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Sample records for primary dentate neuroepithelium

  1. Mosaic organization of the hippocampal neuroepithelium and the multiple germinal sources of dentate granule cells

    International Nuclear Information System (INIS)

    Altman, J.; Bayer, S.A.

    1990-01-01

    This study deals with the site of origin, migration, and settling of the principal cell constituents of the rat hippocampus during the embryonic period. The results indicate that the hippocampal neuroepithelium consists of three morphogenetically discrete components--the Ammonic neuroepithelium, the primary dentate neuroepithelium, and the fimbrial glioepithelium--and that these are discrete sources of the large neurons of Ammon's horn, the smaller granular neurons of the dentate gyrus, and the glial cells of the fimbria. The putative Ammonic neuroepithelium is marked in short-survival thymidine radiograms by a high level of proliferative activity and evidence of interkinetic nuclear migration from day E16 until day E19. On days E16 and E17 a diffuse band of unlabeled cells forms outside the Ammonic neuroepithelium. These postmitotic cells are considered to be stratum radiatum and stratum oriens neurons, which are produced in large numbers as early as day E15. A cell-dense layer, the incipient stratum pyramidale, begins to form on day E18 and spindle-shaped cells can be traced to it from the Ammonic neuroepithelium. This migratory band increases in size for several days, then declines, and finally disappears by day E22. It is inferred that this migration contains the pyramidal cells of Ammon's horn that are produced mostly on days E17 through E20. The putative primary dentate neuroepithelium is distinguished from the Ammonic neuroepithelium during the early phases of embryonic development by its location, shape, and cellular dynamics. It is located around a ventricular indentation, the dentate notch, contains fewer mitotic cells near the lumen of the ventricle than the Ammonic neuroepithelium, and shows a different labeling pattern both in short-survival and sequential-survival thymidine radiograms

  2. Cytotoxic effects of chemotherapeutic drugs and heterocyclic compounds at application on the cells of primary culture of neuroepithelium tumors.

    Science.gov (United States)

    Kulchitsky, Vladimir A; Potkin, Vladimir I; Zubenko, Yuri S; Chernov, Alexander N; Talabaev, Michael V; Demidchik, Yuri E; Petkevich, Sergei K; Kazbanov, Vladimir V; Gurinovich, Tatiana A; Roeva, Margarita O; Grigoriev, Dmitry G; Kletskov, Alexei V; Kalunov, Vladimir N

    2012-01-01

    Neuroepithelial tumor cells were cultured in vitro. The biopsy material was taken from 93 children at removal of the brain tumors during neurosurgical operations. The individual features of the cells sensitivity of primary cultures in respect to protocol-approved chemotherapy drugs and changes in the Interleukin-6 (Il-6) level in the culture medium after the application of chemotherapy were established. The initial level of Il-6 exceeded 600.0 pg/ml in the cultural medium with histologically verified pilomyxoid astrocytoma cells, and ranged from 100.0 to 200.0 pg/ml in the medium at cultivation of ganglioneuroblastoma and pilocytic astrocytoma. A decrease in the Il-6 level in the medium culture of primary tumors cells was observed after the application of chemotherapeutic agents on the cells of pilomyxoid astrocytoma, astrocytomas, and pilocytic desmoplastic/nodular medulloblastoma. The production of Il-6 increased after application of cytostatic drugs on the cells of oligoastrocytomas. A decrease in Il-6 level after application of Cisplatin and Methotrexate and a 5-10 fold increase in the level of Il-6 after application of Etoposide, Carboplatin, Cytarabine, and Gemcitabine were registered in the medium with ganglioneuroblastoma. To improve the cytotoxic action of chemotherapeutic agents, the combined application of cytostatics with heterocyclic compounds was carried out. A computer modeling of ligand-protein complexes of carbamide using the Dock 6.4 and USF Chimera program packages was performed with molecular mechanics method. Special attention was drawn to the ability of several isoxazole heterocycles and isothiazolyl to inhibit the tyrosine kinase. It was proved in vitro that the joint application of chemotherapeutic agents and heterocyclic compounds could reduce the concentration of the cytostatic factor by 10 or more times, having maintained the maximum cytotoxic effect. It was assumed that the target amplification of cytotoxic action of chemotherapeutic

  3. Expression of calmodulin mRNA in rat olfactory neuroepithelium.

    Science.gov (United States)

    Biffo, S; Goren, T; Khew-Goodall, Y S; Miara, J; Margolis, F L

    1991-04-01

    A calmodulin (CaM) cDNA was isolated by differential hybridization screening of a lambda gt10 library prepared from rat olfactory mucosa. This cDNA fragment, containing most of the open reading frame of the rat CaMI gene, was subcloned and used to characterize steady-state expression of CaM mRNA in rat olfactory neuroepithelium and bulb. Within the bulb mitral cells are the primary neuronal population expressing CaM mRNA. The major CaM mRNA expressed in the olfactory mucosa is 1.7 kb with smaller contributions from mRNAs of 4.0 and 1.4 kb. CaM mRNA was primarily associated with the olfactory neurons and, despite the cellular complexity of the tissue and the known involvement of CaM in diverse cellular processes, was only minimally evident in sustentacular cells, gland cells or respiratory epithelium. Following bulbectomy CaM mRNA declines in the olfactory neuroepithelium as does olfactory marker protein (OMP) mRNA. In contrast to the latter, CaM mRNA makes a partial recovery by one month after surgery. These results, coupled with those from in situ hybridization, indicate that CaM mRNA is expressed in both mature and immature olfactory neurons. The program regulating CaM gene expression in olfactory neurons is distinct from those controlling expression of B50/GAP43 in immature, or OMP in mature, neurons respectively.

  4. Dentate Gyrus

    OpenAIRE

    Allen Institute for Brain Science; Rachel A. Dalley; Lydia L. Ng; Angela L. Guillozet-Bongaarts

    2008-01-01

    This report contains a gene expression summary of the dentate gyrus (DG), derived from the Allen Brain Atlas (ABA) _in situ_ hybridization mouse data set. The structure's location and morphological characteristics in the mouse brain are described using the Nissl data found in the Allen Reference Atlas. Using an established algorithm, the expression values of the dentate gyrus were compared to the values of the macro/parent-structure, in this case the hippocampal region, for the purpose o...

  5. Reduction of the immunostainable length of the hippocampal dentate granule cells’ primary cilia in 3xAD-transgenic mice producing human Aβ1-42 and tau

    International Nuclear Information System (INIS)

    Chakravarthy, Balu; Gaudet, Chantal; Ménard, Michel; Brown, Leslie; Atkinson, Trevor; LaFerla, Frank M.; Ito, Shingo; Armato, Ubaldo; Dal Prà, Ilaria; Whitfield, James

    2012-01-01

    Highlights: ► Aβ and tau-induced neurofibrillary tangles play a key role in Alzheimer’s disease. ► Aβ 1-42 and mutant tau protein together reduce the primary cilium length. ► This shortening likely reduces cilium-dependent neurogenesis and memory function. ► This provides a model of an Aβ/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75 NTR ). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6–24-months-old triple transgenic Alzheimer’s disease model mice (3xTg-AD) producing both Aβ 1-42 and the mutant human tau protein tau P301L, the dentate granule cells still had immunostainable SSTR3- and p75 NTR -bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of Aβ 1-42 or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of Aβ 1-42 and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

  6. Apoptosis induced by glufosinate ammonium in the neuroepithelium of developing mouse embryos in culture.

    Science.gov (United States)

    Watanabe, T

    1997-01-24

    Glufosinate ammonium structurally resembles glutamate and blocks glutamine synthetase. Glufosinate was recently found to be dysmorphogenic in mammals in vitro. The present study examined the cell death induced specifically by glufosinate in the neuroepithelium of mouse embryos. Electron micrograph revealed characteristic chromatin condensation and segregation, extracellular apoptotic bodies, and cell fragments phagocytosed in macrophages in the neuroepithelium of the brain vesicle and neural tube. Moreover neuroepithelial cells undergoing DNA fragmentation were histochemically identified. DNA gel electrophoresis of the neuroepithelial layer revealed a DNA ladder. These observations demonstrate that glufosinate specifically induced apoptosis in the neuroepithelium of embryos.

  7. Live imaging of individual cell divisions in mouse neuroepithelium shows asymmetry in cilium formation and Sonic hedgehog response

    Directory of Open Access Journals (Sweden)

    Piotrowska-Nitsche Karolina

    2012-05-01

    Full Text Available Abstract Background Primary cilia are microtubule-based sensory organelles that play important roles in developmental signaling pathways. Recent work demonstrated that, in cell culture, the daughter cell that inherits the older mother centriole generates a primary cilium and responds to external stimuli prior to its sister cell. This asynchrony in timing of cilia formation could be especially critical during development as cell divisions are required for both differentiation and maintenance of progenitor cell niches. Methods Here we integrate several fluorescent markers and use ex vivo live imaging of a single cell division within the mouse E8.5 neuroepithelium to reveal both the formation of a primary cilium and the transcriptional response to Sonic hedgehog in the daughter cells. Results We show that, upon cell division, cilia formation and the Sonic hedgehog response are asynchronous between the daughter cells. Conclusions Our results demonstrate that we can directly observe single cell divisions within the developing neuroepithelium and concomitantly monitor cilium formation or Sonic hedgehog response. We expect this method to be especially powerful in examining whether cellular behavior can lead to both differentiation and maintenance of cells in a progenitor niche.

  8. The dentate mossy fibers

    DEFF Research Database (Denmark)

    Blaabjerg, Morten; Zimmer, Jens

    2007-01-01

    Hippocampal mossy fibers are the axons of the dentate granule cells and project to hippocampal CA3 pyramidal cells and mossy cells of the dentate hilus (CA4) as well as a number of interneurons in the two areas. Besides their role in hippocampal function, studies of which are still evolving...

  9. The dentate gyrus: fundamental neuroanatomical organization (dentate gyrus for dummies).

    OpenAIRE

    Amaral David G; Scharfman Helen E; Lavenex Pierre

    2007-01-01

    The dentate gyrus is a simple cortical region that is an integral portion of the larger functional brain system called the hippocampal formation. In this review, the fundamental neuroanatomical organization of the dentate gyrus is described, including principal cell types and their connectivity, and a summary of the major extrinsic inputs of the dentate gyrus is provided. Together, this information provides essential information that can serve as an introduction to the dentate gyrus — a “dent...

  10. Reduction of the immunostainable length of the hippocampal dentate granule cells' primary cilia in 3xAD-transgenic mice producing human A{beta}{sub 1-42} and tau

    Energy Technology Data Exchange (ETDEWEB)

    Chakravarthy, Balu, E-mail: Balu.Chakravarthy@nrc-cnrc.gc.ca [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); Gaudet, Chantal; Menard, Michel; Brown, Leslie; Atkinson, Trevor [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); LaFerla, Frank M. [Department of Neurobiology and Behavior, University of California, Irvine, CA (United States); Ito, Shingo [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada); Armato, Ubaldo; Dal Pra, Ilaria [Department of Life and Reproduction Sciences, University of Verona Medical School, Verona (Italy); Whitfield, James [Human Health Therapeutics, National Research Council of Canada, Ottawa, ON (Canada)

    2012-10-12

    Highlights: Black-Right-Pointing-Pointer A{beta} and tau-induced neurofibrillary tangles play a key role in Alzheimer's disease. Black-Right-Pointing-Pointer A{beta}{sub 1-42} and mutant tau protein together reduce the primary cilium length. Black-Right-Pointing-Pointer This shortening likely reduces cilium-dependent neurogenesis and memory function. Black-Right-Pointing-Pointer This provides a model of an A{beta}/tau targeting of a neuronal signaling organelle. -- Abstract: The hippocampal dentate gyrus is one of the two sites of continuous neurogenesis in adult rodents and humans. Virtually all dentate granule cells have a single immobile cilium with a microtubule spine or axoneme covered with a specialized cell membrane loaded with receptors such as the somatostatin receptor 3 (SSTR3), and the p75 neurotrophin receptor (p75{sup NTR}). The signals from these receptors have been reported to stimulate neuroprogenitor proliferation and the post-mitotic maturation of newborn granule cells into functioning granule cells. We have found that in 6-24-months-old triple transgenic Alzheimer's disease model mice (3xTg-AD) producing both A{beta}{sub 1-42} and the mutant human tau protein tau{sub P301L,} the dentate granule cells still had immunostainable SSTR3- and p75{sup NTR}-bearing cilia but they were only half the length of the immunostained cilia in the corresponding wild-type mice. However, the immunostainable length of the granule cell cilia was not reduced either in 2xTg-AD mice accumulating large amounts of A{beta}{sub 1-42} or in mice accumulating only a mutant human tau protein. Thus it appears that a combination of A{beta}{sub 1-42} and tau protein accumulation affects the levels of functionally important receptors in 3xTg-AD mice. These observations raise the important possibility that structural and functional changes in granule cell cilia might have a role in AD.

  11. Qualitative analysis neurons in the adult human dentate nucleus

    Directory of Open Access Journals (Sweden)

    Marić Dušica

    2012-01-01

    Full Text Available Although many relevant findings regarding to the morphology and cytoarchitectural development of the dentate nucleus have been presented so far, very little qualitative information has been collected on neuronal morphology in the adult human dentate nucleus. The neurons were labelled by Golgi staining from thirty human cerebella, obtained from medico-legal forensic autopsies of adult human bodies and free of significant brain pathology. The human dentate neurons were qualitatively analyzed and these cells were classified into two main classes: the small and the large multipolar neurons. Considering the shape of the cell body, number of the primary dendrites, shape of the dendritic tree and their position within the dentate nucleus, three subclasses of the large multipolar neurons have been recognized. The classification of neurons from the human dentate nucleus has been qualitatively confirmed in fetuses and premature infants. This study represents the first qualitative analysis and classification of the large multipolar neurons in the dentate nucleus of the adult human.

  12. The small GTPase RhoA is required to maintain spinal cord neuroepithelium organization and the neural stem cell pool

    DEFF Research Database (Denmark)

    Herzog, Dominik; Loetscher, Pirmin; van Hengel, Jolanda

    2011-01-01

    ablation. We show that, in the spinal cord neuroepithelium, RhoA is essential to localize N-cadherin and ß-catenin to AJs and maintain apical-basal polarity of neural progenitor cells. Ablation of RhoA caused the loss of AJs and severe abnormalities in the organization of cells within the neuroepithelium......Dia1), does not localize to apical AJs in which it likely stabilizes intracellular adhesion by promoting local actin polymerization and microtubule organization. Furthermore, expressing a dominant-negative form of mDia1 in neural stem/progenitor cells results in a similar phenotype compared...... with that of the RhoA conditional knock-out, namely the loss of AJs and apical polarity. Together, our data show that RhoA signaling is necessary for AJ regulation and for the maintenance of mammalian neuroepithelium organization preventing precocious cell-cycle exit and differentiation....

  13. Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis

    International Nuclear Information System (INIS)

    Dencker, L.; Nau, H.; D'Argy, R.

    1990-01-01

    Valproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C-labeled valproic acid (sodium-salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 microCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low-dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium

  14. PlexinA2 Forward Signaling through Rap1 GTPases Regulates Dentate Gyrus Development and Schizophrenia-like Behaviors

    Directory of Open Access Journals (Sweden)

    Xiao-Feng Zhao

    2018-01-01

    Full Text Available Summary: Dentate gyrus (DG development requires specification of granule cell (GC progenitors in the hippocampal neuroepithelium, as well as their proliferation and migration into the primordial DG. We identify the Plexin family members Plxna2 and Plxna4 as important regulators of DG development. Distribution of immature GCs is regulated by Sema5A signaling through PlxnA2 and requires a functional PlxnA2 GTPase-activating protein (GAP domain and Rap1 small GTPases. In adult Plxna2−/− but not Plxna2-GAP-deficient mice, the dentate GC layer is severely malformed, neurogenesis is compromised, and mossy fibers form aberrant synaptic boutons within CA3. Behavioral studies with Plxna2−/− mice revealed deficits in associative learning, sociability, and sensorimotor gating—traits commonly observed in neuropsychiatric disorder. Remarkably, while morphological defects are minimal in Plxna2-GAP-deficient brains, defects in fear memory and sensorimotor gating persist. Since allelic variants of human PLXNA2 and RAP1 associate with schizophrenia, our studies identify a biochemical pathway important for brain development and mental health. : Zhao et al. find that Sema5A-PlexinA2 forward signaling through Rap1 GTPases is required for progenitor distribution in the developing mouse dentate gyrus. Adult Plxna2−/−, but not Plxna2-GAP-deficient, mice show defects in dentate morphology, neurogenesis, and mossy fiber connectivity. Plxna2−/− and Plxna2-GAP mice exhibit behavioral defects suggestive of neuropsychiatric illness. Keywords: PlexinA2, semaphoring, Rap1, GAP, dentate gyrus, adult neurogenesis, mossy fiber, fear memory, sensorimotor gating, schizophrenia

  15. IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care.

    Science.gov (United States)

    Clarkson, Jan E; Ramsay, Craig R; Averley, Paul; Bonetti, Debbie; Boyers, Dwayne; Campbell, Louise; Chadwick, Graham R; Duncan, Anne; Elders, Andrew; Gouick, Jill; Hall, Andrew F; Heasman, Lynne; Heasman, Peter A; Hodge, Penny J; Jones, Clare; Laird, Marilyn; Lamont, Thomas J; Lovelock, Laura A; Madden, Isobel; McCombes, Wendy; McCracken, Giles I; McDonald, Alison M; McPherson, Gladys; Macpherson, Lorna E; Mitchell, Fiona E; Norrie, John Dt; Pitts, Nigel B; van der Pol, Marjon; Ricketts, David Nj; Ross, Margaret K; Steele, James G; Swan, Moira; Tickle, Martin; Watt, Pauline D; Worthington, Helen V; Young, Linda

    2013-10-26

    -efficacy and net benefits. IQuaD will provide evidence for the most clinically-effective and cost-effective approach to managing periodontal disease in dentate adults in Primary Care. This will support general dental practitioners and patients in treatment decision making. Protocol ID: ISRCTN56465715.

  16. IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care

    Science.gov (United States)

    2013-01-01

    gingival margin; oral hygiene self-efficacy and net benefits. Discussion IQuaD will provide evidence for the most clinically-effective and cost-effective approach to managing periodontal disease in dentate adults in Primary Care. This will support general dental practitioners and patients in treatment decision making. Trial registration Protocol ID: ISRCTN56465715 PMID:24160246

  17. Evaluation of the effect of cigarette smoking on the olfactory neuroepithelium of New Zealand white rabbit, using scanning electron microscope.

    Science.gov (United States)

    Iskander, Nagi M; El-Hennawi, Diaa M; Yousef, Tarek F; El-Tabbakh, Mohammed T; Elnahriry, Tarek A

    2017-06-01

    To detect ultra-structural changes of Rabbit's olfactory neuro-epithelium using scanning electron microscope after exposure to cigarette smoking. Sixty six rabbits (Pathogen free New Zealand white rabbits weighing 1-1.5 kg included in the study were randomly assigned into one of three groups: control group did not expose to cigarette smoking, study group 1 was exposed to cigarette smoking for 3 months and study group 2 was exposed to cigarette smoking 3 months and then stopped for 2 months. Olfactory neuro-epithelium from all rabbits were dissected and examined under Philips XL-30 scanning electron microscope. Changes that were found in the rabbits of study group 1 in comparison to control group were loss of microvilli of sustentacular cells (p = 0.016) and decreases in distribution of specialized cilia of olfactory receptor cells (p = 0.046). Also respiratory metaplasia was detected. These changes were reversible in study group 2. Cigarette smoking causes ultra-structural changes in olfactory neuro-epithelium which may explain why smell was affected in cigarette smokers. Most of these changes were reversible after 45 days of cessation of cigarette smoking to the rabbits.

  18. Early natural stimulation through environmental enrichment accelerates neuronal development in the mouse dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Na Liu

    Full Text Available The dentate gyrus is the primary afferent into the hippocampal formation, with important functions in learning and memory. Granule cells, the principle neuronal type in the dentate gyrus, are mostly formed postnatally, in a process that continues into adulthood. External stimuli, including environmental enrichment, voluntary exercise and learning, have been shown to significantly accelerate the generation and maturation of dentate granule cells in adult rodents. Whether, and to what extent, such environmental stimuli regulate the development and maturation of dentate granule cells during early postnatal development is largely unknown. Furthermore, whether natural stimuli affect the synaptic properties of granule cells had been investigated neither in newborn neurons of the adult nor during early development. To examine the effect of natural sensory stimulation on the dentate gyrus, we reared newborn mice in an enriched environment (EE. Using immunohistochemistry, we showed that dentate granule cells from EE-reared mice exhibited earlier morphological maturation, manifested as faster peaking of doublecortin expression and elevated expression of mature neuronal markers (including NeuN, calbindin and MAP2 at the end of the second postnatal week. Also at the end of the second postnatal week, we found increased density of dendritic spines across the entire dentate gyrus, together with elevated levels of postsynaptic scaffold (post-synaptic density 95 and receptor proteins (GluR2 and GABA(ARγ2 of excitatory and inhibitory synapses. Furthermore, dentate granule cells of P14 EE-reared mice had lower input resistances and increased glutamatergic and GABAergic synaptic inputs. Together, our results demonstrate that EE-rearing promotes morphological and electrophysiological maturation of dentate granule cells, underscoring the importance of natural environmental stimulation on development of the dentate gyrus.

  19. Endocannabinoids in the Dentate Gyrus

    OpenAIRE

    Frazier, Charles J.

    2007-01-01

    Recent years have produced rapid and enormous growth in our understanding of endocannabinoid-mediated signalling in the CNS. While much of the recent progress has focused on other areas of the brain, a significant body of evidence has developed that indicates the presence of a robust system for endocannabinoid-mediated signalling in the dentate gyrus. This chapter will provide an overview of our current understanding of that system based on available anatomical and physiological data.

