping stone for future deciphering of the role of

  7. 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.

  8. Escitalopram reduces increased hippocampal cytogenesis in a genetic rat depression model

    DEFF Research Database (Denmark)

    Petersén, Asa; Wörtwein, Gitta; Gruber, Susanne H M

    2008-01-01

    to stressors, but, so far, not in models of depression. Here we report that the number of BrdU positive cells in hippocampus was (1) significantly higher in a rat model of depression, the Flinders Sensitive Line (FSL) compared to control FRL, (2) increased in both FSL and FRL following maternal separation, (3......) reduced by escitalopram treatment in maternally separated animals to the level found in non-separated animals. These results argue against the prevailing hypothesis that adult cytogenesis is reduced in depression and that the common mechanism underlying antidepressant treatments is to increase adult...

  9. Incorporating Parameter Uncertainty in Bayesian Segmentation Models: Application to Hippocampal Subfield Volumetry

    DEFF Research Database (Denmark)

    Iglesias, J. E.; Sabuncu, M. R.; Van Leemput, Koen

    2012-01-01

    Many successful segmentation algorithms are based on Bayesian models in which prior anatomical knowledge is combined with the available image information. However, these methods typically have many free parameters that are estimated to obtain point estimates only, whereas a faithful Bayesian anal...

  10. A Communication Theoretical Modeling of Axonal Propagation in Hippocampal Pyramidal Neurons.

    Science.gov (United States)

    Ramezani, Hamideh; Akan, Ozgur B

    2017-06-01

    Understanding the fundamentals of communication among neurons, known as neuro-spike communication, leads to reach bio-inspired nanoscale communication paradigms. In this paper, we focus on a part of neuro-spike communication, known as axonal transmission, and propose a realistic model for it. The shape of the spike during axonal transmission varies according to previously applied stimulations to the neuron, and these variations affect the amount of information communicated between neurons. Hence, to reach an accurate model for neuro-spike communication, the memory of axon and its effect on the axonal transmission should be considered, which are not studied in the existing literature. In this paper, we extract the important factors on the memory of axon and define memory states based on these factors. We also describe the transition among these states and the properties of axonal transmission in each of them. Finally, we demonstrate that the proposed model can follow changes in the axonal functionality properly by simulating the proposed model and reporting the root mean square error between simulation results and experimental data.

  11. A Model of Amygdala-Hippocampal-Prefrontal Interaction in Fear Conditioning and Extinction in Animals

    Science.gov (United States)

    Moustafa, Ahmed A.; Gilbertson, Mark W.; Orr, Scott P.; Herzallah, Mohammad M.; Servatius, Richard J.; Myers, Catherine E.

    2013-01-01

    Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus…

  12. A model to environmental monitoring based on glutathione-S-transferase activity and branchial lesions in catfish

    Science.gov (United States)

    Neta, Raimunda Nonata Fortes Carvalho; Torres, Audalio Rebelo

    2017-11-01

    In this work, we validate the glutathione-S-transferase and branchial lesions as biomarkers in catfish Sciades herzbergii to obtain a predictive model of the environmental impact effects in a harbor of Brazil. The catfish were sampled from a port known to be contaminated with heavy metals and organic compounds and from a natural reserve in São Marcos Bay, Maranhão. Two biomarkers, hepatic glutathione S-transferase (GST) activity and branchial lesions were analyzed. The values for GST activity were modeled with the occurrence of branchial lesions by fitting a third order polynomial. Results from the mathematical model indicate that GST activity has a strong polynomial relationship with the occurrence of branchial lesions in both the wet and the dry seasons, but only at the polluted port site. Our mathematic model indicates that when the GST ceases to act, serious branchial lesions are observed in the catfish of the contaminated port area.

  13. Local Inflammation, Dissemination and Coalescence of Lesions Are Key for the Progression toward Active Tuberculosis: The Bubble Model.

    Science.gov (United States)

    Prats, Clara; Vilaplana, Cristina; Valls, Joaquim; Marzo, Elena; Cardona, Pere-Joan; López, Daniel

    2016-01-01

    The evolution of a tuberculosis (TB) infection toward active disease is driven by a combination of factors mostly related to the host response. The equilibrium between control of the bacillary load and the pathology generated is crucial as regards preventing the growth and proliferation of TB lesions. In addition, some experimental evidence suggests an important role of both local endogenous reinfection and the coalescence of neighboring lesions. Herein we propose a mathematical model that captures the essence of these factors by defining three hypotheses: (i) lesions grow logistically due to the inflammatory reaction; (ii) new lesions can appear as a result of extracellular bacilli or infected macrophages that escape from older lesions; and (iii) lesions can merge when they are close enough. This model was implemented in Matlab to simulate the dynamics of several lesions in a 3D space. It was also fitted to available microscopy data from infected C3HeB/FeJ mice, an animal model of active TB that reacts against Mycobacterium tuberculosis with an exaggerated inflammatory response. The results of the simulations show the dynamics observed experimentally, namely an initial increase in the number of lesions followed by fluctuations, and an exponential increase in the mean area of the lesions. In addition, further analysis of experimental and simulation results show a strong coincidence of the area distributions of lesions at day 21, thereby highlighting the consistency of the model. Three simulation series removing each one of the hypothesis corroborate their essential role in the dynamics observed. These results demonstrate that three local factors, namely an exaggerated inflammatory response, an endogenous reinfection, and a coalescence of lesions, are needed in order to progress toward active TB. The failure of one of these factors stops induction of the disease. This mathematical model may be used as a basis for developing strategies to stop the progression of

  14. Local inflammation, dissemination and coalescence of lesions are key for the progression towards active tuberculosis: the bubble model

    Directory of Open Access Journals (Sweden)

    Clara ePrats

    2016-02-01

    Full Text Available The evolution of a tuberculosis (TB infection towards active disease is driven by a combination of factors mostly related to the host response. The equilibrium between control of the bacillary load and the pathology generated is crucial as regards preventing the growth and proliferation of TB lesions. In addition, some experimental evidence suggests an important role of both local endogenous reinfection and the coalescence of neighboring lesions.Herein we propose a mathematical model that captures the essence of these factors by defining three hypotheses: (i lesions grow logistically due to the inflammatory reaction; (ii new lesions can appear as a result of extracellular bacilli or infected macrophages that escape from older lesions; and (iii lesions can merge when they are close enough. This model was implemented in Matlab to simulate the dynamics of several lesions in a 3D space. It was also fitted to available microscopy data from infected C3HeB/FeJ mice, an animal model of active TB that reacts against Mycobacterium tuberculosis with an exaggerated inflammatory response.The results of the simulations show the dynamics observed experimentally, namely an initial increase in the number of lesions followed by oscillations, and an exponential increase in the mean area of the lesions. In addition, further analysis of experimental and simulation results show a strong coincidence of the area distributions of lesions at day 21, thereby highlighting the consistency of the model. Three simulation series removing each one of the hypothesis corroborate their essential role in the dynamics observed.These results demonstrate that three local factors, namely an exaggerated inflammatory response, an endogenous reinfection and a coalescence of lesions, are needed in order to progress towards active TB. The failure of one of these factors stops induction of the disease. This mathematical model may be used as a basis for developing strategies to stop the

  15. Repair of model compounds of photoinduced lesions in DNA. Electrochemical approaches

    International Nuclear Information System (INIS)

    Boussicault, F.

    2006-09-01

    The goal of this work is to better understand the repair mechanism of photoinduced lesions in DNA (cyclobutane dimers and pyrimidine (6-4) pyrimidone adducts) by photolyase redox enzymes, using tools and concepts of molecular electrochemistry. Thanks to the study of model compounds of cyclobutane lesions by cyclic voltametry, we have been able to mimic the key step of the enzymatic repair (dissociative electron transfer) and to monitor the repair of model compounds by Escherichia coli DNA photolyase. From these results, we have discussed the repair mechanism, especially the stepwise or concerted character of the process. Repair mechanism of (6-4) adducts is not known now, but a possible pathway implies an electron transfer coupled to the cleavage of two bonds in the closed form of the lesions (oxetanes). Voltammetric study of reduction and oxidation of model oxetanes and their repair by E. coli DNA photolyase gave some experimental evidence confirming the proposed mechanism and allowing a better understanding of it. (author)

  16. Nortriptyline mediates behavioral effects without affecting hippocampal cytogenesis in a genetic rat depression model

    DEFF Research Database (Denmark)

    Petersén, Asa; Wörtwein, Gitta; Gruber, Susanne H M

    2009-01-01

    A prevailing hypothesis is that neurogenesis is reduced in depression and that the common mechanism for antidepressant treatments is to increase it in adult hippocampus. Reduced neurogenesis has been shown in healthy rats exposed to stress, but it has not yet been demonstrated in depressed patients....... These results strengthen the arguments against hypothesis of neurogenesis being necessary in etiology of depression and as requisite for effects of antidepressants, and illustrate the importance of using a disease model and not healthy animals to assess effects of potential therapies for major depressive...

  17. Evaluation of the chemical model of vestibular lesions induced by arsanilate in rats

    International Nuclear Information System (INIS)

    Vignaux, G.; Chabbert, C.; Gaboyard-Niay, S.; Travo, C.; Machado, M.L.; Denise, P.; Comoz, F.; Hitier, M.; Landemore, G.; Philoxène, B.; Besnard, S.

    2012-01-01

    Several animal models of vestibular deficits that mimic the human pathology phenotype have previously been developed to correlate the degree of vestibular injury to cognate vestibular deficits in a time-dependent manner. Sodium arsanilate is one of the most commonly used substances for chemical vestibular lesioning, but it is not well described in the literature. In the present study, we used histological and functional approaches to conduct a detailed exploration of the model of vestibular lesions induced by transtympanic injection of sodium arsanilate in rats. The arsanilate-induced damage was restricted to the vestibular sensory organs without affecting the external ear, the oropharynx, or Scarpa's ganglion. This finding strongly supports the absence of diffusion of arsanilate into the external ear or Eustachian tubes, or through the eighth cranial nerve sheath leading to the brainstem. One of the striking observations of the present study is the complete restructuring of the sensory epithelia into a non sensory epithelial monolayer observed at 3 months after arsanilate application. This atrophy resembles the monolayer epithelia observed postmortem in the vestibular epithelia of patients with a history of lesioned vestibular deficits such as labyrinthectomy, antibiotic treatment, vestibular neuritis, or Ménière's disease. In cases of Ménière's disease, aminoglycosides, and platinum-based chemotherapy, vestibular hair cells are destroyed, regardless of the physiopathological process, as reproduced with the arsanilate model of vestibular lesion. These observations, together with those presented in this study of arsanilate vestibular toxicity, suggest that this atrophy process relies on a common mechanism of degeneration of the sensory epithelia.

  18. Evaluation of the chemical model of vestibular lesions induced by arsanilate in rats

    Energy Technology Data Exchange (ETDEWEB)

    Vignaux, G. [INSERM, ERI27, Caen, F-14000 (France); Univ Caen, Caen, F-14000 (France); Chabbert, C.; Gaboyard-Niay, S.; Travo, C. [INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, F-34090,France (France); Machado, M.L. [INSERM, ERI27, Caen, F-14000 (France); Univ Caen, Caen, F-14000 (France); Denise, P. [INSERM, ERI27, Caen, F-14000 (France); Univ Caen, Caen, F-14000 (France); CHRU Caen, Explorations Fonctionnelles, Caen, F-14000 (France); Comoz, F. [CHRU Caen, Laboratoire d' anatomopathologie, Caen, F-14000 (France); Hitier, M. [CHRU Caen, Service d' Otorhinolaryngologie, Caen, F-14000,France (France); Landemore, G. [CHRU Caen, Laboratoire d' anatomopathologie, Caen, F-14000 (France); Philoxène, B. [INSERM, ERI27, Caen, F-14000 (France); Univ Caen, Caen, F-14000 (France); CHRU Caen, Explorations Fonctionnelles, Caen, F-14000 (France); Besnard, S., E-mail: besnard-s@phycog.org [INSERM, ERI27, Caen, F-14000 (France); Univ Caen, Caen, F-14000 (France); CHRU Caen, Explorations Fonctionnelles, Caen, F-14000 (France)

    2012-01-01

    Several animal models of vestibular deficits that mimic the human pathology phenotype have previously been developed to correlate the degree of vestibular injury to cognate vestibular deficits in a time-dependent manner. Sodium arsanilate is one of the most commonly used substances for chemical vestibular lesioning, but it is not well described in the literature. In the present study, we used histological and functional approaches to conduct a detailed exploration of the model of vestibular lesions induced by transtympanic injection of sodium arsanilate in rats. The arsanilate-induced damage was restricted to the vestibular sensory organs without affecting the external ear, the oropharynx, or Scarpa's ganglion. This finding strongly supports the absence of diffusion of arsanilate into the external ear or Eustachian tubes, or through the eighth cranial nerve sheath leading to the brainstem. One of the striking observations of the present study is the complete restructuring of the sensory epithelia into a non sensory epithelial monolayer observed at 3 months after arsanilate application. This atrophy resembles the monolayer epithelia observed postmortem in the vestibular epithelia of patients with a history of lesioned vestibular deficits such as labyrinthectomy, antibiotic treatment, vestibular neuritis, or Ménière's disease. In cases of Ménière's disease, aminoglycosides, and platinum-based chemotherapy, vestibular hair cells are destroyed, regardless of the physiopathological process, as reproduced with the arsanilate model of vestibular lesion. These observations, together with those presented in this study of arsanilate vestibular toxicity, suggest that this atrophy process relies on a common mechanism of degeneration of the sensory epithelia.

  19. Thinking After Drinking: Impaired Hippocampal Dependent Cognition in Human Alcoholics and Animal Models of Alcohol Dependence

    Directory of Open Access Journals (Sweden)

    Miranda Staples

    2016-09-01

    Full Text Available Alcohol use disorder currently affects approximately 18 million Americans, with at least half of these individuals having significant cognitive impairments subsequent to their chronic alcohol use. This is most widely apparent as frontal cortex dependent cognitive dysfunction, where executive function and decision making are severely compromised, as well as hippocampus dependent cognitive dysfunction, where contextual and temporal reasoning are negatively impacted. This review discusses the relevant clinical literature to support the theory that cognitive recovery in tasks dependent on the prefrontal cortex and hippocampus is temporally different across extended periods of abstinence from alcohol. Additional studies from preclinical models are discussed to support clinical findings. Finally, the unique cellular composition of the hippocampus and cognitive impairment dependent on the hippocampus is highlighted in the context of alcohol dependence.

  20. Hippocampal transcriptomic and proteomic alterations in the BTBR mouse model of autism spectrum disorder

    Directory of Open Access Journals (Sweden)

    Caitlin M Daimon

    2015-11-01

    Full Text Available Autism spectrum disorders (ASD are complex heterogeneous neurodevelopmental disorders of an unclear etiology, and no cure currently exists. Prior studies have demonstrated that the black and tan, brachyury (BTBR T+ Itpr3tf/J mouse strain displays a behavioral phenotype with ASD-like features. BTBR T+ Itpr3tf/J mice (referred to simply as BTBR display deficits in social functioning, lack of communication ability, and engagement in stereotyped behavior. Despite extensive behavioral phenotypic characterization, little is known about the genes and proteins responsible for the presentation of the ASD-like phenotype in the BTBR mouse model. In this study, we employed bioinformatics techniques to gain a wide-scale understanding of the transcriptomic and proteomic changes associated with the ASD-like phenotype in BTBR mice. We found a number of genes and proteins to be significantly altered in BTBR mice compared to C57BL/6J (B6 control mice controls such as BDNF, Shank3, and ERK1, which are highly relevant to prior investigations of ASD. Furthermore, we identified distinct functional pathways altered in BTBR mice compared to B6 controls that have been previously shown to be altered in both mouse models of ASD, some human clinical populations, and have been suggested as a possible etiological mechanism of ASD, including axon guidance and regulation of actin cytoskeleton. In addition, our wide-scale bioinformatics approach also discovered several previously unidentified genes and proteins associated with the ASD phenotype in BTBR mice, such as Caskin1, suggesting that bioinformatics could be an avenue by which novel therapeutic targets for ASD are uncovered. As a result, we believe that informed use of synergistic bioinformatics applications represents an invaluable tool for elucidating the etiology of complex disorders like ASD.

  1. An Improved Mouse Model of Atopic Dermatitis and Suppression of Skin Lesions by an Inhibitor of Tec Family Kinases

    Directory of Open Access Journals (Sweden)

    Yuko Kawakami

    2007-01-01

    Conclusions: We established a highly efficient, highly reproducible protocol to induce skin lesions in NC/Nga mice and successfully applied it to show the efficacy of terreic acid in treating skin lesions. This mouse model of atopic dermatitis will be useful to study the pathogenetic processes of atopic dermatitis and to evaluate the efficacy of drug candidates.

  2. Repeated lysergic acid diethylamide in an animal model of depression: Normalisation of learning behaviour and hippocampal serotonin 5-HT2 signalling.

    Science.gov (United States)

    Buchborn, Tobias; Schröder, Helmut; Höllt, Volker; Grecksch, Gisela

    2014-06-01

    A re-balance of postsynaptic serotonin (5-HT) receptor signalling, with an increase in 5-HT1A and a decrease in 5-HT2A signalling, is a final common pathway multiple antidepressants share. Given that the 5-HT1A/2A agonist lysergic acid diethylamide (LSD), when repeatedly applied, selectively downregulates 5-HT2A, but not 5-HT1A receptors, one might expect LSD to similarly re-balance the postsynaptic 5-HT signalling. Challenging this idea, we use an animal model of depression specifically responding to repeated antidepressant treatment (olfactory bulbectomy), and test the antidepressant-like properties of repeated LSD treatment (0.13 mg/kg/d, 11 d). In line with former findings, we observe that bulbectomised rats show marked deficits in active avoidance learning. These deficits, similarly as we earlier noted with imipramine, are largely reversed by repeated LSD administration. Additionally, bulbectomised rats exhibit distinct anomalies of monoamine receptor signalling in hippocampus and/or frontal cortex; from these, only the hippocampal decrease in 5-HT2 related [(35)S]-GTP-gamma-S binding is normalised by LSD. Importantly, the sham-operated rats do not profit from LSD, and exhibit reduced hippocampal 5-HT2 signalling. As behavioural deficits after bulbectomy respond to agents classified as antidepressants only, we conclude that the effect of LSD in this model can be considered antidepressant-like, and discuss it in terms of a re-balance of hippocampal 5-HT2/5-HT1A signalling. © The Author(s) 2014.

  3. Temporal and Spatial Characterization of Gait Pattern in Rodents as an Animal model of Cerebrovascular Lesion

    Directory of Open Access Journals (Sweden)

    Jaison D Cucarián

    2017-09-01

    Full Text Available Animal experimentation is crucial for the advance in the understanding of pathophysiological mechanisms and their application on both clinical diagnosis and neuro-rehabilitation. Particularly, rodent brain lesion is commonly used in the modeling of locomotor, somatosensory and cognitive symptoms. The automated rodent gait analysis has been proposed as a tool for studying locomotor and sensory abilities and its use includes the identification of functional alterations, structural adaptations as well as neuro-rehabilitation mechanisms. From that standpoint, the effectiveness of many therapeutic intervention (i.e. physical exercises has been documented in rodents and humans. The translation from experimental data to clinical conditions requires the continuous collaboration and feedback between researchers and health clinicians looking for the selection of the best rehabilitation protocols obtained from animal research. Here we will show some locomotor alterations, the traditional methods used to assess motor dysfunction and gait abnormalities in rodent models with stroke. The aim of this review is to show some motor deficiencies and some methods used to establish gait disturbances in rodents with cerebrovascular lesion. The review included the search of defined terms (MeSH in PychINFO, Medline and Web of Science, between January 2000 and January 2017. Qualitative and narrative reports, dissertations, end course works and conference resumes were discarded. The review focuses on some clinical signs, their effects on rodent locomotor activity, some methodologies used to create lesion and to study motor function, some assessment methods and some translational aspects.

  4. Detection of questionable occlusal carious lesions using an electrical bioimpedance method with fractional electrical model

    Energy Technology Data Exchange (ETDEWEB)

    Morais, A. P. [Biomedical Engineering Program, COPPE, Rio de Janeiro (Brazil); Salgado de Oliveira University, Marechal Deodoro Street, 217 – Centro, Niterói, Rio de Janeiro (Brazil); Pino, A. V. [Biomedical Engineering Program, COPPE, Rio de Janeiro (Brazil); Souza, M. N. [Biomedical Engineering Program, COPPE, Rio de Janeiro (Brazil); Electronics Department at Polytechnic School, Federal University of Rio de Janeiro, Centro de Tecnologia Bloco H sala 217, Ilha do Fundão, Rio de Janeiro (Brazil)

    2016-08-15

    This in vitro study evaluated the diagnostic performance of an alternative electric bioimpedance spectroscopy technique (BIS-STEP) detect questionable occlusal carious lesions. Six specialists carried out the visual (V), radiography (R), and combined (VR) exams of 57 sound or non-cavitated occlusal carious lesion teeth classifying the occlusal surfaces in sound surface (H), enamel caries (EC), and dentinal caries (DC). Measurements were based on the current response to a step voltage excitation (BIS-STEP). A fractional electrical model was used to predict the current response in the time domain and to estimate the model parameters: Rs and Rp (resistive parameters), and C and α (fractional parameters). Histological analysis showed caries prevalence of 33.3% being 15.8% hidden caries. Combined examination obtained the best traditional diagnostic results with specificity = 59.0%, sensitivity = 70.9%, and accuracy = 60.8%. There were statistically significant differences in bioimpedance parameters between the H and EC groups (p = 0.016) and between the H and DC groups (Rs, p = 0.006; Rp, p = 0.022, and α, p = 0.041). Using a suitable threshold for the Rs, we obtained specificity = 60.7%, sensitivity = 77.9%, accuracy = 73.2%, and 100% of detection for deep lesions. It can be concluded that BIS-STEP method could be an important tool to improve the detection and management of occlusal non-cavitated primary caries and pigmented sites.

  5. Detection of questionable occlusal carious lesions using an electrical bioimpedance method with fractional electrical model

    International Nuclear Information System (INIS)

    Morais, A. P.; Pino, A. V.; Souza, M. N.

    2016-01-01

    This in vitro study evaluated the diagnostic performance of an alternative electric bioimpedance spectroscopy technique (BIS-STEP) detect questionable occlusal carious lesions. Six specialists carried out the visual (V), radiography (R), and combined (VR) exams of 57 sound or non-cavitated occlusal carious lesion teeth classifying the occlusal surfaces in sound surface (H), enamel caries (EC), and dentinal caries (DC). Measurements were based on the current response to a step voltage excitation (BIS-STEP). A fractional electrical model was used to predict the current response in the time domain and to estimate the model parameters: Rs and Rp (resistive parameters), and C and α (fractional parameters). Histological analysis showed caries prevalence of 33.3% being 15.8% hidden caries. Combined examination obtained the best traditional diagnostic results with specificity = 59.0%, sensitivity = 70.9%, and accuracy = 60.8%. There were statistically significant differences in bioimpedance parameters between the H and EC groups (p = 0.016) and between the H and DC groups (Rs, p = 0.006; Rp, p = 0.022, and α, p = 0.041). Using a suitable threshold for the Rs, we obtained specificity = 60.7%, sensitivity = 77.9%, accuracy = 73.2%, and 100% of detection for deep lesions. It can be concluded that BIS-STEP method could be an important tool to improve the detection and management of occlusal non-cavitated primary caries and pigmented sites.

  6. Early maternal alcohol consumption alters hippocampal DNA methylation, gene expression and volume in a mouse model.

    Directory of Open Access Journals (Sweden)

    Heidi Marjonen

    Full Text Available The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v ethanol for the first 8 days of gestation (GD 0.5-8.5. Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60: we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in

  7. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome.

    Science.gov (United States)

    Dinel, Anne-Laure; André, Caroline; Aubert, Agnès; Ferreira, Guillaume; Layé, Sophie; Castanon, Nathalie

    2011-01-01

    Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS). However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus) of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device), but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task), but unaltered object recognition memory (hippocampus-independent task). In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6) and reduced expression of brain-derived neurotrophic factor (BDNF) in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

  8. Cognitive and emotional alterations are related to hippocampal inflammation in a mouse model of metabolic syndrome.

    Directory of Open Access Journals (Sweden)

    Anne-Laure Dinel

    Full Text Available Converging clinical data suggest that peripheral inflammation is likely involved in the pathogenesis of the neuropsychiatric symptoms associated with metabolic syndrome (MetS. However, the question arises as to whether the increased prevalence of behavioral alterations in MetS is also associated with central inflammation, i.e. cytokine activation, in brain areas particularly involved in controlling behavior. To answer this question, we measured in a mouse model of MetS, namely the diabetic and obese db/db mice, and in their healthy db/+ littermates emotional behaviors and memory performances, as well as plasma levels and brain expression (hippocampus; hypothalamus of inflammatory cytokines. Our results shows that db/db mice displayed increased anxiety-like behaviors in the open-field and the elevated plus-maze (i.e. reduced percent of time spent in anxiogenic areas of each device, but not depressive-like behaviors as assessed by immobility time in the forced swim and tail suspension tests. Moreover, db/db mice displayed impaired spatial recognition memory (hippocampus-dependent task, but unaltered object recognition memory (hippocampus-independent task. In agreement with the well-established role of the hippocampus in anxiety-like behavior and spatial memory, behavioral alterations of db/db mice were associated with increased inflammatory cytokines (interleukin-1β, tumor necrosis factor-α and interleukin-6 and reduced expression of brain-derived neurotrophic factor (BDNF in the hippocampus but not the hypothalamus. These results strongly point to interactions between cytokines and central processes involving the hippocampus as important contributing factor to the behavioral alterations of db/db mice. These findings may prove valuable for introducing novel approaches to treat neuropsychiatric complications associated with MetS.

  9. Network models predict that reduced excitatory fluctuations can give rise to hippocampal network hyper-excitability in MeCP2-null mice.

    Directory of Open Access Journals (Sweden)

    Ernest C Y Ho

    Full Text Available Rett syndrome is a severe pediatric neurological disorder caused by loss of function mutations within the gene encoding methyl CpG-binding protein 2 (MeCP2. Although MeCP2 is expressed near ubiquitously, the primary pathophysiology of Rett syndrome stems from impairments of nervous system function. One alteration within different regions of the MeCP2-deficient brain is the presence of hyper-excitable network responses. In the hippocampus, such responses exist despite there being an overall decrease in spontaneous excitatory drive within the network. In this study, we generated and used mathematical, neuronal network models to resolve this apparent paradox. We did this by taking advantage of previous mathematical modelling insights that indicated that decreased excitatory fluctuations, but not mean excitatory drive, more critically explain observed changes in hippocampal network oscillations from MeCP2-null mouse slices. Importantly, reduced excitatory fluctuations could also bring about hyper-excitable responses in our network models. Therefore, these results indicate that diminished excitatory fluctuations may be responsible for the hyper-excitable state of MeCP2-deficient hippocampal circuitry.

  10. Comparison of volumetric modulated arc therapy and intensity modulated radiation therapy for whole brain hippocampal sparing treatment plans based on radiobiological modeling

    Directory of Open Access Journals (Sweden)

    Ethan Kendall

    2018-01-01

    Full Text Available Introduction: In this article, we report the results of our investigation on comparison of radiobiological aspects of treatment plans with linear accelerator-based intensity-modulated radiation therapy and volumetric-modulated arc therapy for patients having hippocampal avoidance whole-brain radiation therapy. Materials and Methods: In this retrospective study using the dose-volume histogram, we calculated and compared biophysical indices of equivalent uniform dose, tumor control probability, and normal tissue complication probability (NTCP for 15 whole-brain radiotherapy patients. Results and Discussions: Dose-response models for tumors and critical structures were separated into two groups: mechanistic and empirical. Mechanistic models formulate mathematically with describable relationships while empirical models fit data through empirical observations to appropriately determine parameters giving results agreeable to those given by mechanistic models. Conclusions: Techniques applied in this manuscript could be applied to any other organs or types of cancer to evaluate treatment plans based on radiobiological modeling.

  11. 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

  12. Alteration of synaptic transmission in the hippocampal-mPFC pathway during extinction trials of context-dependent fear memory in juvenile rat stress models.

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    Koseki, Hiroyo; Matsumoto, Machiko; Togashi, Hiroko; Miura, Yoshihide; Fukushima, Kazuaki; Yoshioka, Mitsuhiro

    2009-09-01

    The medial prefrontal cortex (mPFC) has been proposed to be essential for extinction of fear memory, but its neural mechanism has been poorly understood. The present study examined whether synaptic transmission in the hippocampal-mPFC pathway is related to extinction of context-dependent fear memory in freely moving rats using electrophysiological approaches combined with behavioral analysis. Population spike amplitude in the mPFC was decreased during the first extinction trial by exposure to contextual fear conditioning. This synaptic inhibition was reversed by repeated extinction trials, accompanied by decreases in fear-related freezing behavior. These results suggest that alteration of synaptic transmission in the hippocampal-mPFC pathway is associated with the extinction processes of context-dependent fear memory. Further experiments were performed to elucidate whether early postnatal stress alters the synaptic response in the mPFC during extinction trials using a juvenile stress model, based on our previous findings that early postnatal stress affects the behavioral response to emotional stress. Adult rats that previously were exposed to five footshocks (FS) (shock intensity, 0.5 mA; intershock interval, 28 seconds; shock duration, 2 seconds) at postnatal day 21 to 25 (week 3; 3W-FS) exhibited impaired reversal of both inhibitory synaptic transmission and freezing behavior induced by repeated extinction trials. The neuronal and behavioral deficits observed in the 3W-FS group were prevented by pretreatment with the serotonin(1A) receptor agonist tandospirone (1 mg/kg, i.p.). These results indicate the possiblity that aversive stress exposure during the third postnatal week impaired extinction processes of context-dependent fear memory. The deficits in extinction observed in the 3W-FS group might be attributable to dysfunction of hippocampal-mPFC neural circuits involving 5-HT(1A) receptor mechanisms. 2009 Wiley-Liss, Inc.

  13. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease

    International Nuclear Information System (INIS)

    Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

    2009-01-01

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP swe /PS1 ΔE9 mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP swe /PS1 ΔE9 transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  14. Modification of hippocampal markers of synaptic plasticity by memantine in animal models of acute and repeated restraint stress: implications for memory and behavior.

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    Amin, Shaimaa Nasr; El-Aidi, Ahmed Amro; Ali, Mohamed Mostafa; Attia, Yasser Mahmoud; Rashed, Laila Ahmed

    2015-06-01

    Stress is any condition that impairs the balance of the organism physiologically or psychologically. The response to stress involves several neurohormonal consequences. Glutamate is the primary excitatory neurotransmitter in the central nervous system, and its release is increased by stress that predisposes to excitotoxicity in the brain. Memantine is an uncompetitive N-methyl D-aspartate glutamatergic receptors antagonist and has shown beneficial effect on cognitive function especially in Alzheimer's disease. The aim of the work was to investigate memantine effect on memory and behavior in animal models of acute and repeated restraint stress with the evaluation of serum markers of stress and the expression of hippocampal markers of synaptic plasticity. Forty-two male rats were divided into seven groups (six rats/group): control, acute restraint stress, acute restraint stress with Memantine, repeated restraint stress, repeated restraint stress with Memantine and Memantine groups (two subgroups as positive control). Spatial working memory and behavior were assessed by performance in Y-maze. We evaluated serum cortisol, tumor necrotic factor, interleukin-6 and hippocampal expression of brain-derived neurotrophic factor, synaptophysin and calcium-/calmodulin-dependent protein kinase II. Our results revealed that Memantine improved spatial working memory in repeated stress, decreased serum level of stress markers and modified the hippocampal synaptic plasticity markers in both patterns of stress exposure; in ARS, Memantine upregulated the expression of synaptophysin and brain-derived neurotrophic factor and downregulated the expression of calcium-/calmodulin-dependent protein kinase II, and in repeated restraint stress, it upregulated the expression of synaptophysin and downregulated calcium-/calmodulin-dependent protein kinase II expression.

  15. Correlation between local hemodynamics and lesion distribution in a novel aortic regurgitation murine model of atherosclerosis.

    Science.gov (United States)

    Hoi, Yiemeng; Zhou, Yu-Qing; Zhang, Xiaoli; Henkelman, R Mark; Steinman, David A

    2011-05-01

    Following surgical induction of aortic valve regurgitation (AR), extensive atherosclerotic plaque development along the descending thoracic and abdominal aorta of Ldlr⁻/⁻ mice has been reported, with distinct spatial distributions suggestive of a strong local hemodynamic influence. The objective of this study was to test, using image-based computational fluid dynamics (CFD), whether this is indeed the case. The lumen geometry was reconstructed from micro-CT scanning of a control Ldlr⁻/⁻ mouse, and CFD simulations were carried out for both AR and control flow conditions derived from Doppler ultrasound measurements and literature data. Maps of time-averaged wall shear stress magnitude (TAWSS), oscillatory shear index (OSI) and relative residence time (RRT) were compared against the spatial distributions of plaque stained with oil red O, previously acquired in a group of AR and control mice. Maps of OSI and RRT were found to be consistent with plaque distributions in the AR mice and the absence of plaque in the control mice. TAWSS was uniformly lower under control vs. AR flow conditions, suggesting that levels (> 100 dyn/cm²) exceeded those required to alone induce a pro-atherogenic response. Simulations of a straightened CFD model confirmed the importance of anatomical curvature for explaining the spatial distribution of lesions in the AR mice. In summary, oscillatory and retrograde flow induced in the AR mice, without concomitant low shear, may exacerbate or accelerate lesion formation, but the distinct anatomical curvature of the mouse aorta is responsible for the spatial distribution of lesions.

  16. A new background distribution-based active contour model for three-dimensional lesion segmentation in breast DCE-MRI

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Hui; Liu, Yiping; Qiu, Tianshuang [Department of Biomedical Engineering, Dalian University of Technology, Dalian 116024 (China); Zhao, Zuowei, E-mail: liuhui@dlut.edu.cn [Second Affiliated Hospital, Dalian Medical University, Dalian 116027 (China); Zhang, Lina [Department of Radiology, First Affiliated Hospital, Dalian Medical University, Dalian 116027 (China)

    2014-08-15

    Purpose: To develop and evaluate a computerized semiautomatic segmentation method for accurate extraction of three-dimensional lesions from dynamic contrast-enhanced magnetic resonance images (DCE-MRIs) of the breast. Methods: The authors propose a new background distribution-based active contour model using level set (BDACMLS) to segment lesions in breast DCE-MRIs. The method starts with manual selection of a region of interest (ROI) that contains the entire lesion in a single slice where the lesion is enhanced. Then the lesion volume from the volume data of interest, which is captured automatically, is separated. The core idea of BDACMLS is a new signed pressure function which is based solely on the intensity distribution combined with pathophysiological basis. To compare the algorithm results, two experienced radiologists delineated all lesions jointly to obtain the ground truth. In addition, results generated by other different methods based on level set (LS) are also compared with the authors’ method. Finally, the performance of the proposed method is evaluated by several region-based metrics such as the overlap ratio. Results: Forty-two studies with 46 lesions that contain 29 benign and 17 malignant lesions are evaluated. The dataset includes various typical pathologies of the breast such as invasive ductal carcinoma, ductal carcinomain situ, scar carcinoma, phyllodes tumor, breast cysts, fibroadenoma, etc. The overlap ratio for BDACMLS with respect to manual segmentation is 79.55% ± 12.60% (mean ± s.d.). Conclusions: A new active contour model method has been developed and shown to successfully segment breast DCE-MRI three-dimensional lesions. The results from this model correspond more closely to manual segmentation, solve the weak-edge-passed problem, and improve the robustness in segmenting different lesions.