  20. Proteomic profiling of the epileptic dentate gyrus

    OpenAIRE

    Li, Aiqing; Choi, Yun-Sik; Dziema, Heather; Cao, Ruifeng; Cho, Hee-Yeon; Jung, Yeon Joo; Obrietan, Karl

    2010-01-01

    The development of epilepsy is often associated with marked changes in central nervous system cell structure and function. Along these lines, reactive gliosis and granule cell axonal sprouting within the dentate gyrus of the hippocampus are commonly observed in individuals with temporal lobe epilepsy. Here we used the pilocarpine model of temporal lobe epilepsy in mice to screen the proteome and phosphoproteome of the dentate gyrus to identify molecular events that are altered as part of the ...

  1. Diminished Dentate Gyrus Filtering of Cortical Input Leads to Enhanced Area Ca3 Excitability after Mild Traumatic Brain Injury.

    Science.gov (United States)

    Folweiler, Kaitlin A; Samuel, Sandy; Metheny, Hannah E; Cohen, Akiva S

    2018-04-06

    Mild traumatic brain injury (mTBI) disrupts hippocampal function and can lead to long-lasting episodic memory impairments. The encoding of episodic memories relies on spatial information processing within the hippocampus. As the primary entry point for spatial information into the hippocampus, the dentate gyrus is thought to function as a physiological gate, or filter, of afferent excitation before reaching downstream area Cornu Ammonis (CA3). Although injury has previously been shown to alter dentate gyrus network excitability, it is unknown whether mTBI affects dentate gyrus output to area CA3. In this study, we assessed hippocampal function, specifically the interaction between the dentate gyrus and CA3, using behavioral and electrophysiological techniques in ex vivo brain slices 1 week following mild lateral fluid percussion injury (LFPI). Behaviorally, LFPI mice were found to be impaired in an object-place recognition task, indicating that spatial information processing in the hippocampus is disrupted. Extracellular recordings and voltage-sensitive dye imaging demonstrated that perforant path activation leads to the aberrant spread of excitation from the dentate gyrus into area CA3 along the mossy fiber pathway. These results suggest that after mTBI, the dentate gyrus has a diminished capacity to regulate cortical input into the hippocampus, leading to increased CA3 network excitability. The loss of the dentate filtering efficacy reveals a potential mechanism by which hippocampal-dependent spatial information processing is disrupted, and may contribute to memory dysfunction after mTBI.

  2. In Vivo Dentate Nucleus Gamma-aminobutyric Acid Concentration in Essential Tremor vs. Controls.

    Science.gov (United States)

    Louis, Elan D; Hernandez, Nora; Dyke, Jonathan P; Ma, Ruoyun E; Dydak, Ulrike

    2018-04-01

    Despite its high prevalence, essential tremor (ET) is among the most poorly understood neurological diseases. The presence and extent of Purkinje cell (PC) loss in ET is the subject of controversy. PCs are a major storehouse of central nervous system gamma-aminobutyric acid (GABA), releasing GABA at the level of the dentate nucleus. It is therefore conceivable that cerebellar dentate nucleus GABA concentration could be an in vivo marker of PC number. We used in vivo 1 H magnetic resonance spectroscopy (MRS) to quantify GABA concentrations in two cerebellar volumes of interest, left and right, which included the dentate nucleus, comparing 45 ET cases to 35 age-matched controls. 1 H MRS was performed using a 3.0-T Siemens Tim Trio scanner. The MEGA-PRESS J-editing sequence was used for GABA detection in two cerebellar volumes of interest (left and right) that included the dentate nucleus. The two groups did not differ with respect to our primary outcome of GABA concentration (given in institutional units). For the right dentate nucleus, [GABA] in ET cases = 2.01 ± 0.45 and [GABA] in controls = 1.86 ± 0.53, p = 0.17. For the left dentate nucleus, [GABA] in ET cases = 1.68 ± 0.49 and [GABA] controls = 1.80 ± 0.53, p = 0.33. The controls had similar dentate nucleus [GABA] in the right vs. left dentate nucleus (p = 0.52); however, in ET cases, the value on the right was considerably higher than that on the left (p = 0.001). We did not detect a reduction in dentate nucleus GABA concentration in ET cases vs. One interpretation of the finding is that it does not support the existence of PC loss in ET; however, an alternative interpretation is the observed pattern could be due to the effects of terminal sprouting in ET (i.e., collateral sprouting from surviving PCs making up for the loss of GABA-ergic terminals from PC degeneration). Further research is needed.

  3. Is the goal of mastication reached in young dentates, aged dentates and aged denture wearers?

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    Mishellany-Dutour, Anne; Renaud, Johanne; Peyron, Marie-Agnès; Rimek, Frank; Woda, Alain

    2008-01-01

    The objective of the present study was to assess the impact of age and dentition status on masticatory function. A three-arm case-control study was performed. Group 1 (n 14) was composed of young fully dentate subjects (age 35.6 +/- 10.6 years), group 2 (n 14) of aged fully dentate subjects (age 68.8 +/- 7.0 years) and group 3 (n 14) of aged full denture wearers (age 68.1 +/- 7.2 years). Mastication adaptation was assessed in the course of chewing groundnuts and carrots to swallowing threshold. Particle size distribution of the chewed food, electromyographic (EMG) activity of the masseter and temporalis muscles during chewing, and resting and stimulated whole saliva rates were measured. Aged dentate subjects used significantly more chewing strokes to reach swallowing threshold than younger dentate subjects (P < 0.05), with increased particle size reduction, longer chewing sequence duration (P < 0.05) and greater total EMG activity (P < 0.05) for both groundnuts and carrots. In addition, aged denture wearers made significantly more chewing strokes than aged dentate subjects (P < 0.001) to reach swallowing threshold for groundnuts. Particle size reduction at time of swallowing was significantly poorer for denture wearers than for their aged dentate counterparts, despite an increase in chewing strokes, sequence duration and EMG activity per sequence. Masticatory function was thus adapted to ageing, but was impaired in denture wearers, who failed to adapt fully to their deficient masticatory apparatus.

  4. Early postischemic 45Ca accumulation in rat dentate hilus

    International Nuclear Information System (INIS)

    Benveniste, H.; Diemer, N.H.

    1988-01-01

    Several studies have found postischemic regional accumulation of calcium to be time-dependent and coincident with the progression of ischemic cell change. In the most vulnerable cells in the hippocampus one would therefore expect to find a primary and specific early uptake of calcium after ischemia. Autoradiograms of 45 Ca and 3 H-inulin distribution were investigated before and 1 h after 20 min ischemia in the rat hippocampus. Two different methodological approaches were used for administration of 45 Ca: (a) administration via microdialysis probes, (b) intraventricular injection. During control conditions the 45 Ca autoradiograms showed variations in distribution volume in accordance with 3 H-inulin determination of extracellular space size. One hour after ischemia a massive accumulation of 45 Ca was found in the dentate hilus. No change in the distribution pattern of 3 H-inulin could be demonstrated 1 h after ischemia. We suggest that 45 Ca accumulation in dentate hilus 1 h after ischemia is a result of increased Ca 2+ uptake before irreversible cell damage occurs and is not due to passive influx of calcium across a leaky plasma membrane

  5. Cannabis Users Show Enhanced Expression of CB1-5HT2A Receptor Heteromers in Olfactory Neuroepithelium Cells.

    Science.gov (United States)

    Galindo, Liliana; Moreno, Estefanía; López-Armenta, Fernando; Guinart, Daniel; Cuenca-Royo, Aida; Izquierdo-Serra, Mercè; Xicota, Laura; Fernandez, Cristina; Menoyo, Esther; Fernández-Fernández, José M; Benítez-King, Gloria; Canela, Enric I; Casadó, Vicent; Pérez, Víctor; de la Torre, Rafael; Robledo, Patricia

    2018-01-02

    Cannabinoid CB1 receptors (CB 1 R) and serotonergic 2A receptors (5HT 2A R) form heteromers in the brain of mice where they mediate the cognitive deficits produced by delta-9-tetrahydrocannabinol. However, it is still unknown whether the expression of this heterodimer is modulated by chronic cannabis use in humans. In this study, we investigated the expression levels and functionality of CB 1 R-5HT 2A R heteromers in human olfactory neuroepithelium (ON) cells of cannabis users and control subjects, and determined their molecular characteristics through adenylate cyclase and the ERK 1/2 pathway signaling studies. We also assessed whether heteromer expression levels correlated with cannabis consumption and cognitive performance in neuropsychological tests. ON cells from controls and cannabis users expressed neuronal markers such as βIII-tubulin and nestin, displayed similar expression levels of genes related to cellular self-renewal, stem cell differentiation, and generation of neural crest cells, and showed comparable Na + currents in patch clamp recordings. Interestingly, CB 1 R-5HT 2A R heteromer expression was significantly increased in cannabis users and positively correlated with the amount of cannabis consumed, and negatively with age of onset of cannabis use. In addition, a negative correlation was found between heteromer expression levels and attention and working memory performance in cannabis users and control subjects. Our findings suggest that cannabis consumption regulates the formation of CB 1 R-5HT 2A R heteromers, and may have a key role in cognitive processing. These heterodimers could be potential new targets to develop treatment alternatives for cognitive impairments.

  6. Electrophysiological characterization of granule cells in the dentate gyrus immediately after birth

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    Andrea ePedroni

    2014-02-01

    Full Text Available Granule cells (GCs in the dentate gyrus are generated mainly postnatally. Between embryonic day 10 and 14, neural precursors migrate from the primary dentate matrix to the dentate gyrus where they differentiate into neurons. Neurogenesis reaches a peak at the end of the first postnatal week and it is completed at the end of the first postnatal month. This process continues at a reduced rate throughout life. Interestingly, immediately after birth, GCs exhibit a clear GABAergic phenotype. Only later they integrate the classical glutamatergic trisynaptic hippocampal circuit. Here, whole patch clamp recordings, in current clamp mode, were performed from immature GCs, intracellularly loaded with biocytin (in hippocampal slices from P0-P3 old rats in order to compare their morphological characteristics with their electrophysiological properties. The vast majority of GCs were very immature with small somata, few dendritic branches terminating with small varicosities and growth cones. In spite of their immaturity their axons reached often the CA3 area. Immature GCs generated, upon membrane depolarization, either rudimentary sodium spikes or more clear overshooting action potentials that fired repetitively. They exhibited also low threshold calcium spikes. In addition, most spiking neurons showed spontaneous synchronized network activity, reminiscent of giant depolarizing potentials (GDPs generated in the hippocampus by the synergistic action of glutamate and GABA, both depolarizing and excitatory. This early synchronized activity, absent during adult neurogenesis, may play a crucial role in the refinement of local neuronal circuits within the developing dentate gyrus.

  7. Bone marrow chimeric mice reveal a role for CX₃CR1 in maintenance of the monocyte-derived cell population in the olfactory neuroepithelium.

    Science.gov (United States)

    Vukovic, Jana; Blomster, Linda V; Chinnery, Holly R; Weninger, Wolfgang; Jung, Steffen; McMenamin, Paul G; Ruitenberg, Marc J

    2010-10-01

    Macrophages in the olfactory neuroepithelium are thought to play major roles in tissue homeostasis and repair. However, little information is available at present about possible heterogeneity of these monocyte-derived cells, their turnover rates, and the role of chemokine receptors in this process. To start addressing these issues, this study used Cx₃cr1(gfp) mice, in which the gene sequence for eGFP was knocked into the CX₃CR1 gene locus in the mutant allele. Using neuroepithelial whole-mounts from Cx₃cr1(gfp/+) mice, we show that eGFP(+) cells of monocytic origin are distributed in a loose network throughout this tissue and can be subdivided further into two immunophenotypically distinct subsets based on MHC-II glycoprotein expression. BM chimeric mice were created using Cx₃cr1(gfp/+) donors to investigate turnover of macrophages (and other monocyte-derived cells) in the olfactory neuroepithelium. Our data indicate that the monocyte-derived cell population in the olfactory neuroepithelium is actively replenished by circulating monocytes and under the experimental conditions, completely turned over within 6 months. Transplantation of Cx₃cr1(gfp/gfp) (i.e., CX₃CR1-deficient) BM partially impaired the replenishment process and resulted in an overall decline of the total monocyte-derived cell number in the olfactory epithelium. Interestingly, replenishment of the CD68(low)MHC-II(+) subset appeared minimally affected by CX₃CR1 deficiency. Taken together, the established baseline data about heterogeneity of monocyte-derived cells, their replenishment rates, and the role of CX₃CR1 provide a solid basis to further examine the importance of different monocyte subsets for neuroregeneration at this unique frontier with the external environment.

  8. Dissection of Hippocampal Dentate Gyrus from Adult Mouse

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    Hagihara, Hideo; Toyama, Keiko; Yamasaki, Nobuyuki; Miyakawa, Tsuyoshi

    2009-01-01

    The hippocampus is one of the most widely studied areas in the brain because of its important functional role in memory processing and learning, its remarkable neuronal cell plasticity, and its involvement in epilepsy, neurodegenerative diseases, and psychiatric disorders. The hippocampus is composed of distinct regions; the dentate gyrus, which comprises mainly granule neurons, and Ammon's horn, which comprises mainly pyramidal neurons, and the two regions are connected by both anatomic and functional circuits. Many different mRNAs and proteins are selectively expressed in the dentate gyrus, and the dentate gyrus is a site of adult neurogenesis; that is, new neurons are continually generated in the adult dentate gyrus. To investigate mRNA and protein expression specific to the dentate gyrus, laser capture microdissection is often used. This method has some limitations, however, such as the need for special apparatuses and complicated handling procedures. In this video-recorded protocol, we demonstrate a dissection technique for removing the dentate gyrus from adult mouse under a stereomicroscope. Dentate gyrus samples prepared using this technique are suitable for any assay, including transcriptomic, proteomic, and cell biology analyses. We confirmed that the dissected tissue is dentate gyrus by conducting real-time PCR of dentate gyrus-specific genes, tryptophan 2,3-dioxygenase (TDO2) and desmoplakin (Dsp), and Ammon's horn enriched genes, Meis-related gene 1b (Mrg1b) and TYRO3 protein tyrosine kinase 3 (Tyro3). The mRNA expressions of TDO2 and Dsp in the dentate gyrus samples were detected at obviously higher levels, whereas Mrg1b and Tyro3 were lower levels, than those in the Ammon's horn samples. To demonstrate the advantage of this method, we performed DNA microarray analysis using samples of whole hippocampus and dentate gyrus. The mRNA expression of TDO2 and Dsp, which are expressed selectively in the dentate gyrus, in the whole hippocampus of alpha

  9. Sampling the Mouse Hippocampal Dentate Gyrus

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    Lisa Basler

    2017-12-01

    Full Text Available Sampling is a critical step in procedures that generate quantitative morphological data in the neurosciences. Samples need to be representative to allow statistical evaluations, and samples need to deliver a precision that makes statistical evaluations not only possible but also meaningful. Sampling generated variability should, e.g., not be able to hide significant group differences from statistical detection if they are present. Estimators of the coefficient of error (CE have been developed to provide tentative answers to the question if sampling has been “good enough” to provide meaningful statistical outcomes. We tested the performance of the commonly used Gundersen-Jensen CE estimator, using the layers of the mouse hippocampal dentate gyrus as an example (molecular layer, granule cell layer and hilus. We found that this estimator provided useful estimates of the precision that can be expected from samples of different sizes. For all layers, we found that a smoothness factor (m of 0 generally provided better estimates than an m of 1. Only for the combined layers, i.e., the entire dentate gyrus, better CE estimates could be obtained using an m of 1. The orientation of the sections impacted on CE sizes. Frontal (coronal sections are typically most efficient by providing the smallest CEs for a given amount of work. Applying the estimator to 3D-reconstructed layers and using very intense sampling, we observed CE size plots with m = 0 to m = 1 transitions that should also be expected but are not often observed in real section series. The data we present also allows the reader to approximate the sampling intervals in frontal, horizontal or sagittal sections that provide CEs of specified sizes for the layers of the mouse dentate gyrus.

  10. Mandibular thickness measurements in young dentate adults.

    Science.gov (United States)

    Beaty, Narlin B; Le, Thomas T

    2009-09-01

    To measure thicknesses in clinical landmark areas of the dentate mandibles of young men and women. Using standard radiologic software, we obtained mean (SD) thickness measurements at the inferior or posterior borders of the mandible at the following 7 surgically useful sites: (1) the symphysis, (2) a point halfway between the symphysis and the mental nerve, (3) the mental nerve, (4) a point halfway between the mental nerve and the facial artery notch, (5) the facial artery notch, (6) the angle vertex, and (7) the ramus-condylar neck border. University hospital. A total of 150 dentate men and 75 dentate women aged 18 to 30 years who had undergone computed tomography of the head and neck region during the period of December 20, 2006 to February 20, 2007. Thicknesses of 7 mandibular sites. Mean (SD) thicknesses at the 7 mandibular sites were as follows: symphysis, 14.03 (1.53) mm for men and 13.21 (1.46) mm for women; halfway between the symphysis and the mental nerve, 11.17 (1.37) mm for men and 10.00 (1.08) mm for women; mental nerve, 9.48 (1.28) mm for men and 8.72 (1.00) mm for women; halfway between the mental nerve and the facial artery notch, 10.33 (1.24) mm for men and 9.45 (0.92) mm for women; facial artery notch, 7.27 (0.82) mm for men and 7.10 (0.88) mm for women; angle vertex, 5.42 (0.90) mm for men and 5.39 (0.66) mm for women; and ramus-condylar neck border, 5.90 (0.86) mm for men and 5.85 (0.71) mm for women. Clinical landmark areas in young dentate mandibles have mean thicknesses with limited SDs. The thickness measurements obtained at the sites in this study provide practical reference information for mandibular reconstruction and bicortical screw length estimation.

  11. Extended Interneuronal Network of the Dentate Gyrus

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    Gergely G. Szabo

    2017-08-01

    Full Text Available Local interneurons control principal cells within individual brain areas, but anecdotal observations indicate that interneuronal axons sometimes extend beyond strict anatomical boundaries. Here, we use the case of the dentate gyrus (DG to show that boundary-crossing interneurons with cell bodies in CA3 and CA1 constitute a numerically significant and diverse population that relays patterns of activity generated within the CA regions back to granule cells. These results reveal the existence of a sophisticated retrograde GABAergic circuit that fundamentally extends the canonical interneuronal network.

  12. IQuaD dental trial; improving the quality of dentistry: a multicentre randomised controlled trial comparing oral hygiene advice and periodontal instrumentation for the prevention and management of periodontal disease in dentate adults attending dental primary care

    OpenAIRE

    Clarkson, Jan E; Ramsay, Craig R; Averley, Paul; Bonetti, Debbie; Boyers, Dwayne; Campbell, Louise; Chadwick, Graham R; Duncan, Anne; Elders, Andrew; Gouick, Jill; Hall, Andrew F; Heasman, Lynne; Heasman, Peter A; Hodge, Penny J; Jones, Clare

    2013-01-01

    Background:\\ud Periodontal disease is the most common oral disease affecting adults, and although it is largely preventable it remains the major cause of poor oral health worldwide. Accumulation of microbial dental plaque is the primary aetiological factor for both periodontal disease and caries. Effective self-care (tooth brushing and interdental aids) for plaque control and removal of risk factors such as calculus, which can only be removed by periodontal instrumentation (PI), are considere...

  13. Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus

    Science.gov (United States)

    Li, Bin; Yamamori, Hidenaga; Tatebayashi, Yoshitaka; Shafit-Zagardo, Bridget; Tanimukai, Hitoshi; Chen, She; Iqbal, Khalid; Grundke-Iqbal, Inge

    2011-01-01

    The dentate gyrus, an important anatomic structure of the hippocampal formation, is one of the major areas in which neurogenesis takes place in the adult mammalian brain. Neurogenesis in the dentate gyrus is thought to play an important role in hippocampus-dependent learning and memory. Neurogenesis has been reported to be increased in the dentate gyrus of patients with Alzheimer disease, but it is not known whether the newly generated neurons differentiate into mature neurons. In this study, the expression of the mature neuronal marker high molecular weight microtubule-associated protein (MAP) isoforms MAP2a and b was found to be dramatically decreased in Alzheimer disease dentate gyrus, as determined by immunohistochemistry and in situ hybridization. The total MAP2, including expression of the immature neuronal marker, the MAP2c isoform, was less affected. These findings suggest that newly generated neurons in Alzheimer disease dentate gyrus do not become mature neurons, although neuroproliferation is increased. PMID:18091557

  14. Olfactory ensheathing glia : their contribution to primary olfactory nervous system regeneration and their regenerative potential following transplantation into the injured spinal cord

    NARCIS (Netherlands)

    Franssen, Elske H P; de Bree, Freddy M; Verhaagen, J.