  17. [Role of hippocampal neuronal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia].

    Science.gov (United States)

    Ming, Hong; Chen, Rui; Wang, Jing; Ju, Jingmei; Sun, Li; Zhang, Guoxing

    2014-12-01

    To investigate the role of hippocampal intracellular calcium overload in modulating cognitive dysfunction and the neuronprotective effect of mematine in a mouse model of chronic intermittent hypoxia. 45 ICR male mice were randomly divided into 3 groups: the unhandled control group (UC group, n = 15), the chronic intermittent hypoxia (CIH group, n = 15) and the pretreatment memantine group (MEM group, n = 15). CIH and MEM mice were subjected to intermittent hypoxia while UC mice to room air for 8 h per day during 4 weeks. Mice in the MEM group were pretreated with memantine (5 mg/kg) by intraperitoneal injection before the cycle started, and those in the UC group and the CIH group were treated with same volume of physiological saline. Neurobehavioral assessments were performed by Open filed and Morris water maze, [Ca²⁺]i in hippocampal neurons was evaluate by flow cytometry, and the expression of cleaved caspase-3, phospho-ERK1/2 in hippocampus were detected by Western blotting. Compared with the UC group, CIH mice displayed markedly more locomotor activity (P overload, neuron apoptosis, dephosphorylation of ERK1/2, which can be attenuated by memantine. Memantine may have a therapeutic effect in the neurocognitive impairment associated with OSAHS.

  18. Effect of dose reduction on the detection of mammographic lesions: A mathematical observer model analysis

    International Nuclear Information System (INIS)

    Chawla, Amarpreet S.; Samei, Ehsan; Saunders, Robert; Abbey, Craig; Delong, David

    2007-01-01

    The effect of reduction in dose levels normally used in mammographic screening procedures on the detection of breast lesions were analyzed. Four types of breast lesions were simulated and inserted into clinically-acquired digital mammograms. Dose reduction by 50% and 75% of the original clinically-relevant exposure levels were simulated by adding corresponding simulated noise into the original mammograms. The mammograms were converted into luminance values corresponding to those displayed on a clinical soft-copy display station and subsequently analyzed by Laguerre-Gauss and Gabor channelized Hotelling observer models for differences in detectability performance with reduction in radiation dose. Performance was measured under a signal known exactly but variable detection task paradigm in terms of receiver operating characteristics (ROC) curves and area under the ROC curves. The results suggested that luminance mapping of digital mammograms affects performance of model observers. Reduction in dose levels by 50% lowered the detectability of masses with borderline statistical significance. Dose reduction did not have a statistically significant effect on detection of microcalcifications. The model results indicate that there is room for optimization of dose level in mammographic screening procedures

  19. Impaired Hippocampal Glutamate and Glutamine Metabolism in the db/db Mouse Model of Type 2 Diabetes Mellitus

    DEFF Research Database (Denmark)

    Andersen, Jens Velde; Nissen, Jakob Dahl; Christensen, Sofie Kjellerup

    2017-01-01

    Type 2 diabetes mellitus (T2DM) is a risk factor for the development of Alzheimer's disease, and changes in brain energy metabolism have been suggested as a causative mechanism. The aim of this study was to investigate the cerebral metabolism of the important amino acids glutamate and glutamine...... significantly reduced 13C labeling in glutamate, glutamine, GABA, citrate, and aspartate from metabolism of [U-13C]glutamate. Additionally, reduced 13C labeling were observed in GABA, citrate, and aspartate from [U-13C]glutamine metabolism in hippocampal slices of db/db mice when compared to controls. None...

  20. Close but no cigar: Spatial precision deficits following medial temporal lobe lesions provide novel insight into theoretical models of navigation and memory.

    Science.gov (United States)

    Kolarik, Branden S; Baer, Trevor; Shahlaie, Kiarash; Yonelinas, Andrew P; Ekstrom, Arne D

    2018-01-01

    Increasing evidence suggests that the human hippocampus contributes to a range of different behaviors, including episodic memory, language, short-term memory, and navigation. A novel theoretical framework, the Precision and Binding Model, accounts for these phenomenon by describing a role for the hippocampus in high-resolution, complex binding. Other theories like Cognitive Map Theory, in contrast, predict a specific role for the hippocampus in allocentric navigation, while Declarative Memory Theory predicts a specific role in delay-dependent conscious memory. Navigation provides a unique venue for testing these predictions, with past results from research with humans providing inconsistent findings regarding the role of the human hippocampus in spatial navigation. Here, we tested five patients with lesions primarily restricted to the hippocampus and those extending out into the surrounding medial temporal lobe cortex on a virtual water maze task. Consistent with the Precision and Binding Model, we found partially intact allocentric memory in all patients, with impairments in the spatial precision of their searches for a hidden target. We found similar impairments at both immediate and delayed testing. Our findings are consistent with the Precision and Binding Model of hippocampal function, arguing for its role across domains in high-resolution, complex binding. Remembering goal locations in one's environment is a critical skill for survival. How this information is represented in the brain is still not fully understood, but is believed to rely in some capacity on structures in the medial temporal lobe. Contradictory findings from studies of both humans and animals have been difficult to reconcile with regard to the role of the MTL, specifically the hippocampus. By assessing impairments observed during navigation to a goal in patients with medial temporal lobe damage we can better understand the role these structures play in such behavior. Utilizing virtual reality

  1. A computational theory of the hippocampal cognitive map.

    Science.gov (United States)

    O'Keefe, J

    1990-01-01

    Evidence from single unit and lesion studies suggests that the hippocampal formation acts as a spatial or cognitive map (O'Keefe and Nadel, 1978). In this chapter, I summarise some of the unit recording data and then outline the most recent computational version of the cognitive map theory. The novel aspects of the present version of the theory are that it identifies two allocentric parameters, the centroid and the eccentricity, which can be calculated from the array of cues in an environment and which can serve as the bases for an allocentric polar co-ordinate system. Computations within this framework enable the animal to identify its location within an environment, to predict the location which will be reached as a result of any specific movement from that location, and conversely, to calculate the spatial transformation necessary to go from the current location to a desired location. Aspects of the model are identified with the information provided by cells in the hippocampus and dorsal presubiculum. The hippocampal place cells are involved in the calculation of the centroid and the presubicular direction cells in the calculation of the eccentricity.

  2. Effects of Chinese herbal medicine Yinsiwei compound on spatial learning and memory ability and the ultrastructure of hippocampal neurons in a rat model of sporadic Alzheimer disease.

    Science.gov (United States)

    Diwu, Yong-chang; Tian, Jin-zhou; Shi, Jing

    2011-02-01

    To study the effects of Chinese herbal medicine Yinsiwei compound (YSW) on spatial learning and memory ability in rats with sporadic Alzheimer disease (SAD) and the ultrastructural basis of the hippocampal neurons. A rat model of SAD was established by intracerebroventricular injection of streptozotocin. The rats were divided into six groups: sham-operation group, model group, donepezil control group, and YSW low, medium and high dose groups. Drug interventions were started on the 21st day after modeling and each treatment group was given the corresponding drugs by gavage for two months. Meanwhile, the model group and the sham-operation group were given the same volume of distilled water by gavage once a day for two months. The Morris water maze was adopted to test spatial learning and memory ability of the rats. The place navigation test and the spatial probe test were conducted. The escape latency, total swimming distance and swimming time in the target quadrant of the rats were recorded. Also, the hippocampus tissues of rats were taken out and the ultrastructure of hippocampus neurons were observed by an electron microscope. In the place navigation test, compared with the model group, the mean escape latency and the total swimming distance of the donepezil group and the YSW low, medium and high dose groups were significantly shortened (Pmicroscope also confirmed the efficacy of the drug treatment. Chinese herbal medicine YSW compound can improve spatial learning and memory impairment of rats with SAD. The ultrastructural basis may be that it can protect the microtubule structures of hippocampal neurons and prevent nerve axons from being damaged.

  3. Inhibition of GSK3β rescues hippocampal development and learning in a mouse model of CDKL5 disorder.

    Science.gov (United States)

    Fuchs, Claudia; Rimondini, Roberto; Viggiano, Rocchina; Trazzi, Stefania; De Franceschi, Marianna; Bartesaghi, Renata; Ciani, Elisabetta

    2015-10-01

    Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a rare neurodevelopmental disorder characterized by early-onset seizures, severe developmental delay, intellectual disability and Rett syndrome-like features. CDKL5 is highly expressed in the brain during early postnatal stages, suggesting its importance for brain maturation. Using a newly-generated Cdkl5 knockout (Cdkl5 -/Y) mouse, we recently found that loss of Cdkl5 impairs postnatal hippocampal development with a reduction in neuronal precursor survival and maturation. These defects were accompanied by increased activity of the glycogen synthase kinase 3β (GSK3β) a crucial inhibitory regulator of many neurodevelopmental processes. The goal of the current study was to establish whether inhibition of GSK3β corrects hippocampal developmental defects due to Cdkl5 loss. We found that treatment with the GSK3β inhibitor SB216763 restored neuronal precursor survival, dendritic maturation, connectivity and hippocampus-dependent learning and memory in the Cdkl5 -/Y mouse. Importantly, these effects were retained one month after treatment cessation. At present, there are no therapeutic strategies to improve the neurological defects of subjects with CDKL5 disorder. Current results point at GSK3β inhibitors as potential therapeutic tools for the improvement of abnormal brain development in CDKL5 disorder. Copyright © 2015. Published by Elsevier Inc.

  4. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease.

    Science.gov (United States)

    Biscaro, Barbara; Lindvall, Olle; Tesco, Giuseppina; Ekdahl, Christine T; Nitsch, Roger M

    2012-01-01

    Activated microglia with macrophage-like functions invade and surround β-amyloid (Aβ) plaques in Alzheimer's disease (AD), possibly contributing to the turnover of Aβ, but they can also secrete proinflammatory factors that may be involved in the pathogenesis of AD. Microglia are known to modulate adult hippocampal neurogenesis. To determine the role of microglia on neurogenesis in brains with Aβ pathology, we inhibited microglial activation with the tetracycline derivative minocycline in doubly transgenic mice expressing mutant human amyloid precursor protein (APP) and mutant human presenilin-1 (PS1). Minocycline increased the survival of new dentate granule cells in APP/PS1 mice indicated by more BrdU+/NeuN+ cells as compared to vehicle-treated transgenic littermates, accompanied by improved behavioral performance in a hippocampus-dependent learning task. Both brain levels of Aβ and Aβ-related morphological deficits in the new neurons labeled with GFP-expressing retrovirus were unaffected in minocycline-treated mice. These results suggest a role for microglia in Aβ-related functional deficits and in suppressing the survival of new neurons, and show that modulation of microglial function with minocycline can protect hippocampal neurogenesis in the presence of Aβ pathology. Copyright © 2012 S. Karger AG, Basel.

  5. 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.

  6. Oral Administration of Pentoxifylline Reduces Endometriosis-Like Lesions in a Nude Mouse Model.

    Science.gov (United States)

    Perelló, Maria; González-Foruria, Iñaki; Castillo, Paola; Martínez-Florensa, Mario; Lozano, Francisco; Balasch, Juan; Carmona, Francisco

    2017-06-01

    Recent reports consider endometriosis to be an immunological disorder, thus suggesting potential efficacy of immunomodulators for its treatment. The aim of this study was to assess the effects of oral administration of pentoxifylline on endometriosis-like lesions in a heterologous mice model. Human endometrial tissue obtained from women (n = 5) undergoing surgery for benign conditions was implanted in nude female mice (n = 30). The animals were distributed into 3 experimental groups receiving: saline 0.1 mL/d (control, group 1); pentoxifylline 100 mg/kg/d (group 2), and pentoxifylline 200 mg/kg/d (group 3). After 28 days, the number of implants and the total volume of surgically extracted tissue were recorded. Immunohistochemical analysis was performed to assess the area of endometriosis and vascularization of endometriosis-like lesions. Cytokine levels in peritoneal fluid samples were measured. Macroscopic quantification showed a trend to dose-dependent reduction in the number of the endometriosis-like lesions after 28 days. The volume was significantly reduced in group 3 versus group 2 and controls (399.10 ± 120.68 mm 3 vs 276.75 ± 94.30 mm 3 and 145.33 ± 38.20 mm 3 , respectively; P = .04). Similarly, the mean area of endometriosis was significantly lower in group 3 (0.12 ± 0.08 mm 2 ) versus group 2 (1.35 ± 0.43 mm 2 ) and control (2.84 ± 0.60 mm 2 ; P = .001). Vascularization and cytokine levels were also reduced posttreatment. Our results suggest that the oral administration of pentoxifylline may be an alternative to current therapies for endometriosis. Nonetheless, further studies are required.

  7. Comparison of QuadrapolarTM radiofrequency lesions produced by standard versus modified technique: an experimental model

    Directory of Open Access Journals (Sweden)

    Safakish R

    2017-06-01

    Full Text Available Ramin Safakish Allevio Pain Management Clinic, Toronto, ON, Canada Abstract: Lower back pain (LBP is a global public health issue and is associated with substantial financial costs and loss of quality of life. Over the years, different literature has provided different statistics regarding the causes of the back pain. The following statistic is the closest estimation regarding our patient population. The sacroiliac (SI joint pain is responsible for LBP in 18%–30% of individuals with LBP. Quadrapolar™ radiofrequency ablation, which involves ablation of the nerves of the SI joint using heat, is a commonly used treatment for SI joint pain. However, the standard Quadrapolar radiofrequency procedure is not always effective at ablating all the sensory nerves that cause the pain in the SI joint. One of the major limitations of the standard Quadrapolar radiofrequency procedure is that it produces small lesions of ~4 mm in diameter. Smaller lesions increase the likelihood of failure to ablate all nociceptive input. In this study, we compare the standard Quadrapolar radiofrequency ablation technique to a modified Quadrapolar ablation technique that has produced improved patient outcomes in our clinic. The methodology of the two techniques are compared. In addition, we compare results from an experimental model comparing the lesion sizes produced by the two techniques. Taken together, the findings from this study suggest that the modified Quadrapolar technique provides longer lasting relief for the back pain that is caused by SI joint dysfunction. A randomized controlled clinical trial is the next step required to quantify the difference in symptom relief and quality of life produced by the two techniques. Keywords: lower back pain, radiofrequency ablation, sacroiliac joint, Quadrapolar radiofrequency ablation

  8. Eccentric Training for Tendon Healing After Acute Lesion: A Rat Model.

    Science.gov (United States)

    Kaux, Jean-François; Libertiaux, Vincent; Leprince, Pierre; Fillet, Marianne; Denoel, Vincent; Wyss, Clémence; Lecut, Christelle; Gothot, André; Le Goff, Caroline; Croisier, Jean-Louis; Crielaard, Jean-Michel; Drion, Pierre

    2017-05-01

    The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore, eccentric exercise seems to improve the mechanical quality of the tendon. A combination of PRP injection and eccentric training might be more effective than either treatment alone. Controlled laboratory study. Adult male rats were anesthetized, an incision was performed in the middle of their left patellar tendon and an injection of physiological fluid (PF) or homologous PRP was randomly made at the lesion level. The rats were then divided into 2 groups: the eccentric group, undergoing eccentric training 3 times a week, and the untrained group, without any training. Thus, 4 groups were compared. After 5 weeks, the tendons were removed and their ultimate tensile strength and energy were measured. Tendons were frozen for proteomic analyses when all biomechanical tests were completed. Statistical analysis was performed with linear mixed effect models. No significant difference was found between the treatments using PF injection or PRP injection alone. However, the value of the ultimate tensile force at rupture was increased by 4.5 N (108% of control, P = .006) when eccentric training was performed. An intragroup analysis revealed that eccentric training significantly improved the ultimate force values for the PRP group. Proteomic analysis revealed that eccentric training led to an increase in abundance of several cytoskeletal proteins in the PF group, while a decrease in abundance of enzymes of the glycolytic pathway occurred in the PRP-treated groups, indicating that this treatment might redirect the exercise-driven metabolic plasticity of the tendon. Eccentric training altered the metabolic plasticity of tendon and led to an improvement of injured tendon resistance regardless of the treatment injected (PF or PRP). This study demonstrates the necessity of eccentric rehabilitation

  9. [Psychotherapy of patients with brain lesions: an integrative model based on neuropsychological and psychodynamic perspectives].

    Science.gov (United States)

    Ouss-Ryngaert, Lisa

    2010-12-01

    Our model of psychotherapy for patients with brain lesions is based on an integrative approach of psychobehavioral symptoms, especially from the neuropsychological and psychodynamic perspectives. Adjustment of technical modalities and aims of psychoanalytical therapy is required for these patients. The analysis of the influence of cognitive disorders on transference and contre-transference plays a major role, including the role of procedural processes in changes in the intersubjective relationship between the patient and the therapist. Two vignettes are presented to illustrate our model, which respects the integrity of the cognitive and psychodynamic approaches and can be implemented by only one therapist, using alternatively each lecture, or by a working team bringing to light the different aspects of the same symptom.

  10. REAC regenerative treatment efficacy in experimental chondral lesions: a pilot study on ovine animal model

    Directory of Open Access Journals (Sweden)

    Sanna Passino E

    2017-09-01

    Full Text Available Eraldo Sanna Passino,1,2 Stefano Rocca,1 Sabrina Caggiu,1 Nicolò Columbano,1,2 Alessandro Castagna,3 Vania Fontani,3–5 Salvatore Rinaldi3–51Department of Veterinary Medicine, University of Sassari, Sassari, Italy; 2Comparative Surgery Research Laboratory, University of Sassari, Sassari, Italy; 3Department of Regenerative Medicine, Rinaldi Fontani Institute, Florence, Italy; 4Research Department, Rinaldi Fontani Foundation, Florence, Italy; 5Research Department, IRF Shanghai Biomedical Sciences, Shanghai, People’s Republic of China Abstract: Radioelectric asymmetric conveyor (REAC technology is a platform designed to optimize cell polarity. Cell polarity is a universal biological phenomenon that is implicated in cell differentiation, proliferation, morphogenesis, aging, and rejuvenation. In this work, we investigate a timing and administration protocol for tissue optimization regenerative treatment type C, in order to treat aging-related chondral damage or injuries and gain insights into regenerative processes of articular cartilage in humans. The chondral lesion produced in this study in an animal model (6 knee joints of 4 adult sheep was 6 mm in diameter and about 2 mm deep. These lesions, which did not involve subchondral bone, tend to increase in size and depth and are not completely repaired with normal hyaline articular cartilage since adult articular cartilage is avascular and has a very slow turnover at the cellular and molecular level. Moreover, the hydration of articular cartilage is reduced with aging and with decreased mitotic activity, synthesis, and population size of chondrocytes. Six months posttreatment, lesions appeared filled, though not completely, with newly generated tissue of the light opalescent color of healthy articular cartilage, which otherwise covered the underlying subchondral bone. The newly formed tissue surface appeared to be quite regular. Nearly complete regeneration of subchondral bone occurred, with

  11. PI3K-Akt signaling activates mTOR-mediated epileptogenesis in organotypic hippocampal culture model of post-traumatic epilepsy.

    Science.gov (United States)

    Berdichevsky, Yevgeny; Dryer, Alexandra M; Saponjian, Yero; Mahoney, Mark M; Pimentel, Corrin A; Lucini, Corrina A; Usenovic, Marija; Staley, Kevin J

    2013-05-22

    mTOR is activated in epilepsy, but the mechanisms of mTOR activation in post-traumatic epileptogenesis are unknown. It is also not clear whether mTOR inhibition has an anti-epileptogenic, or merely anticonvulsive effect. The rat hippocampal organotypic culture model of post-traumatic epilepsy was used to study the effects of long-term (four weeks) inhibition of signaling pathways that interact with mTOR. Ictal activity was quantified by measurement of lactate production and electrical recordings, and cell death was quantified with lactate dehydrogenase (LDH) release measurements and Nissl-stained neuron counts. Lactate and LDH measurements were well correlated with electrographic activity and neuron counts, respectively. Inhibition of PI3K and Akt prevented activation of mTOR, and was as effective as inhibition of mTOR in reducing ictal activity and cell death. A dual inhibitor of PI3K and mTOR, NVP-BEZ235, was also effective. Inhibition of mTOR with rapamycin reduced axon sprouting. Late start of rapamycin treatment was effective in reducing epileptic activity and cell death, while early termination of rapamycin treatment did not result in increased epileptic activity or cell death. The conclusions of the study are as follows: (1) the organotypic hippocampal culture model of post-traumatic epilepsy comprises a rapid assay of anti-epileptogenic and neuroprotective activities and, in this model (2) mTOR activation depends on PI3K-Akt signaling, and (3) transient inhibition of mTOR has sustained effects on epilepsy.

  12. 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.

  13. Biophysics Model of Heavy-Ion Degradation of Neuron Morphology in Mouse Hippocampal Granular Cell Layer Neurons.

    Science.gov (United States)

    Alp, Murat; Cucinotta, Francis A

    2018-03-01

    Exposure to heavy-ion radiation during cancer treatment or space travel may cause cognitive detriments that have been associated with changes in neuron morphology and plasticity. Observations in mice of reduced neuronal dendritic complexity have revealed a dependence on radiation quality and absorbed dose, suggesting that microscopic energy deposition plays an important role. In this work we used morphological data for mouse dentate granular cell layer (GCL) neurons and a stochastic model of particle track structure and microscopic energy deposition (ED) to develop a predictive model of high-charge and energy (HZE) particle-induced morphological changes to the complex structures of dendritic arbors. We represented dendrites as cylindrical segments of varying diameter with unit aspect ratios, and developed a fast sampling method to consider the stochastic distribution of ED by δ rays (secondary electrons) around the path of heavy ions, to reduce computational times. We introduce probabilistic models with a small number of parameters to describe the induction of precursor lesions that precede dendritic snipping, denoted as snip sites. Predictions for oxygen ( 16 O, 600 MeV/n) and titanium ( 48 Ti, 600 MeV/n) particles with LET of 16.3 and 129 keV/μm, respectively, are considered. Morphometric parameters to quantify changes in neuron morphology are described, including reduction in total dendritic length, number of branch points and branch numbers. Sholl analysis is applied for single neurons to elucidate dose-dependent reductions in dendritic complexity. We predict important differences in measurements from imaging of tissues from brain slices with single neuron cell observations due to the role of neuron death through both soma apoptosis and excessive dendritic length reduction. To further elucidate the role of track structure, random segment excision (snips) models are introduced and a sensitivity study of the effects of the modes of neuron death in predictions

  14. Hippocampal proteomics defines pathways associated with memory decline and resilience in normal aging and Alzheimer's disease mouse models.

    Science.gov (United States)

    Neuner, Sarah M; Wilmott, Lynda A; Hoffmann, Brian R; Mozhui, Khyobeni; Kaczorowski, Catherine C

    2017-03-30

    Alzheimer's disease (AD), the most common form of dementia in the elderly, has no cure. Thus, the identification of key molecular mediators of cognitive decline in AD remains a top priority. As aging is the most significant risk factor for AD, the goal of this study was to identify altered proteins and pathways associated with the development of normal aging and AD memory deficits, and identify unique proteins and pathways that may contribute to AD-specific symptoms. We used contextual fear conditioning to diagnose 8-month-old 5XFAD and non-transgenic (Ntg) mice as having either intact or impaired memory, followed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify hippocampal membrane proteins across groups. Subsequent analysis detected 113 proteins differentially expressed relative to memory status (intact vs impaired) in Ntg mice and 103 proteins in 5XFAD mice. Thirty-six proteins, including several involved in neuronal excitability and synaptic plasticity (e.g., GRIA1, GRM3, and SYN1), were altered in both normal aging and AD. Pathway analysis highlighted HDAC4 as a regulator of observed protein changes in both genotypes and identified the REST epigenetic regulatory pathway and G i intracellular signaling as AD-specific pathways involved in regulating the onset of memory deficits. Comparing the hippocampal membrane proteome of Ntg versus AD, regardless of cognitive status, identified 138 differentially expressed proteins, including confirmatory proteins APOE and CLU. Overall, we provide a novel list of putative targets and pathways with therapeutic potential, including a set of proteins associated with cognitive status in normal aging mice or gene mutations that cause AD. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. MK-801 impairs cognitive coordination on a rotating arena (Carousel and contextual specificity of hippocampal immediate-early gene expression in a rat model of psychosis

    Directory of Open Access Journals (Sweden)

    Štěpán eKubík

    2014-03-01

    Full Text Available Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801 used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not fire together before. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between

  16. MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis.

    Science.gov (United States)

    Kubík, Stěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

    2014-01-01

    Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena - Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated

  17. MK-801 Impairs Cognitive Coordination on a Rotating Arena (Carousel) and Contextual Specificity of Hippocampal Immediate-Early Gene Expression in a Rat Model of Psychosis

    Science.gov (United States)

    Kubík, Štěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

    2014-01-01

    Flexible behavior in dynamic, real-world environments requires more than static spatial learning and memory. Discordant and unstable cues must be organized in coherent subsets to give rise to meaningful spatial representations. We model this form of cognitive coordination on a rotating arena – Carousel where arena- and room-bound spatial cues are dissociated. Hippocampal neuronal ensemble activity can repeatedly switch between multiple representations of such an environment. Injection of tetrodotoxin into one hippocampus prevents cognitive coordination during avoidance of a stationary room-defined place on the Carousel and increases coactivity of previously unrelated neurons in the uninjected hippocampus. Place avoidance on the Carousel is impaired after systemic administration of non-competitive NMDAr blockers (MK-801) used to model schizophrenia in animals and people. We tested if this effect is due to cognitive disorganization or other effect of NMDAr antagonism such as hyperlocomotion, spatial memory impairment, or general learning deficit. We also examined if the same dose of MK-801 alters patterns of immediate-early gene (IEG) expression in the hippocampus. IEG expression is triggered in neuronal nuclei in a context-specific manner after behavioral exploration and it is used to map activity in neuronal populations. IEG expression is critical for maintenance of synaptic plasticity and memory consolidation. We show that the same dose of MK-801 that impairs spatial coordination of rats on the Carousel also eliminates contextual specificity of IEG expression in hippocampal CA1 ensembles. This effect is due to increased similarity between ensembles activated in different environments, consistent with the idea that it is caused by increased coactivity between neurons, which did not previously fire together. Our data support the proposition of the Hypersynchrony theory that cognitive disorganization in psychosis is due to increased coactivity between unrelated

  18. 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 ...

  19. Unilateral Superior Laryngeal Nerve Lesion in an Animal Model of Dysphagia and Its Effect on Sucking and Swallowing

    Science.gov (United States)

    Campbell-Malone, Regina; Holman, Shaina D.; Lukasik, Stacey L.; Fukuhara, Takako; Gierbolini-Norat, Estela M.; Thexton, Allan J.; German, Rebecca Z.

    2013-01-01

    We tested two hypotheses relating to the sensory deficit that follows a unilateral superior laryngeal nerve (SLN) lesion in an infant animal model. We hypothesized that it would result in (1) a higher incidence of aspiration and (2) temporal changes in sucking and swallowing. We ligated the right-side SLN in six 2–3-week-old female pigs. Using videofluoroscopy, we recorded swallows in the same pre- and post-lesion infant pigs. We analyzed the incidence of aspiration and the duration and latency of suck and swallow cycles. After unilateral SLN lesioning, the incidence of silent aspiration during swallowing increased from 0.7 to 41.5 %. The durations of the suck containing the swallow, the suck immediately following the swallow, and the swallow itself were significantly longer in the post-lesion swallows, although the suck prior to the swallow was not different. The interval between the start of the suck containing a swallow and the subsequent epiglottal movement was longer in the post-lesion swallows. The number of sucks between swallows was significantly greater in post-lesion swallows compared to pre-lesion swallows. Unilateral SLN lesion increased the incidence of aspiration and changed the temporal relationships between sucking and swallowing. The longer transit time and the temporal coordinative dysfunction between suck and swallow cycles may contribute to aspiration. These results suggest that swallow dysfunction and silent aspiration are common and potentially overlooked sequelae of unilateral SLN injury. This validated animal model of aspiration has the potential for further dysphagia studies. PMID:23417250

  20. 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.

  1. Altered Intrinsic Pyramidal Neuron Properties and Pathway-Specific Synaptic Dysfunction Underlie Aberrant Hippocampal Network Function in a Mouse Model of Tauopathy.

    Science.gov (United States)

    Booth, Clair A; Witton, Jonathan; Nowacki, Jakub; Tsaneva-Atanasova, Krasimira; Jones, Matthew W; Randall, Andrew D; Brown, Jonathan T

    2016-01-13

    The formation and deposition of tau protein aggregates is proposed to contribute to cognitive impairments in dementia by disrupting neuronal function in brain regions, including the hippocampus. We used a battery of in vivo and in vitro electrophysiological recordings in the rTg4510 transgenic mouse model, which overexpresses a mutant form of human tau protein, to investigate the effects of tau pathology on hippocampal neuronal function in area CA1 of 7- to 8-month-old mice, an age point at which rTg4510 animals exhibit advanced tau pathology and progressive neurodegeneration. In vitro recordings revealed shifted theta-frequency resonance properties of CA1 pyramidal neurons, deficits in synaptic transmission at Schaffer collateral synapses, and blunted plasticity and imbalanced inhibition at temporoammonic synapses. These changes were associated with aberrant CA1 network oscillations, pyramidal neuron bursting, and spatial information coding in vivo. Our findings relate tauopathy-associated changes in cellular neurophysiology to altered behavior-dependent network function. Dementia is characterized by the loss of learning and memory ability. The deposition of tau protein aggregates in the brain is a pathological hallmark of dementia; and the hippocampus, a brain structure known to be critical in processing learning and memory, is one of the first and most heavily affected regions. Our results show that, in area CA1 of hippocampus, a region involved in spatial learning and memory, tau pathology is associated with specific disturbances in synaptic, cellular, and network-level function, culminating in the aberrant encoding of spatial information and spatial memory impairment. These studies identify several novel ways in which hippocampal information processing may be disrupted in dementia, which may provide targets for future therapeutic intervention. Copyright © 2016 Booth, Witton et al.

  2. Vorinostat ameliorates impaired fear extinction possibly via the hippocampal NMDA-CaMKII pathway in an animal model of posttraumatic stress disorder.

    Science.gov (United States)

    Matsumoto, Yasutaka; Morinobu, Shigeru; Yamamoto, Shigeto; Matsumoto, Tomoya; Takei, Shiro; Fujita, Yosuke; Yamawaki, Shigeto

    2013-09-01

    Given that impairment of fear extinction plays a pivotal role in the pathophysiology of posttraumatic stress disorder (PTSD), drugs that facilitate fear extinction may be useful as novel treatments for PTSD. Histone deacetylase (HDAC) inhibitors have recently been shown to enhance fear extinction in animal studies. Using a single prolonged stress (SPS) paradigm, an animal model of PTSD, we examined whether the HDAC inhibitor vorinostat can facilitate fear extinction in rats, and elucidated the mechanism by which vorinostat enhanced fear extinction, focusing on the N-methyl-D-aspartate (NMDA) receptor signals in the hippocampus. Seven days after SPS, rats received contextual fear conditioning, followed by 2-day extinction training. Vorinostat was intraperitoneally injected immediately after second extinction training session. Contextual fear response was assessed 24 h after vorinostat injection. Hippocampal tissues were dissected 2 h after vorinostat injection. The levels of mRNA and protein tested were measured by RT-PCR or western blotting, respectively. Systemic administration of vorinostat with extinction training significantly enhanced fear extinction in SPS rats as compared with the controls. Furthermore, vorinostat enhanced the hippocampal levels of NR2B and calcium/calmodulin kinase II (CaMKII) α and β proteins, accompanied by increases in the levels of acetylated histone H3 and H4. These findings suggest that vorinostat ameliorated the impaired fear extinction in SPS rats, and this effect was associated with an increase in histone acetylation and thereby enhancement of NR2B and CaMKII in the hippocampus. Our results may provide new insight into the molecular and therapeutic mechanisms of PTSD.

  3. Distinctive hippocampal and amygdalar cytoarchitectural changes underlie specific patterns of behavioral disruption following stress exposure in an animal model of PTSD.

    Science.gov (United States)

    Cohen, Hagit; Kozlovsky, Nitsan; Matar, Michael A; Zohar, Joseph; Kaplan, Zeev

    2014-12-01

    Alterations in cytoarchitecture and molecular signaling have been observed in adaptive and maladaptive responses to stress and presumably underlie the physiological and behavioral changes observed. The relationship between behavioral responses to stress exposure and changes in cytoarchitecture of subregions of the hippocampus and amygdala was investigated in an animal model of PTSD. Behaviors in elevated plus-maze and acoustic startle response tests were assessed in rats 7 days after exposure to predator scent stress. Brains were harvested 24h later. Neurons from CA1, CA3, and dentate gyrus subregions and basolateral amygdala were reconstructed and subjected to Sholl analysis and spine density estimation. Glucocorticoid receptor, brain-derived neurotrophic factor, phospho-NR1-Ser-889, phospho-GluR1-Ser-845, phospho-calcium/calmodulin dependent protein kinase II-Thy-286, post-synaptic density protein 95 and phospho-CREB-Ser-133 were evaluated in the hippocampus. Data were analyzed by retrospective classification of individual rats into three behavioral response groups. The extent and distribution of changes in the morphology of hippocampal and amygdalar dendrites was significantly associated with stress-induced behavioral response classification. Extreme (PTSD-like) behavioral disruption was associated with extensive neuronal retraction in the hippocampus and proliferation in the amygdala. Neither structure displayed such changes in minimal behavioral responders. Partial behavioral response was associated with identical changes in the hippocampus only. Patterns of change in requisite molecular signaling genes and endophenotypic markers corresponded to the structural and behavioral responses. The extent and distribution of changes in the cytoarchitecture of hippocampal and amygdalar subregions is directly related to the pattern of behavioral response of the individual to stress exposure. Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.

  4. Application of radiosurgical techniques to produce a primate model of brain lesions

    OpenAIRE

    Kunimatsu, Jun; Miyamoto, Naoki; Ishikawa, Masayori; Shirato, Hiroki; Tanaka, Masaki

    2015-01-01

    Behavioral analysis of subjects with discrete brain lesions provides important information about the mechanisms of various brain functions. However, it is generally difficult to experimentally produce discrete lesions in deep brain structures. Here we show that a radiosurgical technique, which is used as an alternative treatment for brain tumors and vascular malformations, is applicable to create non-invasive lesions in experimental animals for the research in systems neuroscience. We deliver...

  5. Spectroscopic evidence of hippocampal abnormalities in neocortical epilepsy

    Science.gov (United States)

    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

  6. Radiofrequency thermal ablation of benign cystic lesion: an experimental pilot study in a porcine gallbladder model

    International Nuclear Information System (INIS)

    Song, Ho Taek; Rhim, Hyun Chul; Choi, Jung Bin; Oh, Jae Cheon; Cho, On Koo; Koh, Byung Hee; Kim, Yong Soo; Seo, Heung Suk; Joo, Kyung Bin

    2001-01-01

    To determine whether radiofrequency thermal ablation can be used to treat benign cystic lesions in a porcine gallbladder model. This experimental study of radiofrequency thermal ablation involved the use of 15 exvivo porcine gallbladders and 15-G expandable needle electrodes. To investigate optimal temperature parameters, three groups of five were designated according to target temperature:Group A: 70 deg C; Group B: 80 deg C; Group C: 90 deg C. After the target temperature was reached, ablation lasted for one minute. Gallbladder width, height and length were measured before and after ablation , and the estimated volume reduction ratios of the three groups were compared. Whether adjacent liver parenchyma around the gallbladder fossa was ablated by heat conducted from hot bile was also determined, and the thickness of the ablated area of the liver was measured. The volume reduction ratio in Group A, B and C was 42.7%, 41.7% and 42.9%, respectively (ρ>.05). In all 15 cases, gallbladder walls lost their transparency and elasticity at about 70 deg C. In nine of ten cases in Groups B and C, the hepatic capsule around the gallbladder fossa was retracted at about 80 deg C. The mean thickness of liver parenchymal damage adjacent to the gallbladder was 5.4 mm in Group B and 9.8 mm in Group C. In Group A livers, only one case showed minimal gradual parenchymal change. Microscopically, all three groups showed complete coagulation necrosis of the wall. On the basis of this feasibility study, radiofrequency thermal ablation is potentially suitable for the ultrasound-guided treatment of symptomatic cystic lesions including benign hepatic or renal cyst

  7. 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.

  8. New Perspectives on the Brain Lesion Approach - Implications for Theoretical Models of Human Memory.

    NARCIS (Netherlands)

    Irish, Muireann; van Kesteren, M.T.R.

    2017-01-01

    Human lesion studies represent the cornerstone of modern day neuropsychology and provide an important adjunct to functional neuroimaging methods. The study of human lesion groups with damage to distinct regions of the brain permits the identification of underlying mechanisms and structures not only

  9. Long-term consequences of a prolonged febrile seizure in a dual pathology model.

    Science.gov (United States)

    Gibbs, Steve; Chattopadhyaya, Bidisha; Desgent, Sébastien; Awad, Patricia N; Clerk-Lamalice, Olivier; Levesque, Maxime; Vianna, Rose-Mari; Rébillard, Rose-Marie; Delsemme, Andrée-Anne; Hébert, David; Tremblay, Luc; Lepage, Martin; Descarries, Laurent; Di Cristo, Graziella; Carmant, Lionel

    2011-08-01

    Clinical evidence suggests that febrile status epilepticus (SE) in children can lead to acute hippocampal injury and subsequent temporal lobe epilepsy. The contribution of febrile SE to the mechanisms underlying temporal lobe epilepsy are however poorly understood. A rat model of temporal lobe epilepsy following hyperthermic SE was previously established in our laboratory, wherein a focal cortical lesion induced at postnatal day 1 (P1), followed by a hyperthermic SE (more than 30 min) at P10, leads to hippocampal atrophy at P22 (dual pathology model) and spontaneous recurrent seizures (SRS) with mild visuospatial memory deficits in adult rats. The goal of this study was to identify the long term electrophysiological, anatomical and molecular changes in this model. Following hyperthermic SE, all cortically lesioned pups developed progressive SRS as adults, characterized by the onset of highly rhythmic activity in the hippocampus. A reduction of hippocampal volume on the side of the lesion preceded the SRS and was associated with a loss of hippocampal neurons, a marked decrease in pyramidal cell spine density, an increase in the hippocampal levels of NMDA receptor NR2A subunit, but no significant change in GABA receptors. These findings suggest that febrile SE in the abnormal brain leads to hippocampal injury that is followed by progressive network reorganization and molecular changes that contribute to the epileptogenesis as well as the observed memory deficits. Copyright © 2011 Elsevier Inc. All rights reserved.

  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. Quantitative 2- and 3-dimensional analysis of pharmacokinetic model-derived variables for breast lesions in dynamic, contrast-enhanced MR mammography

    International Nuclear Information System (INIS)

    Hauth, E.A.M.; Jaeger, H.J.; Maderwald, S.; Muehler, A.; Kimmig, R.; Forsting, M.

    2008-01-01

    Purpose: 2- and 3-dimensional evaluation of quantitative pharmacokinetic parameters derived from the Tofts model modeling dynamic contrast enhancement of lesions in MR mammography. Materials and methods: In 95 patients, MR mammography revealed 127 suspicious lesions. The initial rate of enhancement was coded by color intensity, the post-initial enhancement change is coded by color hue. 2D and 3D analysis of distribution of color hue and intensity, vascular permeability and extracellular volume were performed. Results: In 2D, malignant lesions showed significant higher number of bright red, medium red, dark red, bright green, medium green, dark green and bright blue pixels than benign lesions. In 3D, statistical significant differences between malignant and benign lesions was found for all this parameters. Vascular permeability was significant higher in malignant lesions than in benign lesions. Regression model using the 3D data found that the best discriminator between malignant and benign lesions was combined number of voxels and medium green pixels, with a sensitivity of 79.4% and a specificity of 83.1%. Conclusions: Quantitative analysis of pharmacokinetic variables of contrast kinetics showed significant differences between malignant and benign lesions. 3D analysis showed superior diagnostic differentiation between malignant and benign lesions than 2D analysis. The parametric analysis using a pharmacokinetic model allows objective analysis of contrast enhancement in breast lesions

  12. A new experimental model to study preneoplastic lesions in achalasia of the esophagus

    Directory of Open Access Journals (Sweden)

    Vespúcio Marcelo Vinícius Oliveira

    2005-01-01

    Full Text Available PURPOSE: Develop an experimental model to study esophageal preneoplastic lesions induced by diethylnitrosamine in rats with achalasia. METHODS: Male Wistar rats were divided into four groups: control - C (n=8; rats with megaesophagus - B (n=8; rats treated with DEN - D (n=15 and rats with megaesophagus plus DEN - BD (n=15. Megaesophagus can be experimentally obtained in rats by topical application of benzalkonium choride. The morphology and PCNA labeling index of the epithelium were evaluated. RESULTS: The morphometric analysis showed an increase in epithelial thickness in the animals of group BD (2166?1012mm² when compared to the other groups (C = 878?278mm²; B = 1746?144mm² and D = 1691?697mm², mainly due to basal layer hyperplasia, besides an increase in the keratin of the superficial layer. The PCNA labeling index in the basal layer was significantly higher in the group BD (0,695?0,111 when compared to the other groups (C = 0,490?0,132; B = 0,512?0,215 and D = 0,477?0,198. CONCLUSIONS: Our data confirm in an experimental model the previous observation in humans of increased epithelial cell proliferation during the esophageal carcinogenic process in achalasia and may be useful to further studies on the mechanisms of the esophageal carcinogenesis and the the design of follow-up endoscopic studies for patients with achalasia.

  13. Histological responses of cutaneous vascular lesions following photodynamic therapy with talaporfin sodium: a chicken comb model.

    Science.gov (United States)

    Ohshiro, Takafumi; Nakajima, Tatsuo; Ogata, Hisao; Kishi, Kazuo

    2009-09-01

    Mono-L-aspartyl chlorin e6 (Talaporfin sodium) is a novel photosensitizer, and is currently being used in photodynamic therapy for various malignant tumors in combination with irradiation with a 664 nm laser. An interesting characteristic of Talaporfin sodium is that the skin photosensitivity after injection of this agent disappears faster than any other existing photosensitizers. This study examined the vascular events that occurred postirradiation in the chicken comb as a capillary malformation model after photosensitization with Talaporfin sodium. A single intravenous bolus injections of Talaporfin sodium was administered to the chickens, and a 1 cm diameter area of the comb of each animal was irradiated with a 664 nm visible red laser. The gross changes in the chicken combs were recorded for 7-14 days after photodynamic therapy. For the histological examination, HE, PTAH and Azan stained sections were analyzed. All treated chicken combs had blanched after photodynamic therapy. Microscopy demonstrated an absence of erythrocytes and the vessel lumina were obliterated, leaving the normal overlying epidermis completely intact. Concomitantly with selective destruction of the capillaries in the target area, moderate invasion of inflammatory cells and a slight increase in the stroma were observed. In the chicken comb model, photodynamic therapy with Talaporfin sodium effectively achieved selective destruction of the microvasculature while leaving the epidermis intact. Our results strongly suggest that photodynamic therapy with Talaporfin sodium could be a feasible method to treat dermal hypervascular lesions.

  14. Tiaolipiwei Acupuncture Reduces Albuminuria by Alleviating Podocyte Lesions in a Rat Model of Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Zhilong Zhang

    2018-01-01

    Full Text Available Background. Diabetic nephropathy is a common and serious complication of diabetes and a major cause of end-stage renal disease. Tiaolipiwei acupuncture is a safe treatment approach that may be effective for lowering albuminuria in diabetic nephropathy. Yet, the exact mechanisms of this therapeutic effect are unclear. Methods. A rodent model of type 2 diabetic nephropathy (T2DN was induced by a high-fat diet combined with low-dose streptozotocin. T2DN rats were treated with Tiaolipiwei acupuncture (ACU for 4, 8, or 12 weeks. At the end of treatment, urinary and blood samples were collected for analysis. Transmission electron microscopy was used to observe morphological changes, and protein expression levels of nephrin, CD2AP, podocalyxin, and desmin were quantified in renal tissue. Results. Compared to the T2DN groups, the T2DN + ACU groups showed significant improvements in 24-hour urinary protein, serum urea, cholesterol, and triglycerides at all time points. ACU treatment also improved the density of slit diaphragms. Simultaneously, ACU promoted the renal expression of nephrin, CD2AP, and podocalyxin and decreased the expression of desmin. Conclusion. Our study suggests that Tiaolipiwei acupuncture ameliorates podocyte lesions to reduce albuminuria and prevent the progression of T2DN in a rat model.

  15. Hippocampal atrophy and developmental regression as first sign of linear scleroderma "en coup de sabre".

    Science.gov (United States)

    Verhelst, Helene E; Beele, Hilde; Joos, Rik; Vanneuville, Benedicte; Van Coster, Rudy N

    2008-11-01

    An 8-year-old girl with linear scleroderma "en coup de sabre" is reported who, at preschool age, presented with intractable simple partial seizures more than 1 year before skin lesions were first noticed. MRI revealed hippocampal atrophy, controlaterally to the seizures and ipsilaterally to the skin lesions. In the following months, a mental and motor regression was noticed. Cerebral CT scan showed multiple foci of calcifications in the affected hemisphere. In previously reported patients the skin lesions preceded the neurological signs. To the best of our knowledge, hippocampal atrophy was not earlier reported as presenting symptom of linear scleroderma. Linear scleroderma should be included in the differential diagnosis in patients with unilateral hippocampal atrophy even when the typical skin lesions are not present.

  16. BDNF levels are increased by aminoindan and rasagiline in a double lesion model of Parkinson׳s disease.

    Science.gov (United States)

    Ledreux, Aurélie; Boger, Heather A; Hinson, Vanessa K; Cantwell, Kelsey; Granholm, Ann-Charlotte

    2016-01-15

    The anti-Parkinsonian drug rasagiline is a selective, irreversible inhibitor of monoamine oxidase and is used in the treatment of Parkinson׳s disease (PD). Its postulated neuroprotective effects may be attributed to MAO inhibition, or to its propargylamine moiety. The major metabolite of rasagiline, aminoindan, has shown promising neuroprotective properties in vitro but there is a paucity of studies investigating in vivo effects of this compound. Therefore, we examined neuroprotective effects of rasagiline and its metabolite aminoindan in a double lesion model of PD. Male Fisher 344 rats received i.p. injections of the noradrenergic neurotoxin DSP-4 and intra-striatal stereotaxic microinjections of the dopamine neurotoxin 6-OHDA. Saline, rasagiline or aminoindan (3mg/kg/day s.c.) were delivered via Alzet minipumps for 4 weeks. Rats were then tested for spontaneous locomotion and a novel object recognition task. Following behavioral testing, brain tissue was processed for ELISA measurements of growth factors and immunohistochemistry. Double-lesioned rats treated with rasagiline or aminoindan had reduced behavioral deficits, both in motor and cognitive tasks compared to saline-treated double-lesioned rats. BDNF levels were significantly increased in the hippocampus and striatum of the rasagiline- and aminoindan-lesioned groups compared to the saline-treated lesioned group. Double-lesioned rats treated with rasagiline or aminoindan exhibited a sparing in the mitochondrial marker Hsp60, suggesting mitochondrial involvement in neuroprotection. Tyrosine hydroxylase (TH) immunohistochemistry revealed a sparing of TH-immunoreactive terminals in double-lesioned rats treated with rasagiline or aminoindan in the striatum, hippocampus, and substantia nigra. These data provide evidence of neuroprotection by aminoindan and rasagiline via their ability to enhance BDNF levels. Published by Elsevier B.V.

  17. In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis.

    Directory of Open Access Journals (Sweden)

    Xavier Helluy

    Full Text Available Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis.Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast.This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of

  18. In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis

    Science.gov (United States)

    Helluy, Xavier; Sauter, Martina; Ye, Yu-Xiang; Lykowsky, Gunthard; Kreutner, Jakob; Yilmaz, Ali; Jahns, Roland; Boivin, Valerie; Kandolf, Reinhard; Jakob, Peter M.; Hiller, Karl-Heinz; Klingel, Karin

    2017-01-01

    Objective Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis. Results Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast. Conclusion This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise

  19. Mapping 3D breast lesions from full-field digital mammograms using subject-specific finite element models

    Science.gov (United States)

    García, E.; Oliver, A.; Diaz, O.; Diez, Y.; Gubern-Mérida, A.; Martí, R.; Martí, J.

    2017-03-01

    Patient-specific finite element (FE) models of the breast have received increasing attention due to the potential capability of fusing images from different modalities. During the Magnetic Resonance Imaging (MRI) to X-ray mammography registration procedure, the FE model is compressed mimicking the mammographic acquisition. Subsequently, suspicious lesions in the MRI volume can be projected into the 2D mammographic space. However, most registration algorithms do not provide the reverse information, avoiding to obtain the 3D geometrical information from the lesions localized in the mammograms. In this work we introduce a fast method to localize the 3D position of the lesion within the MRI, using both cranio-caudal (CC) and medio-lateral oblique (MLO) mammographic projections, indexing the tetrahedral elements of the biomechanical model by means of an uniform grid. For each marked lesion in the Full-Field Digital Mammogram (FFDM), the X-ray path from source to the marker is calculated. Barycentric coordinates are computed in the tetrahedrons traversed by the ray. The list of elements and coordinates allows to localize two curves within the MRI and the closest point between both curves is taken as the 3D position of the lesion. The registration errors obtained in the mammographic space are 9.89 +/- 3.72 mm in CC- and 8.04 +/- 4.68 mm in MLO-projection and the error in the 3D MRI space is equal to 10.29 +/- 3.99 mm. Regarding the uniform grid, it is computed spending between 0.1 and 0.7 seconds. The average time spent to compute the 3D location of a lesion is about 8 ms.

  20. [Morphological analysis of the hippocampal region associated with an innate behaviour task in the transgenic mouse model (3xTg-AD) for Alzheimer disease].

    Science.gov (United States)

    Orta-Salazar, E; Feria-Velasco, A; Medina-Aguirre, G I; Díaz-Cintra, S

    2013-10-01

    Different animal models for Alzheimer disease (AD) have been designed to support the hypothesis that the neurodegeneration (loss of neurons and synapses with reactive gliosis) associated with Aβ and tau deposition in these models is similar to that in the human brain. These alterations produce functional changes beginning with decreased ability to carry out daily and social life activities, memory loss, and neuropsychiatric disorders in general. Neuronal alteration plays an important role in early stages of the disease, especially in the CA1 area of hippocampus in both human and animal models. Two groups (WT and 3xTg-AD) of 11-month-old female mice were used in a behavioural analysis (nest building) and a morphometric analysis of the CA1 region of the dorsal hippocampus. The 3xTg-AD mice showed a 50% reduction in nest quality associated with a significant increase in damaged neurons in the CA1 hippocampal area (26%±6%, Pde Neurología. Published by Elsevier Espana. All rights reserved.

  1. PPARα activation differently affects microparticle content in atherosclerotic lesions and liver of a mouse model of atherosclerosis and NASH.

    Science.gov (United States)

    Baron, Morgane; Leroyer, Aurélie S; Majd, Zouher; Lalloyer, Fanny; Vallez, Emmanuelle; Bantubungi, Kadiombo; Chinetti-Gbaguidi, Giulia; Delerive, Philippe; Boulanger, Chantal M; Staels, Bart; Tailleux, Anne

    2011-09-01

    Atherosclerosis and non-alcoholic fatty liver disease (NAFLD) are complex pathologies characterized by lipid accumulation, chronic inflammation and extensive tissue remodelling. Microparticles (MPs), small membrane vesicles produced by activated and apoptotic cells, might not only be biomarkers, but also functional actors in these pathologies. The apoE2-KI mouse is a model of atherosclerosis and NAFLD. Activation of the nuclear receptor PPARα decreases atherosclerosis and components of non-alcoholic steatohepatitis (NASH) in the apoE2-KI mouse. (1) To determine whether MPs are present in atherosclerotic lesions, liver and plasma during atherosclerosis and NASH progression in apoE2-KI mice, and (2) to study whether PPARα activation modulates MP concentrations. ApoE2-KI mice were fed a Western diet to induce atherosclerosis and NASH. MPs were isolated from atherosclerotic lesions, liver and blood and quantified by flow cytometry. An increase of MPs was observed in the atherosclerotic lesions and in the liver of apoE2-KI mice upon Western diet feeding. PPARα activation with fenofibrate decreased MP levels in the atherosclerotic lesions in a PPARα-dependent manner, but did not influence MP concentrations in the liver. Here we report that MPs are present in atherosclerotic lesions and in the liver of apoE2-KI mice. Their concentration increased during atherosclerosis and NASH development. PPARα activation differentially modulates MP levels in a tissue-specific manner. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Introducing a Virtual Lesion Model of Dysphagia Resulting from Pharyngeal Sensory Impairment

    Directory of Open Access Journals (Sweden)

    Paul Muhle

    2018-01-01

    Full Text Available Background/Aims: Performing neurophysiological and functional imaging studies in severely affected patients to investigate novel neurostimulation techniques for the treatment of neurogenic dysphagia is difficult. Therefore, basic research needs to be conducted in healthy subjects. Swallowing is a motor function highly dependent on sensory afferent input. Here we propose a virtual peripheral sensory lesion model to mimic pharyngeal sensory impairment, which is known as a major contributor to dysphagia in neurological disease. Methods: In this randomized crossover study on 11 healthy volunteers, cortical activation during pneumatic pharyngeal stimulation was measured applying magnetoencephalography in two separate sessions, with and without pharyngeal surface anesthesia. Results: Stimulation evoked bilateral event-related desynchronization (ERD mainly in the caudolateral pericentral cortex. In comparison to the no-anesthesia condition, topical anesthesia led to a reduction of ERD in beta (13-30 Hz and low gamma (30-60 Hz frequency ranges (p<0.05 in sensory but also motor cortical areas. Conclusions: Withdrawal of sensory afferent information by topical anesthesia leads to reduced response to pneumatic pharyngeal stimulation in a distributed cortical sensorimotor network in healthy subjects. The proposed paradigm may serve to investigate the effect of neuromodulatory treatments specifically on pharyngeal sensory impairment as relevant cause of neurogenic dysphagia.

  3. Hippocampal P3-Like Auditory Event-Related Potentials are Disrupted in a Rat Model of Cholinergic Degeneration in Alzheimer's Disease: Reversal by Donepezil Treatment

    DEFF Research Database (Denmark)

    Laursen, Bettina; Mørk, Arne; Kristiansen, Uffe

    2014-01-01

    P300 (P3) event-related potentials (ERPs) have been suggested to be an endogenous marker of cognitive function and auditory oddball paradigms are frequently used to evaluate P3 ERPs in clinical settings. Deficits in P3 amplitude and latency reflect some of the neurological dysfunctions related...... cholinergic degeneration induced by SAP. SAP-lesioned rats may constitute a suitable model to test the efficacy of pro-cognitive substances in an applied experimental setup....

  4. Spiking neurons in a hierarchical self-organizing map model can learn to develop spatial and temporal properties of entorhinal grid cells and hippocampal place cells.

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    Praveen K Pilly

    Full Text Available Medial entorhinal grid cells and hippocampal place cells provide neural correlates of spatial representation in the brain. A place cell typically fires whenever an animal is present in one or more spatial regions, or places, of an environment. A grid cell typically fires in multiple spatial regions that form a regular hexagonal grid structure extending throughout the environment. Different grid and place cells prefer spatially offset regions, with their firing fields increasing in size along the dorsoventral axes of the medial entorhinal cortex and hippocampus. The spacing between neighboring fields for a grid cell also increases along the dorsoventral axis. This article presents a neural model whose spiking neurons operate in a hierarchy of self-organizing maps, each obeying the same laws. This spiking GridPlaceMap model simulates how grid cells and place cells may develop. It responds to realistic rat navigational trajectories by learning grid cells with hexagonal grid firing fields of multiple spatial scales and place cells with one or more firing fields that match neurophysiological data about these cells and their development in juvenile rats. The place cells represent much larger spaces than the grid cells, which enable them to support navigational behaviors. Both self-organizing maps amplify and learn to categorize the most frequent and energetic co-occurrences of their inputs. The current results build upon a previous rate-based model of grid and place cell learning, and thus illustrate a general method for converting rate-based adaptive neural models, without the loss of any of their analog properties, into models whose cells obey spiking dynamics. New properties of the spiking GridPlaceMap model include the appearance of theta band modulation. The spiking model also opens a path for implementation in brain-emulating nanochips comprised of networks of noisy spiking neurons with multiple-level adaptive weights for controlling autonomous

  5. Application of the diffusion kurtosis model for the study of breast lesions

    Energy Technology Data Exchange (ETDEWEB)

    Nogueira, Luisa [School of Health Technology of Porto/Polytechnic Institute of Porto (ESTSP/IPP), Department of Radiology, Vila Nova de Gaia (Portugal); Brandao, Sofia; Loureiro, Joana [Hospital de Sao Joao, MRI Unit, Department of Radiology, Porto (Portugal); Matos, Eduarda [University of Porto, Department of Health Community, Institute of Biomedical Sciences Abel Salazar (ICBAS), Porto (Portugal); Nunes, Rita Gouveia; Ferreira, Hugo Alexandre [University of Lisbon, Institute of Biophysics and Biomedical Engineering (IBEB), Faculty of Sciences, Lisboa (Portugal); Ramos, Isabel [Hospital de Sao Joao/Faculty of Medicine of Porto University (FMUP), Head Department of Radiology, Porto (Portugal)

    2014-06-15

    To evaluate diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) in the differentiation and characterisation of breast lesions. Thirty-six women underwent breast magnetic resonance imaging (MRI) including a DWI sequence with multiple b-values (50-3,000 s/mm{sup 2}). Mean values for apparent diffusion coefficient (ADC), mean diffusivity (MD) and mean kurtosis (MK) were calculated by lesion type and histological subtype. Differences and correlation between parameters were determined. Forty-four lesions were found. There were significant differences between benign and malignant lesions for all parameters (ADC, p = 0.017; MD, p = 0.028; MK, p = 0.017). ADC and MD were higher for benign (1.96 ± 0.41 x 10{sup -3} and 2.17 ± 0.42 x 10{sup -3} mm{sup 2}/s, respectively) than for malignant lesions (1.33 ± 0.18 x 10{sup -3} and 1.52 ± 0.50 x 10{sup -3} mm{sup 2}/s). MK was higher for malignant (0.61 ± 0.27) than benign lesions (0.37 ± 0.18). We found differences between invasive ductal carcinoma (IDC) and fibroadenoma (FA) for all parameters (ADC, MD and MK): p = 0.016, 0.022 and 0.016, respectively. FA and fibrocystic change (FC) showed differences only in MK (p = 0.016). Diffusion in breast lesions follows a non-Gaussian distribution. MK enables differentiation and characterisation of breast lesions, providing new insights into microstructural complexity. To confirm these results, further investigation in a broader sample should be performed. (orig.)

  6. Application of the diffusion kurtosis model for the study of breast lesions

    International Nuclear Information System (INIS)

    Nogueira, Luisa; Brandao, Sofia; Loureiro, Joana; Matos, Eduarda; Nunes, Rita Gouveia; Ferreira, Hugo Alexandre; Ramos, Isabel

    2014-01-01

    To evaluate diffusion-weighted imaging (DWI) and diffusion kurtosis imaging (DKI) in the differentiation and characterisation of breast lesions. Thirty-six women underwent breast magnetic resonance imaging (MRI) including a DWI sequence with multiple b-values (50-3,000 s/mm 2 ). Mean values for apparent diffusion coefficient (ADC), mean diffusivity (MD) and mean kurtosis (MK) were calculated by lesion type and histological subtype. Differences and correlation between parameters were determined. Forty-four lesions were found. There were significant differences between benign and malignant lesions for all parameters (ADC, p = 0.017; MD, p = 0.028; MK, p = 0.017). ADC and MD were higher for benign (1.96 ± 0.41 x 10 -3 and 2.17 ± 0.42 x 10 -3 mm 2 /s, respectively) than for malignant lesions (1.33 ± 0.18 x 10 -3 and 1.52 ± 0.50 x 10 -3 mm 2 /s). MK was higher for malignant (0.61 ± 0.27) than benign lesions (0.37 ± 0.18). We found differences between invasive ductal carcinoma (IDC) and fibroadenoma (FA) for all parameters (ADC, MD and MK): p = 0.016, 0.022 and 0.016, respectively. FA and fibrocystic change (FC) showed differences only in MK (p = 0.016). Diffusion in breast lesions follows a non-Gaussian distribution. MK enables differentiation and characterisation of breast lesions, providing new insights into microstructural complexity. To confirm these results, further investigation in a broader sample should be performed. (orig.)

  7. 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.

  8. 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

  9. Deconstructing empathy: Neuroanatomical dissociations between affect sharing and prosocial motivation using a patient lesion model.

    Science.gov (United States)

    Shdo, Suzanne M; Ranasinghe, Kamalini G; Gola, Kelly A; Mielke, Clinton J; Sukhanov, Paul V; Miller, Bruce L; Rankin, Katherine P

    2017-02-14

    Affect sharing and prosocial motivation are integral parts of empathy that are conceptually and mechanistically distinct. We used a neurodegenerative disease (NDG) lesion model to examine the neural correlates of these two aspects of real-world empathic responding. The study enrolled 275 participants, including 44 healthy older controls and 231 patients diagnosed with one of five neurodegenerative diseases (75 Alzheimer's disease, 58 behavioral variant frontotemporal dementia (bvFTD), 42 semantic variant primary progressive aphasia (svPPA), 28 progressive supranuclear palsy, and 28 non-fluent variant primary progressive aphasia (nfvPPA). Informants completed the Revised Self-Monitoring Scale's Sensitivity to the Expressive Behavior of Others (RSMS-EX) subscale and the Interpersonal Reactivity Index's Empathic Concern (IRI-EC) subscale describing the typical empathic behavior of the participants in daily life. Using regression modeling of the voxel based morphometry of T1 brain scans prepared using SPM8 DARTEL-based preprocessing, we isolated the variance independently contributed by the affect sharing and the prosocial motivation elements of empathy as differentially measured by the two scales. We found that the affect sharing component uniquely correlated with volume in right>left medial and lateral temporal lobe structures, including the amygdala and insula, that support emotion recognition, emotion generation, and emotional awareness. Prosocial motivation, in contrast, involved structures such as the nucleus accumbens (NaCC), caudate head, and inferior frontal gyrus (IFG), which suggests that an individual must maintain the capacity to experience reward, to resolve ambiguity, and to inhibit their own emotional experience in order to effectively engage in spontaneous altruism as a component of their empathic response to others. Copyright © 2017. Published by Elsevier Ltd.

  10. Network models provide insights into how oriens–lacunosum-moleculare and bistratified cell interactions influence the power of local hippocampal CA1 theta oscillations

    Directory of Open Access Journals (Sweden)

    Katie A Ferguson

    2015-08-01

    Full Text Available Hippocampal theta is a 4-12 Hz rhythm associated with episodic memory, and although it has been studied extensively, the cellular mechanisms underlying its generation are unclear. The complex interactions between different interneuron types, such as those between oriens--lacunosum-moleculare (OLM interneurons and bistratified cells (BiCs, make their contribution to network rhythms difficult to determine experimentally. We created network models that are tied to experimental work at both cellular and network levels to explore how these interneuron interactions affect the power of local oscillations. Our cellular models were constrained with properties from patch clamp recordings in the CA1 region of an intact hippocampus preparation in vitro. Our network models are composed of three different types of interneurons: parvalbumin-positive (PV+ basket and axo-axonic cells (BC/AACs, PV+ BiCs, and somatostatin-positive OLM cells. Also included is a spatially extended pyramidal cell model to allow for a simplified local field potential representation, as well as experimentally-constrained, theta frequency synaptic inputs to the interneurons. The network size, connectivity, and synaptic properties were constrained with experimental data. To determine how the interactions between OLM cells and BiCs could affect local theta power, we explored a number of OLM-BiC connections and connection strengths.We found that our models operate in regimes in which OLM cells minimally or strongly affected the power of network theta oscillations due to balances that, respectively, allow compensatory effects or not. Inactivation of OLM cells could result in no change or even an increase in theta power. We predict that the dis-inhibitory effect of OLM cells to BiCs to pyramidal cell interactions plays a critical role in the power of network theta oscillations. Our network models reveal a dynamic interplay between different classes of interneurons in influencing local theta

  11. Gypenosides attenuate the development of L-DOPA-induced dyskinesia in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

    Science.gov (United States)

    Shin, Keon Sung; Zhao, Ting Ting; Park, Keun Hong; Park, Hyun Jin; Hwang, Bang Yeon; Lee, Chong Kil; Lee, Myung Koo

    2015-04-21

    Gypenosides (GPS) and ethanol extract of Gynostemma pentaphyllum (GP-EX) show anxiolytic effects on affective disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse model of Parkinson's disease (PD). Long-term administration of L-3,4-dihydroxyphenylalanine (L-DOPA) leads to the development of severe motor side effects such as L-DOPA-induced-dyskinesia (LID) in PD. The present study investigated the effects of GPS and GP-EX on LID in a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD. Daily administration of L-DOPA (25 mg/kg) in the 6-OHDA-lesioned rat model of PD for 22 days induced expression of LID, which was determined by the body and locomotive AIMs scores and contralateral rotational behaviors. However, co-treatments of GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg) with L-DOPA significantly attenuated the development of LID without compromising the anti-parkinsonian effects of L-DOPA. In addition, the increases in ∆FosB expression and ERK1/2 phosphorylation in 6-OHDA-lesioned rats induced by L-DOPA administration were significantly reduced by co-treatment with GPS (25 and 50 mg/kg) or GP-EX (50 mg/kg). These results suggest that GPS (25 and 50 mg/kg) and GP-EX (50 mg/kg) effectively attenuate the development of LID by modulating the biomarker activities of ∆FosB expression and ERK1/2 phosphorylation in the 6-OHDA-lesioned rat model of PD. GPS and GP-EX will be useful adjuvant therapeutics for LID in PD.

  12. 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…

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

    OpenAIRE

    Reas, Emilie T.; Brewer, James B.

    2013-01-01

    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, which 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 hippoca...

  14. Omega-3 polyunsaturated Fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models.

    Directory of Open Access Journals (Sweden)

    Kensuke Tomio

    Full Text Available Omega-3 polyunsaturated fatty acids (omega-3 PUFAs play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE, derived from eicosapentaenoic acid (EPA, and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX-knockout (KO and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6 expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

  15. Omega-3 polyunsaturated Fatty acids suppress the cystic lesion formation of peritoneal endometriosis in transgenic mouse models.

    Science.gov (United States)

    Tomio, Kensuke; Kawana, Kei; Taguchi, Ayumi; Isobe, Yosuke; Iwamoto, Ryo; Yamashita, Aki; Kojima, Satoko; Mori, Mayuyo; Nagamatsu, Takeshi; Arimoto, Takahide; Oda, Katsutoshi; Osuga, Yutaka; Taketani, Yuji; Kang, Jing X; Arai, Hiroyuki; Arita, Makoto; Kozuma, Shiro; Fujii, Tomoyuki

    2013-01-01

    Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) play a role in controlling pathological inflammatory reactions. Endometriosis is characterized by the presence of endometrial tissue on the peritoneum and an exaggerated inflammatory environment around ectopic tissues. Here peritoneal endometriosis was reproduced using a mouse model in which murine endometrial fragments were inoculated into the peritoneal cavity of mice. Fat-1 mice, in which omega-6 can be converted to omega-3 PUFAs, or wild type mice, in which it cannot, were used for the endometriosis model to address the actions of omega-3 PUFAs on the development of endometriotic lesions. The number and weight of cystic endometriotic lesions in fat-1 mice two weeks after inoculation were significantly less than half to those of controls. Mediator lipidomics revealed that cystic endometriotic lesions and peritoneal fluids were abundant in 12/15-hydroxyeicosapentaenoic acid (12/15-HEPE), derived from eicosapentaenoic acid (EPA), and their amount in fat-1 mice was significantly larger than that in controls. 12/15-Lipoxygenase (12/15-LOX)-knockout (KO) and control mice with or without EPA administration were assessed for the endometriosis model. EPA administration decreased the number of lesions in controls but not in 12/15-LOX-KO mice. The peritoneal fluids in EPA-fed 12/15-LOX-KO mice contained reduced levels of EPA metabolites such as 12/15-HEPE and EPA-derived resolvin E3 even after EPA administration. cDNA microarrays of endometriotic lesions revealed that Interleukin-6 (IL-6) expression in fat-1 mice was significantly lower than that in controls. These results suggest that both endogenous and exogenous EPA-derived PUFAs protect against the development of endometriosis through their anti-inflammatory effects and, in particular, the 12/15-LOX-pathway products of EPA may be key mediators to suppress endometriosis.

  16. 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

  17. Involvement of TNF-α converting enzyme in the development of psoriasis-like lesions in a mouse model.

    Directory of Open Access Journals (Sweden)

    Kenji Sato

    Full Text Available TNF-α plays a crucial role in psoriasis; therefore, TNF inhibition has become a gold standard for the treatment of psoriasis. TNF-α is processed from a membrane-bound form by TNF-α converting enzyme (TACE to soluble form, which exerts a number of biological activities. EGF receptor (EGFR ligands, including heparin-binding EGF-like growth factor (HB-EGF, amphiregulin and transforming growth factor (TGF-α are also TACE substrates and are psoriasis-associated growth factors. Vascular endothelial growth factor (VEGF, one of the downstream molecules of EGFR and TNF signaling, plays a key role in angiogenesis for developing psoriasis. In the present study, to assess the possible role of TACE in the pathogenesis of psoriasis, we investigated the involvement of TACE in TPA-induced psoriasis-like lesions in K5.Stat3C mice, which represent a mouse model of psoriasis. In this mouse model, TNF-α, amphiregulin, HB-EGF and TGF-α were significantly up-regulated in the skin lesions, similar to human psoriasis. Treatment of K5.Stat3C mice with TNF-α or EGFR inhibitors attenuated the skin lesions, suggesting the roles of TACE substrates in psoriasis. Furthermore, the skin lesions of K5.Stat3C mice showed down-regulation of tissue inhibitor of metalloproteinase-3, an endogenous inhibitor of TACE, and an increase in soluble TNF-α. A TACE inhibitor abrogated EGFR ligand-dependent keratinocyte proliferation and VEGF production in vitro, suggesting that TACE was involved in both epidermal hyperplasia and angiogenesis during psoriasis development. These results strongly suggest that TACE contributes to the development of psoriatic lesions through releasing two kinds of psoriasis mediators, TNF-α and EGFR ligands. Therefore, TACE could be a potential therapeutic target for the treatment of psoriasis.