    2007-01-01

    Olfactory ensheathing glia (OEG) are a specialized type of glia that guide primary olfactory axons from the neuroepithelium in the nasal cavity to the brain. The primary olfactory system is able to regenerate after a lesion and OEG contribute to this process by providing a growth-supportive

  15. PDK1 Deficit Impairs the Development of the Dentate Gyrus in Mice.

    Science.gov (United States)

    Xu, Min; Han, Xiaoning; Liu, Rui; Li, Yanjun; Qi, Cui; Yang, Zhongzhou; Zhao, Chunjie; Gao, Jun

    2018-02-06

    3-Phosphoinositide-dependent protein kinase-1 (PDK1) is crucial for the development of the dentate gyrus (DG), the first gateway receiving afferent inputs from the entorhinal cortex. However, the role of PDK1 in DG development is unclear. In the present study, by crossing Pdk1fl/fl mice with the Emx1-cre line, we identified that the ablation of PDK1 disrupted the development of DG via decreasing the proliferation, and increasing the differentiation of dentate neural progenitor cells, downregulating AKT activity and upregulating GSK3β signaling. Moreover, PDK1 deletion disrupted the distribution of Reelin+ cells and decreased the level of Reelin mRNA which may contribute to the defective migration of progenitor cells and the disrupted radial glial scaffolds. Furthermore, the inhibition of GSK3β activity partially restored the decreased proliferation of primary neural stem cells in vitro. Taken together, our data indicated that the ablation of PDK1 affected the proliferation and differentiation of dentate neural progenitor cells in mice. © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Hyposalivation and xerostomia in dentate older adults

    Science.gov (United States)

    Wiener, R. Constance; Wu, Bei; Crout, Richard; Wiener, Michael; Plassman, Brenda; Kao, Elizabeth; McNeil, Daniel

    2010-01-01

    Background Older adults are susceptible to reduced saliva production related to certain medications, radiation and chronic conditions. Many of these people have many physical and oral health problems and limited access to dental care. The use of effective screening tools for xerostomia and hyposalivation would be helpful in identifying those at risk. The authors conducted a study to investigate the association between three measures of oral dryness: hyposalivation (low unstimulated salivary flow), self-reported xerostomia and clinically assessed dry mouth. Methods The authors included a convenience sample of 252 nondemented and dentate West Virginia participants 70 years and older who were part of a larger study on oral health and cognition among older adults. Participants completed a self-reported xerostomia index, provided an unstimulated salivary sample and underwent an oral assessment for the study. Results Twenty-eight (11.1 percent) had hyposalivation, eight of whom reported having xerostomia (sensitivity = 28.6 percent). Of the 43 participants who reported having xerostomia, only eight had hyposalivation (positive predictive value = 18.6 percent). Hyposalivation and self-reported xerostomia were not significantly related. Clinically assessed dry mouth correlated modestly, but significantly, with hyposalivation and self-reported xerostomia. Conclusions Obtaining routine unstimulated salivary flow rates in addition to self-reported information and oral evaluations may increase early detection of oral dryness, which would assist in implementing early interventions to improve patients’ quality of life. Clinical Implications Visually inspecting oral tissues for dryness and asking a patient if his or her mouth is dry are insufficient measures for clinicians to use to determine if the patient has hyposalivation. The authors recommend that clinicians determine the patients’ unstimulated salivary flow rate. PMID:20194383

  17. Hilar mossy cell circuitry controlling dentate granule cell excitability

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    Seiichiro eJinde

    2013-02-01

    Full Text Available Glutamatergic hilar mossy cells of the dentate gyrus can either excite or inhibit distant granule cells, depending on whether their direct excitatory projections to granule cells or their projections to local inhibitory interneurons dominate. However, it remains controversial whether the net effect of mossy cell loss is granule cell excitation or inhibition. Clarifying this controversy has particular relevance to temporal lobe epilepsy, which is marked by dentate granule cell hyperexcitability and extensive loss of dentate hilar mossy cells. Two diametrically opposed hypotheses have been advanced to explain this granule cell hyperexcitability – the dormant basket cell and the irritable mossy cell hypotheses. The dormant basket cell hypothesis proposes that mossy cells normally exert a net inhibitory effect on granule cells and therefore their loss causes dentate granule cell hyperexcitability. The irritable mossy cell hypothesis takes the opposite view that mossy cells normally excite granule cells and that the surviving mossy cells in epilepsy increase their activity, causing granule cell excitation. The inability to eliminate mossy cells selectively has made it difficult to test these two opposing hypotheses. To this end, we developed a transgenic toxin-mediated, mossy cell-ablation mouse line. Using these mutants, we demonstrated that the extensive elimination of hilar mossy cells causes granule cell hyperexcitability, although the mossy cell loss observed appeared insufficient to cause clinical epilepsy. In this review, we focus on this topic and also suggest that different interneuron populations may mediate mossy cell-induced translamellar lateral inhibition and intralamellar recurrent inhibition. These unique local circuits in the dentate hilar region may be centrally involved in the functional organization of the dentate gyrus.

  18. a-Band Oscillations in Intracellular Membrane Potentials of Dentate Gyrus Neurons in Awake Rodents

    Science.gov (United States)

    Anderson, Ross W.; Strowbridge, Ben W.

    2014-01-01

    The hippocampus and dentate gyrus play critical roles in processing declarative memories and spatial information. Dentate granule cells, the first relay in the trisynaptic circuit through the hippocampus, exhibit low spontaneous firing rates even during locomotion. Using intracellular recordings from dentate neurons in awake mice operating a…

  19. Intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory.

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna; Ogawa, Taisuke; Takada, Shunsuke; Nakamura, Masatoshi; Fujii, Hiroaki; Ando, Masaki

    2014-11-01

    The role of perforant pathway-dentate granule cell synapses in cognitive behavior was examined focusing on synaptic Zn(2+) signaling in the dentate gyrus. Object recognition memory was transiently impaired when extracellular Zn(2+) levels were decreased by injection of clioquinol and N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylendediamine. To pursue the effect of the loss and/or blockade of Zn(2+) signaling in dentate granule cells, ZnAF-2DA (100 pmol, 0.1 mM/1 µl), an intracellular Zn(2+) chelator, was locally injected into the dentate molecular layer of rats. ZnAF-2DA injection, which was estimated to chelate intracellular Zn(2+) signaling only in the dentate gyrus, affected object recognition memory 1 h after training without affecting intracellular Ca(2+) signaling in the dentate molecular layer. In vivo dentate gyrus long-term potentiation (LTP) was affected under the local perfusion of the recording region (the dentate granule cell layer) with 0.1 mM ZnAF-2DA, but not with 1-10 mM CaEDTA, an extracellular Zn(2+) chelator, suggesting that the blockade of intracellular Zn(2+) signaling in dentate granule cells affects dentate gyrus LTP. The present study demonstrates that intracellular Zn(2+) signaling in the dentate gyrus is required for object recognition memory, probably via dentate gyrus LTP expression. Copyright © 2014 Wiley Periodicals, Inc.

  20. Role of corticosteroid hormones in the dentate gyrus.

    NARCIS (Netherlands)

    Joëls, M.

    2007-01-01

    Dentate granule cells are enriched with receptors for the stress hormone corticosterone, i.e., the high-affinity mineralocorticoid receptor (MR), which is already extensively occupied with low levels of the hormone, and the glucocorticoid receptor (GR), which is particularly activated after stress.

  1. Adult Neurogenesis in the Mammalian Hippocampus: Why the Dentate Gyrus?

    Science.gov (United States)

    Drew, Liam J.; Fusi, Stefano; Hen, René

    2013-01-01

    In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity…

  2. Adult neurogenesis modifies excitability of the dentate gyrus

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    Taruna eIkrar

    2013-12-01

    Full Text Available Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern

  3. Analyzing dendritic growth in a population of immature neurons in the adult dentate gyrus using laminar quantification of disjointed dendrites

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    Shira eRosenzweig

    2011-03-01

    Full Text Available In the dentate gyrus of the hippocampus, new granule neurons are continuously produced throughout adult life. A prerequisite for the successful synaptic integration of these neurons is the sprouting and extension of dendrites into the molecular layer of the dentate gyrus. Thus, studies aimed at investigating the developmental stages of adult neurogenesis often use dendritic growth as an important indicator of neuronal health and maturity. Based on the known topography of the dentate gyrus, characterized by distinct laminar arrangement of granule neurons and their extensions, we have developed a new method for analysis of dendritic growth in immature adult-born granule neurons. The method is comprised of laminar quantification of cell bodies, primary, secondary and tertiary dendrites separately and independently from each other. In contrast to most existing methods, laminar quantification of dendrites does not require the use of exogenous markers and does not involve arbitrary selection of individual neurons. The new method relies on immonuhistochemical detection of endogenous markers such as doublecortin to perform a comprehensive analysis of a sub-population of immature neurons. Disjointed, orphan dendrites that often appear in the thin histological sections are taken into account. Using several experimental groups of rats and mice, we demonstrate here the suitable techniques for quantifying neurons and dendrites, and explain how the ratios between the quantified values can be used in a comparative analysis to indicate variations in dendritic growth and complexity.

  4. Functional circuits of new neurons in the dentate gyrus

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    Carmen eVivar

    2013-02-01

    Full Text Available The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG, a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub cortical inputs to new dentate granule cells. It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, followed after about one month by perirhinal and lateral entorhinal cortex. These cortical areas are deemed relevant to encoding of novel environmental information and may enable pattern separation. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry.  

  5. Dentate Gyrus Neurogenesis, Integration, and microRNAs

    OpenAIRE

    Luikart, Bryan W; Perederiy, Julia V; Westbrook, Gary L

    2011-01-01

    Neurons are born and become a functional part of the synaptic circuitry in adult brains. The proliferative phase of neurogenesis has been extensively reviewed. We therefore focus this review on a few topics addressing the functional role of adult-generated newborn neurons in the dentate gyrus. We discuss the evidence for a link between neurogenesis and behavior. We then describe the steps in the integration of newborn neurons into a functioning mature synaptic circuit. Given the profound effe...

  6. Hilar mossy cells of the dentate gyrus: a historical perspective

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    Helen E Scharfman

    2013-01-01

    Full Text Available The circuitry of the dentate gyrus of the hippocampus is unique compared to other hippocampal subfields because there are two glutamatergic principal cells instead of one: granule cells, which are the vast majority of the cells in the dentate gyrus, and the so-called ‘mossy cells.’ The distinctive appearance of mossy cells, the extensive divergence of their axons, and their vulnerability to excitotoxicity relative to granule cells has led to a great deal of interest in mossy cells. Nevertheless, there is no consensus about the normal functions of mossy cells and the implications of their vulnerability. There even seems to be some ambiguity about exactly what mossy cells are. Here we review initial studies of mossy cells, characteristics that define them, and suggest a practical definition to allow investigators to distinguish mossy cells from other hilar neurons even if all morphological and physiological information is unavailable due to technical limitations of their experiments. In addition, hypotheses are discussed about the role of mossy cells in the dentate gyrus network, reasons for their vulnerability and their implications for disease.

  7. The dentate nucleus in children: normal development and patterns of disease

    Energy Technology Data Exchange (ETDEWEB)

    McErlean, Aoife; Abdalla, Khaled; Donoghue, Veronica; Ryan, Stephanie [Children' s University Hospital, Radiology Department, Dublin (Ireland)

    2010-03-15

    The dentate nuclei lie deep within the cerebellum and play a vital role in the pathways involved in fine motor control and coordination. They are susceptible to a variety of diseases. Some pathological processes preferentially affect the dentate nuclei, while concomitant basal ganglia or white matter involvement can be a striking finding in others. A familiarity with the normal appearance of the dentate nuclei at different ages in combination with the radiological distribution of pathology in the brain allows the paediatric radiologist to develop a logical approach to the interpretation of MR imaging of these deep cerebellar nuclei. In this article we review the normal appearance and MR features of the dentate nuclei, including changes that are seen with myelination. We describe the specific imaging characteristics of childhood diseases that involve the dentate nuclei, and develop a systematic approach to the differential diagnosis of dentate nucleus abnormalities on MR imaging. (orig.)

  8. The dentate nucleus in children: normal development and patterns of disease

    International Nuclear Information System (INIS)

    McErlean, Aoife; Abdalla, Khaled; Donoghue, Veronica; Ryan, Stephanie

    2010-01-01

    The dentate nuclei lie deep within the cerebellum and play a vital role in the pathways involved in fine motor control and coordination. They are susceptible to a variety of diseases. Some pathological processes preferentially affect the dentate nuclei, while concomitant basal ganglia or white matter involvement can be a striking finding in others. A familiarity with the normal appearance of the dentate nuclei at different ages in combination with the radiological distribution of pathology in the brain allows the paediatric radiologist to develop a logical approach to the interpretation of MR imaging of these deep cerebellar nuclei. In this article we review the normal appearance and MR features of the dentate nuclei, including changes that are seen with myelination. We describe the specific imaging characteristics of childhood diseases that involve the dentate nuclei, and develop a systematic approach to the differential diagnosis of dentate nucleus abnormalities on MR imaging. (orig.)

  9. Excess influx of Zn(2+) into dentate granule cells affects object recognition memory via attenuated LTP.

    Science.gov (United States)

    Suzuki, Miki; Fujise, Yuki; Tsuchiya, Yuka; Tamano, Haruna; Takeda, Atsushi

    2015-08-01

    The influx of extracellular Zn(2+) into dentate granule cells is nonessential for dentate gyrus long-term potentiation (LTP) and the physiological significance of extracellular Zn(2+) dynamics is unknown in the dentate gyrus. Excess increase in extracellular Zn(2+) in the hippocampal CA1, which is induced with excitation of zincergic neurons, induces memory deficit via excess influx of Zn(2+) into CA1 pyramidal cells. In the present study, it was examined whether extracellular Zn(2+) induces object recognition memory deficit via excess influx of Zn(2+) into dentate granule cells. KCl (100 mM, 2 µl) was locally injected into the dentate gyrus. The increase in intracellular Zn(2+) in dentate granule cells induced with high K(+) was blocked by co-injection of CaEDTA and CNQX, an extracellular Zn(2+) chelator and an AMPA receptor antagonist, respectively, suggesting that high K(+) increases the influx of Zn(2+) into dentate granule cells via AMPA receptor activation. Dentate gyrus LTP induction was attenuated 1 h after KCl injection into the dentate gyrus and also attenuated when KCl was injected 5 min after the induction. Memory deficit was induced when training of object recognition test was performed 1 h after KCl injection into the dentate gyrus and also induced when KCl was injected 5 min after the training. High K(+)-induced impairments of LTP and memory were rescued by co-injection of CaEDTA. These results indicate that excess influx of Zn(2+) into dentate granule cells via AMPA receptor activation affects object recognition memory via attenuated LTP induction. Even in the dentate gyrus where is scarcely innervated by zincergic neurons, it is likely that extracellular Zn(2+) homeostasis is strictly regulated for cognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Bilateral reorganization of the dentate gyrus in hippocampal sclerosis

    Science.gov (United States)

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

    2009-01-01

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

  11. A practical approach to diseases affecting dentate nuclei

    International Nuclear Information System (INIS)

    Khadilkar, S.; Jaggi, S.; Patel, B.; Yadav, R.; Hanagandi, P.; Faria do Amaral, L.L.

    2016-01-01

    A wide variety of diseases affect the dentate nuclei. When faced with the radiological demonstration of signal changes in the dentate nuclei, radiologists and clinical neurologists have to sieve through the many possibilities, which they do not encounter on a regular basis. This task can be challenging, and therefore, developing a clinical, radiological, and laboratory approach is important. Information on the topic is scattered and the subject has not yet been reviewed. In this review, a combined clinicoradiological approach is presented. The signal changes in T1, T2, fluid-attenuated inversion recovery (FLAIR), diffusion, susceptibility weighted, and gadolinium-enhanced images can give specific or highly suggestive patterns, which are illustrated. The role of computed tomography (CT) in the diagnostic process is discussed. Specific radiological patterns do not exist in a significant proportion of patients where the clinical and laboratory analysis becomes important. In this review, we group the clinical constellations to narrow down the differential diagnosis and highlight the diagnostic clinical signs, such as tendon xanthomas and Kayser–Fleischer rings. As will be seen, a number of these conditions are potentially reversible, and hence, their early diagnosis is desirable. Finally, key diagnostic tests and available therapies are outlined. The practical approach thus begins with the radiologist and winds its way through the clinician, towards carefully selected diagnostic tests defining the therapy options. - Highlights: • Dentate nuclei are affected in leukodystrophies, metabolic, toxic, neurodegenerative, inflammatory and infectious diseases. • A number of these diseases are modifiable or reversible and hence it is important to diagnose them early. • Clinical or radiological tell-tale markers are present in a proportion of them. • In others, a practical approach beginning with radiology and taking help of clinical and laboratory features helps the

  12. Postnatal development of the hippocampal dentate gyrus under normal and experimental conditions

    International Nuclear Information System (INIS)

    Altman, J.; Bayer, S.

    Studies on postnatal maturation of the dentate gyrus are reviewed. Some topics discussed are: normal development of the dentate gyrus, cytogenesis, morphogenesis, synaptogenesis, gleogenesis, myelogenesis, development of the gyrus under experimental conditions, and effects of x radiation on cytogenesis and morphogenesis

  13. Protracted postnatal neurogenesis and radiosensitivity in the rabbit's dentate gyrus

    International Nuclear Information System (INIS)

    Gueneau, G.; Baille, V.; Dubos, M.; Court, L.

    1986-01-01

    In the hippocampal formation of a 3-month-old rabbit submitted to a 4.5 Gy gamma irradiation a cytologic study with light and electron microscopy allowed us to make clear the dentate gyrus particular radiosensitivity as soon as the first hours after irradiation. The pycnosis lesion observed in the subgranular zone has drawn our attention in particular. We apply ourselves to describe and precise the lesion and its evolution; thanks to an autoradiographic study, we have shown its link with late postnatal neurogenesis which goes on in this zone and at last we have used the subgranular cells 'radiosensitivity as a biological test allowing to compare the various rays' effects (gamma and neutron rays). In the brain of a one-month-old monkey submitted to a 4 Gy total irradiation the same pycnotic lesion is observed: 1) in the dentate gyrus's subgranular zone and 2) in the cerebellum's outer granular layer. These two postnatal proliferative zones remain particularly sensitive to ionizing radiations. (orig.)

  14. Immature Dentate Gyrus: An Endophenotype of Neuropsychiatric Disorders

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    Hideo Hagihara

    2013-01-01

    Full Text Available Adequate maturation of neurons and their integration into the hippocampal circuit is crucial for normal cognitive function and emotional behavior, and disruption of this process could cause disturbances in mental health. Previous reports have shown that mice heterozygous for a null mutation in α-CaMKII, which encodes a key synaptic plasticity molecule, display abnormal behaviors related to schizophrenia and other psychiatric disorders. In these mutants, almost all neurons in the dentate gyrus are arrested at a pseudoimmature state at the molecular and electrophysiological levels, a phenomenon defined as “immature dentate gyrus (iDG.” To date, the iDG phenotype and shared behavioral abnormalities (including working memory deficit and hyperlocomotor activity have been discovered in Schnurri-2 knockout, mutant SNAP-25 knock-in, and forebrain-specific calcineurin knockout mice. In addition, both chronic fluoxetine treatment and pilocarpine-induced seizures reverse the neuronal maturation, resulting in the iDG phenotype in wild-type mice. Importantly, an iDG-like phenomenon was observed in post-mortem analysis of brains from patients with schizophrenia/bipolar disorder. Based on these observations, we proposed that the iDG is a potential endophenotype shared by certain types of neuropsychiatric disorders. This review summarizes recent data describing this phenotype and discusses the data’s potential implication in elucidating the pathophysiology of neuropsychiatric disorders.

  15. Interictal psychosis following temporal lobe surgery: dentate gyrus pathology.

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    Thom, M; Kensche, M; Maynard, J; Liu, J; Reeves, C; Goc, J; Marsdon, D; Fluegel, D; Foong, J

    2014-10-01

    De novo interictal psychosis, albeit uncommon, can develop in patients following temporal lobe surgery for epilepsy. Pathological alterations of the dentate gyrus, including cytoarchitectural changes, immaturity and axonal reorganization that occur in epilepsy, may also underpin co-morbid psychiatric disorders. Our aim was to study candidate pathways that may be associated with the development of interictal psychosis post-operatively in patients with hippocampal sclerosis (HS). A total of 11 patients with HS who developed interictal psychosis (HS-P) post-operatively were compared with a matched surgical HS group without psychosis (HS-NP). Resected tissues were investigated for the extent of granule cell dispersion, mossy fibre sprouting and calbindin expression in the granule cells. We quantified doublecortin, mini-chromosome maintenance protein 2 (MCM2) and reelin-expressing neuronal populations in the dentate gyrus as well as the distribution of cannabinoid type 1 receptor (CBR1). The patterns of neuronal loss and gliosis were similar in both groups. HS-P patients demonstrated less mossy fibre sprouting and granule cell dispersion (p gyrus pathology found in HS-P patients could indicate underlying differences in the cellular response to seizures. These mechanisms may predispose to the development of psychosis in epilepsy and warrant further investigation.

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

    Science.gov (United States)

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

    2017-07-01

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

  17. Depleting adult dentate gyrus neurogenesis increases cocaine-seeking behavior.

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    Deroche-Gamonet, Véronique; Revest, Jean-Michel; Fiancette, Jean-François; Balado, Eric; Koehl, Muriel; Grosjean, Noëlle; Abrous, Djoher Nora; Piazza, Pier-Vincenzo

    2018-03-05

    The hippocampus is the main locus for adult dentate gyrus (DG) neurogenesis. A number of studies have shown that aberrant DG neurogenesis correlates with many neuropsychiatric disorders, including drug addiction. Although clear causal relationships have been established between DG neurogenesis and memory dysfunction or mood-related disorders, evidence of the causal role of DG neurogenesis in drug-seeking behaviors has not been established. Here we assessed the role of new DG neurons in cocaine self-administration using an inducible transgenic approach that selectively depletes adult DG neurogenesis. Our results show that transgenic mice with decreased adult DG neurogenesis exhibit increased motivation to self-administer cocaine and a higher seeking response to cocaine-related cues. These results identify adult hippocampal neurogenesis as a key factor in vulnerability to cocaine addiction.