  18. Gypenosides ameliorate memory deficits in MPTP-lesioned mouse model of Parkinson's disease treated with L-DOPA.

    Science.gov (United States)

    Zhao, Ting Ting; Kim, Kyung Sook; Shin, Keon Sung; Park, Hyun Jin; Kim, Hyun Jeong; Lee, Kyung Eun; Lee, Myung Koo

    2017-09-06

    Previous studies have revealed that gypenosides (GPS) improve the symptoms of anxiety disorders in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rat model of Parkinson's disease (PD). The present study aimed to investigate the effects of GPS on memory deficits in an MPTP-lesioned mouse model of PD treated with L-3,4-dihydroxyphenylalanine (L-DOPA). MPTP (30 mg/kg/day, 5 days)-lesioned mice were treated with GPS (50 mg/kg) and/or L-DOPA (10 and 25 mg/kg) for 21 days. After the final treatments, behavioral changes were assessed in all mice using passive avoidance and elevated plus-maze tests. We then evaluated the biochemical influences of GPS treatment on levels of tyrosine hydroxylase (TH), dopamine, N-methyl-D-aspartate (NMDA) receptors, extracellular signal-regulated kinase (ERK1/2), and cyclic AMP-response element binding protein (CREB) phosphorylation. MPTP-lesioned mice exhibited deficits associated with habit learning and spatial memory, which were further aggravated by treatment with L-DOPA (25 mg/kg). However, treatment with GPS (50 mg/kg) ameliorated memory deficits. Treatment with GPS (50 mg/kg) also improved L-DOPA (25 mg/kg)-treated MPTP lesion-induced decreases in retention latency on the passive avoidance test, as well as levels of TH-immunopositive cells and dopamine in the substantia nigra and striatum. GPS treatment also attenuated increases in retention transfer latency on the elevated plus-maze test and in NMDA receptor expression, as well as decreases in the phosphorylation of ERK1/2 and CREB in the hippocampus. Treatment with L-DOPA (10 mg/kg) also ameliorated deficits in habit learning and spatial memory in MPTP-lesioned mice, and this effect was further enhanced by treatment with GPS (50 mg/kg). GPS ameliorate deficits in habit learning and spatial memory by modulating the dopaminergic neuronal and N-methyl-D-aspartate receptor-mediated signaling systems in MPTP-lesioned mice treated with L-DOPA. GPS may serve as an adjuvant

  19. Maxillary Bone Regeneration Based on Nanoreservoirs Functionalized ε-Polycaprolactone Biomembranes in a Mouse Model of Jaw Bone Lesion

    Directory of Open Access Journals (Sweden)

    Marion Strub

    2018-01-01

    Full Text Available Current approaches of regenerative therapies constitute strategies for bone tissue reparation and engineering, especially in the context of genetical diseases with skeletal defects. Bone regeneration using electrospun nanofibers’ implant has the following objectives: bone neoformation induction with rapid healing, reduced postoperative complications, and improvement of bone tissue quality. In vivo implantation of polycaprolactone (PCL biomembrane functionalized with BMP-2/Ibuprofen in mouse maxillary defects was followed by bone neoformation kinetics evaluation using microcomputed tomography. Wild-Type (WT and Tabby (Ta mice were used to compare effects on a normal phenotype and on a mutant model of ectodermal dysplasia (ED. After 21 days, no effect on bone neoformation was observed in Ta treated lesion (4% neoformation compared to 13% in the control lesion. Between the 21st and the 30th days, the use of biomembrane functionalized with BMP-2/Ibuprofen in maxillary bone lesions allowed a significant increase in bone neoformation peaks (resp., +8% in mutant Ta and +13% in WT. Histological analyses revealed a neoformed bone with regular trabecular structure, areas of mineralized bone inside the membrane, and an improved neovascularization in the treated lesion with bifunctionalized membrane. In conclusion, PCL functionalized biomembrane promoted bone neoformation, this effect being modulated by the Ta bone phenotype responsible for an alteration of bone response.

  20. 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....

  1. 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...

  2. A lesion model of envy and Schadenfreude: legal, deservingness and moral dimensions as revealed by neurodegeneration

    Science.gov (United States)

    Santamaría-García, Hernando; Baez, Sandra; Reyes, Pablo; Santamaría-García, José A; Santacruz-Escudero, José M; Matallana, Diana; Arévalo, Analía; Sigman, Mariano; García, Adolfo M; Ibáñez, Agustín

    2017-01-01

    Abstract The study of moral emotions (i.e. Schadenfreude and envy) is critical to understand the ecological complexity of everyday interactions between cognitive, affective, and social cognition processes. Most previous studies in this area have used correlational imaging techniques and framed Schadenfreude and envy as unified and monolithic emotional domains. Here, we profit from a relevant neurodegeneration model to disentangle the brain regions engaged in three dimensions of Schadenfreude and envy: deservingness, morality, and legality. We tested a group of patients with behavioural variant frontotemporal dementia (bvFTD), patients with Alzheimer’s disease, as a contrastive neurodegeneration model, and healthy controls on a novel task highlighting each of these dimensions in scenarios eliciting Schadenfreude and envy. Compared with the Alzheimer’s disease and control groups, patients with bvFTD obtained significantly higher scores on all dimensions for both emotions. Correlational analyses revealed an association between envy and Schadenfreude scores and greater deficits in social cognition, inhibitory control, and behaviour disturbances in bvFTD patients. Brain anatomy findings (restricted to bvFTD and controls) confirmed the partially dissociable nature of the moral emotions’ experiences and highlighted the importance of socio-moral brain areas in processing those emotions. In all subjects, an association emerged between Schadenfreude and the ventral striatum, and between envy and the anterior cingulate cortex. In addition, the results supported an association between scores for moral and legal transgression and the morphology of areas implicated in emotional appraisal, including the amygdala and the parahippocampus. By contrast, bvFTD patients exhibited a negative association between increased Schadenfreude and envy across dimensions and critical regions supporting social-value rewards and social-moral processes (dorsolateral prefrontal cortex, angular

  3. A lesion model of envy and Schadenfreude: legal, deservingness and moral dimensions as revealed by neurodegeneration.

    Science.gov (United States)

    Santamaría-García, Hernando; Baez, Sandra; Reyes, Pablo; Santamaría-García, José A; Santacruz-Escudero, José M; Matallana, Diana; Arévalo, Analía; Sigman, Mariano; García, Adolfo M; Ibáñez, Agustín

    2017-12-01

    The study of moral emotions (i.e. Schadenfreude and envy) is critical to understand the ecological complexity of everyday interactions between cognitive, affective, and social cognition processes. Most previous studies in this area have used correlational imaging techniques and framed Schadenfreude and envy as unified and monolithic emotional domains. Here, we profit from a relevant neurodegeneration model to disentangle the brain regions engaged in three dimensions of Schadenfreude and envy: deservingness, morality, and legality. We tested a group of patients with behavioural variant frontotemporal dementia (bvFTD), patients with Alzheimer's disease, as a contrastive neurodegeneration model, and healthy controls on a novel task highlighting each of these dimensions in scenarios eliciting Schadenfreude and envy. Compared with the Alzheimer's disease and control groups, patients with bvFTD obtained significantly higher scores on all dimensions for both emotions. Correlational analyses revealed an association between envy and Schadenfreude scores and greater deficits in social cognition, inhibitory control, and behaviour disturbances in bvFTD patients. Brain anatomy findings (restricted to bvFTD and controls) confirmed the partially dissociable nature of the moral emotions' experiences and highlighted the importance of socio-moral brain areas in processing those emotions. In all subjects, an association emerged between Schadenfreude and the ventral striatum, and between envy and the anterior cingulate cortex. In addition, the results supported an association between scores for moral and legal transgression and the morphology of areas implicated in emotional appraisal, including the amygdala and the parahippocampus. By contrast, bvFTD patients exhibited a negative association between increased Schadenfreude and envy across dimensions and critical regions supporting social-value rewards and social-moral processes (dorsolateral prefrontal cortex, angular gyrus and

  4. 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

  5. [Establishment of rat model with diabetes mellitus and concomitant periodontitis and the carotid artery lesions in the model rats].

    Science.gov (United States)

    Ren, X Y; Wang, C; Liu, X; Li, H; Gao, J H; Ge, X J

    2017-12-09

    Objectives: To establish SD rat model with type 2 diabetes mellitus (DM) and concomitant chronic periodontitis (CP) and to evaluate the influence of periodontitis on the vascular lesions of type 2 diabetes rats. Methods: Totally 241 clean level SD rats were randomly divided into four groups, group A (normal control, NC, n= 27), group B (DM, n= 34), group C (CP, n= 90) and group D (DM+CP, n= 90). The rats of DM group were fed with high-fat and high-sugar diet for 8 to 10 weeks, and then were multiply injected with small dose streptozotocin under the condition of ice bath. Blood sugar levels after the injection were dynamically monitored at 72 h, 1 week, 2 weeks and 4 weeks, respectively. The CP model was established by means of ligation. Bilateral maxillary first and second molars were selected and ligated using 0.2 mm orthodontic wires binding with 4-0 surgical suture soaked with Porphyromonas gingivalis (Pg) suspension. After a period of 14 weeks, all the rats were put to death. Maxillary samples were subjected to methylene blue staining to observe alveolar bone loss. Bilateral carotid artery specimens were collected. The left carotid artery specimens were used to detect the prevalence of Pg using quantitative real-time PCR. The right carotid artery specimens were used to observe pathological changes. Results: Blood sugar levels of rats in group B and D increased and changed sharply after Streptozotocin injection with in 1 week. Symptoms of 'more drink, more food and body weight loss' appeared. The fasting blood glucose (FBG) was more than 7.8 mmol/L and (or) the random blood glucose (RBG) was more than 17.8 mmol/L. Both FBG and RBG became stable after 2 to 3 weeks. Levels of HbA1C in group B and D ([7.32±0.45]%, [9.41±0.45]%) were significantly higher than that of group A ([4.02±0.45]%) ( Pdiabetes vascular lesions.

  6. Correlation between phosphorylation level of a hippocampal 86kDa protein and extinction of a behaviour in a model of Wernicke-Korsakoff syndrome.

    Science.gov (United States)

    Pires, Rita G W; Pereira, Sílvia R C; Carvalho, Fabiana M; Oliveira-Silva, Ieda F; Ferraz, Vany P; Ribeiro, Angela M

    2007-06-04

    The effects of chronic ethanol and thiamine deficiency, alone or associated, on hippocampal protein phosphorylation profiles ranging in molecular weight from 30 to 250kDa molecular weight, in stimulated (high K(+) concentration) and unstimulated (basal) conditions were investigated. These treatments significantly changed the phosphorylation level of an 86kDa phosphoprotein. Thiamine deficiency, but not chronic ethanol, induced a decrease in a behavioural extinction index, which is significantly correlated to the phosphorylation level of the p86 protein. These data add to and extend previous findings by our laboratory implicating the involvement of hippocampal neurotransmission components in extinction of a behaviour which involves learning of environmental spatial cues.

  7. RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.

    Science.gov (United States)

    Sinkevicius, Kerstin W; Morrison, Thomas R; Kulkarni, Praveen; Cagliostro, Martha K Caffrey; Iriah, Sade; Malmberg, Samantha; Sabrick, Julia; Honeycutt, Jennifer A; Askew, Kim L; Trivedi, Malav; Ferris, Craig F

    2018-05-10

    RNASET2 deficiency in humans is associated with infant cystic leukoencephalopathy, which causes psychomotor impairment, spasticity, and epilepsy. A zebrafish mutant model suggests that loss of RNASET2 function leads to neurodegeneration due to the accumulation of non-degraded RNA in the lysosomes. The goal of this study was to characterize the first rodent model of RNASET2 deficiency. The brains of 3- and 12-month-old RNaseT2 knockout rats were studied using multiple magnetic resonance imaging modalities and behavioral tests. While T1 and T2 weighted images of RNaseT2 knockout rats exhibited no evidence of cystic lesions, the prefrontal cortex and hippocampal complex were enlarged in knockout animals. Diffusion weighted imaging showed altered anisotropy and putative gray matter changes in the hippocampal complex of the RNaseT2 knockout rats. Immunohistochemistry for glial fibrillary acidic protein (GFAP) showed the presence of hippocampal neuroinflammation. Decreased levels of lysosome-associated membrane protein 2 (LAMP2) and elevated acid phosphatase and β-N-Acetylglucosaminidase (NAG) activities indicated that the RNASET2 knockout rats likely had altered lysosomal function and potential defects in autophagy. Object recognition tests confirmed the RNaseT2 knockout rats exhibited memory deficits. However, the Barnes maze, and balance beam and rotarod tests, indicated there were no differences in spatial memory or motor impairments, respectively. Overall, patients with RNASET2 deficiency exhibited a more severe neurodegeneration phenotype than was observed in the RNaseT2 knockout rats. However, the vulnerability of the knockout rat hippocampus as evidenced by neuroinflammation, altered lysosomal function, and cognitive defects indicates this is still a useful in vivo model to study RNASET2 function. © 2018. Published by The Company of Biologists Ltd.

  8. 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...

  9. MRI lesion and epileptogenic focus in temporal lobe epilepsy

    International Nuclear Information System (INIS)

    Matsuda, Kazumi; Yagi, Kazuichi; Mihara, Tadahiro; Tottori, Takayasu; Watanabe, Yutaka; Seino, Masakazu

    1989-01-01

    The spatial relationship between a circumscribed lesion in the temporal lobe detected by MRI and an epileptogenic focus identified by ictal depth EEG along with a correlation of the MRI lesion with neuropathological findings were investigated in patients with medically intractable temporal lobe epilepsy but without any focal lesion on CT. Four parameters (an areal ratio of the temporal lobe against the hemisphere, area and calculated T1, T2 values of the hippocampus) were used to determine the abnormal MRI side. An agreement was reached in 67-72% of 18 patients between the abnormal values of the hippocampal area and of calculated T1, T2 and the side of the epileptogenic focus. In 14 of 17 patients, typical hippocampal sclerosis was demonstrated in resected tissue in accordance with the MRI lesions (atrophy and/or prolonged T2 of hippocampus). These results imply: 1)MRI abnormality thus defined may, if not all, indicate the side of the epileptogenic focus, and 2)also the presence of hippocampal sclerosis. It was emphasized that the MRI lesion would be a usable instrument to explore the causal relationship of hippocampal sclerosis to a generation of epileptogenic lesions as well as for presurgical evalution. (author)

  10. Gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves against acute gastric lesion models in rodents

    Directory of Open Access Journals (Sweden)

    Hélio B Fernandes

    2010-01-01

    Full Text Available Parkia platycephala Benth. (Leguminosae - Mimosoideae, popularly known as "visgueira", fava bean tree or "fava-de-bolota", is widely found in the Northern and Northeastern regions of Brazil. Its pods are used as cattle food supplement in the drought period. Compounds with a gastroprotective activity were obtained from the genus Parkia. Therefore, this study aimed at investigating the gastroprotective effect of the ethanolic extract of Parkia platycephala Benth. leaves (Pp-EtOH, as well as evaluating its possible mechanisms of action in experimental ulcer induction models. Lesions were induced by absolute ethanol, ethanol-HCl, ischemia-reperfusion and indomethacin in rodents. Pp-EtOH showed a protective effect in the lesion models (66, 48 and 52 %, respectively, but it was not able to protect gastric mucosa against indomethacin-induced lesions. Results show a possible participation of the NO-synthase pathway in the gastroprotection and an antioxidant activity, by the increase of the catalase activity. The participation of prostaglandins and potassium channels sensitive to ATP in the gastroprotective effect of Pp-EtOH seems less likely to occur. More comprehensive studies, therefore, should be carried out to elucidate the antiulcerative effects of this promising natural product against this gastrointestinal disorder.

  11. PARP Inhibition Attenuates Histopathological Lesion in Ischemia/Reperfusion Renal Mouse Model after Cold Prolonged Ischemia

    Directory of Open Access Journals (Sweden)

    Raimundo M. G. del Moral

    2013-01-01

    Full Text Available We test the hypothesis that PARP inhibition can decrease acute tubular necrosis (ATN and other renal lesions related to prolonged cold ischemia/reperfusion (IR in kidneys preserved at 4°C in University of Wisconsin (UW solution. Material and Methods. We used 30 male Parp1+/+ wild-type and 15 male Parp10/0 knockout C57BL/6 mice. Fifteen of these wild-type mice were pretreated with 3,4-dihydro-5-[4-(1-piperidinylbutoxyl]-1(2H-isoquinolinone (DPQ at a concentration of 15 mg/kg body weight, used as PARP inhibitor. Subgroups of mice were established (A: IR 45 min/6 h; B: IR + 48 h in UW solution; and C: IR + 48 h in UW solution plus DPQ. We processed samples for morphological, immunohistochemical, ultrastructural, and western-blotting studies. Results. Prolonged cold ischemia time in UW solution increased PARP-1 expression and kidney injury. Preconditioning with PARP inhibitor DPQ plus DPQ supplementation in UW solution decreased PARP-1 nuclear expression in renal tubules and renal damage. Parp10/0 knockout mice were more resistant to IR-induced renal lesion. In conclusion, PARP inhibition attenuates ATN and other IR-related renal lesions in mouse kidneys under prolonged cold storage in UW solution. If confirmed, these data suggest that pharmacological manipulation of PARP activity may have salutary effects in cold-stored organs at transplantation.

  12. Chronic Hippocampal Expression of Notch Intracellular Domain Induces Vascular Thickening, Reduces Glucose Availability, and Exacerbates Spatial Memory Deficits in a Rat Model of Early Alzheimer.

    Science.gov (United States)

    Galeano, Pablo; Leal, María C; Ferrari, Carina C; Dalmasso, María C; Martino Adami, Pamela V; Farías, María I; Casabona, Juan C; Puntel, Mariana; Do Carmo, Sonia; Smal, Clara; Arán, Martín; Castaño, Eduardo M; Pitossi, Fernando J; Cuello, A Claudio; Morelli, Laura

    2018-03-26

    The specific roles of Notch in progressive adulthood neurodegenerative disorders have begun to be unraveled in recent years. A number of independent studies have shown significant increases of Notch expression in brains from patients at later stages of sporadic Alzheimer's disease (AD). However, the impact of Notch canonical signaling activation in the pathophysiology of AD is still elusive. To further investigate this issue, 2-month-old wild-type (WT) and hemizygous McGill-R-Thy1-APP rats (Tg(+/-)) were injected in CA1 with lentiviral particles (LVP) expressing the transcriptionally active fragment of Notch, known as Notch Intracellular Domain (NICD), (LVP-NICD), or control lentivirus particles (LVP-C). The Tg(+/-) rat model captures presymptomatic aspects of the AD pathology, including intraneuronal amyloid beta (Aβ) accumulation and early cognitive deficits. Seven months after LVP administration, Morris water maze test was performed, and brains isolated for biochemical and histological analysis. Our results showed a learning impairment and a worsening of spatial memory in LVP-NICD- as compared to LVP-C-injected Tg(+/-) rats. In addition, immuno histochemistry, ELISA multiplex, Western blot, RT-qPCR, and 1 H-NMR spectrometry of cerebrospinal fluid (CSF) indicated that chronic expression of NICD promoted hippocampal vessel thickening with accumulation of Aβ in brain microvasculature, alteration of blood-brain barrier (BBB) permeability, and a decrease of CSF glucose levels. These findings suggest that, in the presence of early Aβ pathology, expression of NICD may contribute to the development of microvascular abnormalities, altering glucose transport at the BBB with impact on early decline of spatial learning and memory.

  13. Increased stress reactivity is associated with cognitive deficits and decreased hippocampal brain-derived neurotrophic factor in a mouse model of affective disorders.

    Science.gov (United States)

    Knapman, A; Heinzmann, J-M; Hellweg, R; Holsboer, F; Landgraf, R; Touma, C

    2010-07-01

    Cognitive deficits are a common feature of major depression (MD), with largely unknown biological underpinnings. In addition to the affective and cognitive symptoms of MD, a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is commonly observed in these patients. Increased plasma glucocorticoid levels are known to render the hippocampus susceptible to neuronal damage. This structure is important for learning and memory, creating a potential link between HPA axis dysregulation and cognitive deficits in depression. In order to further elucidate how altered stress responsiveness may contribute to the etiology of MD, three mouse lines with high (HR), intermediate (IR), or low (LR) stress reactivity were generated by selective breeding. The aim of the present study was to investigate whether increased stress reactivity is associated with deficits in hippocampus-dependent memory tests. To this end, we subjected mice from the HR, IR, and LR breeding lines to tests of recognition memory, spatial memory, and depression-like behavior. In addition, measurements of brain-derived neurotrophic factor (BDNF) in the hippocampus and plasma of these animals were conducted. Our results demonstrate that HR mice exhibit hippocampus-dependent memory deficits along with decreased hippocampal, but not plasma, BDNF levels. Thus, the stress reactivity mouse lines are a promising animal model of the cognitive deficits in MD with the unique feature of a genetic predisposition for an altered HPA axis reactivity, which provides the opportunity to explore the progression of the symptoms of MD, predisposing genetic factors as well as new treatment strategies. Copyright 2009 Elsevier Ltd. All rights reserved.

  14. The effect of pre-eclampsia-like syndrome induced by L-NAME on learning and memory and hippocampal glucocorticoid receptor expression: A rat model.

    Science.gov (United States)

    Zhu, Hao; Zhu, Weimin; Hu, Rong; Wang, Huijun; Ma, Duan; Li, Xiaotian

    2017-02-01

    We aimed to study the impacts of pre-eclampsia on the cognitive and learning capabilities of adolescent rat offspring and to explore the possible underlying mechanisms at the molecular level. Pregnant rats were subcutaneously injected with saline solution (control) (n = 16) or NG-nitro-L-arginine methyl ester (L-NAME) (n = 16) from the 13th day of gestation until parturition. The brain tissues from fetal rats delivered by cesarean section were examined in both groups with hematoxylin and eosin (H&E) staining. Rats born vaginally in both groups were subjected to the Morris water maze test when 8-week-old and their hippocampi were analyzed for glucocorticoid receptor (GR) expression. A pre-eclampsia-like model was successfully built in pregnant rats by infusion of the NO synthase inhibitor L-NAME, including phenotypes as maternal hypertension and proteinuria, high stillbirth rate, and fetal growth retardation. Neuroepithelial cell proliferation was found in the hippocampus of fetal rats in the L-NAME group. Grown to 8-week-old, the L-NAME group showed significantly longer escape latency than the control group in the beginning as well as in the end of navigation trials. At the same time, the swimming distance achieved by the L-NAME group was significantly longer than that of the control group. Such differences in cognitive and learning capabilities between the two groups were not gender dependent. Besides, the 8-week-old rats in the L-NAME group had increased GR expression in the hippocampus than the control group. Pre-eclampsia would impair cognitive and learning capabilities in adolescent offspring, and the upregulated expression of hippocampal GR may be involved in the underlying mechanisms.

  15. Comparison of the influence of two models of mild stress on hippocampal brain-derived neurotrophin factor (BDNF) immunoreactivity in old age rats.

    Science.gov (United States)

    Badowska-Szalewska, Ewa; Ludkiewicz, Beata; Krawczyk, Rafał; Melka, Natalia; Moryś, Janusz

    2017-01-01

    The way hippocampal neurons function during stress in old age (critical times of life) is dependent on brain derived neurotrophin factor (BDNF). This study examined the influence of acute and chronic forced swim (FS) or high-light open field (HL‑OF) stimulation on the density of BDNF immunoreactive (ir) neurons in the hippocampal pyramidal layers of CA1, CA2, CA3 regions and the granular layer of dentate gyrus (DG) in old (postnatal day 720; P720) Wistar Han rats. Our data showed that in comparison with non-stressed rats, acute FS caused a significant increase in the density of BDNF-ir neurons in CA2 and CA3, while acute HL-OF led to an increase in this factor in all hippocampal subfields with the exception of DG. However, the density of BDNF-ir cells remained unchanged after exposure to chronic FS or HL‑OF in the hippocampal regions in relation to the control rats. These results indicate that acute FS or HL-OF proved to be a stressor that induces an increase in the density of BDNF-ir pyramidal neurons, which was probably connected with up-regulation of HPA axis activity and short‑time memory processing of the stressful situation. Moreover, as far as the influence on BDNF-ir cells in hippocampus is concerned, chronic FS or HL-OF was not an aggravating factor for rats in the ontogenetic periods studied.

  16. The cannabinoid receptor CB1 contributes to the development of ectopic lesions in a mouse model of endometriosis.

    Science.gov (United States)

    Sanchez, Ana-Maria; Quattrone, Federica; Pannese, Maria; Ulisse, Adele; Candiani, Massimo; Diaz-Alonso, Javier; Velasco, Guillermo; Panina-Bordignon, Paola

    2017-01-01

    Does signaling via the cannabinoid (CB 1 ) receptor play a role in the pathogenesis of endometriosis in a mouse model? Mice treated with a CB 1 agonist developed larger ectopic lesions, while less severe lesions developed in the absence of functional CB 1 expression. The expression of components of the endocannabinoid system has been demonstrated in both mouse and human uteri. CB 1 receptors are expressed in human epithelial and stromal cell lines derived from eutopic endometrium and deep infiltrating endometriosis nodules. This was a randomized study in a mouse model of endometriosis. In a first set of experiments, mice with endometriosis were treated with the CB 1 receptor agonist methanandamide (MET) (5 mg/kg, n = 20) on Days 1-5 and 8-12. In a second set of experiments, endometriosis development was evaluated in CB 1 -/- mice and in their wild-type (WT) littermates. Endometriosis-like lesions were induced in Balb/c and C57/Bl6 mice. Two weeks after disease induction, the lesions were counted, measured and either included for immunohistochemistry analysis or frozen for gene expression profiling by semi-quantitative real-time PCR. To limit the role of chance, the experiments were conducted under standardized laboratory conditions with appropriate controls. The lesion total volume was significantly higher in MET-treated compared with vehicle-treated mice (P endometriosis in a mouse model. However, the relative contribution of the CB 1 -mediated signaling pathways active in inflammatory, uterine and peritoneal cells remains to be ascertained. Since the study was performed in a mouse model, the significance of the findings in the human system warrants further investigation. Clarifying the function and regulation of CB 1 and its molecular interactions with endogenous ligands, and how endocannabinoids levels are regulated in women with endometriosis, represent critical areas of research for the potential development of a novel medical treatment of the disease. A

  17. A rat model of post-traumatic stress disorder reproduces the hippocampal deficits seen in the human syndrome

    OpenAIRE

    Goswami, Sonal; Samuel, Sherin; Sierra, Olga R.; Cascardi, Michele; Paré, Denis

    2012-01-01

    Despite recent progress, the causes and pathophysiology of post-traumatic stress disorder (PTSD) remain poorly understood, partly because of ethical limitations inherent to human studies. One approach to circumvent this obstacle is to study PTSD in a valid animal model of the human syndrome. In one such model, extreme and long-lasting behavioral manifestations of anxiety develop in a subset of Lewis rats after exposure to an intense predatory threat that mimics the type of life-and-death situ...

  18. Neuroprotective mechanism of Lycium barbarum polysaccharides against hippocampal-dependent spatial memory deficits in a rat model of obstructive sleep apnea.

    Directory of Open Access Journals (Sweden)

    Chun-Sing Lam

    Full Text Available Chronic intermittent hypoxia (CIH is a hallmark of obstructive sleep apnea (OSA, which induces hippocampal injuries mediated by oxidative stress. This study aims to examine the neuroprotective mechanism of Lycium barbarum polysaccharides (LBP against CIH-induced spatial memory deficits. Adult Sprague-Dawley rats were exposed to hypoxic treatment resembling a severe OSA condition for a week. The animals were orally fed with LBP solution (1 mg/kg daily 2 hours prior to hypoxia or in air for the control. The effect of LBP on the spatial memory and levels of oxidative stress, inflammation, endoplasmic reticulum (ER stress, apoptosis and neurogenesis in the hippocampus was examined. There was a significant deficit in the spatial memory and an elevated level of malondialdehyde with a decreased expression of antioxidant enzymes (SOD, GPx-1 in the hypoxic group when compared with the normoxic control. In addition, redox-sensitive nuclear factor kappa B (NFКB canonical pathway was activated with a translocation of NFКB members (p65, p50 and increased expression levels of NFКB-dependent inflammatory cytokines and mediator (TNFα, IL-1β, COX-2; also, a significantly elevated level of ER stress (GRP78/Bip, PERK, CHOP and autophagic flux in the hypoxic group, leading to neuronal apoptosis in hippocampal subfields (DG, CA1, CA3. Remarkably, LBP administration normalized the elevated level of oxidative stress, neuroinflammation, ER stress, autophagic flux and apoptosis induced by hypoxia. Moreover, LBP significantly mitigated both the caspase-dependent intrinsic (Bax, Bcl2, cytochrome C, cleaved caspase-3 and extrinsic (FADD, cleaved caspase-8, Bid signaling apoptotic cascades. Furthermore, LBP administration prevented the spatial memory deficit and enhanced the hippocampal neurogenesis induced by hypoxia. Our results suggest that LBP is neuroprotective against CIH-induced hippocampal-dependent spatial memory deficits by promoting hippocampal neurogenesis

  19. 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.

  20. Neuroprotective effect of the methanolic extract of Hibiscus asper leaves in 6-hydroxydopamine-lesioned rat model of Parkinson's disease.

    Science.gov (United States)

    Hritcu, Lucian; Foyet, Harquin Simplice; Stefan, Marius; Mihasan, Marius; Asongalem, Acha Emmanuel; Kamtchouing, Pierre

    2011-09-01

    While the Hibiscus asper Hook.f. (Malvaceae) is a traditional herb largely used in tropical region of the Africa as vegetable, potent sedative, tonic and restorative, anti-inflammatory and antidepressive drug, there is very little scientific data concerning the efficacy of this. The antioxidant and antiapoptotic activities of the methanolic extract of Hibiscus asper leaves (50 and 100 mg/kg) were assessed using superoxide dismutase (SOD), glutathione peroxidase (GPX) and catalase (CAT) specific activities, total glutathione (GSH) content, malondialdehyde (MDA) level (lipid peroxidation) and DNA fragmentation assays in male Wistar rats subjected to unilateral 6-hydroxydopamine (6-OHDA)-lesion. In 6-OHDA-lesioned rats, methanolic extract of Hibiscus asper leaves showed potent antioxidant and antiapoptotic activities. Chronic administration of the methanolic extract (50 and 100 mg/kg, i.p., daily, for 7 days) significantly increased antioxidant enzyme activities (SOD, GPX and CAT), total GSH content and reduced lipid peroxidation (MDA level) in rat temporal lobe homogenates, suggesting antioxidant activity. Also, DNA cleavage patterns were absent in the 6-OHDA-lesioned rats treated with methanolic extract of Hibiscus asper leaves, suggesting antiapoptotic activity. Taken together, our results suggest that the methanolic extract of Hibiscus asper leaves possesses neuroprotective activity against 6-OHDA-induced toxicity through antioxidant and antiapoptotic activities in Parkinson's disease model. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  1. Caffeine improves attention deficit in neonatal 6-OHDA lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD).

    Science.gov (United States)

    Caballero, Miguel; Núñez, Fabiana; Ahern, Siobhán; Cuffí, Maria L; Carbonell, Lourdes; Sánchez, Silvia; Fernández-Dueñas, Víctor; Ciruela, Francisco

    2011-04-20

    Nowadays the pharmacological treatment of the attention deficit hyperactivity disorder (ADHD) is based on amphetamine derivatives (i.e. methylphenidate). However, these drugs induce a large array of adverse side effects, thus less aggressive psychostimulant drugs (i.e. caffeine) are being proposed in the management of ADHD. Following this tendency, we decided to study the possible therapeutic use of caffeine in an animal model of ADHD, namely the neonatal 6-hydroxy-dopamine (6-OHDA)-lesioned rat. Therefore, at postnatal day 7 rats were lesioned at the left striatum with 6-OHDA or with saline. Thereafter, at postnatal day 25 their activity and attention were measured with the Olton maze before caffeine was administered ad libitum in the drinking water. Next, after 14 days of caffeine treatment, we repeated these measurements to assess the effect of caffeine on motor activity and attention deficit. Interestingly, while no changes in the motor activity measurements were observed before and after caffeine administration, a significant improvement in the attention deficit of the 6-OHDA lesioned rats was achieved after caffeine treatment. Thus, our results led us to hypothesize that caffeine might be useful to manage the attention deficit during the prepubertal period of ADHD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  2. Model observer for assessing digital breast tomosynthesis for multi-lesion detection in the presence of anatomical noise

    Science.gov (United States)

    Wen, Gezheng; Markey, Mia K.; Miner Haygood, Tamara; Park, Subok

    2018-02-01

    Model observers are widely used in task-based assessments of medical image quality. The presence of multiple abnormalities in a single set of images, such as in multifocal multicentric breast cancer (MFMC), has an immense clinical impact on treatment planning and survival outcomes. Detecting multiple breast tumors is challenging as MFMC is relatively uncommon, and human observers do not know the number or locations of tumors a priori. Digital breast tomosynthesis (DBT), in which an x-ray beam sweeps over a limited angular range across the breast, has the potential to improve the detection of multiple tumors. However, prior studies of DBT image quality all focus on unifocal breast cancers. In this study, we extended our 2D multi-lesion (ML) channelized Hotelling observer (CHO) into a 3D ML-CHO that detects multiple lesions from volumetric imaging data. Then we employed the 3D ML-CHO to identify optimal DBT acquisition geometries for detection of MFMC. Digital breast phantoms with multiple embedded synthetic lesions were scanned by simulated DBT scanners of different geometries (wide/narrow angular span, different number of projections per scan) to simulate MFMC cases. With new implementations of 3D partial least squares (PLS) and modified Laguerre-Gauss (LG) channels, the 3D ML-CHO made detection decisions based upon the overall information from individual DBT slices and their correlations. Our evaluation results show that: (1) the 3D ML-CHO could achieve good detection performance with a small number of channels, and 3D PLS channels on average outperform the counterpart LG channels; (2) incorporating locally varying anatomical backgrounds and their correlations as in the 3D ML-CHO is essential for multi-lesion detection; (3) the most effective DBT geometry for detection of MFMC may vary when the task of clinical interest changes, and a given DBT geometry may not yield images that are equally informative for detecting MF, MC, and unifocal cancers.

  3. Embryonic Cell Grafts in a Culture Model of Spinal Cord Lesion: Neuronal Relay Formation is Essential for Functional Regeneration

    Directory of Open Access Journals (Sweden)

    Anne Tscherter

    2016-09-01

    Full Text Available Presently there exists no cure for spinal cord injury. However, transplantation of embryonic tissue into spinal cord lesions resulted in axon outgrowth across the lesion site and some functional recovery, fostering hope for future stem cell therapies. Although in vivo evidence for functional recovery is given, the exact cellular mechanism of the graft support remains elusive: either the grafted cells provide a permissive environment for the host tissue to regenerate itself or the grafts actually integrate functionally into the host neuronal network reconnecting the separated spinal cord circuits. We tested the two hypotheses in an in vitro spinal cord lesion model that is based on propagation of activity between two rat organotypic spinal cord slices in culture. Transplantation of dissociated cells from E14 rat spinal cord or forebrain re-established the relay of activity over the lesion site and, thus, provoked functional regeneration. Combining patch-clamp recordings from transplanted cells with network activity measurements from the host tissue on multi-electrode arrays we here show that neurons differentiate from the grafted cells and integrate into the host circuits. Optogenetic silencing of neurons developed from transplanted embryonic mouse forebrain cells provides clear evidence that they replace the lost neuronal connections to relay and synchronize activity between the separated spinal cord circuits. In contrast, transplantation of neurospheres induced neither the differentiation of mature neurons from the grafts nor an improvement of functional regeneration. Together these findings suggest, that the formation of neuronal relays from grafted embryonic cells is essential to re-connect segregated spinal cord circuits.

  4. Establishment of a model of cochlear lesions in rats to study potential gene therapy for sensorineural hearing loss.

    Science.gov (United States)

    Wang, Ye; Qiao, Li; Chen, Yang; Wen, Liting; Yue, Bo; Qiu, Jianhua; Wu, Shengxi

    2015-12-01

    Sensorineural hearing loss seriously influences a patient's daily life, and no effective treatments exist to date. Gene therapy is a potential treatment for regenerating hair cells to restore hearing. In this study, we established a cochlear lesions model to study hair cell regeneration by co-administration of kanamycin and furosemide. After the injections, we assessed the survival of outer hair cells (OHC), inner hair cells (IHC), supporting cells (SC), spiral ganglion neurons (SGN) and peripheral axons. Moreover, we used two viral vectors to detect the transgene distribution. Our results showed at 12h post-treatment, numerous OHC were missing in the basal turn. At 24h post-treatment, all OHCs in basal half of the cochlea were lost, and by 48h, OHC loss had spread to the apical coil. Four days after the injections, all OHCs were absent. At 1mo post-treatment, the organ of Corti had collapsed. In contrast, most of the SC remained 4d after the injections. The loss of SGN and peripheral axons was consistent with this time course post-treatment. The results of transgene distribution suggested the correlative gene can be transferred into the organ of Corti using adenoviruses (AdV) vectors and lentiviruses (LV) vectors in our cochlear lesion model. We assessed the details of HC death at more time point and chosen the time point for gene transfer in this model. We conclude that this cochlear lesion model would be suitable for the study of hair cell regeneration. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  5. MICROARRAY PROFILE OF SEIZURE DAMAGE-REFRACTORY HIPPOCAMPAL CA3 IN A MOUSE MODEL OF EPILEPTIC PRECONDITIONING

    OpenAIRE

    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.

    2007-01-01

    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 preconditioni...

  6. A flavonoid agonist of the TrkB receptor for BDNF improves hippocampal neurogenesis and hippocampus-dependent memory in the Ts65Dn mouse model of DS.

    Science.gov (United States)

    Stagni, Fiorenza; Giacomini, Andrea; Guidi, Sandra; Emili, Marco; Uguagliati, Beatrice; Salvalai, Maria Elisa; Bortolotto, Valeria; Grilli, Mariagrazia; Rimondini, Roberto; Bartesaghi, Renata

    2017-12-01

    Intellectual disability is the unavoidable hallmark of Down syndrome (DS), with a heavy impact on public health. Reduced neurogenesis and impaired neuron maturation are considered major determinants of altered brain function in DS. Since the DS brain starts at a disadvantage, attempts to rescue neurogenesis and neuron maturation should take place as soon as possible. The brain-derived neurotrophic factor (BDNF) is a neurotrophin that plays a key role in brain development by specifically binding to tropomyosin-related kinase receptor B (TrkB). Systemic BDNF administration is impracticable because BDNF has a poor blood-brain barrier penetration. Recent screening of a chemical library has identified a flavone derivative, 7,8-dihydroxyflavone (7,8-DHF), a small-molecule that crosses the blood-brain barrier and binds with high affinity and specificity to the TrkB receptor. The therapeutic potential of TrkB agonists for neurogenesis improvement in DS has never been examined. The goal of our study was to establish whether it is possible to restore brain development in the Ts65Dn mouse model of DS by targeting the TrkB receptor with 7,8-DHF. Ts65Dn mice subcutaneously injected with 7,8-DHF in the neonatal period P3-P15 exhibited a large increase in the number of neural precursor cells in the dentate gyrus and restoration of granule cell number, density of dendritic spines and levels of the presynaptic protein synaptophysin. In order to establish the functional outcome of treatment, mice were treated with 7,8-DHF from P3 to adolescence (P45-50) and were tested with the Morris Water Maze. Treated Ts65Dn mice exhibited improvement of learning and memory, indicating that the recovery of the hippocampal anatomy translated into a functional rescue. Our study in a mouse model of DS provides novel evidence that treatment with 7,8-DHF during the early postnatal period restores the major trisomy-linked neurodevelopmental defects, suggesting that therapy with 7,8-DHF may represent a

  7. Effects of hippocampal lesioning on experimental periodontitis in Wistar rats

    NARCIS (Netherlands)

    Breivik, T.; Thrane, P.S.; Gjermo, P.; Cools, A.R.; Myhrer, T.

    2002-01-01

    The hippocampus, which is a brain structure involved in learning and memory processes, plays a key role in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic nervous system, and the subsequent secretion of immuno-modulatory hormones in response to

  8. Effects of hippocampal lesioning on experimental periodontitis in Wistar rats.

    NARCIS (Netherlands)

    Breivik, T.; Thrane, P.S.; Gjermo, P.; Cools, A.R.; Myhrer, T.

    2002-01-01

    The hippocampus, which is a brain structure involved in learning and memory processes, plays a key role in the feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic sympathetic nervous system, and the subsequent secretion of immuno-modulatory hormones in response to

  9. Dorsoventral and Proximodistal Hippocampal Processing Account for the Influences of Sleep and Context on Memory (Reconsolidation: A Connectionist Model

    Directory of Open Access Journals (Sweden)

    Justin Lines

    2017-01-01

    Full Text Available The context in which learning occurs is sufficient to reconsolidate stored memories and neuronal reactivation may be crucial to memory consolidation during sleep. The mechanisms of context-dependent and sleep-dependent memory (reconsolidation are unknown but involve the hippocampus. We simulated memory (reconsolidation using a connectionist model of the hippocampus that explicitly accounted for its dorsoventral organization and for CA1 proximodistal processing. Replicating human and rodent (reconsolidation studies yielded the following results. (1 Semantic overlap between memory items and extraneous learning was necessary to explain experimental data and depended crucially on the recurrent networks of dorsal but not ventral CA3. (2 Stimulus-free, sleep-induced internal reactivations of memory patterns produced heterogeneous recruitment of memory items and protected memories from subsequent interference. These simulations further suggested that the decrease in memory resilience when subjects were not allowed to sleep following learning was primarily due to extraneous learning. (3 Partial exposure to the learning context during simulated sleep (i.e., targeted memory reactivation uniformly increased memory item reactivation and enhanced subsequent recall. Altogether, these results show that the dorsoventral and proximodistal organization of the hippocampus may be important components of the neural mechanisms for context-based and sleep-based memory (reconsolidations.

  10. High-Risk Breast Lesions: A Machine Learning Model to Predict Pathologic Upgrade and Reduce Unnecessary Surgical Excision.

    Science.gov (United States)

    Bahl, Manisha; Barzilay, Regina; Yedidia, Adam B; Locascio, Nicholas J; Yu, Lili; Lehman, Constance D

    2018-03-01

    Purpose To develop a machine learning model that allows high-risk breast lesions (HRLs) diagnosed with image-guided needle biopsy that require surgical excision to be distinguished from HRLs that are at low risk for upgrade to cancer at surgery and thus could be surveilled. Materials and Methods Consecutive patients with biopsy-proven HRLs who underwent surgery or at least 2 years of imaging follow-up from June 2006 to April 2015 were identified. A random forest machine learning model was developed to identify HRLs at low risk for upgrade to cancer. Traditional features such as age and HRL histologic results were used in the model, as were text features from the biopsy pathologic report. Results One thousand six HRLs were identified, with a cancer upgrade rate of 11.4% (115 of 1006). A machine learning random forest model was developed with 671 HRLs and tested with an independent set of 335 HRLs. Among the most important traditional features were age and HRL histologic results (eg, atypical ductal hyperplasia). An important text feature from the pathologic reports was "severely atypical." Instead of surgical excision of all HRLs, if those categorized with the model to be at low risk for upgrade were surveilled and the remainder were excised, then 97.4% (37 of 38) of malignancies would have been diagnosed at surgery, and 30.6% (91 of 297) of surgeries of benign lesions could have been avoided. Conclusion This study provides proof of concept that a machine learning model can be applied to predict the risk of upgrade of HRLs to cancer. Use of this model could decrease unnecessary surgery by nearly one-third and could help guide clinical decision making with regard to surveillance versus surgical excision of HRLs. © RSNA, 2017.

  11. 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.

  12. The frog vestibular system as a model for lesion-induced plasticity: basic neural principles and implications for posture control

    Directory of Open Access Journals (Sweden)

    Francois M Lambert

    2012-04-01

    Full Text Available Studies of behavioral consequences after unilateral labyrinthectomy have a long tradition in the quest of determining rules and limitations of the CNS to exert plastic changes that assist the recuperation from the loss of sensory inputs. Frogs were among the first animal models to illustrate general principles of regenerative capacity and reorganizational neural flexibility after a vestibular lesion. The continuous successful use of the latter animals is in part based on the easy access and identifiability of nerve branches to inner ear organs for surgical intervention, the possibility to employ whole brain preparations for in vitro studies and the limited degree of freedom of postural reflexes for quantification of behavioral impairments and subsequent improvements. Major discoveries that increased the knowledge of post-lesional reactive mechanisms in the central nervous system include alterations in vestibular commissural signal processing and activation of cooperative changes in excitatory and inhibitory inputs to disfacilitated neurons. Moreover, the observed increase of synaptic efficacy in propriospinal circuits illustrates the importance of limb proprioceptive inputs for postural recovery. Accumulated evidence suggests that the lesion-induced neural plasticity is not a goal-directed process that aims towards a meaningful restoration of vestibular reflexes but rather attempts a survival of those neurons that have lost their excitatory inputs. Accordingly, the reaction mechanism causes an improvement of some components but also a deterioration of other aspects as seen by spatio-temporally inappropriate vestibulo-motor responses, similar to the consequences of plasticity processes in various sensory systems and species. The generality of the findings indicate that frogs continue to form a highly amenable vertebrate model system for exploring molecular and physiological events during cellular and network reorganization after a loss of

  13. Vitamin D Repletion Reduces the Progression of Premalignant Squamous Lesions in the NTCU Lung Squamous Cell Carcinoma Mouse Model

    Science.gov (United States)

    Mazzilli, Sarah A.; Hershberger, Pamela A.; Reid, Mary E.; Bogner, Paul N.; Atwood, Kristopher; Trump, Donald L.; Johnson, Candace S.

    2015-01-01

    The chemopreventive actions of vitamin D were examined in the N-nitroso-tris-chloroethylurea (NTCU) mouse model, a progressive model of lung squamous cell carcinoma (SCC). SWR/J mice were fed a deficient diet (D) containing no vitamin D3, a sufficient diet (S) containing 2000 IU/kg vitamin D3, or the same diets in combination with the active metabolite of vitamin D, calcitriol (C) (80 μg/kg, weekly). The percentage (%) of the mucosal surface of large airways occupied by dysplastic lesions was determined in mice after treatment with a total dose of 15 or 25 μmol NTCU (N). After treatment with 15 μmol NTCU, the % of the surface of large airways containing high-grade dysplastic (HGD) lesions were vitamin D-deficient +NTCU (DN), 22.7 % (p<0.05 compared to vitamin D-sufficient +NTCU (SN)); DN + C, 12.3%; SN, 8.7%; and SN + C, 6.6%. The extent of HGD increased with NTCU dose in the DN group. Proliferation, assessed by Ki-67 labeling, increased upon NTCU treatment. The highest Ki-67 labeling index was seen in the DN group. As compared to SN mice, DN mice exhibited a 3-fold increase (p <0.005) in circulating white blood cells (WBC), a 20% (p <0.05) increase in IL-6 levels, and a 4 -fold (p <0.005) increase in WBC in bronchial lavages. Thus, vitamin D repletion reduces the progression of premalignant lesions, proliferation, and inflammation, and may thereby suppress development of lung SCC. Further investigations of the chemopreventive effects of vitamin D in lung SCC are warranted. PMID:26276745

  14. 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.

  15. Environmental enrichment induces behavioral recovery and enhanced hippocampal cell proliferation in an antidepressant-resistant animal model for PTSD.

    Directory of Open Access Journals (Sweden)

    Hendrikus Hendriksen

    Full Text Available BACKGROUND: Post traumatic stress disorder (PTSD can be considered the result of a failure to recover after a traumatic experience. Here we studied possible protective and therapeutic aspects of environmental enrichment (with and without a running wheel in Sprague Dawley rats exposed to an inescapable foot shock procedure (IFS. METHODOLOGY/PRINCIPAL FINDINGS: IFS induced long-lasting contextual and non-contextual anxiety, modeling some aspects of PTSD. Even 10 weeks after IFS the rats showed reduced locomotion in an open field. The antidepressants imipramine and escitalopram did not improve anxiogenic behavior following IFS. Also the histone deacetylase (HDAC inhibitor sodium butyrate did not alleviate the IFS induced immobility. While environmental enrichment (EE starting two weeks before IFS did not protect the animals from the behavioral effects of the shocks, exposure to EE either immediately after the shock or one week later induced complete recovery three weeks after IFS. In the next set of experiments a running wheel was added to the EE to enable voluntary exercise (EE/VE. This also led to reduced anxiety. Importantly, this behavioral recovery was not due to a loss of memory for the traumatic experience. The behavioral recovery correlated with an increase in cell proliferation in hippocampus, a decrease in the tissue levels of noradrenalin and increased turnover of 5-HT in prefrontal cortex and hippocampus. CONCLUSIONS/SIGNIFICANCE: This animal study shows the importance of (physical exercise in the treatment of psychiatric diseases, including post-traumatic stress disorder and points out the possible role of EE in studying the mechanism of recovery from anxiety disorders.

  16. Hippocampal Proteome of Rats Subjected to the Li-Pilocarpine Epilepsy Model and the Effect of Carisbamate Treatment

    Directory of Open Access Journals (Sweden)

    José Eduardo Marques-Carneiro

    2017-07-01

    Full Text Available In adult rats, the administration of lithium–pilocarpine (LiPilo reproduces most clinical and neuropathological features of human temporal lobe epilepsy (TLE. Carisbamate (CRS possesses the property of modifying epileptogenesis in this model. Indeed, about 50% of rats subjected to LiPilo status epilepticus (SE develop non-convulsive seizures (NCS instead of motor seizures when treated with CRS. However, the mechanisms underlying these effects remain unknown. The aim of this study was to perform a proteomic analysis in the hippocampus of rats receiving LiPilo and developing motor seizures or NCS following CRS treatment. Fifteen adult male Sprague–Dawley rats were used. SE was induced by LiPilo injection. CRS treatment was initiated at 1 h and 9 h after SE onset and maintained for 7 days, twice daily. Four groups were studied after video-EEG control of the occurrence of motor seizures: a control group receiving saline (CT n = 3 and three groups that underwent SE: rats treated with diazepam (DZP n = 4, rats treated with CRS displaying NCS (CRS-NCS n = 4 or motor seizures (CRS-TLE n = 4. Proteomic analysis was conducted by 2D-SDS-PAGE. Twenty-four proteins were found altered. In the CRS-NCS group, proteins related to glycolysis and ATP synthesis were down-regulated while proteins associated with pyruvate catabolism were up-regulated. Moreover, among the other proteins differentially expressed, we found proteins related to inflammatory processes, protein folding, tissue regeneration, response to oxidative stress, gene expression, biogenesis of synaptic vesicles, signal transduction, axonal transport, microtubule formation, cell survival, and neuronal plasticity. Our results suggest a global reduction of glycolysis and cellular energy production that might affect brain excitability. In addition, CRS seems to modulate proteins related to many other pathways that could significantly participate in the epileptogenesis-modifying effect observed.

  17. Long-term effect of neonatal inhibition of APP gamma-secretase on hippocampal development in the Ts65Dn mouse model of Down syndrome.

    Science.gov (United States)

    Stagni, Fiorenza; Raspanti, Alessandra; Giacomini, Andrea; Guidi, Sandra; Emili, Marco; Ciani, Elisabetta; Giuliani, Alessandro; Bighinati, Andrea; Calzà, Laura; Magistretti, Jacopo; Bartesaghi, Renata

    2017-07-01

    Neurogenesis impairment is considered a major determinant of the intellectual disability that characterizes Down syndrome (DS), a genetic condition caused by triplication of chromosome 21. Previous evidence obtained in the Ts65Dn mouse model of DS showed that the triplicated gene APP (amyloid precursor protein) is critically involved in neurogenesis alterations. In particular, excessive levels of AICD (amyloid precursor protein intracellular domain) resulting from APP cleavage by gamma-secretase increase the transcription of Ptch1, a Sonic Hedgehog (Shh) receptor that keeps the mitogenic Shh pathway repressed. Previous evidence showed that neonatal treatment with ELND006, an inhibitor of gamma-secretase, reinstates the Shh pathway and fully restores neurogenesis in Ts65Dn pups. In the framework of potential therapies for DS, it is extremely important to establish whether the positive effects of early intervention are retained after treatment cessation. Therefore, the goal of the current study was to establish whether early treatment with ELND006 leaves an enduring trace in the brain of Ts65Dn mice. Ts65Dn and euploid pups were treated with ELND006 in the postnatal period P3-P15 and the outcome of treatment was examined at ~one month after treatment cessation. We found that in treated Ts65Dn mice the pool of proliferating cells in the hippocampal dentate gyrus (DG) and total number of granule neurons were still restored as was the number of pre- and postsynaptic terminals in the stratum lucidum of CA3, the site of termination of the mossy fibers from the DG. Accordingly, patch-clamp recording from field CA3 showed functional normalization of the input to CA3. Unlike in field CA3, the number of pre- and postsynaptic terminals in the DG of treated Ts65Dn mice was no longer fully restored. The finding that many of the positive effects of neonatal treatment were retained after treatment cessation provides proof of principle demonstration of the efficacy of early

  18. Neurobehavioral Deficits in a Rat Model of Recurrent Neonatal Seizures Are Prevented by a Ketogenic Diet and Correlate with Hippocampal Zinc/Lipid Transporter Signals.

    Science.gov (United States)

    Tian, Tian; Ni, Hong; Sun, Bao-liang

    2015-10-01

    The ketogenic diet (KD) has been shown to be effective as an antiepileptic therapy in adults, but it has not been extensively tested for its efficacy in neonatal seizure-induced brain damage. We have previously shown altered expression of zinc/lipid metabolism-related genes in hippocampus following penicillin-induced developmental model of epilepsy. In this study, we further investigated the effect of KD on the neurobehavioral and cognitive deficits, as well as if KD has any influence in the activity of zinc/lipid transporters such as zinc transporter 3 (ZnT-3), MT-3, ApoE, ApoJ (clusterin), and ACAT-1 activities in neonatal rats submitted to flurothyl-induced recurrent seizures. Postnatal day 9 (P9), 48 Sprague-Dawley rats were randomly assigned to two groups: flurothyl-induced recurrent seizure group (EXP) and control group (CONT). On P28, they were further randomly divided into the seizure group without ketogenic diet (EXP1), seizure plus ketogenic diet (EXP2), the control group without ketogenic diet (CONT1), and the control plus ketogenic diet (CONT2). Neurological behavioral parameters of brain damage (plane righting reflex, cliff avoidance reflex, and open field test) were observed from P35 to P49. Morris water maze test was performed during P51-P57. Then hippocampal mossy fiber sprouting and the protein levels of ZnT3, MT3, ApoE, CLU, and ACAT-1 were detected by Timm staining and Western blot analysis, respectively. Flurothyl-induced neurobehavioral toxicology and aberrant mossy fiber sprouting were blocked by KD. In parallel with these behavioral changes, rats treated with KD (EXP2) showed a significant down-regulated expression of ZnT-3, MT-3, ApoE, clusterin, and ACAT-1 in hippocampus when compared with the non-KD-treated EXP1 group. Our findings provide support for zinc/lipid transporter signals being potential targets for the treatment of neonatal seizure-induced brain damage by KD.

  19. Porcine skin visible lesion thresholds for near-infrared lasers including modeling at two pulse durations and spot sizes.

    Science.gov (United States)

    Cain, C P; Polhamus, G D; Roach, W P; Stolarski, D J; Schuster, K J; Stockton, K L; Rockwell, B A; Chen, Bo; Welch, A J

    2006-01-01

    With the advent of such systems as the airborne laser and advanced tactical laser, high-energy lasers that use 1315-nm wavelengths in the near-infrared band will soon present a new laser safety challenge to armed forces and civilian populations. Experiments in nonhuman primates using this wavelength have demonstrated a range of ocular injuries, including corneal, lenticular, and retinal lesions as a function of pulse duration. American National Standards Institute (ANSI) laser safety standards have traditionally been based on experimental data, and there is scant data for this wavelength. We are reporting minimum visible lesion (MVL) threshold measurements using a porcine skin model for two different pulse durations and spot sizes for this wavelength. We also compare our measurements to results from our model based on the heat transfer equation and rate process equation, together with actual temperature measurements on the skin surface using a high-speed infrared camera. Our MVL-ED50 thresholds for long pulses (350 micros) at 24-h postexposure are measured to be 99 and 83 J cm(-2) for spot sizes of 0.7 and 1.3 mm diam, respectively. Q-switched laser pulses of 50 ns have a lower threshold of 11 J cm(-2) for a 5-mm-diam top-hat laser pulse.

  20. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP{sub swe}/PS1{sub {Delta}E9} transgenic mouse model of Alzheimer's disease

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Jun [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Song, Min; Wang, Yanyan [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China); Fan, Xiaotang [Department of Histology and Embryology, Third Military Medical University, Chongqing 400038 (China); Xu, Haiwei, E-mail: haiweixu2001@yahoo.com.cn [Department of Physiology, Third Military Medical University, Chongqing 400038 (China); Bai, Yun, E-mail: baiyungene@gmail.com [Department of Medical Genetics, Third Military Medical University, Chongqing 400038 (China)

    2009-07-31

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP{sub swe}/PS1{sub {Delta}E9} mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP{sub swe}/PS1{sub {Delta}E9} transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  1. 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.

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

    Science.gov (United States)

    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.

  3. Acute Korsakoff-like amnestic syndrome resulting from left thalamic infarction following a right hippocampal hemorrhage.

    Science.gov (United States)

    Rahme, R; Moussa, R; Awada, A; Ibrahim, I; Ali, Y; Maarrawi, J; Rizk, T; Nohra, G; Okais, N; Samaha, E

    2007-04-01

    Korsakoff-like amnestic syndromes have been rarely described following structural lesions of the central nervous system. In this report, we describe a case of acute Korsakoff-like syndrome resulting from the combination of a left anteromedian thalamic infarct and a right hippocampal hemorrhage. We also review the literature relevant to the neuropathology and pathophysiology of Korsakoff syndrome and anterograde amnesia.

  4. Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection

    Directory of Open Access Journals (Sweden)

    Elena Ufimtseva

    2015-01-01

    Full Text Available Tuberculosis (TB is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals.

  5. Mycobacterium-Host Cell Relationships in Granulomatous Lesions in a Mouse Model of Latent Tuberculous Infection

    Science.gov (United States)

    2015-01-01

    Tuberculosis (TB) is a dangerous infectious disease characterized by a tight interplay between mycobacteria and host cells in granulomatous lesions (granulomas) during the latent, asymptomatic stage of infection. Mycobacterium-host cell relationships were analyzed in granulomas obtained from various organs of BALB/c mice with chronic TB infection caused by in vivo exposure to the Bacillus Calmette-Guérin (BCG) vaccine. Acid-fast BCG-mycobacteria were found to be morphologically and functionally heterogeneous (in size, shape, and replication rates in colonies) in granuloma macrophages, dendritic cells, and multinucleate Langhans giant cells. Cord formation by BCG-mycobacteria in granuloma cells has been observed. Granuloma macrophages retained their ability to ingest damaged lymphocytes and thrombocytes in the phagosomes; however, their ability to destroy BCG-mycobacteria contained in these cells was compromised. No colocalization of BCG-mycobacteria and the LysoTracker dye was observed in the mouse cells. Various relationships between granuloma cells and BCG-mycobacteria were observed in different mice belonging to the same line. Several mice totally eliminated mycobacterial infection. Granulomas in the other mice had mycobacteria actively replicating in cells of different types and forming cords, which is an indicator of mycobacterial virulence and, probably, a marker of the activation of tuberculous infection in animals. PMID:26064970

  6. Modelling Cyclic Walking in Femurs With Metastatic Lesions : Femur-Specific Accumulation of Plasticity

    NARCIS (Netherlands)

    Derikx, L.; Janssen, D.; Schepers, J.; Wesseling, M.; Verdonschot, N.; Jonkers, I.; Tanck, E.

    2015-01-01

    Introduction Clinical fracture risk assessment in metastatic bone disease is extremely difficult, but subject-specific finite element (FE) modelling may improve these assessments in the future [Derikx, 2015]. By coupling to musculoskeletal modelling, realistic loading conditions can be implemented

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

    Science.gov (United States)

    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

  8. Assessment of hemodynamics in a rat model of liver cirrhosis with precancerous lesions using multislice spiral CT perfusion imaging.

    Science.gov (United States)

    Ma, Guolin; Bai, Rongjie; Jiang, Huijie; Hao, Xuejia; Ling, Zaisheng; Li, Kefeng

    2013-01-01

    To develop an optimal scanning protocol for multislice spiral CT perfusion (CTP) imaging to evaluate hemodynamic changes in liver cirrhosis with diethylnitrosamine- (DEN-) induced precancerous lesions. Male Wistar rats were randomly divided into the control group (n = 80) and the precancerous liver cirrhosis group (n = 40). The control group received saline injection and the liver cirrhosis group received 50 mg/kg DEN i.p. twice a week for 12 weeks. All animals underwent plain CT scanning, CTP, and contrast-enhanced CT scanning. Scanning parameters were optimized by adjusting the diatrizoate concentration, the flow rate, and the delivery time. The hemodynamics of both groups was further compared using optimized multislice spiral CTP imaging. High-quality CTP images were obtained with following parameters: 150 kV; 150 mAs; 5 mm thickness, 5 mm interval; pitch, 1; matrix, 512 × 512; and FOV, 9.6 cm. Compared to the control group, the liver cirrhosis group had a significantly increased value of the hepatic arterial fraction and the hepatic artery perfusion (P spiral CTP imaging can be used to evaluate the hemodynamic changes in the rat model of liver cirrhosis with precancerous lesions.

  9. 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.

  10. 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

  11. 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

  12. Kinetic modeling of low density lipoprotein oxidation in arterial wall and its application in atherosclerotic lesions prediction.

    Science.gov (United States)

    Karimi, Safoora; Dadvar, Mitra; Modarress, Hamid; Dabir, Bahram

    2013-01-01

    Oxidation of low-density lipoprotein (LDL) is one of the major factors in atherogenic process. Trapped oxidized LDL (Ox-LDL) in the subendothelial matrix is taken up by macrophage and leads to foam cell generation creating the first step in atherosclerosis development. Many researchers have studied LDL oxidation using in vitro cell-induced LDL oxidation model. The present study provides a kinetic model for LDL oxidation in intima layer that can be used in modeling of atherosclerotic lesions development. This is accomplished by considering lipid peroxidation kinetic in LDL through a system of elementary reactions. In comparison, characteristics of our proposed kinetic model are consistent with the results of previous experimental models from other researches. Furthermore, our proposed LDL oxidation model is added to the mass transfer equation in order to predict the LDL concentration distribution in intima layer which is usually difficult to measure experimentally. According to the results, LDL oxidation kinetic constant is an important parameter that affects LDL concentration in intima layer so that existence of antioxidants that is responsible for the reduction of initiating rates and prevention of radical formations, have increased the concentration of LDL in intima by reducing the LDL oxidation rate. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  13. 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 ...

  14. Proangiogenic Tie2+ Macrophages Infiltrate Human and Murine Endometriotic Lesions and Dictate Their Growth in a Mouse Model of the Disease

    Science.gov (United States)

    Capobianco, Annalisa; Monno, Antonella; Cottone, Lucia; Venneri, Mary Anna; Biziato, Daniela; Di Puppo, Francesca; Ferrari, Stefano; De Palma, Michele; Manfredi, Angelo A.; Rovere-Querini, Patrizia

    2011-01-01

    Endometriosis affects women of reproductive age, causing infertility and pain. Although immune cells are recruited in endometriotic lesions, their role is unclear. Tie2-expressing macrophages (TEMs) have nonredundant functions in promoting angiogenesis and growth of experimental tumors. Here we show that human TEMs infiltrate areas surrounding newly formed endometriotic blood vessels. We set up an ad hoc mouse model in which TEMs, and not Tie2-expressing endothelial cells, are targeted. We transplanted in wild-type recipients bone marrow cells expressing a suicide gene (Herpes simplex virus type 1 thymidine kinase) under the Tie2 promoter/enhancer. TEMs infiltrated endometriotic lesions. TEM depletion by ganciclovir administration arrested the growth of established lesions, without toxicity. Lesion architecture was disrupted, with: i) loss of glandular organization, ii) reduced neovascularization, and iii) activation of caspase 3 in CD31+ endothelial cells. Thus, TEMs are important for maintaining the viability of newly formed vessels and represent a potential therapeutic target in endometriosis. PMID:21924227

  15. Anti-inflammatory effects of rebamipide eyedrop administration on ocular lesions in a murine model of primary Sjögren's syndrome.

    Directory of Open Access Journals (Sweden)

    Rieko Arakaki

    Full Text Available Topical therapy is effective for dry eye, and its prolonged effects should help in maintaining the quality of life of patients with dry eye. We previously reported that the oral administration of rebamipide (Reb, a mucosal protective agent, had a potent therapeutic effect on autoimmune lesions in a murine model of Sjögren's syndrome (SS. However, the effects of topical treatment with Reb eyedrops on the ocular lesions in the murine model of SS are unknown.Reb eyedrops were administered to the murine model of SS aged 4-8 weeks four times daily. Inflammatory lesions of the extraorbital and intraorbital lacrimal glands and Harderian gland tissues were histologically evaluated. The direct effects of Reb on the lacrimal glands were analyzed using cultured lacrimal gland cells. Tear secretions of Reb-treated mice were significantly increased compared with those of untreated mice. In addition to the therapeutic effect of Reb treatment on keratoconjunctivitis, severe inflammatory lesions of intraorbital lacrimal gland tissues in this model of SS were resolved. The mRNA expression levels of IL-10 and mucin 5Ac in conjunctival tissues from Reb-treated mice was significantly increased compared with those of control mice. Moreover, lactoferrin production from lacrimal gland cells was restored by Reb treatment.Topical Reb administration had an anti-inflammatory effect on the ocular autoimmune lesions in the murine model of SS and a protective effect on the ocular surfaces.

  16. Ceroid lipofuscinosis in the border collie dog: retinal lesions in an animal model of juvenile Batten disease.

    Science.gov (United States)

    Taylor, R M; Farrow, B R

    1992-02-15

    Ceroid lipofuscinosis, an inherited disorder of lipopigment accumulation, was identified in a group of Border Collie dogs. The dogs developed mental, motor, and visual signs between age 15 and 22 months and progressed rapidly to severe neurological disease. The principal signs were blindness and gait and behavioural abnormalities with progressive dementia. Lipopigment accumulation was severe in neurones and glial cells of the central nervous system and was present in some visceral cells. Inclusions with variable ultrastructure were common in all cells of the retina, but the pigment accumulation did not damage the retinal architecture. The cytoplasmic inclusions were granular, sudanophilic, eosinophilic, and autofluorescent. Ultrastructural morphology varied, but fingerprint and curvilinear patterns predominated. The retinal lesions in the Border Collies were similar to those in English Setters with ceroid lipofuscinosis, but were much less severe than in juvenile human ceroid lipofuscinosis. This disorder bears a close resemblance to ceroid lipofuscinosis in English Setters and is another useful model for Batten's disease.

  17. Involvement of neuronal IL-1β in acquired brain lesions in a rat model of neonatal encephalopathy.

    Science.gov (United States)

    Savard, Alexandre; Lavoie, Karine; Brochu, Marie-Elsa; Grbic, Djordje; Lepage, Martin; Gris, Denis; Sebire, Guillaume

    2013-09-05

    Infection-inflammation combined with hypoxia-ischemia (HI) is the most prevalent pathological scenario involved in perinatal brain damage leading to life-long neurological disabilities. Following lipopolysaccharide (LPS) and/or HI aggression, different patterns of inflammatory responses have been uncovered according to the brain differentiation stage. In fact, LPS pre-exposure has been reported to aggravate HI brain lesions in post-natal day 1 (P1) and P7 rat models that are respectively equivalent - in terms of brain development - to early and late human preterm newborns. However, little is known about the innate immune response in LPS plus HI-induced lesions of the full-term newborn forebrain and the associated neuropathological and neurobehavioral outcomes. An original preclinical rat model has been previously documented for the innate neuroimmune response at different post-natal ages. It was used in the present study to investigate the neuroinflammatory mechanisms that underline neurological impairments after pathogen-induced inflammation and HI in term newborns. LPS and HI exerted a synergistic detrimental effect on rat brain. Their effect led to a peculiar pattern of parasagittal cortical-subcortical infarcts mimicking those in the human full-term newborn with subsequent severe neurodevelopmental impairments. An increased IL-1β response in neocortical and basal gray neurons was demonstrated at 4 h after LPS + HI-exposure and preceded other neuroinflammatory responses such as microglial and astroglial cell activation. Neurological deficits were observed during the acute phase of injury followed by a recovery, then by a delayed onset of profound motor behavior impairment, reminiscent of the delayed clinical onset of motor system impairments observed in humans. Interleukin-1 receptor antagonist (IL-1ra) reduced the extent of brain lesions confirming the involvement of IL-1β response in their pathophysiology. In rat pups at a neurodevelopmental age

  18. 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

  19. Quantitative T2 mapping evaluation for articular cartilage lesions in a rabbit model of anterior cruciate ligament transection osteoarthritis.