  18. Neurons of the dentate molecular layer in the rabbit hippocampus.

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    Francisco J Sancho-Bielsa

    Full Text Available The molecular layer of the dentate gyrus appears as the main entrance gate for information into the hippocampus, i.e., where the perforant path axons from the entorhinal cortex synapse onto the spines and dendrites of granule cells. A few dispersed neuronal somata appear intermingled in between and probably control the flow of information in this area. In rabbits, the number of neurons in the molecular layer increases in the first week of postnatal life and then stabilizes to appear permanent and heterogeneous over the individuals' life span, including old animals. By means of Golgi impregnations, NADPH histochemistry, immunocytochemical stainings and intracellular labelings (lucifer yellow and biocytin injections, eight neuronal morphological types have been detected in the molecular layer of developing adult and old rabbits. Six of them appear as interneurons displaying smooth dendrites and GABA immunoreactivity: those here called as globoid, vertical, small horizontal, large horizontal, inverted pyramidal and polymorphic. Additionally there are two GABA negative types: the sarmentous and ectopic granular neurons. The distribution of the somata and dendritic trees of these neurons shows preferences for a definite sublayer of the molecular layer: small horizontal, sarmentous and inverted pyramidal neurons are preferably found in the outer third of the molecular layer; vertical, globoid and polymorph neurons locate the intermediate third, while large horizontal and ectopic granular neurons occupy the inner third or the juxtagranular molecular layer. Our results reveal substantial differences in the morphology and electrophysiological behaviour between each neuronal archetype in the dentate molecular layer, allowing us to propose a new classification for this neural population.

  19. Hilar Mossy Cell Degeneration Causes Transient Dentate Granule Cell Hyperexcitability and Impaired Pattern Separation

    Science.gov (United States)

    Jinde, Seiichiro; Zsiros, Veronika; Jiang, Zhihong; Nakao, Kazuhito; Pickel, James; Kohno, Kenji; Belforte, Juan E.; Nakazawa, Kazu

    2012-01-01

    Summary Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity’s net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5–6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation. PMID:23259953

  20. Effect of parental morphine addiction on extracellular glutamate concentration of dentate gyrus in rat offsprings

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    rahele Assaee

    2004-01-01

    Findings: In male offsprings of sham control1, sham control2, test1 and test2 basal and electrical stimulated of extracellular glutamate concentration of dentate gyrus were: 0.67±0.04, 1.11±0.1, and in female offsprings were 0.47±0.06, 0.88±0.05 (n=5. The basal and stimulated extra cellular glutamate concentration of dentate gyrus was decreased in both test1 and test2 offsprings. It was less in test1 than test2 offsprings. The glutamate concentration of dentate gyrus in female offsprings of test1 group was less than that of the male offsprings. conclusion: The results suggest that parental morphine addiction may cause learning deficiency through reduction of extracellular glutamate concentration in dentate gyrus so the side effects of parental morphine addiction in offsprings must be considered.

  1. Chronic unpredictable stress alters gene expression in rat single dentate granule cells

    NARCIS (Netherlands)

    Qin, Y.J.; Karst, H.; Joëls, M.

    2004-01-01

    The rat adrenal hormone corticosterone binds to low and high affinity receptors, discretely localized in brain, including the dentate gyrus. Differential activation of the two receptor types under physiological conditions alters gene expression and functional characteristics of hippocampal neurones.

  2. Temporal changes in prosaposin expression in the rat dentate gyrus after birth.

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    Midori Morishita

    Full Text Available Neurogenesis in the hippocampal dentate gyrus occurs constitutively throughout postnatal life. Adult neurogenesis includes a multistep process that ends with the formation of a postmitotic and functionally integrated new neuron. During adult neurogenesis, various markers are expressed, including GFAP, nestin, Pax6, polysialic acid-neural cell adhesion molecule (PSA-NCAM, neuronal nuclei (NeuN, doublecortin, TUC-4, Tuj-1, and calretinin. Prosaposin is the precursor of saposins A-D; it is found in various organs and can be excreted. Strong prosaposin expression has been demonstrated in the developing brain including the hippocampus, and its neurotrophic activity has been proposed. This study investigated changes in prosaposin in the dentate gyrus of young and adult rats using double immunohistochemistry with antibodies to prosaposin, PSA-NCAM, and NeuN. Prosaposin immunoreactivity was intense in the dentate gyrus at postnatal day 3 (P3 and P7, but decreased gradually after P14. In the dentate gyrus at P28, immature PSA-NCAM-positive neurons localized exclusively in the subgranular zone were prosaposin-negative, whereas mature Neu-N-positive neurons were positive for prosaposin. Furthermore, these prosaposin-negative immature neurons were saposin B-positive, suggesting that the neurons take up and degrade prosaposin. In situ hybridization assays showed that prosaposin in the adult dentate gyrus is dominantly the Pro+9 type, a secreted type of prosaposin. These results imply that prosaposin secreted from mature neurons stimulates proliferation and maturation of immature neurons in the dentate gyrus.

  3. Objective assessment of mastication predominance in healthy dentate subjects and patients with unilateral posterior missing teeth.

    Science.gov (United States)

    Yamasaki, Y; Kuwatsuru, R; Tsukiyama, Y; Oki, K; Koyano, K

    2016-08-01

    We aimed to investigate mastication predominance in healthy dentate individuals and patients with unilateral posterior missing teeth using objective and subjective methods. The sample comprised 50 healthy dentate individuals (healthy dentate group) and 30 patients with unilateral posterior missing teeth (partially edentulous group). Subjects were asked to freely chew three kinds of test foods (peanuts, beef jerky and chewing gum). Electromyographic activity of the bilateral masseter muscles was recorded. The chewing side (right side or left side) was judged by the level of root mean square electromyographic amplitude. Mastication predominance was then objectively assessed using the mastication predominant score and the mastication predominant index. Self-awareness of mastication predominance was evaluated using a modified visual analogue scale. Mastication predominance scores of the healthy dentate and partially edentulous groups for each test food were analysed. There was a significant difference in the distribution of the mastication predominant index between the two groups (P mastication predominant score was weakly correlated with self-awareness of mastication predominance in the healthy dentate group, whereas strong correlation was observed in the partially edentulous group (P mastication predominance and were more aware of mastication predominance than healthy dentate individuals. Our findings suggest that an objective evaluation of mastication predominance is more precise than a subjective method. © 2016 John Wiley & Sons Ltd.

  4. Synaptic pathology in the cerebellar dentate nucleus in chronic multiple sclerosis.

    Science.gov (United States)

    Albert, Monika; Barrantes-Freer, Alonso; Lohrberg, Melanie; Antel, Jack P; Prineas, John W; Palkovits, Miklós; Wolff, Joachim R; Brück, Wolfgang; Stadelmann, Christine

    2017-11-01

    In multiple sclerosis, cerebellar symptoms are associated with clinical impairment and an increased likelihood of progressive course. Cortical atrophy and synaptic dysfunction play a prominent role in cerebellar pathology and although the dentate nucleus is a predilection site for lesion development, structural synaptic changes in this region remain largely unexplored. Moreover, the mechanisms leading to synaptic dysfunction have not yet been investigated at an ultrastructural level in multiple sclerosis. Here, we report on synaptic changes of dentate nuclei in post-mortem cerebella of 16 multiple sclerosis patients and eight controls at the histological level as well as an electron microscopy evaluation of afferent synapses of the cerebellar dentate and pontine nuclei of one multiple sclerosis patient and one control. We found a significant reduction of afferent dentate synapses in multiple sclerosis, irrespective of the presence of demyelination, and a close relationship between glial processes and dentate synapses. Ultrastructurally, we show autophagosomes containing degradation products of synaptic vesicles within dendrites, residual bodies within intact-appearing axons and free postsynaptic densities opposed to astrocytic appendages. Our study demonstrates loss of dentate afferent synapses and provides, for the first time, ultrastructural evidence pointing towards neuron-autonomous and neuroglia-mediated mechanisms of synaptic degradation in chronic multiple sclerosis. © 2016 International Society of Neuropathology.

  5. Temporal changes in prosaposin expression in the rat dentate gyrus after birth.

    Science.gov (United States)

    Morishita, Midori; Nabeka, Hiroaki; Shimokawa, Tetsuya; Miyawaki, Kyojy; Doihara, Takuya; Saito, Shouichiro; Kobayashi, Naoto; Matsuda, Seiji

    2014-01-01

    Neurogenesis in the hippocampal dentate gyrus occurs constitutively throughout postnatal life. Adult neurogenesis includes a multistep process that ends with the formation of a postmitotic and functionally integrated new neuron. During adult neurogenesis, various markers are expressed, including GFAP, nestin, Pax6, polysialic acid-neural cell adhesion molecule (PSA-NCAM), neuronal nuclei (NeuN), doublecortin, TUC-4, Tuj-1, and calretinin. Prosaposin is the precursor of saposins A-D; it is found in various organs and can be excreted. Strong prosaposin expression has been demonstrated in the developing brain including the hippocampus, and its neurotrophic activity has been proposed. This study investigated changes in prosaposin in the dentate gyrus of young and adult rats using double immunohistochemistry with antibodies to prosaposin, PSA-NCAM, and NeuN. Prosaposin immunoreactivity was intense in the dentate gyrus at postnatal day 3 (P3) and P7, but decreased gradually after P14. In the dentate gyrus at P28, immature PSA-NCAM-positive neurons localized exclusively in the subgranular zone were prosaposin-negative, whereas mature Neu-N-positive neurons were positive for prosaposin. Furthermore, these prosaposin-negative immature neurons were saposin B-positive, suggesting that the neurons take up and degrade prosaposin. In situ hybridization assays showed that prosaposin in the adult dentate gyrus is dominantly the Pro+9 type, a secreted type of prosaposin. These results imply that prosaposin secreted from mature neurons stimulates proliferation and maturation of immature neurons in the dentate gyrus.

  6. Dentate Gyrus circuitry features improve performance of sparse approximation algorithms.

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    Panagiotis C Petrantonakis

    Full Text Available Memory-related activity in the Dentate Gyrus (DG is characterized by sparsity. Memory representations are seen as activated neuronal populations of granule cells, the main encoding cells in DG, which are estimated to engage 2-4% of the total population. This sparsity is assumed to enhance the ability of DG to perform pattern separation, one of the most valuable contributions of DG during memory formation. In this work, we investigate how features of the DG such as its excitatory and inhibitory connectivity diagram can be used to develop theoretical algorithms performing Sparse Approximation, a widely used strategy in the Signal Processing field. Sparse approximation stands for the algorithmic identification of few components from a dictionary that approximate a certain signal. The ability of DG to achieve pattern separation by sparsifing its representations is exploited here to improve the performance of the state of the art sparse approximation algorithm "Iterative Soft Thresholding" (IST by adding new algorithmic features inspired by the DG circuitry. Lateral inhibition of granule cells, either direct or indirect, via mossy cells, is shown to enhance the performance of the IST. Apart from revealing the potential of DG-inspired theoretical algorithms, this work presents new insights regarding the function of particular cell types in the pattern separation task of the DG.

  7. Hilar mossy cells of the dentate gyrus: a historical perspective

    Science.gov (United States)

    Scharfman, Helen E.; Myers, Catherine E.

    2013-01-01

    The circuitry of the dentate gyrus (DG) of the hippocampus is unique compared to other hippocampal subfields because there are two glutamatergic principal cells instead of one: granule cells, which are the vast majority of the cells in the DG, and the so-called “mossy cells.” The distinctive appearance of mossy cells, the extensive divergence of their axons, and their vulnerability to excitotoxicity relative to granule cells has led to a great deal of interest in mossy cells. Nevertheless, there is no consensus about the normal functions of mossy cells and the implications of their vulnerability. There even seems to be some ambiguity about exactly what mossy cells are. Here we review initial studies of mossy cells, characteristics that define them, and suggest a practical definition to allow investigators to distinguish mossy cells from other hilar neurons even if all morphological and physiological information is unavailable due to technical limitations of their experiments. In addition, hypotheses are discussed about the role of mossy cells in the DG network, reasons for their vulnerability and their implications for disease. PMID:23420672

  8. Effect of dentate gyrus disruption on remembering what happened where

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    Min W Jung

    2015-06-01

    Full Text Available Our previous studies using Bax knockout (Bax-KO mice, in which newly generated granule cells continue to accumulate, disrupting neural circuitry specifically in the dentate gyrus (DG, suggest the involvement of the DG in binding the internally-generated spatial map with sensory information on external landmarks (spatial map-object association in forming a distinct spatial context for each environment. In order to test whether the DG is also involved in binding the internal spatial map with sensory information on external events (spatial map-event association, we tested the behavior of Bax-KO mice in a delayed-non-match-to-place task. Performance of Bax-KO mice was indistinguishable from that of wild-type mice as long as there was no interruption during the delay period (tested up to 5 min, suggesting that on-line maintenance of working memory is intact in Bax-KO mice. However, Bax-KO mice showed profound performance deficits when they were removed from the maze during the delay period (interruption condition with a sufficiently long (65 s delay, suggesting that episodic memory was impaired in Bax-KO mice. Together with previous findings, these results suggest the role of the DG in binding spatial information derived from dead reckoning and nonspatial information, such as external objects and events, in the process of encoding episodic memory.

  9. Proliferation of granule cell precursors in the dentate gyrus of adult monkeys is diminished by stress

    Science.gov (United States)

    Gould, Elizabeth; Tanapat, Patima; McEwen, Bruce S.; Flügge, Gabriele; Fuchs, Eberhard

    1998-01-01

    Although granule cells continue to be added to the dentate gyrus of adult rats and tree shrews, this phenomenon has not been demonstrated in the dentate gyrus of adult primates. To determine whether neurons are produced in the dentate gyrus of adult primates, adult marmoset monkeys (Callithrix jacchus) were injected with BrdU and perfused 2 hr or 3 weeks later. BrdU is a thymidine analog that is incorporated into proliferating cells during S phase. A substantial number of cells in the dentate gyrus of adult monkeys incorporated BrdU and ≈80% of these cells had morphological characteristics of granule neurons and expressed a neuronal marker by the 3-week time point. Previous studies suggest that the proliferation of granule cell precursors in the adult dentate gyrus can be inhibited by stress in rats and tree shrews. To test whether an aversive experience has a similar effect on cell proliferation in the primate brain, adult marmoset monkeys were exposed to a resident-intruder model of stress. After 1 hr in this condition, the intruder monkeys were injected with BrdU and perfused 2 hr later. The number of proliferating cells in the dentate gyrus of the intruder monkeys was compared with that of unstressed control monkeys. We found that a single exposure to this stressful experience resulted in a significant reduction in the number of these proliferating cells. Our results suggest that neurons are produced in the dentate gyrus of adult monkeys and that the rate of precursor cell proliferation can be affected by a stressful experience. PMID:9501234

  10. Status Epilepticus Induced Spontaneous Dentate Gyrus Spikes: In Vivo Current Source Density Analysis.

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    Sean P Flynn

    Full Text Available The dentate gyrus is considered to function as an inhibitory gate limiting excitatory input to the hippocampus. Following status epilepticus (SE, this gating function is reduced and granule cells become hyper-excitable. Dentate spikes (DS are large amplitude potentials observed in the dentate gyrus (DG of normal animals. DS are associated with membrane depolarization of granule cells, increased activity of hilar interneurons and suppression of CA3 and CA1 pyramidal cell firing. Therefore, DS could act as an anti-excitatory mechanism. Because of the altered gating function of the dentate gyrus following SE, we sought to investigate how DS are affected following pilocarpine-induced SE. Two weeks following lithium-pilocarpine SE induction, hippocampal EEG was recorded in male Sprague-Dawley rats with 16-channel silicon probes under urethane anesthesia. Probes were placed dorso-ventrally to encompass either CA1-CA3 or CA1-DG layers. Large amplitude spikes were detected from EEG recordings and subject to current source density analysis. Probe placement was verified histologically to evaluate the anatomical localization of current sinks and the origin of DS. In 9 of 11 pilocarpine-treated animals and two controls, DS were confirmed with large current sinks in the molecular layer of the dentate gyrus. DS frequency was significantly increased in pilocarpine-treated animals compared to controls. Additionally, in pilocarpine-treated animals, DS displayed current sinks in the outer, middle and/or inner molecular layers. However, there was no difference in the frequency of events when comparing between layers. This suggests that following SE, DS can be generated by input from medial and lateral entorhinal cortex, or within the dentate gyrus. DS were associated with an increase in multiunit activity in the granule cell layer, but no change in CA1. These results suggest that following SE there is an increase in DS activity, potentially arising from

  11. Corruption of the dentate gyrus by "dominant" granule cells: Implications for dentate gyrus function in health and disease.

    Science.gov (United States)

    Scharfman, Helen E; Myers, Catherine E

    2016-03-01

    The dentate gyrus (DG) and area CA3 of the hippocampus are highly organized lamellar structures which have been implicated in specific cognitive functions such as pattern separation and pattern completion. Here we describe how the anatomical organization and physiology of the DG and CA3 are consistent with structures that perform pattern separation and completion. We then raise a new idea related to the complex circuitry of the DG and CA3 where CA3 pyramidal cell 'backprojections' play a potentially important role in the sparse firing of granule cells (GCs), considered important in pattern separation. We also propose that GC axons, the mossy fibers, already known for their highly specialized structure, have a dynamic function that imparts variance--'mossy fiber variance'--which is important to pattern separation and completion. Computational modeling is used to show that when a subset of GCs become 'dominant,' one consequence is loss of variance in the activity of mossy fiber axons and a reduction in pattern separation and completion in the model. Empirical data are then provided using an example of 'dominant' GCs--subsets of GCs that develop abnormally and have increased excitability. Notably, these abnormal GCs have been identified in animal models of disease where DG-dependent behaviors are impaired. Together these data provide insight into pattern separation and completion, and suggest that behavioral impairment could arise from dominance of a subset of GCs in the DG-CA3 network. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Releasing dentate nucleus cells from Purkinje cell inhibition generates output from the cerebrocerebellum.

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    Takahiro Ishikawa

    Full Text Available The cerebellum generates its vast amount of output to the cerebral cortex through the dentate nucleus (DN that is essential for precise limb movements in primates. Nuclear cells in DN generate burst activity prior to limb movement, and inactivation of DN results in cerebellar ataxia. The question is how DN cells become active under intensive inhibitory drive from Purkinje cells (PCs. There are two excitatory inputs to DN, mossy fiber and climbing fiber collaterals, but neither of them appears to have sufficient strength for generation of burst activity in DN. Therefore, we can assume two possible mechanisms: post-inhibitory rebound excitation and disinhibition. If rebound excitation works, phasic excitation of PCs and a concomitant inhibition of DN cells should precede the excitation of DN cells. On the other hand, if disinhibition plays a primary role, phasic suppression of PCs and activation of DN cells should be observed at the same timing. To examine these two hypotheses, we compared the activity patterns of PCs in the cerebrocerebellum and DN cells during step-tracking wrist movements in three Japanese monkeys. As a result, we found that the majority of wrist-movement-related PCs were suppressed prior to movement onset and the majority of wrist-movement-related DN cells showed concurrent burst activity without prior suppression. In a minority of PCs and DN cells, movement-related increases and decreases in activity, respectively, developed later. These activity patterns suggest that the initial burst activity in DN cells is generated by reduced inhibition from PCs, i.e., by disinhibition. Our results indicate that suppression of PCs, which has been considered secondary to facilitation, plays the primary role in generating outputs from DN. Our findings provide a new perspective on the mechanisms used by PCs to influence limb motor control and on the plastic changes that underlie motor learning in the cerebrocerebellum.

  13. Sleep loss disrupts Arc expression in dentate gyrus neurons.

    Science.gov (United States)

    Delorme, James E; Kodoth, Varna; Aton, Sara J

    2018-04-07

    Sleep loss affects many aspects of cognition, and memory consolidation processes occurring in the hippocampus seem particularly vulnerable to sleep loss. The immediate-early gene Arc plays an essential role in both synaptic plasticity and memory formation, and its expression is altered by sleep. Here, using a variety of techniques, we have characterized the effects of brief (3-h) periods of sleep vs. sleep deprivation (SD) on the expression of Arc mRNA and Arc protein in the mouse hippocampus and cortex. By comparing the relative abundance of mature Arc mRNA with unspliced pre-mRNA, we see evidence that during SD, increases in Arc across the cortex, but not hippocampus, reflect de novo transcription. Arc increases in the hippocampus during SD are not accompanied by changes in pre-mRNA levels, suggesting that increases in mRNA stability, not transcription, drives this change. Using in situ hybridization (together with behavioral observation to quantify sleep amounts), we find that in the dorsal hippocampus, SD minimally affects Arc mRNA expression, and decreases the number of dentate gyrus (DG) granule cells expressing Arc. This is in contrast to neighboring cortical areas, which show large increases in neuronal Arc expression after SD. Using immunohistochemistry, we find that Arc protein expression is also differentially affected in the cortex and DG with SD - while larger numbers of cortical neurons are Arc+, fewer DG granule cells are Arc+, relative to the same regions in sleeping mice. These data suggest that with regard to expression of plasticity-regulating genes, sleep (and SD) can have differential effects in hippocampal and cortical areas. This may provide a clue regarding the susceptibility of performance on hippocampus-dependent tasks to deficits following even brief periods of sleep loss. Copyright © 2018. Published by Elsevier Inc.

  14. Adiponectin modulates synaptic plasticity in hippocampal dentate gyrus.

    Science.gov (United States)

    Pousti, Farideh; Ahmadi, Ramesh; Mirahmadi, Fatemeh; Hosseinmardi, Narges; Rohampour, Kambiz

    2018-01-01

    Recent studies have suggested the involvement of some metabolic hormones in memory formation and synaptic plasticity. Insulin dysfunction is known as an essential process in the pathogenesis of sporadic Alzheimer's disease (AD). In this study we examined whether adiponectin (ADN), as an insulin-sensitizing adipokine, could affect hippocampal synaptic plasticity. Field potential recordings were performed on intracerebroventricular (icv) cannulated urethane anesthetized rats. After baseline recording from dentate gyrus (DG) and 10min prior to high/low frequency stimulation (HFS/LFS), 10μl icv ADN (600nm) were injected. The slope of field excitatory postsynaptic potentials (fEPSP) and the amplitude of population spikes (PS) were recorded in response to perforanth path (PP) stimulation. Paired pulse stimuli and ADN injection without any stimulation protocols were also evaluated. Application of ADN before HFS increased PS amplitude recorded in DG significantly (P≤0.05) in comparison to HFS only group. ADN suppressed the potency of LFS to induce long-term depression (LTD), causing a significant difference between fEPSP slope (P≤0.05) and PS amplitude (P≤0.01) between ADN+LFS and ADN group. Paired pulse stimuli applied at 20ms intervals showed more paired pulse facilitation (PPF), when applied after ADN (P≤0.05). ADN induced a chemical long-term potentiation (LTP) in which fEPSP slope and PS amplitude increased significantly (P≤0.01 and P≤0.05, respectively). It is concluded that ADN is able to potentiate the HFS-induced LTP and suppress LFS-induced LTD. ADN caused a chemical LTP, when applied without any tetanic protocol. ADN may enhance the presynaptic release probability. Copyright © 2017. Published by Elsevier B.V.