    Science.gov (United States)

    Wei, Zheng-mao; Du, Xiang-ke; Huo, Tian-long; Li, Xu-bin; Quan, Guang-nan; Li, Tian-ran; Cheng, Jin; Zhang, Wei-tao

    2012-03-01

    Quantitative T2 mapping has been a widely used method for the evaluation of pathological cartilage properties, and the histological assessment system of osteoarthritis in the rabbit has been published recently. The aim of the study was to investigate the effectiveness of quantitative T2 mapping evaluation for articular cartilage lesions of a rabbit model of anterior cruciate ligament transection (ACLT) osteoarthritis. Twenty New Zealand White (NZW) rabbits were divided into ACLT surgical group and sham operated group equally. The anterior cruciate ligaments of the rabbits in ACLT group were transected, while the joints were closed intactly in sham operated group. Magnetic resonance (MR) examinations were performed on 3.0T MR unit at week 0, week 6, and week 12. T2 values were computed on GE ADW4.3 workstation. All rabbits were killed at week 13, and left knees were stained with Haematoxylin and Eosin. Semiquantitative histological grading was obtained according to the osteoarthritis cartilage histopathology assessment system. Computerized image analysis was performed to quantitate the immunostained collagen type II. The average MR T2 value of whole left knee cartilage in ACLT surgical group ((29.05±12.01) ms) was significantly higher than that in sham operated group ((24.52±7.97) ms) (P=0.024) at week 6. The average T2 value increased to (32.18±12.79) ms in ACLT group at week 12, but remained near the baseline level ((27.66±8.08) ms) in the sham operated group (P=0.03). The cartilage lesion level of left knee in ACLT group was significantly increased at week 6 (P=0.005) and week 12 (PT2 values had positive correlation with histological grading scores, but inverse correlation with optical densities (OD) of type II collagen. This study demonstrated the reliability and practicability of quantitative T2 mapping for the cartilage injury of rabbit ACLT osteoarthritis model.

  20. Histopathologic characterization of the BTBR mouse model of autistic-like behavior reveals selective changes in neurodevelopmental proteins and adult hippocampal neurogenesis

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    Stephenson Diane T

    2011-05-01

    Full Text Available Abstract Background The inbred mouse strain BTBR T+ tf/J (BTBR exhibits behavioral deficits that mimic the core deficits of autism. Neuroanatomically, the BTBR strain is also characterized by a complete absence of the corpus callosum. The goal of this study was to identify novel molecular and cellular changes in the BTBR mouse, focusing on neuronal, synaptic, glial and plasticity markers in the limbic system as a model for identifying putative molecular and cellular substrates associated with autistic behaviors. Methods Forebrains of 8 to 10-week-old male BTBR and age-matched C57Bl/6J control mice were evaluated by immunohistochemistry using free-floating and paraffin embedded sections. Twenty antibodies directed against antigens specific to neurons, synapses and glia were used. Nissl, Timm and acetylcholinesterase (AchE stains were performed to assess cytoarchitecture, mossy fibers and cholinergic fiber density, respectively. In the hippocampus, quantitative stereological estimates for the mitotic marker bromodeoxyuridine (BrdU were performed to determine hippocampal progenitor proliferation, survival and differentiation, and brain-derived neurotrophic factor (BDNF mRNA was quantified by in situ hybridization. Quantitative image analysis was performed for NG2, doublecortin (DCX, NeuroD, GAD67 and Poly-Sialic Acid Neural Cell Adhesion Molecule (PSA-NCAM. Results In midline structures including the region of the absent corpus callosum of BTBR mice, the myelin markers 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase and myelin basic protein (MBP were reduced, and the oligodendrocyte precursor NG2 was increased. MBP and CNPase were expressed in small ectopic white matter bundles within the cingulate cortex. Microglia and astrocytes showed no evidence of gliosis, yet orientations of glial fibers were altered in specific white-matter areas. In the hippocampus, evidence of reduced neurogenesis included significant reductions in the number of

  1. Divergent Roles of Central Serotonin in Adult Hippocampal Neurogenesis

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    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. Three-dimensional Monte Carlo model of pulsed-laser treatment of cutaneous vascular lesions

    Science.gov (United States)

    Milanič, Matija; Majaron, Boris

    2011-12-01

    We present a three-dimensional Monte Carlo model of optical transport in skin with a novel approach to treatment of side boundaries of the volume of interest. This represents an effective way to overcome the inherent limitations of ``escape'' and ``mirror'' boundary conditions and enables high-resolution modeling of skin inclusions with complex geometries and arbitrary irradiation patterns. The optical model correctly reproduces measured values of diffuse reflectance for normal skin. When coupled with a sophisticated model of thermal transport and tissue coagulation kinetics, it also reproduces realistic values of radiant exposure thresholds for epidermal injury and for photocoagulation of port wine stain blood vessels in various skin phototypes, with or without application of cryogen spray cooling.

  3. Hippocampal activation during the recall of remote spatial memories in radial maze tasks.

    Science.gov (United States)

    Schlesiger, Magdalene I; Cressey, John C; Boublil, Brittney; Koenig, Julie; Melvin, Neal R; Leutgeb, Jill K; Leutgeb, Stefan

    2013-11-01

    Temporally graded retrograde amnesia is observed in human patients with medial temporal lobe lesions as well as in animal models of medial temporal lobe lesions. A time-limited role for these structures in memory recall has also been suggested by the observation that the rodent hippocampus and entorhinal cortex are activated during the retrieval of recent but not of remote memories. One notable exception is the recall of remote memories for platform locations in the water maze, which requires an intact hippocampus and results in hippocampal activation irrespective of the age of the memory. These findings raise the question whether the hippocampus is always involved in the recall of spatial memories or, alternatively, whether it might be required for procedural computations in the water maze task, such as for calculating a path to a hidden platform. We performed spatial memory testing in radial maze tasks to distinguish between these possibilities. Radial maze tasks require a choice between spatial locations on a center platform and thus have a lesser requirement for navigation than the water maze. However, we used a behavioral design in the radial maze that retained other aspects of the standard water maze task, such as the use of multiple start locations and retention testing in a single trial. Using the immediate early gene c-fos as a marker for neuronal activation, we found that all hippocampal subregions were more activated during the recall of remote compared to recent spatial memories. In areas CA3 and CA1, activation during remote memory testing was higher than in rats that were merely reexposed to the testing environment after the same time interval. Conversely, Fos levels in the dentate gyrus were increased after retention testing to the extent that was also observed in the corresponding exposure control group. This pattern of hippocampal activation was also obtained in a second version of the task that only used a single start arm instead of multiple

  4. Evidence of Hippocampal Structural Alterations in Gulf War Veterans With Predicted Exposure to the Khamisiyah Plume.

    Science.gov (United States)

    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.

  5. Reduction in training time of a deep learning model in detection of lesions in CT

    Science.gov (United States)

    Makkinejad, Nazanin; Tajbakhsh, Nima; Zarshenas, Amin; Khokhar, Ashfaq; Suzuki, Kenji

    2018-02-01

    Deep learning (DL) emerged as a powerful tool for object detection and classification in medical images. Building a well-performing DL model, however, requires a huge number of images for training, and it takes days to train a DL model even on a cutting edge high-performance computing platform. This study is aimed at developing a method for selecting a "small" number of representative samples from a large collection of training samples to train a DL model for the could be used to detect polyps in CT colonography (CTC), without compromising the classification performance. Our proposed method for representative sample selection (RSS) consists of a K-means clustering algorithm. For the performance evaluation, we applied the proposed method to select samples for the training of a massive training artificial neural network based DL model, to be used for the classification of polyps and non-polyps in CTC. Our results show that the proposed method reduce the training time by a factor of 15, while maintaining the classification performance equivalent to the model trained using the full training set. We compare the performance using area under the receiveroperating- characteristic curve (AUC).

  6. Analysis of the model of pulmonary lesions of the cyberknife system tracking

    International Nuclear Information System (INIS)

    Floriano Pardal, A.; Santa-Olalla, I.; Sanchez-Reyes, A.

    2013-01-01

    The CyberKnife VSI system has the ability to carry out treatments for injuries that move with respiration through tracking Synchrony system, compensating for the breathing of the patient through the robotic arm, and thus allowing the reduction of the volume of treatment PTV margins. Tumor tracking is based on a model of correspondence between the positions of internal fiduciales brands previously introduced in the patient, and the external positions of infrared transmitters placed on the patient. This model is associated with a few errors that should be taken into account. The objective of the study is twofold: on the one hand to study the movement of the PTV based on location, and on the other analyze errors associated with this respiratory model. (Author)

  7. 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.

  8. Targeting of macrophages for the scintigraphic evaluation of inflammatory lesions in a model of radio-induced inflammation in pigs

    International Nuclear Information System (INIS)

    Hoffschir, D.; Daburon, F.; Normier, G.; Binz, H.; Le Pape, A.

    1991-01-01

    For a new scintigraphic strategy based on the targeting of macrophages recruited by inflammatory lesions, a specific ligand able to interact with these cells both in vitro and in vivo has been developed. J001 is a 34 KDa acylated peptidopoly 1-3 galactoside isolated from proteoglycans of a non pathogenic strain of klebsiella. When labelled with 99mTc then administrated by aerosol, this agent has been demonstrated to be a potent tool for the scintigraphic imaging of inflammatory lymph nodes in experimental berylliosis and in patients with sarcoidosis, lung tumors and ganglionic metastases. An experimental model was developed in pigs using an acute and localized muscular γ irradiation in the limb and skin resection to prevent ulceration. Dynamic imaging was performed during two hours after intravenous injection of 1 mg J001 labelled with 370 MBq 99mTc in the presence of 0.125 mg stannous fluoride. The perfusion of the lesions was evaluated from scintigraphic data obtained both 15 min after IV injection of J001 or 99mTc 04-. The intensity of the fixation of J001 was quantified 2 hours after injection and expressed as a scintigraphic ratio: R2h = cpm in lesion / cpm in a defined healthy area in the same limb. After induction of irradiation, scintigraphic ratios exhibited a progressive increase to reach a maximum (R2h = 3.6) after 3 months. Then, they decreased to recover a normal value about 6 months after irradiation. At that time, histological controls and clinical observations exhibited a significant decrease in inflammatory reaction, macrophages recruitment and apparition of fibrosis. J001 fixation was very sensitive to corticosteroids that resulted in a complete clearing of the scintigraphic images 12 to 24 hours after treatment. Two weeks were then required for a complete recovery of the inflammatory reaction and J001 fixation. So, targeting of macrophages with J001 should offer a sensitive and specific tool for the scintigraphic assessment of inflammation and

  9. 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

  10. Numerical investigation and identification of susceptible sites of atherosclerotic lesion formation in a complete coronary artery bypass model.

    Science.gov (United States)

    Zhang, Jun-Mei; Chua, Leok Poh; Ghista, Dhanjoo N; Yu, Simon Ching Man; Tan, Yong Seng

    2008-07-01

    As hemodynamics is widely believed to correlate with anastomotic stenosis in coronary bypass surgery, this paper investigates the flow characteristics and distributions of the hemodynamic parameters (HPs) in a coronary bypass model (which includes both proximal and distal anastomoses), under physiological flow conditions. Disturbed flows (flow separation/reattachment, vertical and secondary flows) as well as regions of high oscillatory shear index (OSI) with low wall shear stress (WSS), i.e., high-OSI-and-low-WSS and low-OSI-and-high-WSS were found in the proximal and distal anastomoses, especially at the toe and heel regions of distal anastomosis, which indicate highly suspected sites for the onset of the atherosclerotic lesions. The flow patterns found in the graft and distal anastomoses of our model at deceleration phases are different from those of the isolated distal anastomosis model. In addition, a huge significant difference in segmental averages of HPs was found between the distal and proximal anastomoses. These findings further suggest that intimal hyperplasia would be more prone to form in the distal anastomosis than in the proximal anastomosis, particularly along the suture line at the toe and heel of distal anastomosis.

  11. Hippocampal Abnormalities and Seizure Recurrence

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    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.

  12. Establishment of a mathematical model for the influence of respiratory movement upon the position of an intrahepatic space-occupying lesion

    International Nuclear Information System (INIS)

    Yu Yonghua; Luo Limin; Li Baosheng; Yu Jinming; Liang Chaoqian; Zhao Yuehuan

    2002-01-01

    Objective: To investigate the extent of liver lesion shifting with respiration in an attempt to establish a relevant mathematical model. Methods: We measured breathing movements with B ultrasonography in 84 primary or metastatic liver tumors and defined the relation between the lesion shifting extent with age, sex, height, weight, lesion location and size analyzed with the SPSS statistic software. Results: The Z, X and Y breathing-axis motions were 1.029±0.321 cm (range: 0.6-1.9 cm), 0.301 ± 0.131 cm (range: 0.0-0.6 cm) and 0.387±0.130 cm (range: 0.2-0.7 cm), respectively. The movement-related factor analysis revealed that age, weight and (right lobe) lesion location presented a negative relationship but height, sex and lesion size presented a positive relationship for Z, Y and X breathing-axis motions. Their mathematical regression models were established as Z = -2.660 + 2.952 H-1.539 x 10 -2 W-3.928 x 10 -3 A; Y = -0. 926 + 0. 987 H-4.992 x 10 -3 W, and X = 0.507 + 7.629 x 10 -2 S-3.686 x 10 -3 W [H : height (m), W : weight (kg) A : age (year), S : sex(M:1, F: 0)]. The liver breathing movement was verified with the model in another 11 patients and the conformation rate was up to 91%. Conclusions: The impact of breathing movement on the location of intrahepatic lesion is mainly focused on the Z-axis motion. The practical accuracy in anticipating breathing movement with the mathematical model is so justified that the use of this model be recommended in stereotactic radiotherapy

  13. 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

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

    Directory of Open Access Journals (Sweden)

    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

  15. 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.

  16. Predictive modeling of human perception subjectivity: feasibility study of mammographic lesion similarity

    Science.gov (United States)

    Xu, Songhua; Hudson, Kathleen; Bradley, Yong; Daley, Brian J.; Frederick-Dyer, Katherine; Tourassi, Georgia

    2012-02-01

    The majority of clinical content-based image retrieval (CBIR) studies disregard human perception subjectivity, aiming to duplicate the consensus expert assessment of the visual similarity on example cases. The purpose of our study is twofold: i) discern better the extent of human perception subjectivity when assessing the visual similarity of two images with similar semantic content, and (ii) explore the feasibility of personalized predictive modeling of visual similarity. We conducted a human observer study in which five observers of various expertise were shown ninety-nine triplets of mammographic masses with similar BI-RADS descriptors and were asked to select the two masses with the highest visual relevance. Pairwise agreement ranged between poor and fair among the five observers, as assessed by the kappa statistic. The observers' self-consistency rate was remarkably low, based on repeated questions where either the orientation or the presentation order of a mass was changed. Various machine learning algorithms were explored to determine whether they can predict each observer's personalized selection using textural features. Many algorithms performed with accuracy that exceeded each observer's self-consistency rate, as determined using a cross-validation scheme. This accuracy was statistically significantly higher than would be expected by chance alone (two-tailed p-value ranged between 0.001 and 0.01 for all five personalized models). The study confirmed that human perception subjectivity should be taken into account when developing CBIR-based medical applications.

  17. 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.

  18. A comparison of balloon injury models of endovascular lesions in rat arteries

    Directory of Open Access Journals (Sweden)

    Gussenhoven Elma J

    2002-09-01

    Full Text Available Abstract Background Balloon injury (BI of the rat carotid artery (CCA is widely used to study intimal hyperplasia (IH and decrease in lumen diameter (LD, but CCA's small diameter impedes the evaluation of endovascular therapies. Therefore, we validated BI in the aorta (AA and iliac artery (CIA to compare it with CCA. Methods Rats underwent BI or a sham procedure (control. Light microscopic evaluation was performed either directly or at 1, 2, 3, 4 and 16 weeks follow-up. The area of IH and the change in LD (LD at 16 weeks minus LD post BI were compared. Results In the BI-groups the area of IH increased to 0.14 ± 0.08 mm2 (CCA, 0.14 ± 0.03 mm2 (CIA and 0.12 ± 0.04 mm2 (AA at 16 weeks (NS. The LD decreased with 0.49 ± 0.07 mm (CCA, compared to 0.22 ± 0.07 mm (CIA and 0.07 ± 0.10 mm (AA at 16 weeks (p Conclusions BI resulted in: (1. a decrease in LD in CCA due to IH, (2. a decrease in LD in CIA due to IH and CVR, (3. no change in LD in AA, (4. Comparable IH development in all arteries, (5. CCA has no vasa vasorum compared to CIA and AA, (6. The CIA model combines good access for 2 F endovascular catheters with a decrease in LD due to IH and CVR after BI.

  19. The potential cost-effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for treating de novo, severely calcified coronary lesions: an economic modeling approach.

    Science.gov (United States)

    Chambers, Jeffrey; Généreux, Philippe; Lee, Arthur; Lewin, Jack; Young, Christopher; Crittendon, Janna; Mann, Marita; Garrison, Louis P

    2016-04-01

    Patients who undergo percutaneous coronary intervention (PCI) for severely calcified coronary lesions have long been known to have worse clinical and economic outcomes than patients with no or mildly calcified lesions. We sought to assess the likely cost-effectiveness of using the Diamondback 360(®) Orbital Atherectomy System (OAS) in the treatment of de novo, severely calcified lesions from a health-system perspective. In the absence of a head-to-head trial and long-term follow up, cost-effectiveness was based on a modeled synthesis of clinical and economic data. A cost-effectiveness model was used to project the likely economic impact. To estimate the net cost impact, the cost of using the OAS technology in elderly (⩾ 65 years) Medicare patients with de novo severely calcified lesions was compared with cost offsets. Elderly OAS patients from the ORBIT II trial (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) [ClinicalTrials.gov identifier: NCT01092426] were indirectly compared with similar patients using observational data. For the index procedure, the comparison was with Medicare data, and for both revascularization and cardiac death in the following year, the comparison was with a pooled analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)/Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials. After adjusting for differences in age, gender, and comorbidities, the ORBIT II mean index procedure costs were 17% (p economic modeling, the recently approved coronary OAS device is projected to be highly cost-effective for patients who undergo PCI for severely calcified lesions. © The Author(s), 2015.

  20. Unilateral lesion of dorsal hippocampus in adult rats impairs contralateral long-term potentiation in vivo and spatial memory in the early postoperative phase.

    Science.gov (United States)

    Li, Hongjie; Wu, Xiaoyan; Bai, Yanrui; Huang, Yan; He, Wenting; Dong, Zhifang

    2012-05-01

    It is well documented that bilateral hippocampal lesions or unilateral hippocampal lesion at birth causes impairment of contralateral LTP and long-term memory. However, effects of unilateral hippocampal lesion in adults on contralateral in vivo LTP and memory are not clear. We here examined the influence of unilateral electrolytic dorsal hippocampal lesion in adult rats on contralateral LTP in vivo and spatial memory during different postoperative phases. We found that acute unilateral hippocampal lesion had no effect on contralateral LTP. However, contralateral LTP was impaired at 1 week after lesion, and was restored to the control level at postoperative week 4. Similarly, spatial memory was also impaired at postoperative week 1, and was restored at postoperative week 4. In addition, the rats at postoperative week 1 showed stronger spatial exploratory behavior in a novel open-field environment. The sham operation had no effects on contralateral LTP, spatial memory and exploration at either postoperative week 1 or week 4. These results suggest that unilateral dorsal hippocampal lesion in adult rats causes transient contralateral LTP impairment and spatial memory deficit. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. 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.

  2. New diagnosis and therapy model for ischemic-type biliary lesions following liver transplantation--a retrospective cohort study.

    Directory of Open Access Journals (Sweden)

    Ying-cai Zhang

    Full Text Available Ischemic-type biliary lesions (ITBLs are a major cause of graft loss and mortality after orthotopic liver transplantation (OLT. Impaired blood supply to the bile ducts may cause focal or extensive damage, resulting in intra- or extrahepatic bile duct strictures or dilatations that can be detected by ultrasonography, computed tomography, magnetic resonance cholangiopancreatography, and cholangiography. However, the radiographic changes occur at an advanced stage, after the optimal period for therapeutic intervention. Endoscopic retrograde cholangio-pancreatography (ERCP and percutaneous transhepatic cholangiodrainage (PTCD are the gold standard methods of detecting ITBLs, but these procedures cannot be used for continuous monitoring. Traditional methods of follow-up and diagnosis result in delayed diagnosis and treatment of ITBLs. Our center has used the early diagnosis and intervention model (EDIM for the diagnosis and treatment of ITBLs since February 2008. This model mainly involves preventive medication to protect the epithelial cellular membrane of the bile ducts, regular testing of liver function, and weekly monitor of contrast-enhanced ultrasonography (CEUS to detect ischemic changes to the bile ducts. If the liver enzyme levels become abnormal or CEUS shows low or no enhancement of the wall of the hilar bile duct during the arterial phase, early ERCP and PTCD are performed to confirm the diagnosis and to maintain biliary drainage. Compared with patients treated by the traditional model used prior to February 2008, patients in the EDIM group had a lower incidence of biliary tract infection (28.6% vs. 48.6%, P = 0.04, longer survival time of liver grafts (24±9.6 months vs. 17±12.3 months, P = 0.02, and better outcomes after treatment of ITBLs.

  3. 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.

  4. Co-micronized palmitoylethanolamide/polydatin treatment causes endometriotic lesion regression in a rodent model of surgically-induced endometriosis

    Directory of Open Access Journals (Sweden)

    Rosanna Di Paola

    2016-10-01

    Full Text Available Endometriosis is a chronic, painful disease characterized by the presence of endometrial glands and stroma outside the uterine cavity. Palmitoylethanolamide (PEA, an endogenous fatty acid amide, has anti-inflammatory and neuroprotective effects. PEA lacks free radical scavenging activity, unlike polydatin (PLD, a natural precursor of resveratrol. The aim of this study was to investigate the effect of orally administered co-micronized PEA/polydatin (m(PEA/PLD in an autologous rat model of surgically-induced endometriosis. Endometriosis was induced in female Wistar albino rats by auto-transplantation of uterine squares (implants into the intestinal mesentery and peritoneal cavity. Rats were distributed into one control group and one treatment group (10 animals each: m(PEA/PLD 10 mg/kg/day. At 28 days after surgery the relative volume of the endometrioma was determined. Endometrial-like tissue was confirmed by histology: Masson trichrome and toluidine blue were used to detect fibrosis and mast cells, respectively. The treated group displayed a smaller cyst diameter, with improved fibrosis score and mast cell number decrease. m(PEA/PLD administration decreased angiogenesis (vascular endothelial growth factor, nerve growth factor, intercellular adhesion molecule, matrix metalloproteinase 9 expression and lymphocyte accumulation. m(PEA/PLD treatment also reduced peroxynitrite formation, (poly-ADPribose polymerase activation, IkBα phosphorylation and nuclear facor-kB traslocation in the nucleus. Our results suggested that m(PEA/PLD may be of use to inhibit development of endometriotic lesions in rats.

  5. Supply-and-demand discrepancy in academic pigmented lesion clinics: a case for a new health care delivery model.

    Science.gov (United States)

    Vickery, Erin L; Seidler, Elizabeth M; Jones, Todd E; Veledar, Emir; Chen, Suephy C

    2014-11-01

    .9%), and all other diagnoses being better represented among additional screening visits (P = .04). No particular patient characteristic described those who sought additional screening visits. A substantial proportion of additional screening PLC visits exist and are desired by all patients with pigmented lesions. We propose alternative clinic models, such as diagnosis-specific, adjunctive fee-for-additional-service, and teledermatology clinics to meet patient needs while creating resources to expand PLC visits.

  6. Gynostemma pentaphyllum Ethanolic Extract Protects Against Memory Deficits in an MPTP-Lesioned Mouse Model of Parkinson's Disease Treated with L-DOPA.

    Science.gov (United States)

    Kim, Kyung Sook; Zhao, Ting Ting; Shin, Keon Sung; Park, Hyun Jin; Cho, Yoon Jeong; Lee, Kyung Eun; Kim, Seung Hwan; Lee, Myung Koo

    2017-01-01

    This study investigated the effects of ethanol extract from Gynostemma pentaphyllum (GP-EX) on memory deficits in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) (MPTP-lesioned mice). MPTP (30 mg/kg/day, 5 days)-lesioned mice showed deficits of habit learning memory and spatial memory, which were further aggravated by treatment with L-3,4-dihydroxyphenylalanine (L-DOPA) (25 mg/kg, 21 days). However, treatment with GP-EX (50 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice treated with L-DOPA (25 mg/kg): GP-EX prevented the decreases in retention latency time in the passive avoidance test and tyrosine hydroxylase-immunopositive cells and dopamine levels in the nigrostriatum. GP-EX also reduced increases in retention transfer latency time of the elevated plus-maze test and expression of N-methyl-D-aspartate (NMDA) receptor and improved decreases in phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB) in the hippocampus in the same models. By contrast, L-DOPA treatment (10 mg/kg, 21 days) ameliorated memory deficits in MPTP-lesioned mice, which were further improved by GP-EX treatment. These results suggest that GP-EX ameliorates habit learning memory deficits by activating dopaminergic neurons and spatial memory deficits by modulating NMDA receptor-ERK1/2-CREB system in MPTP-lesioned mice treated with L-DOPA. GP-EX may serve as an adjuvant phytonutrient for memory deficits in PD.

  7. 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.

  8. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease

    International Nuclear Information System (INIS)

    Zheng, Rui; Zhang, Zhong-Hao; Chen, Chen; Chen, Yao; Jia, Shi-Zheng; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-01-01

    The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1–10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective

  9. Selenomethionine promoted hippocampal neurogenesis via the PI3K-Akt-GSK3β-Wnt pathway in a mouse model of Alzheimer's disease.

    Science.gov (United States)

    Zheng, Rui; Zhang, Zhong-Hao; Chen, Chen; Chen, Yao; Jia, Shi-Zheng; Liu, Qiong; Ni, Jia-Zuan; Song, Guo-Li

    2017-03-25

    The maintenance of neural system integrity and function is the ultimate goal for the treatment of neurodegenerative disease such as Alzheimer's disease (AD). Neurogenesis plays an integral role in the maintenance of neural and cognitive functions, and its dysfunction is regarded as a major cause of cognitive impairment in AD. Moreover, the induction of neurogenesis by targeting endogenous neural stem cells (NSCs) is considered as one of the most promising treatment strategies. Our previous studies demonstrated that selenomethionine (Se-Met) was able to reduce β-amyloid peptide (Aβ) deposition, decrease Tau protein hyperphosphorylation and markedly improve cognitive functions in triple transgenic (3xTg) AD mice. In this study, we reported that the therapeutic effect of Se-Met on AD could also be due to neurogenesis modulation. By using the cultured hippocampal NSCs from 3xTg AD mice, we discovered that Se-Met (1-10 μM) with low concentration could promote NSC proliferation, while the one with a high concentration (50,100 μM) inhibiting proliferation. In subsequent studies, we also found that Se-Met activated the signaling pathway of PI3K/Akt, and thereby inhibited the GSK3β activity, which would further activated the β-catenin/Cyclin-D signaling pathway and promote NSC proliferation. Besides, after the induction of Se-Met, the number of neurons differentiated from NSCs significantly increased, and the number of astrocytes decreased. After a 90-day treatment with Se-Met (6 μg/mL), the number of hippocampal neurons in 4-month-old AD mice increased significantly, while the one of astrocyte saw a sharp drop. Thus, Se-Met treatment promoted NSCs differentiation into neurons, and subsequently repaired damaged neural systems in AD mice. Being consistent with our in vitro studies, Se-Met acts through the PI3K-Akt- GSK3β-Wnt signaling pathway in vivo. This study provides an unparalleled evidence that selenium (Se) compounds are, to some extent, effective in

  10. 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.

  11. 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.

  12. 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.

  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. In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain.

    Science.gov (United States)

    Saffarpour, S; Shaabani, M; Naghdi, N; Farahmandfar, M; Janzadeh, A; Nasirinezhad, F

    2017-06-01

    Patients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. In this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. We showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (PGABA increased in hippocampal CA1 region (PGABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Effect of Vitamin D in HN9.10e Embryonic Hippocampal Cells and in Hippocampus from MPTP-Induced Parkinson’s Disease Mouse Model

    Directory of Open Access Journals (Sweden)

    Samuela Cataldi

    2018-02-01

    Full Text Available It has long been proven that neurogenesis continues in the adult brains of mammals in the dentatus gyrus of the hippocampus due to the presence of neural stem cells. Although a large number of studies have been carried out to highlight the localization of vitamin D receptor in hippocampus, the expression of vitamin D receptor in neurogenic dentatus gyrus of hippocampus in Parkinson’s disease (PD and the molecular mechanisms triggered by vitamin D underlying the production of differentiated neurons from embryonic cells remain unknown. Thus, we performed a preclinical in vivo study by inducing PD in mice with MPTP and showed a reduction of glial fibrillary acidic protein (GFAP and vitamin D receptor in the dentatus gyrus of hippocampus. Then, we performed an in vitro study by inducing embryonic hippocampal cell differentiation with vitamin D. Interestingly, vitamin D stimulates the expression of its receptor. Vitamin D receptor is a transcription factor that probably is responsible for the upregulation of microtubule associated protein 2 and neurofilament heavy polypeptide genes. The latter increases heavy neurofilament protein expression, essential for neurofilament growth. Notably N-cadherin, implicated in activity for dendritic outgrowth, is upregulated by vitamin D.

  16. Effect of Pre-nutrion of Flax Seed Oil (Linum Usitatissimum on the amount of Cerebral ischemic lesion and motor nerve disorders in animal model rat.

    Directory of Open Access Journals (Sweden)

    SV Hosseini

    2015-10-01

    Full Text Available Background & aim: Stroke is the third death agent (factor in industrial countries after cardiovascular disease and cancer. With regard to high content of antioxidant materials in flax seed oil like &alpha-linolenic acid, lignan as well as phenolic combinations like secoisolarisirsinol (SDG, this study performed for studding relationship between of cerebral ischemic lesion and motor-nerve disorders in model of stroke in rat. Methods: in the study, 35 male mice from strain Wistar divided to 5 groups. The groups included control, sham and 3 experimental groups. They received doses 0.25, 0.5 and 0.75 ml/kg from flax seed oil orally. By gavage for 30 days two control and sham groups received aqua distillate (distil water. Two hours after the last gavaged dose, overly group with 7 pieces operated for measurement of the amount of cerebral lesion and motor-nerve disorders. (Middle Cerebral Artery Occlusion Model. Middle cerebral Artery Occlusion by the model resulted in local ischemic stroke in animal. Data analyzed by software SPSS, test ANOVA and disorders by test mann-Whitney. Findings: Average of records of motor-nerve disorders decreased significantly in group with dose 0.5 and 0.75 using flax seed oil (P<0.05. The amount of cerebral ischemic lesion in doses 0.5 and 0.75 than to control group is indicated meaning full different, but percent of the total cerebral lesion in control group in compared group with dose 0.25 is not indicated meaningful different. Percent of the amount of ischemic lesion in region penumbra in group 0.75 and 0.5 than to control group is indicated meaningful different, but percent of the amount of lesion in region penumbra in control group in compared region penumbra in group with dose 0.25 is not indicated meaning full different. Results: Findings of the study indicated that flax seed oil, particular in doses 0.5 and 0.75 resulted to decrease of the amount of cerebral ischemic lesion and decrease of motor-nerve disorders in

  17. A Pencil Rescues Impaired Performance on a Visual Discrimination Task in Patients with Medial Temporal Lobe Lesions

    Science.gov (United States)

    Knutson, Ashley R.; Hopkins, Ramona O.; Squire, Larry R.

    2013-01-01

    We tested proposals that medial temporal lobe (MTL) structures support not just memory but certain kinds of visual perception as well. Patients with hippocampal lesions or larger MTL lesions attempted to identify the unique object among twin pairs of objects that had a high degree of feature overlap. Patients were markedly impaired under the more…

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

    Directory of Open Access Journals (Sweden)

    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

  19. 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.

  20. Peritoneal macrophages mediated delivery of chitosan/siRNA nanoparticle to the lesion site in a murine radiation-induced fibrosis model

    DEFF Research Database (Denmark)

    Nawroth, Isabel; Alsner, Jan; Deleuran, B.W.

    2013-01-01

    of chitosan/siRNA nanoparticles directed towards silencing TNF alpha in local macrophage populations, but the mechanism for the therapeutic effect at the lesion site remains unclear. Methods. Using the same murine RIF model we utilized an optical imaging technique and fluorescence microscopy to investigate...... the uptake of chitosan/fluorescently labeled siRNA nanoparticles by peritoneal macrophages and their subsequent migration to the inflamed tissue in the RIF model. Results. We observed strong accumulation of the fluorescent signal in the lesion site of the irradiated leg up to 24 hours using the optical...... imaging system. We further confirm by immunohistochemical staining that Cy3 labeled siRNA resides in macrophages of the irradiated leg. Conclusion. We provide a proof-of-concept for host macrophage trafficking towards the inflamed region in a murine RIF model, which thereby suggests that the chitosan...

  1. 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

  2. Effects of 1H + 16O Charged Particle Irradiation on Short-Term Memory and Hippocampal Physiology in a Murine Model.

    Science.gov (United States)

    Kiffer, Frederico; Carr, Hannah; Groves, Thomas; Anderson, Julie E; Alexander, Tyler; Wang, Jing; Seawright, John W; Sridharan, Vijayalakshmi; Carter, Gwendolyn; Boerma, Marjan; Allen, Antiño R

    2018-01-01

    Radiation from galactic cosmic rays (GCR) poses a significant health risk for deep-space flight crews. GCR are unique in their extremely high-energy particles. With current spacecraft shielding technology, some of the predominant particles astronauts would be exposed to are 1 H + 16 O. Radiation has been shown to cause cognitive deficits in mice. The hippocampus plays a key role in memory and cognitive tasks; it receives information from the cortex, undergoes dendritic-dependent processing and then relays information back to the cortex. In this study, we investigated the effects of combined 1 H + 16 O irradiation on cognition and dendritic structures in the hippocampus of adult male mice three months postirradiation. Six-month-old male C57BL/6 mice were irradiated first with 1 H (0.5 Gy, 150 MeV/n) and 1 h later with 16 O (0.1 Gy, 600 MeV/n) at the NASA Space Radiation Laboratory (Upton, NY). Three months after irradiation, animals were tested for hippocampus-dependent cognitive performance using the Y-maze. Upon sacrifice, molecular and morphological assessments were performed on hippocampal tissues. During Y-maze testing, the irradiated mice failed to distinguish the novel arm, spending approximately the same amount of time in all three arms during the retention trial relative to sham-treated controls. Irradiated animals also showed changes in expression of glutamate receptor subunits and synaptic density-associated proteins. 1 H + 16 O radiation compromised dendritic morphology in the cornu ammonis 1 and dentate gyrus within the hippocampus. These data indicate cognitive injuries due to 1 H + 16 O at three months postirradiation.

  3. Time-Dependent Alterations in the Expression of NMDA Receptor Subunits along the Dorsoventral Hippocampal Axis in an Animal Model of Nascent Psychosis.

    Science.gov (United States)

    Dubovyk, Valentyna; Manahan-Vaughan, Denise

    2018-04-10

    Psychosis is a mental condition that is characterized by hallucinations, delusions, disordered thought, as well as socio-emotional and cognitive impairments. Once developed, it tends to progress into a chronic psychotic illness. Here, the duration of untreated psychosis plays a crucial role: the earlier the treatment begins, relative to the first episode of the disease, the better the patient's functional prognosis. To what extent the success of early interventions relate to progressive changes at the neurotransmitter receptor level is as yet unclear. In fact, very little is known as to how molecular changes develop, transform, and become established following the first psychotic event. One neurotransmitter receptor for which a specific role in psychosis has been discussed is the N-methyl-d-aspartate receptor (NMDAR). This receptor is especially important for information encoding in the hippocampus. The hippocampus is one of the loci of functional change in psychosis, to which a role in the pathophysiology of psychosis has been ascribed. Here, we examined whether changes in NMDAR subunit expression occur along the dorsoventral axis of the hippocampus 1 week and 3 months after systemic treatment with an NMDAR antagonist (MK801) that initiates a psychosis-like state in adult rats. We found early (1 week) upregulation of the GluN2B levels in the dorso-intermediate hippocampus and late (3 month) downregulation of GluN2A expression across the entire CA1 region. The ventral hippocampus did not exhibit subunit expression changes. These data suggest that a differing vulnerability of the hippocampal longitudinal axis may occur in response to MK801-treatment and provide a time-resolved view of the putative development of pathological changes of NMDAR subunit expression in the hippocampus that initiate with an emulated first episode and progress through to the chronic stabilization of a psychosis-like state in rodents.

  4. Assay of Calcium Transients and Synapses in Rat Hippocampal Neurons by Kinetic Image Cytometry and High-Content Analysis: An In Vitro Model System for Postchemotherapy Cognitive Impairment.

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    McDonough, Patrick M; Prigozhina, Natalie L; Basa, Ranor C B; Price, Jeffrey H

    2017-07-01

    Postchemotherapy cognitive impairment (PCCI) is commonly exhibited by cancer patients treated with a variety of chemotherapeutic agents, including the endocrine disruptor tamoxifen (TAM). The etiology of PCCI is poorly understood. Our goal was to develop high-throughput assay methods to test the effects of chemicals on neuronal function applicable to PCCI. Rat hippocampal neurons (RHNs) were plated in 96- or 384-well dishes and exposed to test compounds (forskolin [FSK], 17β-estradiol [ES]), TAM or fulvestrant [FUL], aka ICI 182,780) for 6-14 days. Kinetic Image Cytometry™ (KIC™) methods were developed to quantify spontaneously occurring intracellular calcium transients representing the activity of the neurons, and high-content analysis (HCA) methods were developed to quantify the expression, colocalization, and puncta formed by synaptic proteins (postsynaptic density protein-95 [PSD-95] and presynaptic protein Synapsin-1 [Syn-1]). As quantified by KIC, FSK increased the occurrence and synchronization of the calcium transients indicating stimulatory effects on RHN activity, whereas TAM had inhibitory effects. As quantified by HCA, FSK also increased PSD-95 puncta and PSD-95:Syn-1 colocalization, whereas ES increased the puncta of both PSD-95 and Syn-1 with little effect on colocalization. The estrogen receptor antagonist FUL also increased PSD-95 puncta. In contrast, TAM reduced Syn-1 and PSD-95:Syn-1 colocalization, consistent with its inhibitory effects on the calcium transients. Thus TAM reduced activity and synapse formation by the RHNs, which may relate to the ability of this agent to cause PCCI. The results illustrate that KIC and HCA can be used to quantify neurotoxic and neuroprotective effects of chemicals in RHNs to investigate mechanisms and potential therapeutics for PCCI.

  5. Coexistence of meningoencephalocele and hippocampal sclerosis: a new type of dual pathology.

    Science.gov (United States)

    Martinoni, Matteo; Marucci, Gianluca; Gagliardini, Gabriele; Tinuper, Paolo; Michelucci, Roberto; Giulioni, Marco

    2017-05-01

    Both temporal lobe meningoencephalocele (TE) and hippocampal sclerosis (HS) are causes of drug-resistant temporal lobe epilepsy. Spontaneous TE constitutes a rare but well-known and increasingly recognised cause of refractory epilepsy. It is well known that HS may be associated with another neocortical lesion (dual pathology). Here we report for the first time a new type of dual pathology; namely, the coexistence of temporal pole meningoencephalocele and HS.

  6. Flat-Panel Detector—Based Volume Computed Tomography: A Novel 3D Imaging Technique to Monitor Osteolytic Bone Lesions in a Mouse Tumor Metastasis Model

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    Jeannine Missbach-Guentner

    2007-09-01

    Full Text Available Skeletal metastasis is an important cause of mortality in patients with breast cancer. Hence, animal models, in combination with various imaging techniques, are in high demand for preclinical assessment of novel therapies. We evaluated the applicability of flat-panel volume computed tomography (fpVCT to noninvasive detection of osteolytic bone metastases that develop in severe immunodeficient mice after intracardial injection of MDA-MB-231 breast cancer cells. A single fpVCT scan at 200-wm isotropic resolution was employed to detect osteolysis within the entire skeleton. Osteolytic lesions identified by fpVCT correlated with Faxitron X-ray analysis and were subsequently confirmed by histopathological examination. Isotropic three-dimensional image data sets obtained by fpVCT were the basis for the precise visualization of the extent of the lesion within the cortical bone and for the measurement of bone loss. Furthermore, fpVCT imaging allows continuous monitoring of growth kinetics for each metastatic site and visualization of lesions in more complex regions of the skeleton, such as the skull. Our findings suggest that fpVCT is a powerful tool that can be used to monitor the occurrence and progression of osteolytic lesions in vivo and can be further developed to monitor responses to antimetastatic therapies over the course of the disease.

  7. Proangiogenic Tie2(+) macrophages infiltrate human and murine endometriotic lesions and dictate their growth in a mouse model of the disease.

    Science.gov (United States)

    Capobianco, Annalisa; Monno, Antonella; Cottone, Lucia; Venneri, Mary Anna; Biziato, Daniela; Di Puppo, Francesca; Ferrari, Stefano; De Palma, Michele; Manfredi, Angelo A; Rovere-Querini, Patrizia

    2011-11-01

    Endometriosis affects women of reproductive age, causing infertility and pain. Although immune cells are recruited in endometriotic lesions, their role is unclear. Tie2-expressing macrophages (TEMs) have nonredundant functions in promoting angiogenesis and growth of experimental tumors. Here we show that human TEMs infiltrate areas surrounding newly formed endometriotic blood vessels. We set up an ad hoc mouse model in which TEMs, and not Tie2-expressing endothelial cells, are targeted. We transplanted in wild-type recipients bone marrow cells expressing a suicide gene (Herpes simplex virus type 1 thymidine kinase) under the Tie2 promoter/enhancer. TEMs infiltrated endometriotic lesions. TEM depletion by ganciclovir administration arrested the growth of established lesions, without toxicity. Lesion architecture was disrupted, with: i) loss of glandular organization, ii) reduced neovascularization, and iii) activation of caspase 3 in CD31(+) endothelial cells. Thus, TEMs are important for maintaining the viability of newly formed vessels and represent a potential therapeutic target in endometriosis. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  8. Analysis of the effects of exposure to acute hypoxia on oxidative lesions and tumour progression in a transgenic mouse breast cancer model

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    Lunt Sarah

    2008-05-01

    Full Text Available Abstract Background Tumour hypoxia is known to be a poor prognostic indicator, predictive of increased risk of metastatic disease and reduced survival. Genomic instability has been proposed as one of the potential mechanisms for hypoxic tumour progression. Both of these features are commonly found in many cancer types, but their relationship and association with tumour progression has not been examined in the same model. Methods To address this issue, we determined the effects of 6 week in vivo acute hypoxic exposure on the levels of mutagenic lipid peroxidation product, malondialdehyde, and 8-oxo-7,8-dihydro-2'-deoxyguanosine DNA (8-oxo-dG lesions in the transgenic polyomavirus middle T (PyMT breast cancer mouse model. Results We observed significantly increased plasma lipid peroxidation and 8-oxo-dG lesion levels in the hypoxia-exposed mice. Consumption of malondialdehyde also induced a significant increase in the PyMT tumour DNA lesion levels, however, these increases did not translate into enhanced tumour progression. We further showed that the in vivo exposure to acute hypoxia induced accumulation of F4/80 positive tumour-associated macrophages (TAMs, demonstrating a relationship between hypoxia and macrophages in an experimental model. Conclusion These data suggest that although exposure to acute hypoxia causes an increase in 8-oxo-dG lesions and TAMs in the PyMT tumours, these increases do not translate into significant changes in tumour progression at the primary or metastatic levels in this strong viral oncogene-driven breast cancer model.

  9. Local CD34-positive capillaries decrease in mouse models of kidney disease associating with the severity of glomerular and tubulointerstitial lesions.

    Science.gov (United States)

    Masum, Md Abdul; Ichii, Osamu; Elewa, Yaser Hosny Ali; Nakamura, Teppei; Kon, Yasuhiro

    2017-09-04

    The renal vasculature plays important roles in both homeostasis and pathology. In this study, we examined pathological changes in the renal microvascular in mouse models of kidney diseases. Glomerular lesions (GLs) in autoimmune disease-prone male BXSB/MpJ-Yaa (Yaa) mice and tubulointerstitial lesions (TILs) in male C57BL/6 mice subjected to unilateral ureteral obstruction (UUO) for 7 days were studied. Collected kidneys were examined using histopathological techniques. A nonparametric Mann-Whitney U test (P < 0.05) was performed to compare healthy controls and the experimental mice. The Kruskal-Wallis test was used to compare three or more groups, and multiple comparisons were performed using Scheffe's method when significant differences were observed (P < 0.05). Yaa mice developed severe autoimmune glomerulonephritis, and the number of CD34 + glomerular capillaries decreased significantly in GLs compared to that in control mice. However, UUO-treated mice showed severe TILs only, and CD34 + tubulointerstitial capillaries were decreased significantly in TILs with the progression of tubulointerstitial fibrosis compared to those in untreated control kidneys. Infiltrations of B-cells, T-cells, and macrophages increased significantly in the respective lesions of both disease models (P < 0.05). In observations of vascular corrosion casts by scanning electron microscopy and of microfil rubber-perfused thick kidney sections by fluorescence microscopy, segmental absences of capillaries were observed in the GLs and TILs of Yaa and UUO-treated mice, respectively. Further, transmission electron microscopy revealed capillary endothelial injury in the respective lesions of both models. The numbers of CD34 + glomerular and tubulointerstitial capillaries were negatively correlated with all examined parameters in GLs (P < 0.05) and TILs (P < 0.01), respectively. From the analysis of mouse models, we identified inverse pathological correlations between the number of

  10. Ultra-low-dose lung screening CT with model-based iterative reconstruction: an assessment of image quality and lesion conspicuity.

    Science.gov (United States)

    Ju, Yun Hye; Lee, Geewon; Lee, Ji Won; Hong, Seung Baek; Suh, Young Ju; Jeong, Yeon Joo

    2018-05-01

    Background Reducing radiation dose inevitably increases image noise, and thus, it is important in low-dose computed tomography (CT) to maintain image quality and lesion detection performance. Purpose To assess image quality and lesion conspicuity of ultra-low-dose CT with model-based iterative reconstruction (MBIR) and to determine a suitable protocol for lung screening CT. Material and Methods A total of 120 heavy smokers underwent lung screening CT and were randomly and equally assigned to one of five groups: group 1 = 120 kVp, 25 mAs, with FBP reconstruction; group 2 = 120 kVp, 10 mAs, with MBIR; group 3 = 100 kVp, 15 mAs, with MBIR; group 4 = 100 kVp, 10 mAs, with MBIR; and group 5 = 100 kVp, 5 mAs, with MBIR. Two radiologists evaluated intergroup differences with respect to radiation dose, image noise, image quality, and lesion conspicuity using the Kruskal-Wallis test and the Chi-square test. Results Effective doses were 61-87% lower in groups 2-5 than in group 1. Image noises in groups 1 and 5 were significantly higher than in the other groups ( P image quality was best in group 1, but diagnostic acceptability of overall image qualities in groups 1-3 was not significantly different (all P values > 0.05). Lesion conspicuities were similar in groups 1-4, but were significantly poorer in group 5. Conclusion Lung screening CT with MBIR obtained at 100 kVp and 15 mAs enables a ∼60% reduction in radiation dose versus low-dose CT, while maintaining image quality and lesion conspicuity.

  11. Mathematical models of differential diagnostics and prognosis in chronic pancreatitis and cancer with a primary lesion of the pancreatic head

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    I. A. Kryvoruchko

    2017-02-01

    Methods. Analyzed the results of surgical treatment of 132 patients, including 68 - for cancer of the pancreatic head (in 46 - with jaundice and 64 - chronic pancreatitis (CP with a primary lesion of the pancreatic head (16 - with jaundice. The distribution of patients into groups was carried out with a maximum value of classification functions calculated by special formulas. Next studied indicators of endothelial dysfunction for differential diagnosis.  Results. It was defined the threshold of VEGF = 346 pg/ml, which shared the group of chronic pancreatitis or cancer of the pancreatic head, which was determined based on the Pareto criterion. This model sensitivity was 72.1% and specificity of 75% for the overall accuracy of 72.7%. Even more precision indicator was on the threshold of VEGF = 248 pg/ml, which compared groups of patients with cancer and software of the control group (125.9 pg/ml and the sensitivity was 86.8%, specificity 82.4%, and overall accuracy of 82.3%. At about the same accuracy had this test and the comparison group of patients with chronic pancreatitis and control: sensitivity 84.4% and specificity of 76.5% overall accuracy of 81.5% in the threshold VEGF of 155 pg/ml (p<0,05. To develop a prognosis of a pathological process, along with the use of diagnostic data used a method of classification trees. The model showed that the index VEGF is the criterion that discriminates for pancreas- pancreatic cancer-pancreas, but relative differences in the presence of jaundice in patients defined using S-nitrozothiol. The accuracy of the proposed method of prediction was 89%, the price of cross-checking - 82,6% (p<0,05. Pancreatoduodenal resection for Whipple was performed in 23 patients, for Traverso-Longmire - in 8, subtotal right sided pancreatectomy for Fortner - in 3, hepaticojejunostomy by Roux - in 8, duodenopreserving resection for Beger - in 6, her Bernese option - in 7, operation Frey - in 51. In 26 (19.7% patients, minimally invasive

  12. The potential cost-effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for treating de novo, severely calcified coronary lesions: an economic modeling approach

    Science.gov (United States)

    Chambers, Jeffrey; Généreux, Philippe; Lee, Arthur; Lewin, Jack; Young, Christopher; Crittendon, Janna; Mann, Marita; Garrison, Louis P.

    2015-01-01

    Background: Patients who undergo percutaneous coronary intervention (PCI) for severely calcified coronary lesions have long been known to have worse clinical and economic outcomes than patients with no or mildly calcified lesions. We sought to assess the likely cost-effectiveness of using the Diamondback 360® Orbital Atherectomy System (OAS) in the treatment of de novo, severely calcified lesions from a health-system perspective. Methods and results: In the absence of a head-to-head trial and long-term follow up, cost-effectiveness was based on a modeled synthesis of clinical and economic data. A cost-effectiveness model was used to project the likely economic impact. To estimate the net cost impact, the cost of using the OAS technology in elderly (⩾ 65 years) Medicare patients with de novo severely calcified lesions was compared with cost offsets. Elderly OAS patients from the ORBIT II trial (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) [ClinicalTrials.gov identifier: NCT01092426] were indirectly compared with similar patients using observational data. For the index procedure, the comparison was with Medicare data, and for both revascularization and cardiac death in the following year, the comparison was with a pooled analysis of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI)/Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trials. After adjusting for differences in age, gender, and comorbidities, the ORBIT II mean index procedure costs were 17% (p < 0.001) lower, approximately US$2700. Estimated mean revascularization costs were lower by US$1240 in the base case. These cost offsets in the first year, on average, fully cover the cost of the device with an additional 1.2% cost savings. Even in the low-value scenario, the use of the OAS is cost-effective with a cost per life-year gained of US$11,895. Conclusions: Based on economic modeling

  13. 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.

  14. Why and how to spare the hippocampus during brain radiotherapy: the developing role of hippocampal avoidance in cranial radiotherapy

    International Nuclear Information System (INIS)

    Kazda, Tomas; Slampa, Pavel; Laack, Nadia N; Jancalek, Radim; Pospisil, Petr; Sevela, Ondrej; Prochazka, Tomas; Vrzal, Miroslav; Burkon, Petr; Slavik, Marek; Hynkova, Ludmila

    2014-01-01

    The goal of this review is to summarize the rationale for and feasibility of hippocampal sparing techniques during brain irradiation. Radiotherapy is the most effective non-surgical treatment of brain tumors and with the improvement in overall survival for these patients over the last few decades, there is an effort to minimize potential adverse effects leading to possible worsening in quality of life, especially worsening of neurocognitive function. The hippocampus and associated limbic system have long been known to be important in memory formation and pre-clinical models show loss of hippocampal stem cells with radiation as well as changes in architecture and function of mature neurons. Cognitive outcomes in clinical studies are beginning to provide evidence of cognitive effects associated with hippocampal dose and the cognitive benefits of hippocampal sparing. Numerous feasibility planning studies support the feasibility of using modern radiotherapy systems for hippocampal sparing during brain irradiation. Although results of the ongoing phase II and phase III studies are needed to confirm the benefit of hippocampal sparing brain radiotherapy on neurocognitive function, it is now technically and dosimetrically feasible to create hippocampal sparing treatment plans with appropriate irradiation of target volumes. The purpose of this review is to provide a brief overview of studies that provide a rationale for hippocampal avoidance and provide summary of published feasibility studies in order to help clinicians prepare for clinical usage of these complex and challenging techniques

  15. Frequency and characteristics of dual pathology in patients with lesional epilepsy.

    Science.gov (United States)

    Cendes, F; Cook, M J; Watson, C; Andermann, F; Fish, D R; Shorvon, S D; Bergin, P; Free, S; Dubeau, F; Arnold, D L

    1995-11-01

    We studied 167 patients who had identifiable lesions and temporal or extratemporal partial epilepsy. Pathology included neuronal migration disorders (NMDs) (48), low-grade tumors (52), vascular malformations (34), porencephalic cysts (16), and gliotic lesions as a result of cerebral insults early in life (17). MRI volumetric studies using thin (1.5- or 3-mm) coronal images were performed in all patients and in 44 age-matched normal controls. An atrophic hippocampal formation (HF), indicating dual pathology, was present in 25 patients (15%). Abnormal HF volumes were present in those with lesions involving temporal (17%) but also extratemporal (14%) areas. Age at onset and duration of epilepsy did not influence the presence of HF atrophy. However, febrile seizures in early childhood were more frequently, although not exclusively, found in patients with hippocampal atrophy. The frequency of hippocampal atrophy in our patients with low-grade tumors (2%) and vascular lesions (9%) was low. Dual pathology was far more common in patients with NMDs (25%), porencephalic cysts (31%), and reactive gliosis (23.5%). Some structural lesions, such as NMDs, are more likely to be associated with hippocampal atrophy, independent of the distance of the lesion from the HF. In other types of lesions, such as vascular malformations, dual pathology was found when the lesion was close to the HF. A common pathogenic mechanism during pre- or perinatal development may explain the occurrence of concomitant mesial temporal sclerosis and other structural lesions because of either (1) associated developmental abnormalities or (2) predisposition to prolonged febrile convulsions.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Neuronal response of the hippocampal formation to injury: blood flow, glucose metabolism, and protein synthesis

    International Nuclear Information System (INIS)

    Kameyama, M.; Wasterlain, C.G.; Ackermann, R.F.; Finch, D.; Lear, J.; Kuhl, D.E.

    1983-01-01

    The reaction of the hippocampal formation to entorhinal lesions was studied from the viewpoints of cerebral blood flow ([ 123 I]isopropyl-iodoamphetamine[IMP])-glucose utilization ([ 14 C]2-deoxyglucose), and protein synthesis ([ 14 C]leucine), using single- and double-label autoradiography. Researchers' studies showed decreased glucose utilization in the inner part, and increased glucose utilization in the outer part of the molecular layer of the dentate gyrus, starting 3 days after the lesion; increased uptake of [ 123 I]IMP around the lesion from 1 to 3 days postlesion; and starting 3 days after the lesion, marked decrease in [ 14 C]leucine incorporation into proteins and cell loss in the dorsal CA1 and dorsal subiculum in about one-half of the rats. These changes were present only in animals with lesions which invaded the ventral hippocampal formation in which axons of CA1 cells travel. By contrast, transsection of the 3rd and 4th cranial nerves resulted, 3 to 9 days after injury, in a striking increase in protein synthesis in the oculomotor and trochlear nuclei. These results raise the possibility that in some neurons the failure of central regeneration may result from the cell's inability to increase its rate of protein synthesis in response to axonal injury

  17. Regional hippocampal vulnerability in early multiple sclerosis: Dynamic pathological spreading from dentate gyrus to CA1.

    Science.gov (United States)

    Planche, Vincent; Koubiyr, Ismail; Romero, José E; Manjon, José V; Coupé, Pierrick; Deloire, Mathilde; Dousset, Vincent; Brochet, Bruno; Ruet, Aurélie; Tourdias, Thomas

    2018-04-01

    Whether hippocampal subfields are differentially vulnerable at the earliest stages of multiple sclerosis (MS) and how this impacts memory performance is a current topic of debate. We prospectively included 56 persons with clinically isolated syndrome (CIS) suggestive of MS in a 1-year longitudinal study, together with 55 matched healthy controls at baseline. Participants were tested for memory performance and scanned with 3 T MRI to assess the volume of 5 distinct hippocampal subfields using automatic segmentation techniques. At baseline, CA4/dentate gyrus was the only hippocampal subfield with a volume significantly smaller than controls (p < .01). After one year, CA4/dentate gyrus atrophy worsened (-6.4%, p < .0001) and significant CA1 atrophy appeared (both in the stratum-pyramidale and the stratum radiatum-lacunosum-moleculare, -5.6%, p < .001 and -6.2%, p < .01, respectively). CA4/dentate gyrus volume at baseline predicted CA1 volume one year after CIS (R 2  = 0.44 to 0.47, p < .001, with age, T2 lesion-load, and global brain atrophy as covariates). The volume of CA4/dentate gyrus at baseline was associated with MS diagnosis during follow-up, independently of T2-lesion load and demographic variables (p < .05). Whereas CA4/dentate gyrus volume was not correlated with memory scores at baseline, CA1 atrophy was an independent correlate of episodic verbal memory performance one year after CIS (ß = 0.87, p < .05). The hippocampal degenerative process spread from dentate gyrus to CA1 at the earliest stage of MS. This dynamic vulnerability is associated with MS diagnosis after CIS and will ultimately impact hippocampal-dependent memory performance. © 2018 Wiley Periodicals, Inc.

  18. Application of the Physical Disector Principle for Quantification of Dopaminergic Neuronal Loss in a Rat 6-Hydroxydopamine Nigral Lesion Model of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Katrine Fabricius

    2017-12-01

    Full Text Available Stereological analysis is the optimal tool for quantitative assessment of brain morphological and cellular changes induced by neurotoxic lesions or treatment interventions. Stereological methods based on random sampling techniques yield unbiased estimates of particle counts within a defined volume, thereby providing a true quantitative estimate of the target cell population. Neurodegenerative diseases involve loss of specific neuron types, such as the midbrain tyrosine hydroxylase-positive dopamine neurons in Parkinson's disease and in animal models of nigrostriatal degeneration. Therefore, we applied an established automated physical disector principle in a fractionator design for efficient stereological quantitative analysis of tyrosine hydroxylase (TH-positive dopamine neurons in the substantia nigra pars compacta of hemiparkinsonian rats with unilateral 6-hydroxydopamine (6-OHDA lesions. We obtained reliable estimates of dopamine neuron numbers, and established the relationship between behavioral asymmetry and dopamine neuron loss on the lesioned side. In conclusion, the automated physical disector principle provided a useful and efficient tool for unbiased estimation of TH-positive neurons in rat midbrain, and should prove valuable for investigating neuroprotective strategies in 6-OHDA model of parkinsonism, while generalizing to other immunohistochemically-defined cell populations.

  19. Acquisition of a non-matching to place task by rats with neonatal hippocampal lesion induced by ionizing radiation / Aquisição de uma tarefa espacial por ratos submetidos a lesão hipocampal neonatal induzida por radiação ionizante

    Directory of Open Access Journals (Sweden)

    Valéria Catelli Infantozzi Costa

    2007-01-01

    Full Text Available Costa, Bueno e Xavier (2005 showed that rats with hippocampus dentate gyrus lesions produced by colchicine have post-surgical tests deficits in spatial tasks involving conditional discrimination (non-matching-to-place, NMTP, although repetitive training does promote the recovery of the lamed subject's performance. The purpose of this experiment was to assess the performance of rats with selective lesions of dentate gyrus induced by neonatal ionizing radiation in the NMTP task. The irradiated group showed deficits in the first training sessions when compared to the control group. Nevertheless, the performance of lesion and control groups was similar at the end of the sessions, as previously reported. The results are discussed in light of the cognitive map theory.

  20. Fluoxetine normalizes disrupted light-induced entrainment, fragmented ultradian rhythms and altered hippocampal clock gene expression in an animal model of high trait anxiety- and depression-related behavior.

    Science.gov (United States)

    Schaufler, Jörg; Ronovsky, Marianne; Savalli, Giorgia; Cabatic, Maureen; Sartori, Simone B; Singewald, Nicolas; Pollak, Daniela D

    2016-01-01

    Disturbances of circadian rhythms are a key symptom of mood and anxiety disorders. Selective serotonin reuptake inhibitors (SSRIs) - commonly used antidepressant drugs - also modulate aspects of circadian rhythmicity. However, their potential to restore circadian disturbances in depression remains to be investigated. The effects of the SSRI fluoxetine on genetically based, depression-related circadian disruptions at the behavioral and molecular level were examined using mice selectively bred for high anxiety-related and co-segregating depression-like behavior (HAB) and normal anxiety/depression behavior mice (NAB). The length of the circadian period was increased in fluoxetine-treated HAB as compared to NAB mice while the number of activity bouts and light-induced entrainment were comparable. No difference in hippocampal Cry2 expression, previously reported to be dysbalanced in untreated HAB mice, was observed, while Per2 and Per3 mRNA levels were higher in HAB mice under fluoxetine treatment. The present findings provide evidence that fluoxetine treatment normalizes disrupted circadian locomotor activity and clock gene expression in a genetic mouse model of high trait anxiety and depression. An interaction between the molecular mechanisms mediating the antidepressant response to fluoxetine and the endogenous regulation of circadian rhythms in genetically based mood and anxiety disorders is proposed.

  1. 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.

  2. 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

  3. Effects of (-)-sesamin on motor and memory deficits in an MPTP-lesioned mouse model of Parkinson's disease treated with l-DOPA.

    Science.gov (United States)

    Zhao, T T; Shin, K S; Kim, K S; Park, H J; Kim, H J; Lee, K E; Lee, M K

    2016-12-17

    The present study investigated the effects of (-)-sesamin on motor and memory deficits in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse model of Parkinson's disease (PD) with l-3,4-dihydroxyphenylalanine (l-DOPA). MPTP-lesioned (30mg/kg/day, 5days) mice showed deficits in memory including habit learning memory and spatial memory, which were further aggravated by daily treatment with 25mg/kg l-DOPA for 21days. However, daily treatment with (-)-sesamin (25 and 50mg/kg) for 21days ameliorated memory deficits in an MPTP-lesioned mouse model of PD treated with l-DOPA (25mg/kg). Both (-)-sesamin doses reduced decreases in the retention latency time in the passive avoidance test, latency to fall of rotarod test and distance traveled in the open field test, and attenuated decreases in tyrosine hydroxylase (TH)-immunopositive cells, dopamine, and its metabolites in the substantia nigra-striatum. (-)-Sesamin reduced increases in the retention transfer latency time in the elevated plus-maze test and N-methyl-d-aspartate receptor (NMDAR) expression and reduced decreases in the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and cyclic AMP-response element binding protein (CREB) in the hippocampus. In contrast, daily treatment with 10mg/kg l-DOPA for 21days ameliorated memory deficits in MPTP-lesioned mice, and this effect was further improved by treatment with (-)-sesamin (25 and 50mg/kg). These results suggest that (-)-sesamin protects against habit learning memory deficits by activating the dopamine neuronal system, while spatial memory deficits are decreased by its modulatory effects on the NMDAR-ERK1/2-CREB system. Accordingly, (-)-sesamin may act as an adjuvant phytonutrient for motor and memory deficits in patients with PD receiving l-DOPA. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  4. Differential Atrophy of Hippocampal Subfields: A Comparative Study of Dementia with Lewy Bodies and Alzheimer Disease.

    Science.gov (United States)

    Mak, Elijah; Su, Li; Williams, Guy B; Watson, Rosie; Firbank, Michael; Blamire, Andrew; O'Brien, John

    2016-02-01

    Dementia with Lewy bodies (DLB) is characterized by relative preservation of the medial temporal lobe compared with Alzheimer disease (AD). The differential involvement of the hippocampal subfields in both diseases has not been clearly established, however. We aim to investigate hippocampal subfield differences in vivo in a clinical cohort of DLB and AD subjects. 104 participants (35 DLBs, 36 ADs, and 35 healthy comparison [HC] subjects) underwent clinical assessment and 3T T1-weighted imaging. A Bayesian model implemented in Freesurfer was used to automatically segment the hippocampus and its subfields. We also examined associations between hippocampal subfields and tests of memory function. Both the AD and DLB groups demonstrated significant atrophy of the total hippocampus relative to HC but the DLB group was characterized by preservation of the cornu ammonis 1 (CA1), fimbria, and fissure. In contrast, all the hippocampal subfields except the fissure were significantly atrophied in AD compared with both DLB and HC groups. Among DLB subjects, CA1 was correlated with the Recent Memory score of the CAMCOG and Delayed Recall subscores of the HVLT. DLB is characterized by milder hippocampal atrophy that was accompanied by preservation of the CA1. The CA1 was also associated with memory function in DLB. Our findings highlight the promising role of hippocampal subfield volumetry, particularly that of the CA1, as a biomarker for the distinction between AD and DLB. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  5. 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.

  6. 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.

  7. 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.

  8. Prophylactic clipping for the prevention of bleeding following wide-field endoscopic mucosal resection of laterally spreading colorectal lesions: an economic modeling study.

    Science.gov (United States)

    Bahin, Farzan F; Rasouli, Khalid N; Williams, Stephen J; Lee, Eric Y T; Bourke, Michael J

    2016-08-01

    Clinically significant bleeding (CSPEB) is the most common adverse event following endoscopic mucosal resection (EMR) of large sessile and laterally spreading colorectal lesions (LSLs), and is associated with morbidity and resource utilization. CSPEB occurs more frequently with proximal LSLs. Prophylactic clipping of the post-EMR defect may be beneficial in CSPEB prevention. The aim of this study was to determine the cost-effectiveness of a prophylactic clipping strategy. We hypothesized that prophylactic clipping in the proximal colon was cost-effective. An economic model was applied to outcomes from the Australian Colonic Endoscopic Mucosal Resection (ACE) Study. Clip distances of 3, 5, 8, and 10 mm were analyzed. The cost of treating CSPEB was determined from an independent costing agency. The funds needed to spend (FNS) was the cost incurred in order to prevent one episode of CSPEB. A break-even analysis was performed to determine cost equivalence of the costs of clipping and CSPEB. Outcomes of 1717 LSLs (mean size 35.8 mm; 52.6 % proximal colon) that underwent EMR were analyzed. The overall rate of CSPEB was 6.4 % (proximal 8.9 %; distal 3.7 %). Endoscopic management was required in 45 % of CSPEB episodes. With a clip distance of 3 mm, the expected cost of prophylactic clipping was € 1106 per lesion compared with € 157 per lesion for the expected cost of CSPEB without clipping. At 100 % clipping efficacy, the FNS was € 14 826 (proximal and distal lesions € 9309 and € 29 540, respectively). A clip price of € 10.35 was required for the cost of clipping to offset the cost of CSPEB. A prophylactic clipping strategy is not cost-effective and at present cannot be justified for all lesions or selectively for lesions in the proximal colon. ClinicalTrials.gov (NCT01368289). © Georg Thieme Verlag KG Stuttgart · New York.

  9. Virtual In-Silico Modeling Guided Catheter Ablation Predicts Effective Linear Ablation Lesion Set for Longstanding Persistent Atrial Fibrillation: Multicenter Prospective Randomized Study.

    Science.gov (United States)

    Shim, Jaemin; Hwang, Minki; Song, Jun-Seop; Lim, Byounghyun; Kim, Tae-Hoon; Joung, Boyoung; Kim, Sung-Hwan; Oh, Yong-Seog; Nam, Gi-Byung; On, Young Keun; Oh, Seil; Kim, Young-Hoon; Pak, Hui-Nam

    2017-01-01

    Objective: Radiofrequency catheter ablation for persistent atrial fibrillation (PeAF) still has a substantial recurrence rate. This study aims to investigate whether an AF ablation lesion set chosen using in-silico ablation (V-ABL) is clinically feasible and more effective than an empirically chosen ablation lesion set (Em-ABL) in patients with PeAF. Methods: We prospectively included 108 patients with antiarrhythmic drug-resistant PeAF (77.8% men, age 60.8 ± 9.9 years), and randomly assigned them to the V-ABL ( n = 53) and Em-ABL ( n = 55) groups. Five different in-silico ablation lesion sets [1 pulmonary vein isolation (PVI), 3 linear ablations, and 1 electrogram-guided ablation] were compared using heart-CT integrated AF modeling. We evaluated the feasibility, safety, and efficacy of V-ABL compared with that of Em-ABL. Results: The pre-procedural computing time for five different ablation strategies was 166 ± 11 min. In the Em-ABL group, the earliest terminating blinded in-silico lesion set matched with the Em-ABL lesion set in 21.8%. V-ABL was not inferior to Em-ABL in terms of procedure time ( p = 0.403), ablation time ( p = 0.510), and major complication rate ( p = 0.900). During 12.6 ± 3.8 months of follow-up, the clinical recurrence rate was 14.0% in the V-ABL group and 18.9% in the Em-ABL group ( p = 0.538). In Em-ABL group, clinical recurrence rate was significantly lower after PVI+posterior box+anterior linear ablation, which showed the most frequent termination during in-silico ablation (log-rank p = 0.027). Conclusions: V-ABL was feasible in clinical practice, not inferior to Em-ABL, and predicts the most effective ablation lesion set in patients who underwent PeAF ablation.

  10. Development of occlusive neointimal lesions in distal pulmonary arteries of endothelin B receptor-deficient rats: a new model of severe pulmonary arterial hypertension.