  15. Insomnia severity is associated with a decreased volume of the CA3/Dentate Gyrus Hippocampal Subfield

    Science.gov (United States)

    Neylan, Thomas C.; Mueller, Susanne G.; Wang, Zhen; Metzler, Thomas J.; Lenoci, Maryann; Truran, Diana; Marmar, Charles R.; Weiner, Michael W.; Schuff, Norbert

    2010-01-01

    Background Prolonged disruption of sleep in animal studies is associated with decreased neurogenesis in the dentate gyrus. Our objective was to determine if insomnia severity in a sample of PTSD and controls was associated with decreased volume in the CA3/dentate hippocampal subfield. Methods Volumes of hippocampal subfields in seventeen veteran males positive for PTSD (41 ±12 years) and nineteen age-matched male veterans negative for PTSD were measured using 4 Tesla MRI. Subjective sleep quality was measured by the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index (PSQI). Results Higher scores on the ISI, indicating worse insomnia, were associated with smaller volumes of the CA3/dentate subfields (r= −.48, p < 0.01) in the combined sample. Adding the ISI score as a predictor for CA3/dentate volume to a hierarchical linear regression model after first controlling for age and PTSD symptoms accounted for a 13 % increase in incremental variance (t= −2.47, p= 0.02). Conclusions The findings indicate for the first time in humans that insomnia severity is associated with volume loss of the CA3/dentate subfields. This is consistent with animal studies showing that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures. PMID:20598672

  16. A brief period of sleep deprivation causes spine loss in the dentate gyrus of mice.

    Science.gov (United States)

    Raven, Frank; Meerlo, Peter; Van der Zee, Eddy A; Abel, Ted; Havekes, Robbert

    2018-03-24

    Sleep and sleep loss have a profound impact on hippocampal function, leading to memory impairments. Modifications in the strength of synaptic connections directly influences neuronal communication, which is vital for normal brain function, as well as the processing and storage of information. In a recently published study, we found that as little as five hours of sleep deprivation impaired hippocampus-dependent memory consolidation, which was accompanied by a reduction in dendritic spine numbers in hippocampal area CA1. Surprisingly, loss of sleep did not alter the spine density of CA3 neurons. Although sleep deprivation has been reported to affect the function of the dentate gyrus, it is unclear whether a brief period of sleep deprivation impacts spine density in this region. Here, we investigated the impact of a brief period of sleep deprivation on dendritic structure in the dentate gyrus of the dorsal hippocampus. We found that five hours of sleep loss reduces spine density in the dentate gyrus with a prominent effect on branched spines. Interestingly, the inferior blade of the dentate gyrus seems to be more vulnerable in terms of spine loss than the superior blade. This decrease in spine density predominantly in the inferior blade of the dentate gyrus may contribute to the memory deficits observed after sleep loss, as structural reorganization of synaptic networks in this subregion is fundamental for cognitive processes. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Defects in the medial entorhinal cortex and dentate gyrus in the mouse model of Sanfilippo syndrome type B.

    Directory of Open Access Journals (Sweden)

    Kazuhiro Ohmi

    Full Text Available Sanfilippo syndrome type B (MPS IIIB is characterized by profound mental retardation in childhood, dementia and death in late adolescence; it is caused by deficiency of α-N-acetylglucosaminidase and resulting lysosomal storage of heparan sulfate. A mouse model, generated by homologous recombination of the Naglu gene, was used to study pathological changes in the brain. We found earlier that neurons in the medial entorhinal cortex (MEC and the dentate gyrus showed a number of secondary defects, including the presence of hyperphosphorylated tau (Ptau detected with antibodies raised against Ptau in Alzheimer disease brain. By further use of immunohistochemistry, we now show staining in neurons of the same area for beta amyloid, extending the resemblance to Alzheimer disease. Ptau inclusions in the dentate gyrus of MPS IIIB mice were reduced in number when the mice were administered LiCl, a specific inhibitor of Gsk3β. Additional proteins found elevated in MEC include proteins involved in autophagy and the heparan sulfate proteoglycans, glypicans 1 and 5, the latter closely related to the primary defect. The level of secondary accumulations was associated with elevation of glypican, as seen by comparing brains of mice at different ages or with different mucopolysaccharide storage diseases. The MEC of an MPS IIIA mouse had the same intense immunostaining for glypican 1 and other markers as MPS IIIB, while MEC of MPS I and MPS II mice had weak staining, and MEC of an MPS VI mouse had no staining at all for the same proteins. A considerable amount of glypican was found in MEC of MPS IIIB mice outside of lysosomes. We propose that it is the extralysosomal glypican that would be harmful to neurons, because its heparan sulfate branches could potentiate the formation of Ptau and beta amyloid aggregates, which would be toxic as well as difficult to degrade.

  18. Toll-like receptor 2 promotes neurogenesis from the dentate gyrus after photothrombotic cerebral ischemia in mice.

    Science.gov (United States)

    Seong, Kyung-Joo; Kim, Hyeong-Jun; Cai, Bangrong; Kook, Min-Suk; Jung, Ji-Yeon; Kim, Won-Jae

    2018-03-01

    The subgranular zone (SGZ) of hippocampal dentate gyrus (HDG) is a primary site of adult neurogenesis. Toll-like receptors (TLRs), are involved in neural system development of Drosophila and innate immune response of mammals. TLR2 is expressed abundantly in neurogenic niches such as adult mammalian hippocampus. It regulates adult hippocampal neurogenesis. However, the role of TLR2 in adult neurogenesis is not well studied in global or focal cerebral ischemia. Therefore, this study aimed to investigate the role of TLR2 in adult neurogenesis after photochemically induced cerebral ischemia. At 7 days after photothrombotic ischemic injury, the number of bromodeoxyuridine (BrdU)-positive cells was increased in both TLR2 knock-out (KO) mice and wild-type (WT) mice. However, the increment rate of BrdU-positive cells was lower in TLR2 KO mice compared to that in WT mice. The number of doublecortin (DCX) and neuronal nuclei (NeuN)-positive cells in HDG was decreased after photothrombotic ischemia in TLR2 KO mice compared to that in WT mice. The survival rate of cells in HDG was decreased in TLR2 KO mice compared to that in WT mice. In contrast, the number of cleaved-caspase 3 (apoptotic marker) and the number of GFAP (glia marker)/BrdU double-positive cells in TLR2 KO mice were higher than that in WT mice. These results suggest that TLR2 can promote adult neurogenesis from neural stem cell of hippocampal dentate gyrus through increasing proliferation, differentiation, and survival from neural stem cells after ischemic injury of the brain.

  19. Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencing.

    Science.gov (United States)

    Hochgerner, Hannah; Zeisel, Amit; Lönnerberg, Peter; Linnarsson, Sten

    2018-02-01

    The dentate gyrus of the hippocampus is a brain region in which neurogenesis persists into adulthood; however, the relationship between developmental and adult dentate gyrus neurogenesis has not been examined in detail. Here we used single-cell RNA sequencing to reveal the molecular dynamics and diversity of dentate gyrus cell types in perinatal, juvenile, and adult mice. We found distinct quiescent and proliferating progenitor cell types, linked by transient intermediate states to neuroblast stages and fully mature granule cells. We observed shifts in the molecular identity of quiescent and proliferating radial glia and granule cells during the postnatal period that were then maintained through adult stages. In contrast, intermediate progenitor cells, neuroblasts, and immature granule cells were nearly indistinguishable at all ages. These findings demonstrate the fundamental similarity of postnatal and adult neurogenesis in the hippocampus and pinpoint the early postnatal transformation of radial glia from embryonic progenitors to adult quiescent stem cells.

  20. Hilar somatostatin interneuron loss reduces dentate gyrus inhibition in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Hofmann, Gabrielle; Balgooyen, Laura; Mattis, Joanna; Deisseroth, Karl; Buckmaster, Paul S

    2016-06-01

    In patients with temporal lobe epilepsy, seizures usually start in the hippocampus, and dentate granule cells are hyperexcitable. Somatostatin interneurons are a major subpopulation of inhibitory neurons in the dentate gyrus, and many are lost in patients and animal models. However, surviving somatostatin interneurons sprout axon collaterals and form new synapses, so the net effect on granule cell inhibition remains unclear. The present study uses optogenetics to activate hilar somatostatin interneurons and measure the inhibitory effect on dentate gyrus perforant path-evoked local field potential responses in a mouse model of temporal lobe epilepsy. In controls, light activation of hilar somatostatin interneurons inhibited evoked responses up to 40%. Epileptic pilocarpine-treated mice exhibited loss of hilar somatostatin interneurons and less light-induced inhibition of evoked responses. These findings suggest that severe epilepsy-related loss of hilar somatostatin interneurons can overwhelm the surviving interneurons' capacity to compensate by sprouting axon collaterals. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  1. 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.

  2. Local and Long-Range Circuit Connections to Hilar Mossy Cells in the Dentate Gyrus

    Science.gov (United States)

    Sun, Yanjun; Grieco, Steven F.; Holmes, Todd C.

    2017-01-01

    Abstract Hilar mossy cells are the prominent glutamatergic cell type in the dentate hilus of the dentate gyrus (DG); they have been proposed to have critical roles in the DG network. To better understand how mossy cells contribute to DG function, we have applied new viral genetic and functional circuit mapping approaches to quantitatively map and compare local and long-range circuit connections of mossy cells and dentate granule cells in the mouse. The great majority of inputs to mossy cells consist of two parallel inputs from within the DG: an excitatory input pathway from dentate granule cells and an inhibitory input pathway from local DG inhibitory neurons. Mossy cells also receive a moderate degree of excitatory and inhibitory CA3 input from proximal CA3 subfields. Long range inputs to mossy cells are numerically sparse, and they are only identified readily from the medial septum and the septofimbrial nucleus. In comparison, dentate granule cells receive most of their inputs from the entorhinal cortex. The granule cells receive significant synaptic inputs from the hilus and the medial septum, and they also receive direct inputs from both distal and proximal CA3 subfields, which has been underdescribed in the existing literature. Our slice-based physiological mapping studies further supported the identified circuit connections of mossy cells and granule cells. Together, our data suggest that hilar mossy cells are major local circuit integrators and they exert modulation of the activity of dentate granule cells as well as the CA3 region through “back-projection” pathways. PMID:28451637

  3. Characteristic of Extracellular Zn2+ Influx in the Middle-Aged Dentate Gyrus and Its Involvement in Attenuation of LTP.

    Science.gov (United States)

    Takeda, Atsushi; Koike, Yuta; Osaw, Misa; Tamano, Haruna

    2018-03-01

    An increased influx of extracellular Zn 2+ into neurons is a cause of cognitive decline. The influx of extracellular Zn 2+ into dentate granule cells was compared between young and middle-aged rats because of vulnerability of the dentate gyrus to aging. The influx of extracellular Zn 2+ into dentate granule cells was increased in middle-aged rats after injection of AMPA and high K + into the dentate gyrus, but not in young rats. Simultaneously, high K + -induced attenuation of LTP was observed in middle-aged rats, but not in young rats. The attenuation was rescued by co-injection of CaEDTA, an extracellular Zn 2+ chelator. Intracellular Zn 2+ in dentate granule cells was also increased in middle-aged slices with high K + , in which the increase in extracellular Zn 2+ was the same as young slices with high K + , suggesting that ability of extracellular Zn 2+ influx into dentate granule cells is greater in middle-aged rats. Furthermore, extracellular zinc concentration in the hippocampus was increased age-dependently. The present study suggests that the influx of extracellular Zn 2+ into dentate granule cells is more readily increased in middle-aged rats and that its increase is a cause of age-related attenuation of LTP in the dentate gyrus.

  4. Pyramid-like basket cells in the granular layer of the dentate gyrus in the rat.

    Science.gov (United States)

    Seress, L

    1978-01-01

    Basket cells of the dentate gyrus were identified using Nissl (cresyl violet) staining. It has been found that the ratio between basket and granule cells is 1:150--210. Only a few glial cells, mainly astroglia, were found in the granular layer of the dentate gyrus. In accordance with earlier data it was found that the granule cells and glial cells originate mainly postnatally, but the basket cells, like the pyramidal cells of the hippocampus, originate prenatally. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 Fig. 6 PMID:701192

  5. Prenatal alcohol exposure affects progenitor cell numbers in olfactory bulbs and dentate gyrus of vervet monkeys

    DEFF Research Database (Denmark)

    Burke, Mark W; Inyatkin, Alexey; Ptito, Maurice

    2016-01-01

    vervet monkey (Chlorocebus sabeus) to (1) investigate the normal developmental sequence of post-natal proliferation in the olfactory bulb and dentate gyrus and (2) determine the effects of naturalistic prenatal ethanol exposure on proliferation at three different ages (neonate, five months and two years......). Using design-based stereology, we found an age-related decrease of actively proliferating cells in the olfactory bulb and dentate gyrus for both control and FAE groups. Furthermore, at the neonatal time point, the FAE group had fewer actively proliferating cells as compared to the control group...

  6. A modified occlusal wafer for managing partially dentate orthognathic patients--a case series.

    Science.gov (United States)

    Soneji, Bhavin Kiritkumar; Esmail, Zaid; Sharma, Pratik

    2015-03-01

    A multidisciplinary approach is essential in orthognathic surgery to achieve stable and successful outcomes. The model surgery planning is an important aspect in achieving the desired aims. An occlusal wafer used at the time of surgery aids the surgeon during correct placement of the jaws. When dealing with partially dentate patients, the design of the occlusal wafer requires modification to appropriately position the jaw. Two cases with partially dentate jaws are presented in which the occlusal wafer has been modified to provide stability at the time of surgery.

  7. Migration and distribution of two populations of hippocampal granule cell precursors during the perinatal and postnatal periods

    International Nuclear Information System (INIS)

    Altman, J.; Bayer, S.A.

    1990-01-01

    Methacrylate-embedded sections and short-survival thymidine radiograms of the hippocampal dentate gyrus were examined in perinatal and postnatal rats in order to trace the site of origin and migration of the precursors of granule cells and study the morphogenesis of the granular layer. The densely packed, spindle-shaped cells of the secondary dentate matrix (a derivative of the primary dentate neuroepithelium) stream in a subpial position towards the granular layer of the internal dentate limb during the perinatal and early postnatal periods. By an accretionary process, the crest of the granular layer forms on day E21 and on the subsequent days the granular layer of the internal dentate limb expands progressively in a lateral direction. Granule cells differentiation, as judged by the transformation of polymorph, darkly staining small cells into rounder, lightly staining larger granule cells, follows the same gradient from the external dentate limb to the internal dentate limb. The secondary dentate matrix is in a process of dissolution by day P5. This matrix is the source of what will later become the outer shell of the granular layer composed of early generated granule cells. The thicker inner shell of the granular layer, formed during the infantile and juvenile periods, derives from an intrinsic, tertiary germinal matrix. On day E22, the dentate migration of the secondary dentate matrix becomes partitioned into two components: (a) the subpial component of extradentate origin, referred to in this context as the first dentate migration, and (b) the second dentate migration. The latter is distributed in the basal polymorph layer throughout the entire dentate gyrus and is henceforth recognized as the tertiary dentate matrix. The tertiary dentate matrix is prominent between days P3 and P10

  8. Structural plasticity in the dentate gyrus- revisiting a classic injury model.

    Directory of Open Access Journals (Sweden)

    Julia V. Perederiy

    2013-02-01

    Full Text Available The adult brain is in a continuous state of remodeling. This is nowhere more true than in the dentate gyrus, where competing forces such as neurodegeneration and neurogenesis dynamically modify neuronal connectivity, and can occur simultaneously. This plasticity of the adult nervous system is particularly important in the context of traumatic brain injury or deafferentation. In this review, we summarize a classic injury model, lesioning of the perforant path, which removes the main extrahippocampal input to the dentate gyrus. Early studies revealed that in response to deafferentation, axons of remaining fiber systems and dendrites of mature granule cells undergo lamina-specific changes, providing one of the first examples of structural plasticity in the adult brain. Given the increasing role of adult-generated new neurons in the function of the dentate gyrus, we also compare the response of newborn and mature granule cells following lesioning of the perforant path. These studies provide insights not only to plasticity in the dentate gyrus, but also to the response of neural circuits to brain injury.

  9. Antisense to the glucocorticoid receptor in hippocampal dentate gyrus reduces immobility in forced swim test

    NARCIS (Netherlands)

    Korte, S.M.; de Kloet, E.R.; Buwalda, B; Bouman, S.D.; Bohus, B

    1996-01-01

    Immobility time of rats in the forced swim test was reduced after bilateral infusion of an 18-mer antisense phosphorothioate oligodeoxynucleotide targeted to the glucocorticoid receptor mRNA into the dentate gyrus of the hippocampus. Vehicle-, sense- and scrambled sequence-treated animals spent

  10. Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis.

    Science.gov (United States)

    Planche, Vincent; Panatier, Aude; Hiba, Bassem; Ducourneau, Eva-Gunnel; Raffard, Gerard; Dubourdieu, Nadège; Maitre, Marlène; Lesté-Lasserre, Thierry; Brochet, Bruno; Dousset, Vincent; Desmedt, Aline; Oliet, Stéphane H; Tourdias, Thomas

    2017-02-01

    Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Expression of glutamic acid decarboxylase and identification of GABAergic cells in the ischemic rat dentate gyrus

    DEFF Research Database (Denmark)

    Müller, Georg Johannes; Dogonowski, Anne-Marie; Finsen, Bente

    2006-01-01

    We have investigated the glutamic acid dexcarboxylase (GAD) mRNA and protein isoforms as markers for ischemic loss of GABAergic neurons in the dentate hilus. Stereological counts of these neurons were performed in rats surviving 8 days after 10 min of transient forebrain ischemia, and in control...

  12. [Dissertation 25 years after date 39. Oral self-care by dentate elderly

    NARCIS (Netherlands)

    Kluter, W.J.; Baat, C. de

    2015-01-01

    In 1989, the dissertation 'Oral self-care for dentate elderly' was published. Among other things, the effect of an information leaflet on oral self-care was investigated in a randomised, controlled trial. The outcome of the entire intervention was positive. Subsequent to this dissertation no

  13. Ex vivo study of dentate gyrus neurogenesis in human pharmacoresistant temporal lobe epilepsy.

    Science.gov (United States)

    Paradisi, M; Fernández, M; Del Vecchio, G; Lizzo, G; Marucci, G; Giulioni, M; Pozzati, E; Antonelli, T; Lanzoni, G; Bagnara, G P; Giardino, L; Calzà, L

    2010-10-01

    Neurogenesis in adult humans occurs in at least two areas of the brain, the subventricular zone of the telencephalon and the subgranular layer of the dentate gyrus in the hippocampal formation. We studied dentate gyrus subgranular layer neurogenesis in patients subjected to tailored antero-mesial temporal resection including amygdalohippocampectomy due to pharmacoresistant temporal lobe epilepsy (TLE) using the in vitro neurosphere assay. Sixteen patients were enrolled in the study; mesial temporal sclerosis (MTS) was present in eight patients. Neurogenesis was investigated by ex vivo neurosphere expansion in the presence of mitogens (epidermal growth factor + basic fibroblast growth factor) and spontaneous differentiation after mitogen withdrawal. Growth factor synthesis was investigated by qRT-PCR in neurospheres. We demonstrate that in vitro proliferation of cells derived from dentate gyrus of TLE patients is dependent on disease duration. Moreover, the presence of MTS impairs proliferation. As long as in vitro proliferation occurs, neurogenesis is maintained, and cells expressing a mature neurone phenotype (TuJ1, MAP2, GAD) are spontaneously formed after mitogen withdrawal. Finally, formed neurospheres express mRNAs encoding for growth (vascular endothelial growth factor) as well as neurotrophic factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor). We demonstrated that residual neurogenesis in the subgranular layer of the dentate gyrus in TLE is dependent on diseases duration and absent in MTS. © 2010 The Authors. Neuropathology and Applied Neurobiology © 2010 British Neuropathological Society.

  14. Colchicine induced intraneuronal free zinc accumulation and dentate granule cell degeneration.

    Science.gov (United States)

    Choi, Bo Young; Lee, Bo Eun; Kim, Jin Hee; Kim, Hyun Jung; Sohn, Min; Song, Hong Ki; Chung, Tae Nyoung; Suh, Sang Won

    2014-08-01

    Colchicine has been discovered to inhibit many inflammatory processes such as gout, familial Mediterranean fever, pericarditis and Behcet disease. Other than these beneficial anti-inflammatory effects, colchicine blocks microtubule-assisted axonal transport, which results in the selective loss of dentate granule cells of the hippocampus. The mechanism of the colchicine-induced dentate granule cell death and depletion of mossy fiber terminals still remains unclear. In the present study, we hypothesized that colchicine-induced dentate granule cell death may be caused by accumulation of labile intracellular zinc. 10 μg kg(-1) of colchicine was injected into the adult rat hippocampus and then brain sections were evaluated at 1 day or 1 week later. Neuronal cell death was evaluated by H&E staining or Fluoro-Jade B. Zinc accumulation and vesicular zinc were detected by N-(6-methoxy-8-quinolyl)-para-toluene sulfonamide (TSQ) staining. To test whether an extracellular zinc chelator can prevent this process, CaEDTA was injected into the hippocampus over a 5 min period with colchicine. To test whether other microtubule toxins also produce similar effects as colchicine, vincristine was injected into the hippocampus. The present study found that colchicine injection induced intracellular zinc accumulation in the dentate granule cells and depleted vesicular zinc from mossy fiber terminals. Injection of a zinc chelator, CaEDTA, did not block the zinc accumulation and neuronal death. Vincristine also produced intracellular zinc accumulation and neuronal death. These results suggest that colchicine-induced dentate granule cell death is caused by blocking axonal zinc flow and accumulation of intracellular labile zinc.

  15. Blockade of intracellular Zn2+ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP.

    Science.gov (United States)

    Tamano, Haruna; Minamino, Tatsuya; Fujii, Hiroaki; Takada, Shunsuke; Nakamura, Masatoshi; Ando, Masaki; Takeda, Atsushi

    2015-08-01

    There is no evidence on the precise role of synaptic Zn2+ signaling on the retention and recall of recognition memory. On the basis of the findings that intracellular Zn2+ signaling in the dentate gyrus is required for object recognition, short-term memory, the present study deals with the effect of spatiotemporally blocking Zn2+ signaling in the dentate gyrus after LTP induction and learning. Three-day-maintained LTP was impaired 1 day after injection of clioquinol into the dentate gyrus, which transiently reduced intracellular Zn2+ signaling in the dentate gyrus. The irreversible impairment was rescued not only by co-injection of ZnCl2 , which ameliorated the loss of Zn2+ signaling, but also by pre-injection of Jasplakinolide, a stabilizer of F-actin, prior to clioquinol injection. Simultaneously, 3-day-old space recognition memory was impaired 1 day after injection of clioquinol into the dentate gyrus, but not by pre-injection of Jasplakinolide. Jasplakinolide also rescued both impairments of 3-day-maintained LTP and 3-day-old memory after injection of ZnAF-2DA into the dentate gyrus, which blocked intracellular Zn2+ signaling in the dentate gyrus. The present paper indicates that the blockade and/or loss of intracellular Zn2+ signaling in the dentate gyrus coincidently impair maintained LTP and recognition memory. The mechanism maintaining LTP via intracellular Zn2+ signaling in dentate granule cells, which may be involved in the formation of F-actin, may retain space recognition memory. © 2015 Wiley Periodicals, Inc.

  16. Weakened Intracellular Zn2+-Buffering in the Aged Dentate Gyrus and Its Involvement in Erasure of Maintained LTP.

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna; Murakami, Taku; Nakada, Hiroyuki; Minamino, Tatsuya; Koike, Yuta

    2018-05-01

    Memory is lost by the increased influx of extracellular Zn 2+ into neurons. It is possible that intracellular Zn 2+ dynamics is modified even at non-zincergic medial perforant pathway-dentate granule cell synapses along with aging and that vulnerability to the modification is linked to age-related cognitive decline. To examine these possibilities, vulnerability of long-term potentiation (LTP) maintenance, which underlies memory retention, to modification of synaptic Zn 2+ dynamics was compared between young and aged rats. The influx of extracellular Zn 2+ into dentate granule cells was increased in aged rats after injection of high K + into the dentate gyrus, but not in young rats. This increase impaired maintained LTP in aged rats. However, the impairment was rescued by co-injection of CaEDTA, an extracellular Zn 2+ chelator, or CNQX, an AMPA receptor antagonist, which suppressed the Zn 2+ influx. Maintained LTP was also impaired in aged rats after injection of ZnAF-2DA into the dentate gyrus that chelates intracellular Zn 2+ , but not in young rats. Interestingly, the capacity of chelating intracellular Zn 2+ with intracellular ZnAF-2 was almost lost in the aged dentate gyrus 2 h after injection of ZnAF-2DA into the dentate gyrus, suggesting that intracellular Zn 2+ -buffering is weakened in the aged dentate gyrus, compared to the young dentate gyrus. In the dentate gyrus of aged rats, maintained LTP is more vulnerable to modification of intracellular Zn 2+ dynamics than in young rats, probably due to weakened intracellular Zn 2+ -buffering.

  17. Kindled seizures selectively reduce a subpopulation of (/sup 3/H)quinuclidinyl benzilate binding sites in rat dentate gyrus

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    Savage, D.D.; McNamara, J.O.

    1982-09-01

    Amygdala-kindled seizures reduced significantly the total number of (/sup 3/H)quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis.

  18. Radial glial cells in the adult dentate gyrus: what are they and where do they come from?

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    Berg, Daniel A; Bond, Allison M; Ming, Guo-Li; Song, Hongjun

    2018-01-01

    Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.

  19. Kindled seizures selectively reduce a subpopulation of [3H]quinuclidinyl benzilate binding sites in rat dentate gyrus

    International Nuclear Information System (INIS)

    Savage, D.D.; McNamara, J.O.

    1982-01-01

    Amygdala-kindled seizures reduced significantly the total number of [ 3 H]quinuclidinyl benzilate binding sites in both dentate and hippocampal gyri compared to electrode implanted unstimulated controls. Both high and low affinity carbachol displaceable binding site populations were significantly reduced in hippocampal gyrus. By contrast, a selective decline of low affinity sites was found in dentate gyrus membranes. The selectivity of the decline in dentate but not hippocampus gyrus underscores the specificity of this molecular response to amygdala-kindled seizures. We suggest that these receptor alterations underlie adaptive mechanisms which antagonize kindled epileptogenesis

  20. Relationship between chewing behavior and body weight status in fully dentate healthy adults.

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    Zhu, Yong; Hollis, James H

    2015-03-01

    Recent research indicates that chewing behavior may influence energy intake and energy expenditure. However, little is known about the relationship between chewing behavior and body weight status. In the present study, 64 fully dentate normal-weight or overweight/obese adults were asked to consume five portions of a test food and the number of chewing cycles, chewing duration before swallowing and chewing rate were measured. Adjusting for age and gender, normal-weight participants used a higher number of chewing cycles (p = 0.003) and a longer chewing duration (p chewing rate (p = 0.597). A statistically significant negative correlation between body mass index and the number of chewing cycles (r = -0.296, p = 0.020) and chewing duration (r = -0.354, p = 0.005) was observed. In conclusion, these results suggest that chewing behavior is associated with body weight status in fully dentate healthy adults.

  1. Long-term potentiation expands information content of hippocampal dentate gyrus synapses.

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    Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B; Hubbard, Dusten D; Hanka, Dakota C; Gonzalez, Paola V; Kuwajima, Masaaki; Mendenhall, John M; Parker, Patrick H; Abraham, Wickliffe C; Sejnowski, Terrence J; Harris, Kristen M

    2018-03-06

    An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

  2. Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

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    Du, Huiyun; Deng, Wei; Aimone, James B.; Ge, Minyan; Parylak, Sarah

    2016-01-01

    Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

  3. Long-term potentiation in hilar circuitry modulates gating by the dentate gyrus.

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    Wright, Brandon J; Jackson, Meyer B

    2014-07-16

    The dentate gyrus serves as a gateway to the hippocampus, filtering and processing sensory inputs as an animal explores its environment. The hilus occupies a strategic position within the dentate gyrus from which it can play a pivotal role in these functions. Inputs from dentate granule cells converge on the hilus, and excitatory hilar mossy cells redistribute these signals back to granule cells to transform a pattern of cortical input into a new pattern of output to the hippocampal CA3 region. Using voltage-sensitive dye to image electrical activity in rat hippocampal slices, we explored how long-term potentiation (LTP) of different excitatory synapses modifies the flow of information. Theta burst stimulation of the perforant path potentiated responses throughout the molecular layer, but left responses in the CA3 region unchanged. By contrast, theta burst stimulation of the granule cell layer potentiated responses throughout the molecular layer, as well as in the CA3 region. Theta burst stimulation of the granule cell layer potentiated CA3 responses not only to granule cell layer stimulation but also to perforant path stimulation. Potentiation of responses in the CA3 region reflected NMDA receptor-dependent LTP of upstream synapses between granule cells and mossy cells, with no detectable contribution from NMDA receptor-independent LTP of local CA3 mossy fiber synapses. Potentiation of transmission to the CA3 region required LTP in both granule cell→mossy cell and mossy cell→granule cell synapses. This bidirectional plasticity enables hilar circuitry to regulate the flow of information through the dentate gyrus and on to the hippocampus. Copyright © 2014 the authors 0270-6474/14/349743-11$15.00/0.

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

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    Xiang Gao

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

  5. Loss of Ensemble Segregation in Dentate Gyrus, but Not in Somatosensory Cortex, during Contextual Fear Memory Generalization

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    Marie Yokoyama

    2016-11-01

    Full Text Available The details of contextual or episodic memories are lost and generalized with the passage of time. Proper generalization may underlie the formation and assimilation of semantic memories and enable animals to adapt to ever-changing environments, whereas overgeneralization of fear memory evokes maladaptive fear responses to harmless stimuli, which is a symptom of anxiety disorders such as post-traumatic stress disorder (PTSD. To understand the neural basis of fear memory generalization, we investigated the patterns of neuronal ensemble reactivation during memory retrieval when contextual fear memory expression is generalized using transgenic mice that allowed us to visualize specific neuronal ensembles activated during memory encoding and retrieval. We found preferential reactivations of neuronal ensembles in the primary somatosensory cortex, when mice were returned to the conditioned context to retrieve their memory 1 day after conditioning. In the hippocampal dentate gyrus (DG, exclusively separated ensemble reactivation was observed when mice were exposed to a novel context. These results suggest that the DG as well as the somatosensory cortex were likely to distinguish the two different contexts at the ensemble activity level when memory is not generalized at the behavioral level. However, 9 days after conditioning when animals exhibited generalized fear, the unique reactivation pattern in the DG, but not in the somatosensory cortex, was lost. Our results suggest that the alternations in the ensemble representation within the DG, or in upstream structures that link the sensory cortex to the hippocampus, may underlie generalized contextual fear memory expression.

  6. COUP-TFI mitotically regulates production and migration of dentate granule cells and modulates hippocampal Cxcr4 expression.

    Science.gov (United States)

    Parisot, Joséphine; Flore, Gemma; Bertacchi, Michele; Studer, Michèle

    2017-06-01

    Development of the dentate gyrus (DG), the primary gateway for hippocampal inputs, spans embryonic and postnatal stages, and involves complex morphogenetic events. We have previously identified the nuclear receptor COUP-TFI as a novel transcriptional regulator in the postnatal organization and function of the hippocampus. Here, we dissect its role in DG morphogenesis by inactivating it in either granule cell progenitors or granule neurons. Loss of COUP-TFI function in progenitors leads to decreased granule cell proliferative activity, precocious differentiation and increased apoptosis, resulting in a severe DG growth defect in adult mice. COUP-TFI-deficient cells express high levels of the chemokine receptor Cxcr4 and migrate abnormally, forming heterotopic clusters of differentiated granule cells along their paths. Conversely, high COUP-TFI expression levels downregulate Cxcr4 expression, whereas increased Cxcr4 expression in wild-type hippocampal cells affects cell migration. Finally, loss of COUP-TFI in postmitotic cells leads to only minor and transient abnormalities, and to normal Cxcr4 expression. Together, our results indicate that COUP-TFI is required predominantly in DG progenitors for modulating expression of the Cxcr4 receptor during granule cell neurogenesis and migration. © 2017. Published by The Company of Biologists Ltd.

  7. Prenatal Alcohol Exposure Affects Progenitor Cell Numbers in Olfactory Bulbs and Dentate Gyrus of Vervet Monkeys

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    Mark W. Burke

    2016-10-01

    Full Text Available Fetal alcohol exposure (FAE alters hippocampal cell numbers in rodents and primates, and this may be due, in part, to a reduction in the number or migration of neuronal progenitor cells. The olfactory bulb exhibits substantial postnatal cellular proliferation and a rapid turnover of newly formed cells in the rostral migratory pathway, while production and migration of postnatal neurons into the dentate gyrus may be more complex. The relatively small size of the olfactory bulb, compared to the hippocampus, potentially makes this structure ideal for a rapid analysis. This study used the St. Kitts vervet monkey (Chlorocebus sabeus to (1 investigate the normal developmental sequence of post-natal proliferation in the olfactory bulb and dentate gyrus and (2 determine the effects of naturalistic prenatal ethanol exposure on proliferation at three different ages (neonate, five months and two years. Using design-based stereology, we found an age-related decrease of actively proliferating cells in the olfactory bulb and dentate gyrus for both control and FAE groups. Furthermore, at the neonatal time point, the FAE group had fewer actively proliferating cells as compared to the control group. These data are unique with respect to fetal ethanol effects on progenitor proliferation in the primate brain and suggest that the olfactory bulb may be a useful structure for studies of cellular proliferation.

  8. Early effects of trimethyltin on the dentate gyrus basket cells: a morphological study

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    Chang, L.W.; Dyer, R.S.

    1985-01-01

    Electrophysiological evidence for reduction of recurrent inhibition in the dentate gyrus in animals exposed to trimethyltin (TMT) suggested alterations in the inhibitory neurons (basket cells) by TMT. The present study was designed to investigate the morphology of basket cells after TMT exposure. Long-Evans hooded rats were injected with TMT chloride in a dose of 6.0 mg/kg body weight (b.w.). Tissue samples from the dentate gyri were examined by both light and electron microscopy at 24 and 72 h after TMT exposure. Except for isolated basket cell damage at 72 h, no remarkable pathological changes were observed with light microscopy. Consistent with previous data, electron microscopy revealed that the basket cells of the dentate gyrus are large neurons situated just below the granule cell layer with characteristic large, infolded nuclei and intranuclear filamentous rods. Increased cytoplasmic density and degenerative changes of the Golgi complex were evident in the basket cells as early as 24 h after TMT exposure. By 72 h, neuronal vacuolation, accumulation of lysosomes, and occasional neuronal necrosis were observed. No significant pathological changes were found among the granule cells at this time. This report provides the first morphological evidence for early damage to the basket cells by TMT, which may account for the reduction of recurrent inhibition and hyperexcitability among the granule cells reported previously.

  9. Molecular and functional characterization of GAD67-expressing, newborn granule cells in mouse dentate gyrus

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    Carolina eCabezas

    2013-04-01

    Full Text Available Dentate gyrus granule cells (GCs have been suggested to synthesize both GABA and glutamate immediately after birth and under pathological conditions in the adult. Expression of the GABA synthesizing enzyme GAD67 by GCs during the first few weeks of postnatal development may then allow for transient GABA synthesis and synaptic release from these cells. Here, using the GAD67-EGFP transgenic strain G42, we explored the phenotype of GAD67-expressing GCs in the mouse dentate gyrus. We report a transient, GAD67-driven EGFP expression in differentiating GCs throughout ontogenesis. EGFP expression correlates with the expression of GAD and molecular markers of GABA release and uptake in 2-4 weeks postmitotic GCs. These rather immature cells are able to fire action potentials and are synaptically integrated in the hippocampal network. Yet they show physiological properties that differentiate them from mature GCs. Finally, GAD67-expressing GCs express a specific complement of GABAA receptor subunits as well as distinctive features of synaptic and tonic GABA signaling. Our results reveal that GAD67 expression in dentate gyrus granule cells is a transient marker of late differentiation that persists throughout life and the G42 strain may be used to visualize newborn GCs at a specific, well-defined differentiation stage.

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

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

    2009-09-29

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

  11. Differential Involvement of the Dentate Gyrus in Adaptive Forgetting in the Rat.

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    Mickaël Antoine Joseph

    Full Text Available How does the brain discriminate essential information aimed to be stored permanently from information required only temporarily, and that needs to be cleared away for not saturating our precious memory space? Reference Memory (RM refers to the long-term storage of invariable information whereas Working Memory (WM depends on the short-term storage of trial-unique information. Previous work has revealed that WM tasks are very sensitive to proactive interference. In order to prevent such interference, irrelevant old memories must be forgotten to give new ones the opportunity to be stabilized. However, unlike memory, physiological processes underlying this adaptive form of forgetting are still poorly understood. Here, we precisely ask what specific brain structure(s could be responsible for such process to occur. To answer this question, we trained rats in a radial maze using three paradigms, a RM task and two WM tasks involving or not the processing of interference but strictly identical in terms of locomotion or motivation. We showed that an inhibition of the expression of Zif268 and c-Fos, two indirect markers of neuronal activity and synaptic plasticity, was observed in the dentate gyrus of the dorsal hippocampus when processing such interfering previously stored information. Conversely, we showed that inactivating the dentate gyrus impairs both RM and WM, but improves the processing of interference. Altogether, these results strongly suggest for the first time that the dentate gyrus could be a key structure involved in adaptive forgetting.

  12. BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus

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    Hailong Hou

    2017-07-01

    Full Text Available BACE1 is validated as Alzheimer's β-secretase and a therapeutic target for Alzheimer's disease. In examining BACE1-null mice, we discovered that BACE1 deficiency develops abnormal clusters of immature neurons, forming doublecortin-positive neuroblasts, in the developing dentate gyrus, mainly in the subpial zone (SPZ. Such clusters were rarely observed in wild-type SPZ and not reported in other mouse models. To understand their origins and fates, we examined how neuroblasts in BACE1-null SPZ mature and migrate during early postnatal development. We show that such neuroblasts are destined to form Prox1-positive granule cells in the dentate granule cell layer, and mainly mature to form excitatory neurons, but not inhibitory neurons. Mechanistically, higher levels of reelin potentially contribute to abnormal neurogenesis and timely migration in BACE1-null SPZ. Altogether, we demonstrate that BACE1 is a critical regulator in forming the dentate granule cell layer through timely maturation and migration of SPZ neuroblasts.

  13. Role of hippocampal dentate gyrus neurons in the protective effects of heat shock factor 1 on working memory

    Institute of Scientific and Technical Information of China (English)

    Min Peng; Xiongzhao Zhu; Ming Cheng; Xiangyi Chen; Shuqiao Yao

    2011-01-01

    Increasing evidence suggests that heat shock factor 1 exerts endogenous protective effects on working memory under conditions of chronic psychological stress. However, the precise underlying mechanisms remain poorly understood. This study examined the protective factors affecting working memory in heat shock transcription factor 1 gene knockout mice. The results indicated that the number of correct T maze alternations decreased following mild chronic psychological stress in knockout mice. This change was accompanied by a decrease in neurogenesis and an increase in neuronal apoptosis in the hippocampal dentate gyrus. The number of correct T maze alternations was positively correlated with neurogenesis in hippocampal dentate gyrus, and negatively correlated with neuronal apoptosis. In wild type mice, no significant difference was detected in the number of correct T maze alternations or neuronal apoptosis in hippocampal dentate gyrus. These results indicate that the heat shock factor 1 gene has an endogenous protective role in working memory during mild chronic psychological stress associated with dentate gyrus neuronal apoptosis.Moreover, dentate gyrus neurogenesis appears to participate in the protective mechanism.

  14. Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

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    Lapanowski Karen

    2010-02-01

    Full Text Available Abstract Background Sublethal doses of whole brain irradiation (WBI are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE inhibitor, ramipril, as a mitigator of radiation injury in this context. Methods Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks. Results Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats. Conclusions Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory

  15. Ramipril mitigates radiation-induced impairment of neurogenesis in the rat dentate gyrus

    International Nuclear Information System (INIS)

    Jenrow, Kenneth A; Brown, Stephen L; Liu, Jianguo; Kolozsvary, Andrew; Lapanowski, Karen; Kim, Jae Ho

    2010-01-01

    Sublethal doses of whole brain irradiation (WBI) are commonly administered therapeutically and frequently result in late delayed radiation injuries, manifesting as severe and irreversible cognitive impairment. Neural progenitors within the subgranular zone (SGZ) of the dentate gyrus are among the most radiosensitive cell types in the adult brain and are known to participate in hippocampal plasticity and normal cognitive function. These progenitors and the specialized SZG microenvironment required for neuronal differentiation are the source of neurogenic potential in the adult dentate gyrus, and provide a continuous supply of immature neurons which may then migrate into the adjacent granule cell layer to become mature granule cell neurons. The extreme radiosensitivity of these progenitors and the SGZ microenvironment suggests the hippocampus as a prime target for radiation-induced cognitive impairment. The brain renin-angiotensin system (RAS) has previously been implicated as a potent modulator of neurogenesis within the SGZ and selective RAS inhibitors have been implicated as mitigators of radiation brain injury. Here we investigate the angiotensin converting enzyme (ACE) inhibitor, ramipril, as a mitigator of radiation injury in this context. Adult male Fisher 344 rats received WBI at doses of 10 Gy and 15 Gy. Ramipril was administered beginning 24 hours post-WBI and maintained continuously for 12 weeks. Ramipril produced small but significant reductions in the deleterious effects of radiation on progenitor proliferation and neuronal differentiation in the rat dentate gyrus following 10 Gy-WBI, but was not effective following 15 Gy-WBI. Ramipril also reduced the basal rate of neurogenesis within the SGZ in unirradiated control rats. Our results indicate that chronic ACE inhibition with ramipril, initiated 24 hours post-irradiation, may reduce apoptosis among SGZ progenitors and/or inflammatory disruption of neurogenic signaling within SGZ microenvironment, and

  16. Trajectory Analysis Unveils Reelin's Role in the Directed Migration of Granule Cells in the Dentate Gyrus.

    Science.gov (United States)

    Wang, Shaobo; Brunne, Bianka; Zhao, Shanting; Chai, Xuejun; Li, Jiawei; Lau, Jeremie; Failla, Antonio Virgilio; Zobiak, Bernd; Sibbe, Mirjam; Westbrook, Gary L; Lutz, David; Frotscher, Michael

    2018-01-03

    Reelin controls neuronal migration and layer formation. Previous studies in reeler mice deficient in Reelin focused on the result of the developmental process in fixed tissue sections. It has remained unclear whether Reelin affects the migratory process, migration directionality, or migrating neurons guided by the radial glial scaffold. Moreover, Reelin has been regarded as an attractive signal because newly generated neurons migrate toward the Reelin-containing marginal zone. Conversely, Reelin might be a stop signal because migrating neurons in reeler , but not in wild-type mice, invade the marginal zone. Here, we monitored the migration of newly generated proopiomelanocortin-EGFP -expressing dentate granule cells in slice cultures from reeler , reeler -like mutants and wild-type mice of either sex using real-time microscopy. We discovered that not the actual migratory process and migratory speed, but migration directionality of the granule cells is controlled by Reelin. While wild-type granule cells migrated toward the marginal zone of the dentate gyrus, neurons in cultures from reeler and reeler -like mutants migrated randomly in all directions as revealed by vector analyses of migratory trajectories. Moreover, live imaging of granule cells in reeler slices cocultured to wild-type dentate gyrus showed that the reeler neurons changed their directions and migrated toward the Reelin-containing marginal zone of the wild-type culture, thus forming a compact granule cell layer. In contrast, directed migration was not observed when Reelin was ubiquitously present in the medium of reeler slices. These results indicate that topographically administered Reelin controls the formation of a granule cell layer. SIGNIFICANCE STATEMENT Neuronal migration and the various factors controlling its onset, speed, directionality, and arrest are poorly understood. Slice cultures offer a unique model to study the migration of individual neurons in an almost natural environment. In the

  17. Nutritional status in edentulous people as compared to age matched dentate individuals-a cross-sectional study

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    Sukhabogi Jagadeeswara Rao

    2013-01-01

    Full Text Available Objectives: To assess the nutritional status in completely edentulous subjects and to compare with age matched dentate individuals. Materials and Method: The study was carried out in 60 individuals divided into two groups. Group one consisted of 30 edentulous subjects and 30 dentate individuals formed the second group Body Mass Index (BMI, serum albumin and hemoglobin values were analyzed in both the groups. Independent sample t- test was employed to check for the difference between the groups and Pearson′s correlation was done to ascertain the association between the variables within the groups. Results: There was a significant difference in all the biomarkers evaluated in between the groups. The values were negatively correlated with the period of edentulism within the groups. Conclusion: Edentulous people had lower nutritional values than their dentate counterparts and maintaining a healthy and normal dentition may have significant bearing on the overall health of an individual. body mass index, serum albumin, malnutrition, edentulous, dental status

  18. Amyloid β-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit.

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    Atsushi Takeda

    Full Text Available We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn2+ transport system due to a local increase in amyloid-β (Aβ concentration. A single injection of Aβ (25 pmol into the dentate gyrus affected dentate gyrus long-term potentiation (LTP 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Aβ-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn2+ is involved in Aβ action. When Aβ was injected into the dentate gyrus, intracellular Zn2+ levels were increased only in the injected area in the dentate gyrus, suggesting that Aβ induces the influx of Zn2+ into cells in the injected area. When Aβ was added to hippocampal slices, Aβ did not increase intracellular Zn2+ levels in the dentate granule cell layer in ACSF without Zn2+, but in ACSF containing Zn2+. The increase in intracellular Zn2+ levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Aβ-mediated Zn2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn2+ may play a key role for transiently Aβ-induced cognition deficits.