    Science.gov (United States)

    Ivy, D Dunbar; McMurtry, Ivan F; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

    2005-06-07

    Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ET(B) receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ET(B) receptor-deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT(+/+)) and ET(B) receptor-deficient (MCT(sl/sl)) rats at 6 weeks of age were assessed. MCT(sl/sl) rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCT(sl/sl) rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCT(sl/sl) rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ET(B) receptors was decreased in MCT(sl/sl) rat lungs, ET(A) receptor expression increased. Deficiency of the ET(B) receptor markedly accelerates the progression of

  11. Development of Occlusive Neointimal Lesions in Distal Pulmonary Arteries of Endothelin B Receptor–Deficient Rats: A New Model of Severe Pulmonary Arterial Hypertension

    Science.gov (United States)

    Ivy, D. Dunbar; McMurtry, Ivan F.; Colvin, Kelley; Imamura, Masatoshi; Oka, Masahiko; Lee, Dong-Seok; Gebb, Sarah; Jones, Peter Lloyd

    2007-01-01

    Background Human pulmonary arterial hypertension (PAH) is characterized by proliferation of vascular smooth muscle and, in its more severe form, by the development of occlusive neointimal lesions. However, few animal models of pulmonary neointimal proliferation exist, thereby limiting a complete understanding of the pathobiology of PAH. Recent studies of the endothelin (ET) system demonstrate that deficiency of the ETB receptor predisposes adult rats to acute and chronic hypoxic PAH, yet these animals fail to develop neointimal lesions. Herein, we determined and thereafter showed that exposure of ETB receptor–deficient rats to the endothelial toxin monocrotaline (MCT) leads to the development of neointimal lesions that share hallmarks of human PAH. Methods and Results The pulmonary hemodynamic and morphometric effects of 60 mg/kg MCT in control (MCT+/+) and ETB receptor–deficient (MCTsl/sl) rats at 6 weeks of age were assessed. MCTsl/sl rats developed more severe PAH, characterized by elevated pulmonary artery pressure, diminished cardiac output, and right ventricular hypertrophy. In MCTsl/sl rats, morphometric evaluation revealed the presence of neointimal lesions within small distal pulmonary arteries, increased medial wall thickness, and decreased arterial-to-alveolar ratio. In keeping with this, barium angiography revealed diminished distal pulmonary vasculature of MCTsl/sl rat lungs. Cells within neointimal lesions expressed smooth muscle and endothelial cell markers. Moreover, cells within neointimal lesions exhibited increased levels of proliferation and were located in a tissue microenvironment enriched with vascular endothelial growth factor, tenascin-C, and activated matrix metalloproteinase-9, factors already implicated in human PAH. Finally, assessment of steady state mRNA showed that whereas expression of ETB receptors was decreased in MCTsl/sl rat lungs, ETA receptor expression increased. Conclusions Deficiency of the ETB receptor markedly

  12. 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.

  13. 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.

  14. Hippocampus lesions induced deficits in social and spatial recognition in Octodon degus.

    Science.gov (United States)

    Uekita, Tomoko; Okanoya, Kazuo

    2011-06-01

    Previous studies of rodents reported that the hippocampus plays an important role in social behavior as well as spatial behavior. However, there are inconsistencies between reports of the effects of hippocampal lesions on social behavior. The present study sought to clarify the aspects of social behavior in which the hippocampus plays a role in the degu, Octodon degus, a social rodent. We examined the effects of hippocampal lesions on social behavior in the degu using familiar and novel partners. When placed in a familiar environment with a familiar partner after surgery, sham operation control (S.Cont) degus exhibited affinitive behavior longer compared with hippocampal lesioned (HPC) degus. In a novel environment, S.Cont degus exhibited longer aggressive behavior toward novel partners, and longer affinitive behavior with familiar partners compared with HPC degus. HPC degus did not show evidence of differentiation in social behavior, regardless of partner's novelty. The results of an anxiety test confirmed that these findings could not be attributed to changes in emotional state. We conducted an object-recognition test with the same subjects. HPC degus showed an impairment in spatial recognition but not object recognition. Taken together, these results suggest that the degu hippocampus plays an important role not only in spatial recognition but also social recognition. The changes in social behavior resulting from hippocampal lesions were interpreted as due to an impairment of social recognition rather than an impairment in novelty detection. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Complexity and multifractality of neuronal noise in mouse and human hippocampal epileptiform dynamics

    Science.gov (United States)

    Serletis, Demitre; Bardakjian, Berj L.; Valiante, Taufik A.; Carlen, Peter L.

    2012-10-01

    Fractal methods offer an invaluable means of investigating turbulent nonlinearity in non-stationary biomedical recordings from the brain. Here, we investigate properties of complexity (i.e. the correlation dimension, maximum Lyapunov exponent, 1/fγ noise and approximate entropy) and multifractality in background neuronal noise-like activity underlying epileptiform transitions recorded at the intracellular and local network scales from two in vitro models: the whole-intact mouse hippocampus and lesional human hippocampal slices. Our results show evidence for reduced dynamical complexity and multifractal signal features following transition to the ictal epileptiform state. These findings suggest that pathological breakdown in multifractal complexity coincides with loss of signal variability or heterogeneity, consistent with an unhealthy ictal state that is far from the equilibrium of turbulent yet healthy fractal dynamics in the brain. Thus, it appears that background noise-like activity successfully captures complex and multifractal signal features that may, at least in part, be used to classify and identify brain state transitions in the healthy and epileptic brain, offering potential promise for therapeutic neuromodulatory strategies for afflicted patients suffering from epilepsy and other related neurological disorders. This paper is based on chapter 5 of Serletis (2010 PhD Dissertation Department of Physiology, Institute of Biomaterials and Biomedical Engineering, University of Toronto).

  16. 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.

  17. Tissue tropisms, infection kinetics, histologic lesions, and antibody response of the MR766 strain of Zika virus in a murine model.

    Science.gov (United States)

    Kawiecki, Anna B; Mayton, E Handly; Dutuze, M Fausta; Goupil, Brad A; Langohr, Ingeborg M; Del Piero, Fabio; Christofferson, Rebecca C

    2017-04-18

    The appearance of severe Zika virus (ZIKV) disease in the most recent outbreak has prompted researchers to respond through the development of tools to quickly characterize transmission and pathology. We describe here another such tool, a mouse model of ZIKV infection and pathogenesis using the MR766 strain of virus that adds to the growing body of knowledge regarding ZIKV kinetics in small animal models. We infected mice with the MR766 strain of ZIKV to determine infection kinetics via serum viremia. We further evaluated infection-induced lesions via histopathology and visualized viral antigen via immunohistochemical labeling. We also investigated the antibody response of recovered animals to both the MR766 and a strain from the current outbreak (PRVABC59). We demonstrate that the IRF3/7 DKO mouse is a susceptible, mostly non-lethal model well suited for the study of infection kinetics, pathological progression, and antibody response. Infected mice presented lesions in tissues that have been associated with ZIKV infection in the human population, such as the eyes, male gonads, and central nervous system. In addition, we demonstrate that infection with the MR766 strain produces cross-neutralizing antibodies to the PRVABC59 strain of the Asian lineage. This model provides an additional tool for future studies into the transmission routes of ZIKV, as well as for the development of antivirals and other therapeutics, and should be included in the growing list of available tools for investigations of ZIKV infection and pathogenesis.

  18. Development of vicarious trial-and-error behavior in odor discrimination learning in the rat: relation to hippocampal function?

    Science.gov (United States)

    Hu, D; Griesbach, G; Amsel, A

    1997-06-01

    Previous work from our laboratory has suggested that hippocampal electrolytic lesions result in a deficit in simultaneous, black-white discrimination learning and reduce the frequency of vicarious trial-and-error (VTE) at a choice-point. VTE is a term Tolman used to describe the rat's conflict-like behavior, moving its head from one stimulus to the other at a choice point, and has been proposed as a major nonspatial feature of hippocampal function in both visual and olfactory discrimination learning. Simultaneous odor discrimination and VTE behavior were examined at three different ages. The results were that 16-day-old pups made fewer VTEs and learned much more slowly than 30- and 60-day-olds, a finding in accord with levels of hippocampal maturity in the rat.

  19. Evaluation of a C57BL/6J × 129S1/SvImJ Hybrid Nestin-Thymidine Kinase Transgenic Mouse Model for Studying the Functional Significance of Exercise-Induced Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Hamilton, G F; Majdak, P; Miller, D S; Bucko, P J; Merritt, J R; Krebs, C P; Rhodes, J S

    2015-01-01

    New neurons are continuously generated in the adult hippocampus but their function remains a mystery. The nestin thymidine kinase (nestin-TK) transgenic method has been used for selective and conditional reduction of neurogenesis for the purpose of testing the functional significance of new neurons in learning, memory and motor performance. Here we explored the nestin-TK model on a hybrid genetic background (to increase heterozygosity, and "hybrid vigor"). Transgenic C57BL/6J (B6) were crossed with 129S1/SvImJ (129) producing hybrid offspring (F1) with the B6 half of the genome carrying a herpes simplex virus thymidine kinase (TK) transgene regulated by a modified nestin promoter. In the presence of exogenously administered valganciclovir, new neurons expressing TK undergo apoptosis. Female B6 nestin-TK mice ( n = 80) were evaluated for neurogenesis reduction as a positive control. Male and female F1 nestin-TK mice ( n = 223) were used to determine the impact of neurogenesis reduction on the Morris water maze (MWM) and rotarod. All mice received BrdU injections to label dividing cells and either valganciclovir or control chow, with or without a running wheel for 30 days. Both the F1 and B6 background displayed approximately 50% reduction in neurogenesis, a difference that did not impair learning and memory on the MWM or rotarod performance. Running enhanced neurogenesis and performance on the rotarod but not MWM suggesting the F1 background may not be suitable for studying pro-cognitive effects of exercise on MWM. Greater reduction of neurogenesis may be required to observe behavioral impacts. Alternatively, new neurons may not play a critical role in learning, or compensatory mechanisms in pre-existing neurons could have masked the deficits. Further work using these and other models for selectively reducing neurogenesis are needed to establish the functional significance of adult hippocampal neurogenesis in behavior.

  20. Circadian system functionality, hippocampal oxidative stress, and spatial memory in the APPswe/PS1dE9 transgenic model of Alzheimer disease: effects of melatonin or ramelteon.

    Science.gov (United States)

    Baño Otalora, Beatriz; Popovic, Natalija; Gambini, Juan; Popovic, Miroljub; Viña, José; Bonet-Costa, Vicent; Reiter, Russel J; Camello, Pedro Javier; Rol, Maria Ángeles; Madrid, Juan Antonio

    2012-08-01

    Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not significantly affected in these AD mice. During the day, though, Tg controls (Tg-CON) showed significantly higher mean activity and body temperature (BT) than wild-type (WT) mice. Overall, BT rhythm amplitude was significantly lower in Tg than in WT mice. Although melatonin treatment had no effect, ramelteon significantly reduced the amplitude of the BT rhythm in Tg mice. Towards the end of the experiment, Tg mice treated with ramelteon (Tg-RAM) showed significantly higher circadian rhythm fragmentation than Tg-CON and reduced circadian BT rhythm strength. The free-running period (τ) for the BT and locomotor activity (LA) rhythms of Tg-CON was RAM compared with Tg-CON animals. These results suggest that not all aspects of the circadian system are affected in the APPswe/PS1 mice. Therefore, care should be taken when extending the results obtained in Tg mice to develop new therapies in humans. This study also revealed the complexity in the therapeutic actions of melatonin

  1. Morphological Variations of Hippocampal Formation in Epilepsy

    Directory of Open Access Journals (Sweden)

    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.

  2. 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.

  3. 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

  4. 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.

  5. Are dinucleoside monophosphates relevant models for the study of DNA intrastrand cross-link lesions? The example of g[8-5m]T.

    Science.gov (United States)

    Garrec, Julian; Dumont, Elise

    2014-07-21

    Oxidatively generated tandem lesions such as G[8-5m]T pose a potent threat to genome integrity. Direct experimental studies of the kinetics and thermodynamics of a specific lesion within DNA are very challenging, mostly due to the variety of products that can be formed in oxidative conditions. Dinucleoside monophosphates (DM) involving only the reactive nucleobases in water represent appealing alternative models on which most physical chemistry and structural techniques can be applied. However, it is not yet clear how relevant these models are. Here, we present QM/MM MD simulations of the cyclization step involved in the formation of G[8-5m]T from the guanine-thymine (GpT) DM in water, with the aim of comparing our results to our previous investigation of the same reaction in DNA ( Garrec , J. , Patel , C. , Rothlisberger , U. , and Dumont , E. ( 2012 ) J. Am. Chem. Soc. 134 , 2111 - 2119 ). We show that, despite the different levels of preorganization of the two systems, the corresponding reactions share many energetic and structural characteristics. The main difference lies in the angle between the G and T bases, which is slightly higher in the transition state (TS) and product of the reaction in water than in the reaction in DNA. This effect is due to the Watson-Crick H-bonds, which are absent in the {GpT+water} system and restrain the relative positioning of the reactive nucleobases in DNA. However, since the lesion is accommodated easily in the DNA macromolecule, the induced energetic penalty is relatively small. The high similarity between the two reactions strongly supports the use of GpT in water as a model of the corresponding reaction in DNA.

  6. TLR4 Gene Expression and Pro-Inflammatory Cytokines in Alzheimer's Disease and in Response to Hippocampal Deafferentation in Rodents.

    Science.gov (United States)

    Miron, Justin; Picard, Cynthia; Frappier, Josée; Dea, Doris; Théroux, Louise; Poirier, Judes

    2018-01-01

    One important aspect in Alzheimer's disease pathology is the presence of chronic inflammation. Considering its role as a key receptor in the microglial innate immune system, TLR4 was shown to regulate the binding and phagocytosis of amyloid plaques by microglia in several mouse models of amyloidosis, as well as the production of pro-inflammatory cytokines. To our knowledge, TLR4 and its association with cytokines have not been thoroughly examined in the brains of subjects affected with Alzheimer's disease. Using quantitative reverse transcription polymerase chain reaction (qRT-PCR) in postmortem human brains, we observed increased expression for the TLR4 and TNF genes (p = 0.001 and p = 0.025, respectively), as well as a trend for higher IL6 gene expression in the frontal cortex of AD subjects when compared to age-matched controls. Similarly, using a mouse model of hippocampal deafferentation without amyloidosis, (i.e., the entorhinal cortex lesioned mouse), we observed significant increases in the expression of both the Tlr4 (p = 0.0367 and p = 0.0193 compared to sham-lesioned mice or to the contralateral side, respectively) and Il1b (p = 0.0055 and p = 0.0066 compared to sham-lesioned mice or to the contralateral side, respectively) genes in the deafferentation phase, but not during the ensuing reinnervation process. In conclusion, we suggest that the modulation of cytokines by TLR4 is differentially regulated whether by the presence of amyloid plaques or by the ongoing deafferentation process.

  7. Long-term effects of immunotoxic cholinergic lesions in the septum on acquisition of the cone-field task and noncognitive measures in rats

    NARCIS (Netherlands)

    Staay, van der F.J.; Bouger, P.; Lehmann, O.; Lazarus, C.; Cosquer, B.; Koenig, J.; Stump, V.; Cassel, J.C.

    2006-01-01

    In rats, nonspecific mechanical or neurotoxic lesions of the septum impair spatial memory in, e.g., Morris water- and radial-maze tasks. Unfortunately, the lack of specificity of such lesions limits inferences about the role of the cholinergic hippocampal projections in spatial cognition. We

  8. In vivo analysis of tissue by Raman microprobe: examination of human skin lesions and esophagus Barrett's mucosa on an animal model

    Science.gov (United States)

    Tfayli, Ali; Piot, Olivier; Derancourt, Sylvie; Cadiot, Guillaume; Diebold, Marie D.; Bernard, Philippe; Manfait, Michel

    2006-02-01

    In the last few years, Raman spectroscopy has been increasingly used for the characterization of normal and pathological tissues. A new Raman system, constituted of optic fibers bundle coupled to an axial Raman spectrometer (Horiba Jobin Yvon SAS), was developed for in vivo investigations. Here, we present in vivo analysis on two tissues: human skin and esophagus mucosa on a rat model. The skin is a directly accessible organ, representing a high diversity of lesions and cancers. Including malignant melanoma, basal cell carcinoma and the squamous cell carcinoma, skin cancer is the cancer with the highest incidence worldwide. Several Raman investigations were performed to discriminate and classify different types of skin lesions, on thin sections of biopsies. Here, we try to characterize in vivo the different types of skin cancers in order to be able to detect them in their early stages of development and to define precisely the exeresis limits. Barrett's mucosa was also studied by in vivo examination of rat's esophagus. Barrett's mucosa, induced by gastro-esophageal reflux, is a pretumoral state that has to be carefully monitored due to its high risk of evolution in adenocarcinoma. A better knowledge of the histological transformation of esophagus epithelium in a Barrett's type will lead to a more efficient detection of the pathology for its early diagnosis. To study these changes, an animal model (rats developing Barrett's mucosa after duodenum - esophagus anastomosis) was used. Potential of vibrational spectroscopy for Barrett's mucosa identification is assessed on this model.

  9. High post-partum levels of corticosterone given to dams influence postnatal hippocampal cell proliferation and behavior of offspring: A model of post-partum stress and possible depression.

    Science.gov (United States)

    Brummelte, Susanne; Pawluski, Jodi L; Galea, Liisa A M

    2006-09-01

    Post-partum stress and depression (PPD) have a significant effect on child development and behavior. Depression is associated with hypercortisolism in humans, and the fluctuating levels of hormones, including corticosterone, during pregnancy and the post-partum, may contribute to PPD. The present study was developed to investigate the effects of high-level corticosterone (CORT) post-partum in the mother on postnatal neurogenesis and behavior in the offspring. Sprague-Dawley dams were treated with either CORT (40 mg/kg) or sesame oil injections daily for 26 days beginning the day after giving birth. Dams were tested in the forced swim test (FST) and in the open field test (OFT) on days 24-26 post-partum. Results showed that the dams exposed to CORT expressed "depressive-like" behavior compared to controls, with decreased struggling behavior and increased immobility in the FST. To investigate the effects of treatment on hippocampal postnatal cell proliferation and survival in the offspring, males and females from treated dams were injected with BrdU (50 mg/kg) on postnatal day 21 and perfused either 24 h (cell proliferation) or 21 days (cell survival) later. Furthermore, male and female offspring from each litter were tested in adulthood on various behavioral tests, including the forced swim test, open field test, resistance to capture test and elevated plus maze. Intriguingly, male, but not female, offspring of CORT-treated dams exhibited decreased postnatal cell proliferation in the dentate gyrus. Both male and female offspring of CORT-treated dams showed higher resistance to capture and greater locomotor activity as assessed in the open field test. As high levels of CORT may be a characteristic of stress and/or depression, these findings support a model of 'CORT-induced' post-partum stress and possibly depression and demonstrate that the offspring of affected dams can exhibit changes in postnatal neurogenesis and behavior in adulthood.

  10. Histomorphological spetrum of breast lesions.

    Science.gov (United States)

    Parajuli, S; Koirala, U; Khatri, R; Acharya, L; Suwal, A

    2011-04-01

    Cancer of the breast is the second most common cause of cancer in women. Mass in the breast, whether benign or malignant is a cause of anxiety to the patients and the family members. All breast lumps are considered to be carcinomas until proved otherwise and are the causes of concern both for the patient and surgeon. This is a retrospective study conducted in Kathmandu Model Hospital for a total duration of three years from August 2007 to August 2010. 114 sample of breast tissue sent for histopathology were studied. Peak incidence of benign lesion was in between 21-30 years and malignant lesions in between 31-50 years. No breast lesions were seen in the first decade of life. Cancer of the breast was seen in 12.28% of cases. Fibroadenoma and fibrocystic disease were the commonest benign lesion and infiltrating ductal carcinoma was the commonest malignant lesion. Specimens from 10 male breasts were received. Gynaecomastia was the most common lesion encountered in males. Infiltrating ductal carcinoma was seen in a 70 year old male. Breast cancer is one of the commonest causes of breast lump particularly in women and is growing public health problem in Nepal.

  11. Premalignant Lesions in the Kidney

    Directory of Open Access Journals (Sweden)

    Ziva Kirkali

    2001-01-01

    Full Text Available Renal cell carcinoma (RCC is the most malignant urologic disease. Different lesions, such as dysplasia in the tubules adjacent to RCC, atypical hyperplasia in the cyst epithelium of von Hippel-Lindau syndrome, and adenoma have been described for a number of years as possible premalignant changes or precursor lesions of RCC. In two recent papers, kidneys adjacent to RCC or removed from other causes were analyzed, and dysplastic lesions were identified and defined in detail. Currently renal intraepithelial neoplasia (RIN is the proposed term for classification. The criteria for a lesion to be defined as premalignant are (1 morphological similarity; (2 spatial association; (3 development of microinvasive carcinoma; (4 higher frequency, severity, and extent then invasive carcinoma; (5 progression to invasive cancer; and (6 similar genetic alterations. RIN resembles the neoplastic cells of RCC. There is spatial association. Progression to invasive carcinoma is described in experimental cancer models, and in some human renal tumors. Similar molecular alterations are found in some putative premalignant changes. The treatment for RCC is radical or partial nephrectomy. Preneoplastic lesions may remain in the renal remnant in patients treated by partial nephrectomy and may be the source of local recurrences. RIN seems to be a biologic precursor of some RCCs and warrants further investigation. Interpretation and reporting of these lesions would reveal important resources for the biological nature and clinical significance. The management of RIN diagnosed in a renal biopsy and partial nephrectomy needs to be answered.

  12. The effect of intrathecal delivery of bone marrow stromal cells on hippocampal neurons in rat model of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Mina Eftekharzadeh

    2015-05-01

    Full Text Available Objective(s: Intracerebral injection of bone marrow stromal cells (BMSCs is being investigated as a therapeutic tool to prevent Alzheimer's disease (AD. Our aim was to investigate the effects of BMSCs by intrathecal injection in AD rat model. Materials and Methods: BMSCs were obtained from the bone marrow of Wistar rat and transplanted into AD rat model via intrathecal injection. The rat model had received an injection of β amyloid into the hippocampus for histological and immunohistochemical studies. Results: Histological examination of the brains in transplanted rats compared to controls demonstrated the migration of BrdU-labeled BMSCs from the site of delivery, confirmed the differentiation of BMSCs transplanted cells into the cholinergic neurons, and increased number of healthy and decreased number of dark neurons. Conclusion: Our results showed that BMSCs intratechal administration could be a promising method for treatment ofAlzheimer’s disease in rat model.

  13. Regional Hippocampal Atrophy and Higher Levels of Plasma Amyloid-Beta Are Associated With Subjective Memory Complaints in Nondemented Elderly Subjects

    DEFF Research Database (Denmark)

    Cantero, Jose L; Iglesias, Juan E.; Van Leemput, Koen

    2016-01-01

    Background: Evidence suggests a link between the presence of subjective memory complaints (SMC) and lower volume of the hippocampus, one of the first regions to show neuropathological lesions in Alzheimer's disease. However, it remains unknown whether this pattern of hippocampal atrophy is region...

  14. Oropharynx lesion biopsy

    Science.gov (United States)

    ... as papilloma) Fungal infections (such as candida) Histoplasmosis Oral lichen planus Precancerous sore (leukoplakia) Viral infections (such as Herpes simplex) Risks Risks of the procedure may ... Throat lesion biopsy; Biopsy - mouth or throat; Mouth lesion biopsy; Oral cancer - biopsy ...

  15. Model applied to wistar rats for analysis of atrial alteration radioinduced: role of the TGFBeta1 cytokine on the lesions development

    International Nuclear Information System (INIS)

    Silva, Viviane Fernandes da; Andrade, Cherley Borba V. de; Nascimento, Ana Lucia Rosa do; Silva, Claudia Marcello da; Ribeiro, Andreia Fortes; Mandarim-de-Lacerda, Carlos Alberto; Carvalho, Jorge Jose de; Almeida, Carlos Eduardo de

    2009-01-01

    This paper develops a radiobiological model on Wistar rats for evaluation of atrium radioinduced alterations. Male Wistar rats were anaesthetised, immobilized and irradiated with 500, 1000 and 1500 cGy irradiated doses in the cardiac volume, pre-define through tomography. The animals were sacrificed after 15 days irradiation. The atriums were collected, fixed in formaldehyde and soaked into paraffin. A part of samples were dyed with hematoxyline-eosin (HE) and another submitted to immunohistochemistry for visualization of the cytokine TGFbeta1 expression. The observation of samples with HE indicated lesions om blood vessels and discrete inflamed infiltrated on some samples. The immunohistochemistry shown an intense expression of the TGFbeta1 cytokine, mainly on the only intine of the blood vessels. The data indicate that the atria develop alterations compatible to inflammatory answer as reaction to the damage caused by the tissue irradiation, and this answer is responsible by the production of TGFbeta1 cytokine, considered a cytokine pro-fibrotic on various models of cardiac disease. The lesions at atrium level can reflect on the correct functioning of the system generator of cardiac impulse, and can induce arrythmias and to prejudice the production of natriuretic peptides, molecules involved on the cardiac homeostasis

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Managing Carious Lesions

    DEFF Research Database (Denmark)

    Schwendicke, F; Frencken, J E; Bjørndal, L

    2016-01-01

    should be prioritized, while in shallow or moderately deep lesions, restoration longevity becomes more important. For teeth with shallow or moderately deep cavitated lesions, carious tissue removal is performed according toselective removal to firm dentine.In deep cavitated lesions in primary......The International Caries Consensus Collaboration undertook a consensus process and here presents clinical recommendations for carious tissue removal and managing cavitated carious lesions, including restoration, based on texture of demineralized dentine. Dentists should manage the disease dental...

  2. Aquisição de uma tarefa espacial por ratos submetidos a lesão hipocampal neonatal induzida por radiação ionizante Acquisition of a non-matching to place task by rats with neonatal hippocampal lesion induced by ionizing radiation

    Directory of Open Access Journals (Sweden)

    Valéria Catelli Infantozzi Costa

    2007-01-01

    Full Text Available Costa, Bueno e Xavier (2005 mostraram que ratos com lesão do giro denteado hipocampal produzida por colchicina apresentam prejuízo de desempenho em testes pós-operatórios em uma tarefa espacial de discriminação condicional (tarefa de non-matching-to-place, NMTP, embora o treino repetitivo promova recuperação do desempenho dos animais lesados. O objetivo do presente estudo foi avaliar o desempenho de ratos com danos seletivos no giro denteado, induzidos pela exposição neonatal a radiação ionizante, na tarefa de NMTP. O grupo irradiado apresentou prejuízo nas primeiras sessões de treino quando comparado ao grupo controle; porém, seu desempenho se igualou ao dos animais controles nas últimas sessões, replicando resultados anteriores. Os resultados são discutidos no contexto da teoria do mapa espacial cognitivo.Costa, Bueno e Xavier (2005 showed that rats with hippocampus dentate gyrus lesions produced by colchicine have post-surgical tests deficits in spatial tasks involving conditional discrimination (non-matching-to-place, NMTP, although repetitive training does promote the recovery of the lamed subject's performance. The purpose of this experiment was to assess the performance of rats with selective lesions of dentate gyrus induced by neonatal ionizing radiation in the NMTP task. The irradiated group showed deficits in the first training sessions when compared to the control group. Nevertheless, the performance of lesion and control groups was similar at the end of the sessions, as previously reported. The results are discussed in light of the cognitive map theory.

  3. Synaptic conditions for auto-associative memory storage and pattern completion in Jensen et al.'s model of hippocampal area CA3.

    Science.gov (United States)

    Cheu, Eng Yeow; Yu, Jiali; Tan, Chin Hiong; Tang, Huajin

    2012-12-01

    Jensen et al. (Learn Memory 3(2-3):243-256, 1996b) proposed an auto-associative memory model using an integrated short-term memory (STM) and long-term memory (LTM) spiking neural network. Their model requires that distinct pyramidal cells encoding different STM patterns are fired in different high-frequency gamma subcycles within each low-frequency theta oscillation. Auto-associative LTM is formed by modifying the recurrent synaptic efficacy between pyramidal cells. In order to store auto-associative LTM correctly, the recurrent synaptic efficacy must be bounded. The synaptic efficacy must be upper bounded to prevent re-firing of pyramidal cells in subsequent gamma subcycles. If cells encoding one memory item were to re-fire synchronously with other cells encoding another item in subsequent gamma subcycle, LTM stored via modifiable recurrent synapses would be corrupted. The synaptic efficacy must also be lower bounded so that memory pattern completion can be performed correctly. This paper uses the original model by Jensen et al. as the basis to illustrate the following points. Firstly, the importance of coordinated long-term memory (LTM) synaptic modification. Secondly, the use of a generic mathematical formulation (spiking response model) that can theoretically extend the results to other spiking network utilizing threshold-fire spiking neuron model. Thirdly, the interaction of long-term and short-term memory networks that possibly explains the asymmetric distribution of spike density in theta cycle through the merger of STM patterns with interaction of LTM network.

  4. Prefrontal-hippocampal interactions for spatial navigation.

    Science.gov (United States)

    Ito, Hiroshi T

    2018-04-01

    Animals have the ability to navigate to a desired location by making use of information about environmental landmarks and their own movements. While decades of neuroscience research have identified neurons in the hippocampus and parahippocampal structures that represent an animal's position in space, it is still largely unclear how an animal can choose the next movement direction to reach a desired goal. As the goal destination is typically located somewhere outside of the range of sensory perception, the animal is required to rely on the internal metric of space to estimate the direction and distance of the destination to plan a next action. Therefore, the hippocampal spatial map should interact with action-planning systems in other cortical regions. In accordance with this idea, several recent studies have indicated the importance of functional interactions between the hippocampus and the prefrontal cortex for goal-directed navigation. In this paper, I will review these studies and discuss how an animal can estimate its future positions correspond to a next movement. Investigation of the navigation problem may further provide general insights into internal models of the brain for action planning. Copyright © 2017 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  5. Moxibustion upregulates hippocampal progranulin expression

    Directory of Open Access Journals (Sweden)

    Tao Yi

    2016-01-01

    Full Text Available In China, moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome, but its mechanisms are largely unknown. More recently, the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome, and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis. In the present study, we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms. Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome. The acupoints Guanyuan (CV4 and Zusanli (ST36, bilateral were simultaneously administered moxibustion. Untreated chronic fatigue syndrome rats and normal rats were used as controls. Results from the forced swimming test, open field test, tail suspension test, real-time PCR, enzyme-linked immunosorbent assay, and western blot assay showed that moxibustion treatment decreased mRNA expression of corticotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone and corticosterone levels in plasma, and markedly increased progranulin mRNA and protein expression in the hippocampus. These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome, at least in part, by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

  6. Retinoic acid suppresses growth of lesions, inhibits peritoneal cytokine secretion, and promotes macrophage differentiation in an immunocompetent mouse model of endometriosis.

    Science.gov (United States)

    Wieser, Friedrich; Wu, Juanjuan; Shen, Zhaoju; Taylor, Robert N; Sidell, Neil

    2012-06-01

    To determine the effects of all-trans-retinoic acid (RA) on establishment and growth of endometrial lesions, peritoneal interleukin-6 (IL-6) and macrophage chemotactic factor-1 (MCP-1) concentrations, and CD38, CD11b, and F4/80 expression on peritoneal macrophages in an immunocompetent mouse model of endometriosis. Experimental transplantation study using mice. Academic medical center. C57BL/6 recipient mice and syngeneic green fluorescent protein transgenic (GFP+) mice. Recipient mice were inoculated with GFP+ minced uterine tissue to induce endometriosis and treated with RA (400 nmol/day) or vehicle for 17 days (3 days before to 14 days after tissue injection). Total number of GFP+ implants in recipient mice, number of implants showing visible blood vessels, total volume of established lesions per mouse, concentrations of IL-6 and MCP-1 in peritoneal fluid, and expression of CD11b, F4/80, and CD38 on peritoneal macrophages. Retinoic acid treatment for 17 days reduced the number of implants versus controls and decreased the frequency of lesions with vessels. Peritoneal washings in RA-treated animals had lower concentrations of IL-6 and MCP-1 than controls 3 days after endometrial inoculation and lower levels of IL-6 on day 14 after inoculation. Concomitant with these effects on day 14, CD38, CD11b, and F4/80 were higher on macrophages from RA-treated mice versus controls. The development of endometriotic implants is inhibited by RA. This effect may be caused, at least in part, by reduced IL-6 and MCP-1 production and enhanced differentiation of peritoneal macrophages. Copyright © 2012 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  7. Age- and Sex-Dependent Laterality of Rat Hippocampal Cholinergic System in Relation to Animal Models of Neurodevelopmental and Neurodegenerative Disorders

    Czech Academy of Sciences Publication Activity Database

    Krištofíková, Z.; Šťastný, F.; Bubeníková, V.; Druga, R.; Klaschka, Jan; Španiel, F.

    2004-01-01

    Roč. 29, č. 4 (2004), s. 671-680 ISSN 0364-3190 R&D Projects: GA MZd NF6031 Institutional research plan: CEZ:AV0Z1030915 Keywords : laterality * cholinergic * excitotoxic * rat model * schizophrenia * Alzheimer disease Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.218, year: 2004

  8. MK-801 impairs cognitive coordination on a rotating arena (Carousel) and contextual specificity of hippocampal immediate-early gene expression in a rat model of psychosis

    Czech Academy of Sciences Publication Activity Database

    Kubík, Štěpán; Buchtová, Helena; Valeš, Karel; Stuchlík, Aleš

    2014-01-01

    Roč. 8, Mar 12 (2014), s. 75 ISSN 1662-5153 R&D Projects: GA ČR(CZ) GPP303/10/P191 Grant - others:EC(XE) PIR06-GA/2009-256581 Institutional support: RVO:67985823 Keywords : cognitive coordination * learning * dizocilpine * animal model * psychosis Subject RIV: FH - Neurology Impact factor: 3.270, year: 2014

  9. Effect of gene dosage on single-cell hippocampal electrophysiology in a murine model of SSADH deficiency (gamma-hydroxybutyric aciduria)

    DEFF Research Database (Denmark)

    Dósa, Zita; Nieto-Gonzalez, Jose Luis; Korshoej, Anders Rosendal

    2010-01-01

    phasic GABAergic neurotransmission was unaffected in the same cells. Our results indicate global disruption of cortical networks in SSADH KO mice, affecting both excitatory and inhibitory neurons. Our findings provide new clues concerning seizure evolution in the murine model (absence-->tonic-clonic-->status...... epilepticus), and extend pathophysiological insight into human SSADH deficiency....

  10. Extensive training and hippocampus or striatum lesions: effect on place and response strategies.

    Science.gov (United States)

    Jacobson, Tara K; Gruenbaum, Benjamin F; Markus, Etan J

    2012-02-01

    The hippocampus has been linked to spatial navigation and the striatum to response learning. The current study focuses on how these brain regions continue to interact when an animal is very familiar with the task and the environment and must continuously switch between navigation strategies. Rats were trained to solve a plus maze using a place or a response strategy on different trials within a testing session. A room cue (illumination) was used to indicate which strategy should be used on a given trial. After extensive training, animals underwent dorsal hippocampus, dorsal lateral striatum or sham lesions. As expected hippocampal lesions predominantly caused impairment on place but not response trials. Striatal lesions increased errors on both place and response trials. Competition between systems was assessed by determining error type. Pre-lesion and sham animals primarily made errors to arms associated with the wrong (alternative) strategy, this was not found after lesions. The data suggest a qualitative change in the relationship between hippocampal and striatal systems as a task is well learned. During acquisition the two systems work in parallel, competing with each other. After task acquisition, the two systems become more integrated and interdependent. The fact that with extensive training (as something becomes a "habit"), behaviors become dependent upon the dorsal lateral striatum has been previously shown. The current findings indicate that dorsal lateral striatum involvement occ