  19. Amyloid β-mediated Zn2+ influx into dentate granule cells transiently induces a short-term cognitive deficit.

    Science.gov (United States)

    Takeda, Atsushi; Nakamura, Masatoshi; Fujii, Hiroaki; Uematsu, Chihiro; Minamino, Tatsuya; Adlard, Paul A; Bush, Ashley I; Tamano, Haruna

    2014-01-01

    We examined an idea that short-term cognition is transiently affected by a state of confusion in Zn2+ transport system due to a local increase in amyloid-β (Aβ) concentration. A single injection of Aβ (25 pmol) into the dentate gyrus affected dentate gyrus long-term potentiation (LTP) 1 h after the injection, but not 4 h after the injection. Simultaneously, 1-h memory of object recognition was affected when the training was performed 1 h after the injection, but not 4 h after the injection. Aβ-mediated impairments of LTP and memory were rescued in the presence of zinc chelators, suggesting that Zn2+ is involved in Aβ action. When Aβ was injected into the dentate gyrus, intracellular Zn2+ levels were increased only in the injected area in the dentate gyrus, suggesting that Aβ induces the influx of Zn2+ into cells in the injected area. When Aβ was added to hippocampal slices, Aβ did not increase intracellular Zn2+ levels in the dentate granule cell layer in ACSF without Zn2+, but in ACSF containing Zn2+. The increase in intracellular Zn2+ levels was inhibited in the presence of CaEDTA, an extracellular zinc chelator, but not in the presence of CNQX, an AMPA receptor antagonist. The present study indicates that Aβ-mediated Zn2+ influx into dentate granule cells, which may occur without AMPA receptor activation, transiently induces a short-term cognitive deficit. Extracellular Zn2+ may play a key role for transiently Aβ-induced cognition deficits.

  20. MDMA Increases Excitability in the Dentate Gyrus: Role of 5HT2A Receptor Induced PGE2 Signaling

    Science.gov (United States)

    Collins, Stuart A.; Huff, Courtney; Chiaia, Nicolas; Gudelsky, Gary A.; Yamamoto, Bryan K.

    2015-01-01

    MDMA is a widely abused psychostimulant which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA treated rats which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA treated rats. PMID:26670377

  1. Prolonged induction of c-fos in neuropeptide Y- and somatostatin-immunoreactive neurons of the rat dentate gyrus after electroconvulsive stimulation

    DEFF Research Database (Denmark)

    Woldbye, D P; Greisen, M H; Bolwig, T G

    1996-01-01

    Induction of c-fos mRNA and Fos was studied in the hilus and granular layer of the dentate gyrus at various times up to 24 h after single electroconvulsive stimulation (ECS) using in situ hybridization and immunocytochemistry. In both areas of the dentate gyrus, a prominent induction of c-fos m...

  2. Oxytocin Depolarizes Fast-Spiking Hilar Interneurons and Induces GABA Release onto Mossy Cells of the Rat Dentate Gyrus

    Science.gov (United States)

    Harden, Scott W.; Frazier, Charles J.

    2016-01-01

    Delivery of exogenous oxytocin (OXT) to central oxytocin receptors (OXT-Rs) is currently being investigated as a potential treatment for conditions such as post-traumatic stress disorder (PTSD), depression, social anxiety, and autism spectrum disorder (ASD). Despite significant research implicating central OXT signaling in modulation of mood, affect, social behavior, and stress response, relatively little is known about the cellular and synaptic mechanisms underlying these complex actions, particularly in brain regions which express the OXT-R but lie outside of the hypothalamus (where OXT-synthesizing neurons reside). We report that bath application of low concentrations of the selective OXT-R agonist Thr4,Gly7-OXT (TGOT) reliably and robustly drives GABA release in the dentate gyrus in an action potential dependent manner. Additional experiments led to identification of a small subset of small hilar interneurons that are directly depolarized by acute application of TGOT. From a physiological perspective, TGOT-responsive hilar interneurons have high input resistance, rapid repolarization velocity during an action potential, and a robust afterhyperpolarization. Further, they fire irregularly (or stutter) in response to moderate depolarization, and fire quickly with minimal spike frequency accommodation in response to large current injections. From an anatomical perspective, TGOT responsive hilar interneurons have dense axonal arborizations in the hilus that were found close proximity with mossy cell somata and/or proximal dendrites, and also invade the granule cell layer. Further, they have primary dendrites that always extend into the granule cell layer, and sometimes have clear arborizations in the molecular layer. Overall, these data reveal a novel site of action for OXT in an important limbic circuit, and represent a significant step towards better understanding how endogenous OXT may modulate flow of information in hippocampal networks. PMID:27068005

  3. Tricyclic antidepressant amitriptyline indirectly increases the proliferation of adult dentate gyrus-derived neural precursors: an involvement of astrocytes.

    Directory of Open Access Journals (Sweden)

    Shuken Boku

    Full Text Available Antidepressants increase the proliferation of neural precursors in adult dentate gyrus (DG, which is considered to be involved in the therapeutic action of antidepressants. However, the mechanism underlying it remains unclear. By using cultured adult rat DG-derived neural precursors (ADP, we have already shown that antidepressants have no direct effects on ADP. Therefore, antidepressants may increase the proliferation of neural precursors in adult DG via unknown indirect mechanism. We have also shown that amitriptyline (AMI, a tricyclic antidepressant, induces the expressions of GDNF, BDNF, FGF2 and VEGF, common neurogenic factors, in primary cultured astrocytes (PCA. These suggest that AMI-induced factors in astrocytes may increase the proliferation of neural precursors in adult DG. To test this hypothesis, we examined the effects of AMI-induced factors and conditioned medium (CM from PCA treated with AMI on ADP proliferation. The effects of CM and factors on ADP proliferation were examined with BrdU immunocytochemistry. AMI had no effect on ADP proliferation, but AMI-treated CM increased it. The receptors of GDNF, BDNF and FGF2, but not VEGF, were expressed in ADP. FGF2 significantly increased ADP proliferation, but not BDNF and GDNF. In addition, both of a specific inhibitor of FGF receptors and anti-FGF2 antibody significantly counteracted the increasing effect of CM on ADP proliferation. In addition, FGF2 in brain is mainly derived from astrocytes that are key components of the neurogenic niches in adult DG. These suggest that AMI may increase ADP proliferation indirectly via PCA and that FGF2 may a potential candidate to mediate such an indirect effect of AMI on ADP proliferation via astrocytes.

  4. Btg1 is Required to Maintain the Pool of Stem and Progenitor Cells of the Dentate Gyrus and Subventricular Zone

    OpenAIRE

    Farioli-Vecchioli, Stefano; Micheli, Laura; Saraulli, Daniele; Ceccarelli, Manuela; Cannas, Sara; Scardigli, Raffaella; Leonardi, Luca; Cinà, Irene; Costanzi, Marco; Ciotti, Maria Teresa; Moreira, Pedro; Rouault, Jean-Pierre; Cestari, Vincenzo; Tirone, Felice

    2012-01-01

    Btg1 belongs to a family of cell cycle inhibitory genes. We observed that Btg1 is highly expressed in adult neurogenic niches, i.e., the dentate gyrus and subventricular zone (SVZ). Thus, we generated Btg1 knockout mice to analyze the role of Btg1 in the process of generation of adult new neurons. Ablation of Btg1 causes a transient increase of the proliferating dentate gyrus stem and progenitor cells at post-natal day 7; however, at 2 months of age the number of these proliferating cells, as...

  5. BTG1 is required to maintain the pool of stem and progenitor cells of dentate gyrus and subventricular zone

    OpenAIRE

    Stefano eFarioli-Vecchioli; Laura eMicheli; Daniele eSaraulli; Manuela eCeccarelli; Sara eCannas; Raffaella eScardigli; Luca eLeonardi; Irene eCinà; Marco eCostanzi; Maria Teresa eCiotti; Pedro eMoreira; Jean-Pierre eRouault; Vincenzo eCestari; Felice eTirone

    2012-01-01

    Btg1 belongs to a family of cell cycle inhibitory genes. We observed that Btg1 is highly expressed in adult neurogenic niches, i.e., the dentate gyrus and subventricular zone (SVZ). Thus, we generated Btg1 knockout mice to analyze the role of Btg1 in the process of generation of adult new neurons.Ablation of Btg1 causes a transient increase of the proliferating dentate gyrus stem and progenitor cells at post-natal day 7; however, at two months of age the number of these proliferating cells, a...

  6. The lysine acetyltransferase activator Brpf1 governs dentate gyrus development through neural stem cells and progenitors.

    Directory of Open Access Journals (Sweden)

    Linya You

    2015-03-01

    Full Text Available Lysine acetylation has recently emerged as an important post-translational modification in diverse organisms, but relatively little is known about its roles in mammalian development and stem cells. Bromodomain- and PHD finger-containing protein 1 (BRPF1 is a multidomain histone binder and a master activator of three lysine acetyltransferases, MOZ, MORF and HBO1, which are also known as KAT6A, KAT6B and KAT7, respectively. While the MOZ and MORF genes are rearranged in leukemia, the MORF gene is also mutated in prostate and other cancers and in four genetic disorders with intellectual disability. Here we show that forebrain-specific inactivation of the mouse Brpf1 gene causes hypoplasia in the dentate gyrus, including underdevelopment of the suprapyramidal blade and complete loss of the infrapyramidal blade. We trace the developmental origin to compromised Sox2+ neural stem cells and Tbr2+ intermediate neuronal progenitors. We further demonstrate that Brpf1 loss deregulates neuronal migration, cell cycle progression and transcriptional control, thereby causing abnormal morphogenesis of the hippocampus. These results link histone binding and acetylation control to hippocampus development and identify an important epigenetic regulator for patterning the dentate gyrus, a brain structure critical for learning, memory and adult neurogenesis.

  7. How informative are spatial CA3 representations established by the dentate gyrus?

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    Erika Cerasti

    2010-04-01

    Full Text Available In the mammalian hippocampus, the dentate gyrus (DG is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers. Mossy fiber synapses appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the dentate gyrus and to CA3. Computational models of episodic memory have hypothesized that the function of the mossy fibers is to enforce a new, well-separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Can this hypothesis apply also to spatial representations, as described by recent neurophysiological recordings in rats? To address this issue quantitatively, we estimate the amount of information DG can impart on a new CA3 pattern of spatial activity, using both mathematical analysis and computer simulations of a simplified model. We confirm that, also in the spatial case, the observed sparse connectivity and level of activity are most appropriate for driving memory storage-and not to initiate retrieval. Surprisingly, the model also indicates that even when DG codes just for space, much of the information it passes on to CA3 acquires a non-spatial and episodic character, akin to that of a random number generator. It is suggested that further hippocampal processing is required to make full spatial use of DG inputs.

  8. Norepinephrine induces pathway-specific long-lasting potentiation and depression in the hippocampal dentate gyrus.

    Science.gov (United States)

    Dahl, D; Sarvey, J M

    1989-01-01

    The study presented here indicates that norepinephrine (NE) selectively induces long-lasting modifications of synaptically mediated responses in the dentate gyrus of the rat hippocampal slice. A low concentration of NE (1.0 microM; in the presence of 50 microM phentolamine, an alpha-adrenergic antagonist) or a 1.0 microM concentration of the specific beta-adrenergic agonist isoproterenol induced long-lasting pathway-specific alterations of granule cell electrophysiological responses. Excitatory postsynaptic potentials and population spikes evoked by stimulation of the medial perforant pathway (PP) were potentiated for more than 45 min. In contrast, responses to lateral PP stimulation were depressed for the same period. Both potentiation and depression were blocked by the beta-adrenergic antagonist propranolol (1.0 microM). These results indicate that NE can act differentially on projections to the dentate gyrus arising in the entorhinal cortex. Such selective persistent modifications of cortical circuits may be involved in processes in the mammalian brain underlying attention, learning, and memory. PMID:2734319

  9. Differences in chewing behaviors between healthy fully dentate young and older adults assessed by electromyographic recordings.

    Science.gov (United States)

    Zhu, Yong; Hollis, James H

    2015-01-01

    To characterize changes in chewing behaviors associated with healthy aging, 10 young and 10 older fully dentate healthy participants were enrolled in this study. They chewed carrot samples that differed in hardness until their normal swallowing threshold. Their chewing behaviors were assessed using an electromyographic recording device. Adjusting for gender and body mass index, older adults had a higher number of chewing cycles (p = 0.020), a longer chewing duration (p chewing rate (p = 0.002), a greater maximal electromyographic voltage (p = 0.003) and a greater muscle activity (p = 0.002) before they could comfortably swallow the food bolus. A statistically significant main effect of food hardness on the number of chewing cycles, chewing duration, chewing rate and muscle activity was also observed (p < 0.001 for all). These results suggest that reduced mastication efficiency is associated with healthy aging in fully dentate adults. This ingestive behavior may contribute to aging-related reduction in appetite in older adults.

  10. Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats

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    Jiro Kasahara

    2016-01-01

    Full Text Available Poststroke depression is one of the major symptoms observed in the chronic stage of brain stroke such as cerebral ischemia. Its pathophysiological mechanisms, however, are not well understood. Using the transient right middle cerebral artery occlusion- (MCAO-, 90 min operated rats as an ischemia model in this study, we first observed that aggravation of anhedonia spontaneously occurred especially after 20 weeks of MCAO, and it was prevented by chronic antidepressants treatment (imipramine or fluvoxamine. The anhedonia specifically associated with loss of the granular neurons in the ipsilateral side of hippocampal dentate gyrus and was also prevented by an antidepressant imipramine. Immunohistochemical analysis showed increased apoptosis inside the granular cell layer prior to and associated with the neuronal loss, and imipramine seemed to recover the survival signal rather than suppressing the death signal to prevent neurons from apoptosis. Proliferation and development of the neural stem cells were increased transiently in the subgranular zone of both ipsi- and contralateral hippocampus within one week after MCAO and then decreased and almost ceased after 6 weeks of MCAO, while chronic imipramine treatment prevented them partially. Overall, our study suggests new insights for the mechanistic correlation between poststroke depression and the delayed neurodegenerative changes in the hippocampal dentate gyrus with effective use of antidepressants on them.

  11. Environmental impoverishment and aging alter object recognition, spatial learning, and dentate gyrus astrocytes.

    Science.gov (United States)

    Diniz, Daniel G; Foro, César A R; Rego, Carla M D; Gloria, David A; de Oliveira, Fabio R R; Paes, Juliana M P; de Sousa, Aline A; Tokuhashi, Tatyana P; Trindade, Lucas S; Turiel, Maíra C P; Vasconcelos, Erick G R; Torres, João B; Cunnigham, Colm; Perry, Victor H; Vasconcelos, Pedro F da Costa; Diniz, Cristovam W P

    2010-08-01

    Environmental and age-related effects on learning and memory were analysed and compared with changes observed in astrocyte laminar distribution in the dentate gyrus. Aged (20 months) and young (6 months) adult female albino Swiss mice were housed from weaning either in impoverished conditions or in enriched conditions, and tested for episodic-like and water maze spatial memories. After these behavioral tests, brain hippocampal sections were immunolabeled for glial fibrillary acid protein to identify astrocytes. The effects of environmental enrichment on episodic-like memory were not dependent on age, and may protect water maze spatial learning and memory from declines induced by aging or impoverished environment. In the dentate gyrus, the number of astrocytes increased with both aging and enriched environment in the molecular layer, increased only with aging in the polymorphic layer, and was unchanged in the granular layer. We suggest that long-term experience-induced glial plasticity by enriched environment may represent at least part of the circuitry groundwork for improvements in behavioral performance in the aged mice brain.

  12. Novel environments enhance the induction and maintenance of long-term potentiation in the dentate gyrus.

    Science.gov (United States)

    Davis, Cyndy D; Jones, Floretta L; Derrick, Brian E

    2004-07-21

    The induction of long-term potentiation (LTP) in the hippocampal formation can be modulated by different behavioral states. However, few studies have addressed modulation of LTP during behavioral states in which the animal is likely acquiring new information. Here, we demonstrate that both the induction and the longevity of LTP in the dentate gyrus are enhanced when LTP is induced during the initial exploration of a novel environment. These effects are independent from locomotor activity, changes in brain temperature, and theta rhythm. Previous exposure to the novel environment attenuated this enhancement, suggesting that the effects of novelty habituate with familiarity. LTP longevity also was enhanced when induced in familiar environments containing novel objects. Together, these data indicate that both LTP induction and maintenance are enhanced when LTP is induced while rats investigate novel stimuli. We suggest that novelty initiates a transition of the hippocampal formation to a mode that is particularly conducive to synaptic plasticity, a process that could allow for new learning while preserving the stability of previously stored information. In addition, LTP induced in novel environments elicited a sustained late LTP. This suggests that a single synaptic population can display distinct profiles of LTP maintenance and that this depends on the animal's behavioral state during its induction. Furthermore, the duration of LTP enhanced by novelty parallels the time period during which the hippocampal formation is thought necessary for memory, consistent with the view that dentate LTP is of a duration sufficient to sustain memory in the hippocampal formation.

  13. PTEN deletion from adult-generated dentate granule cells disrupts granule cell mossy fiber axon structure.

    Science.gov (United States)

    LaSarge, Candi L; Santos, Victor R; Danzer, Steve C

    2015-03-01

    Dysregulation of the mTOR-signaling pathway is implicated in the development of temporal lobe epilepsy. In mice, deletion of PTEN from hippocampal dentate granule cells leads to mTOR hyperactivation and promotes the rapid onset of spontaneous seizures. The mechanism by which these abnormal cells initiate epileptogenesis, however, is unclear. PTEN-knockout granule cells develop abnormally, exhibiting morphological features indicative of increased excitatory input. If these cells are directly responsible for seizure genesis, it follows that they should also possess increased output. To test this prediction, dentate granule cell axon morphology was quantified in control and PTEN-knockout mice. Unexpectedly, PTEN deletion increased giant mossy fiber bouton spacing along the axon length, suggesting reduced innervation of CA3. Increased width of the mossy fiber axon pathway in stratum lucidum, however, which likely reflects an unusual increase in mossy fiber axon collateralization in this region, offsets the reduction in boutons per axon length. These morphological changes predict a net increase in granule cell innervation of CA3. Increased diameter of axons from PTEN-knockout cells would further enhance granule cell communication with CA3. Altogether, these findings suggest that amplified information flow through the hippocampal circuit contributes to seizure occurrence in the PTEN-knockout mouse model of temporal lobe epilepsy. Copyright © 2015 Elsevier Inc. All rights reserved.

  14. A Comparative Rugoscopic Study of the Dentate and Edentulous Individuals in the South Indian Population

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    Jagdish Prasad Rajguru

    2014-01-01

    Full Text Available This study analyzes the rugae pattern in dentulous and edentulous patients and also evaluates the association of rugae pattern between males and females. Aims and Objectives. This study aims to investigate rugae patterns in dentulous and edentulous patients of both sexes in South Indian population and to find whether palatoscopy is a useful tool in human identification. Materials and Methods. Four hundred outpatients from Sree Balaji Dental College and Hospital, Chennai, were included in the study. The study group was equally divided between the sexes, which was further categorized into 100 dentulous and edentulous patients, respectively. Results. The edentulous male showed the highest mean of wavy pattern and total absence of circular pattern while the edentulous female group showed the highest mean of curved pattern and total absence of nonspecific pattern, while dentate population showed similar value as that of the overall population such as straight, wavy, and curved patterns. Conclusion. The present study concludes that there is similar rugae pattern of distribution between male and female dentate population while there is varied pattern between the sexes of edentulous population. However, the most predominant patterns were straight, wavy, and circular patterns.

  15. Contribution of constitutively proliferating precursor cell subtypes to dentate neurogenesis after cortical infarcts

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    Oberland Julia

    2010-11-01

    Full Text Available Abstract Background It is well known that focal ischemia increases neurogenesis in the adult dentate gyrus of the hippocampal formation but the cellular mechanisms underlying this proliferative response are only poorly understood. We here investigated whether precursor cells which constitutively proliferate before the ischemic infarct contribute to post-ischemic neurogenesis. To this purpose, transgenic mice expressing green fluorescent protein (GFP under the control of the nestin promoter received repetitive injections of the proliferation marker bromodeoxyuridine (BrdU prior to induction of cortical infarcts. We then immunocytochemically analyzed the fate of these BrdU-positive precursor cell subtypes from day 4 to day 28 after the lesion. Results Quantification of BrdU-expressing precursor cell populations revealed no alteration in number of radial glia-like type 1 cells but a sequential increase of later precursor cell subtypes in lesioned animals (type 2a cells at day 7, type 3 cells/immature neurons at day 14. These alterations result in an enhanced survival of mature neurons 4 weeks postinfarct. Conclusions Focal cortical infarcts recruit dentate precursor cells generated already before the infarct and significantly contribute to an enhanced neurogenesis. Our findings thereby increase our understanding of the complex cellular mechanisms of postlesional neurogenesis.

  16. Suspension of Mitotic Activity in Dentate Gyrus of the Hibernating Ground Squirrel

    Directory of Open Access Journals (Sweden)

    Victor I. Popov

    2011-01-01

    Full Text Available Neurogenesis occurs in the adult mammalian hippocampus, a region of the brain important for learning and memory. Hibernation in Siberian ground squirrels provides a natural model to study mitosis as the rapid fall in body temperature in 24 h (from 35-36°C to +4–6°C permits accumulation of mitotic cells at different stages of the cell cycle. Histological methods used to study adult neurogenesis are limited largely to fixed tissue, and the mitotic state elucidated depends on the specific phase of mitosis at the time of day. However, using an immunohistochemical study of doublecortin (DCX and BrdU-labelled neurons, we demonstrate that the dentate gyrus of the ground squirrel hippocampus contains a population of immature cells which appear to possess mitotic activity. Our data suggest that doublecortin-labelled immature cells exist in a mitotic state and may represent a renewable pool for generation of new neurons within the dentate gyrus.

  17. Cerebellar dentate nuclei lesions reduce motivation in appetitive operant conditioning and open field exploration.

    Science.gov (United States)

    Bauer, David J; Kerr, Abigail L; Swain, Rodney A

    2011-02-01

    Recently identified pathways from the dentate nuclei of the cerebellum to the rostral cerebral cortex via the thalamus suggest a cerebellar role in frontal and prefrontal non-motor functioning. Disturbance of cerebellar morphology and connectivity, particularly involving these cerebellothalamocortical (CTC) projections, has been implicated in motivational and cognitive deficits. The current study explored the effects of CTC disruption on motivation in male Long Evans rats. The results of two experiments demonstrate that electrolytic lesions of the cerebellar dentate nuclei lower breaking points on an operant conditioning progressive ratio schedule and decrease open field exploration compared to sham controls. Changes occurred in the absence of motor impairment, assessed via lever pressing frequency and rotarod performance. Similar elevated plus maze performances between lesioned and sham animals indicated that anxiety did not influence task performance. Our results demonstrate hedonic and purposive motivational reduction and suggest a CTC role in global motivational processes. These implications are discussed in terms of psychiatric disorders such as schizophrenia and autism, in which cerebellar damage and motivational deficits often present concomitantly. Copyright © 2010 Elsevier Inc. All rights reserved.

  18. Neurogenesis in temporal lobe epilepsy: relationship between histological findings and changes in dentate gyrus proliferative properties.

    Science.gov (United States)

    Marucci, Gianluca; Giulioni, Marco; Rubboli, Guido; Paradisi, Michela; Fernández, Mercedes; Del Vecchio, Giovanna; Pozzati, Eugenio

    2013-02-01

    The relationship between hippocampal histopathological abnormalities, epileptogenesis and neurogenesis remains rather unclear. Tissue samples including the subgranular zone of dentate gyrus (DG) were freshly collected for tissue culture for neurospheres generation in 16 patients who underwent surgery for drug-resistant temporal lobe epilepsy. Remaining tissues were histologically examined to assess the presence of mesial temporal sclerosis (MTS) and focal cortical dysplasia. MTS was detected in 8 cases. Neurospheres were formed in 10/16 cases. Only three out of these 10 cases exhibited MTS; on the contrary 5/6 cases lacking neurosphere proliferation presented MTS. There was a significant correlation between presence of MTS and absence of proliferation (p = 0.0389). We also observed a correlation between history of febrile seizures (FS) and presence of MTS (p = 0.0004) and among the 6 cases lacking neurosphere proliferation, 4 cases (66.6%) had experienced prolonged FS. Among "proliferating" cases the percentage of granular cells pathology (GCP) was lower (20% vs 50%) compared to "non proliferating" cases. A decreased potential to generate neurosphere from the SGZ is related to MTS and to alterations of dentate gyrus granule cells, especially in MTS type 1b and GCP type 1. These histological findings may have different prognostic implications, regarding seizure and neuropsychological outcome, compared to patients with other epileptogenic lesions (such as FCD, glioneuronal tumours, vascular lesions). Copyright © 2012 Elsevier B.V. All rights reserved.

  19. Enhanced Dentate Neurogenesis after Brain Injury Undermines Long-Term Neurogenic Potential and Promotes Seizure Susceptibility

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    Eric J. Neuberger

    2017-09-01

    Full Text Available Hippocampal dentate gyrus is a focus of enhanced neurogenesis and excitability after traumatic brain injury. Increased neurogenesis has been proposed to aid repair of the injured network. Our data show that an early increase in neurogenesis after fluid percussion concussive brain injury is transient and is followed by a persistent decrease compared with age-matched controls. Post-injury changes in neurogenesis paralleled changes in neural precursor cell proliferation and resulted in a long-term decline in neurogenic capacity. Targeted pharmacology to restore post-injury neurogenesis to control levels reversed the long-term decline in neurogenic capacity. Limiting post-injury neurogenesis reduced early increases in dentate excitability and seizure susceptibility. Our results challenge the assumption that increased neurogenesis after brain injury is beneficial and show that early post-traumatic increases in neurogenesis adversely affect long-term outcomes by exhausting neurogenic potential and enhancing epileptogenesis. Treatments aimed at limiting excessive neurogenesis can potentially restore neuroproliferative capacity and limit epilepsy after brain injury.

  20. Status epilepticus increases mature granule cells in the molecular layer of the dentate gyrus in rats★

    Science.gov (United States)

    Liang, Zhaoliang; Gao, Fei; Wang, Fajun; Wang, Xiaochen; Song, Xinyu; Liu, Kejing; Zhan, Ren-Zhi

    2013-01-01

    Enhanced neurogenesis in the dentate gyrus of the hippocampus following seizure activity, especially status epilepticus, is associated with ectopic residence and aberrant integration of newborn granule cells. Hilar ectopic granule cells may be detrimental to the stability of dentate circuitry by means of their electrophysiological properties and synaptic connectivity. We hypothesized that status epilepticus also increases ectopic granule cells in the molecular layer. Status epilepticus was induced in male Sprague-Dawley rats by intraperitoneal injection of pilocarpine. Immunostaining showed that many doublecortin-positive cells were present in the molecular layer and the hilus 7 days after the induction of status epilepticus. At least 10 weeks after status epilepticus, the estimated number of cells positive for both prospero homeobox protein 1 and neuron-specific nuclear protein in the hilus was significantly increased. A similar trend was also found in the molecular layer. These findings indicate that status epilepticus can increase the numbers of mature and ectopic newborn granule cells in the molecular layer. PMID:25206705

  1. Tooth replacement related to number of natural teeth in a dentate adult population in Bulgaria: a cross-sectional study

    NARCIS (Netherlands)

    Damyanov, N.D.; Witter, D.J.; Bronkhorst, E.M.; Creugers, N.H.J.

    2013-01-01

    PURPOSE: This study aimed to explore the relationships among tooth replacement, number of present natural teeth, and sociodemographic and behavioral factors in an adult population in Bulgaria. MATERIALS AND METHODS: Quota sampling was used to recruit 2,531 dentate subjects aged 20 years and over

  2. Dentate Gyrus-Specific Knockdown of Adult Neurogenesis Impairs Spatial and Object Recognition Memory in Adult Rats

    Science.gov (United States)

    Jessberger, Sebastian; Clark, Robert E.; Broadbent, Nicola J.; Clemenson, Gregory D., Jr.; Consiglio, Antonella; Lie, D. Chichung; Squire, Larry R.; Gage, Fred H.

    2009-01-01

    New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons…

  3. Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus.

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    Yvonne Imielski

    Full Text Available Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.

  4. Morphological alterations in newly born dentate gyrus granule cells that emerge after status epilepticus contribute to make them less excitable.

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    Julián Tejada

    Full Text Available Computer simulations of external current stimulations of dentate gyrus granule cells of rats with Status Epilepticus induced by pilocarpine and control rats were used to evaluate whether morphological differences alone between these cells have an impact on their electrophysiological behavior. The cell models were constructed using morphological information from tridimensional reconstructions with Neurolucida software. To evaluate the effect of morphology differences alone, ion channel conductances, densities and distributions over the dendritic trees of dentate gyrus granule cells were the same for all models. External simulated currents were injected in randomly chosen dendrites belonging to one of three different areas of dentate gyrus granule cell molecular layer: inner molecular layer, medial molecular layer and outer molecular layer. Somatic membrane potentials were recorded to determine firing frequencies and inter-spike intervals. The results show that morphologically altered granule cells from pilocarpine-induced epileptic rats are less excitable than control cells, especially when they are stimulated in the inner molecular layer, which is the target area for mossy fibers that sprout after pilocarpine-induced cell degeneration. This suggests that morphological alterations may act as a protective mechanism to allow dentate gyrus granule cells to cope with the increase of stimulation caused by mossy fiber sprouting.

  5. D1/D5 Receptors and Histone Deacetylation Mediate the Gateway Effect of LTP in Hippocampal Dentate Gyrus

    Science.gov (United States)

    Huang, Yan-You; Lavine, Amir; Kandel, Denise B.; Yin, Deqi; Colnaghi, Luca; Drisaldi, Bettina; Kandel, Eric R.

    2014-01-01

    The dentate gyrus (DG) of the hippocampus is critical for spatial memory and is also thought to be involved in the formation of drug-related associative memory. Here, we attempt to test an aspect of the Gateway Hypothesis, by studying the effect of consecutive exposure to nicotine and cocaine on long-term synaptic potentiation (LTP) in the DG. We…

  6. Expression of tryptophan 2,3-dioxygenase in mature granule cells of the adult mouse dentate gyrus

    Directory of Open Access Journals (Sweden)

    Ohira, Koji

    2010-09-01

    Full Text Available Abstract New granule cells are continuously generated in the dentate gyrus of the adult hippocampus. During granule cell maturation, the mechanisms that differentiate new cells not only describe the degree of cell differentiation, but also crucially regulate the progression of cell differentiation. Here, we describe a gene, tryptophan 2,3-dioxygenase (TDO, whose expression distinguishes stem cells from more differentiated cells among the granule cells of the adult mouse dentate gyrus. The use of markers for proliferation, neural progenitors, and immature and mature granule cells indicated that TDO was expressed in mature cells and in some immature cells. In mice heterozygous for the alpha-isoform of calcium/calmodulin-dependent protein kinase II, in which dentate gyrus granule cells fail to mature normally, TDO immunoreactivity was substantially downregulated in the dentate gyrus granule cells. Moreover, a 5-bromo-2'-deoxyuridine labeling experiment revealed that new neurons began to express TDO between 2 and 4 wk after the neurons were generated, when the axons and dendrites of the granule cells developed and synaptogenesis occurred. These findings indicate that TDO might be required at a late-stage of granule cell development, such as during axonal and dendritic growth, synaptogenesis and its maturation.

  7. The GABAA Antagonist DPP-4-PIOL Selectively Antagonises Tonic over Phasic GABAergic Currents in Dentate Gyrus Granule Cells

    DEFF Research Database (Denmark)

    Boddum, Kim; Frølund, Bente; Kristiansen, Uffe

    2014-01-01

    that phasic and tonic GABAA receptor currents can be selectively inhibited by the antagonists SR 95531 and the 4-PIOL derivative, 4-(3,3-diphenylpropyl)-5-(4-piperidyl)-3-isoxazolol hydrobromide (DPP-4-PIOL), respectively. In dentate gyrus granule cells, SR 95531 was found approximately 4 times as potent...

  8. Optico-cochleo-dentate degeneration associated with severe peripheral neuropathy and caused by peroxisomal D-bifunctional protein deficiency

    NARCIS (Netherlands)

    Schröder, J. M.; Hackel, V.; Wanders, R. J. A.; Göhlich-Ratmann, G.; Voit, T.

    2004-01-01

    The clinical, neuroradiological, neuropathological and biochemical findings in a patient with optico-cochleo-dentate degeneration (OCDD; OMIM 258700) are presented in a severe case succumbing at the age of 4 years. The electron microscopic and biochemical data showed for the first time that OCDD may

  9. Ethanol extract of Oenanthe javanica increases cell proliferation and neuroblast differentiation in the adolescent rat dentate gyrus

    Directory of Open Access Journals (Sweden)

    Bai Hui Chen

    2015-01-01

    Full Text Available Oenanthe javanica is an aquatic perennial herb that belongs to the Oenanthe genus in Apiaceae family, and it displays well-known medicinal properties such as protective effects against glutamate-induced neurotoxicity. However, few studies regarding effects of Oenanthe javanica on neurogenesis in the brain have been reported. In this study, we examined the effects of a normal diet and a diet containing ethanol extract of Oenanthe javanica on cell proliferation and neuroblast differentiation in the subgranular zone of the hippocampal dentate gyrus of adolescent rats using Ki-67 (an endogenous marker for cell proliferation and doublecortin (a marker for neuroblast. Our results showed that Oenanthe javanica extract significantly increased the number of Ki-67-immunoreactive cells and doublecortin-immunoreactive neuroblasts in the subgranular zone of the dentate gyrus in the adolescent rats. In addition, the immunoreactivity of brain-derived neurotrophic factor was significantly increased in the dentate gyrus of the Oenanthe javanica extract-treated group compared with the control group. However, we did not find that vascular endothelial growth factor expression was increased in the Oenanthe javanica extract-treated group compared with the control group. These results indicate that Oenanthe javanica extract improves cell proliferation and neuroblast differentiation by increasing brain-derived neurotrophic factor immunoreactivity in the rat dentate gyrus.

  10. Regrowing the Adult Brain: NF-κB Controls Functional Circuit Formation and Tissue Homeostasis in the Dentate Gyrus

    Science.gov (United States)

    Imielski, Yvonne; Schwamborn, Jens C.; Lüningschrör, Patrick; Heimann, Peter; Holzberg, Magdalena; Werner, Hendrikje; Leske, Oliver; Püschel, Andreas W.; Memet, Sylvie; Heumann, Rolf; Israel, Alain; Kaltschmidt, Christian; Kaltschmidt, Barbara

    2012-01-01

    Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders. PMID:22312433

  11. Maintained LTP and Memory Are Lost by Zn2+ Influx into Dentate Granule Cells, but Not Ca2+ Influx.

    Science.gov (United States)

    Takeda, Atsushi; Tamano, Haruna; Hisatsune, Marie; Murakami, Taku; Nakada, Hiroyuki; Fujii, Hiroaki

    2018-02-01

    The idea that maintained LTP and memory are lost by either increase in intracellular Zn 2+ in dentate granule cells or increase in intracellular Ca 2+ was examined to clarify significance of the increases induced by excess synapse excitation. Both maintained LTP and space memory were impaired by injection of high K + into the dentate gyrus, but rescued by co-injection of CaEDTA, which blocked high K + -induced increase in intracellular Zn 2+ but not high K + -induced increase in intracellular Ca 2+ . High K + -induced disturbances of LTP and intracellular Zn 2+ are rescued by co-injection of 6-cyano-7-nitroquinoxakine-2,3-dione, an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor antagonist, but not by co-injection of blockers of NMDA receptors, metabotropic glutamate receptors, and voltage-dependent calcium channels. Furthermore, AMPA impaired maintained LTP and the impairment was also rescued by co-injection of CaEDTA, which blocked increase in intracellular Zn 2+ , but not increase in intracellular Ca 2+ . NMDA and glucocorticoid, which induced Zn 2+ release from the internal stores, did not impair maintained LTP. The present study indicates that increase in Zn 2+ influx into dentate granule cells through AMPA receptors loses maintained LTP and memory. Regulation of Zn 2+ influx into dentate granule cells is more critical for not only memory acquisition but also memory retention than that of Ca 2+ influx.

  12. Age-dependent kinetics of dentate gyrus neurogenesis in the absence of cyclin D2

    Directory of Open Access Journals (Sweden)

    Ansorg Anne

    2012-05-01

    Full Text Available Abstract Background Adult neurogenesis continuously adds new neurons to the dentate gyrus and the olfactory bulb. It involves the proliferation and subsequent differentiation of neuronal progenitors, and is thus closely linked to the cell cycle machinery. Cell cycle progression is governed by the successive expression, activation and degradation of regulatory proteins. Among them, D-type cyclins control the exit from the G1 phase of the cell cycle. Cyclin D2 (cD2 has been shown to be required for the generation of new neurons in the neurogenic niches of the adult brain. It is differentially expressed during hippocampal development, and adult cD2 knock out (cD2KO mice virtually lack neurogenesis in the dentate gyrus and olfactory bulb. In the present study we examined the dynamics of postnatal and adult neurogenesis in the dentate gyrus (DG of cD2KO mice. Animals were injected with bromodeoxyuridine at seven time points during the first 10 months of life and brains were immunohistochemically analyzed for their potential to generate new neurons. Results Compared to their WT litters, cD2KO mice had considerably reduced numbers of newly born granule cells during the postnatal period, with neurogenesis becoming virtually absent around postnatal day 28. This was paralleled by a reduction in granule cell numbers, in the volume of the granule cell layer as well as in apoptotic cell death. CD2KO mice did not show any of the age-related changes in neurogenesis and granule cell numbers that were seen in WT litters. Conclusions The present study suggests that hippocampal neurogenesis becomes increasingly dependent on cD2 during early postnatal development. In cD2KO mice, hippocampal neurogenesis ceases at a time point at which the tertiary germinative matrix stops proliferating, indicating that cD2 becomes an essential requirement for ongoing neurogenesis with the transition from developmental to adult neurogenesis. Our data further support the notion that

  13. Reduced tonic inhibition in the dentate gyrus contributes to chronic stress-induced impairments in learning and memory.

    Science.gov (United States)

    Lee, Vallent; MacKenzie, Georgina; Hooper, Andrew; Maguire, Jamie

    2016-10-01

    It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress-induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in EGABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in EGABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABAA receptor (GABAA R) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells, whereas there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABAA R δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABAA R δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABAA R δ subunit-mediated tonic inhibition

  14. Reduced tonic inhibition in the dentate gyrus contributes to chronic stress-induced impairments in learning and memory

    Science.gov (United States)

    Hooper, Andrew; Maguire, Jamie

    2016-01-01

    It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress-induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in EGABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in EGABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABAA receptor (GABAAR) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells; whereas, there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABAAR δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABAAR δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABAAR δ subunit-mediated tonic inhibition in

  15. Effects of Scopolamine and Melatonin Cotreatment on Cognition, Neuronal Damage, and Neurogenesis in the Mouse Dentate Gyrus.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Choi, Soo Young; Lee, Yun Lyul; Kang, Il Jun; Hwang, In Koo; Lee, Tae-Kyeong; Shin, Bich-Na; Lee, Jae-Chul; Hong, Seongkweon; Jeon, Yong Hwan; Shin, Myoung Cheol; Cho, Jun Hwi; Won, Moo-Ho; Lee, Young Joo

    2018-03-01

    It has been demonstrated that melatonin plays important roles in memory improvement and promotes neurogenesis in experimental animals. We examined effects of melatonin on cognitive deficits, neuronal damage, cell proliferation, neuroblast differentiation and neuronal maturation in the mouse dentate gyrus after cotreatment of scopolamine (anticholinergic agent) and melatonin. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally injected for 2 and/or 4 weeks to 8-week-old mice. Scopolamine treatment induced significant cognitive deficits 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly improved spatial learning and short-term memory impairments. Two and 4 weeks after scopolamine treatment, neurons were not damaged/dead in the dentate gyrus, in addition, no neuronal damage/death was shown after cotreatment of scopolamine and melatonin. Ki67 (a marker for cell proliferation)- and doublecortin (a marker for neuroblast differentiation)-positive cells were significantly decreased in the dentate gyrus 2 and 4 weeks after scopolamine treatment, however, cotreatment of scopolamine and melatonin significantly increased Ki67- and doublecortin-positive cells compared with scopolamine-treated group. However, double immunofluorescence for NeuN/BrdU, which indicates newly-generated mature neurons, did not show double-labeled cells (adult neurogenesis) in the dentate gyrus 2 and 4 weeks after cotreatment of scopolamine and melatonin. Our results suggest that melatonin treatment recovers scopolamine-induced spatial learning and short-term memory impairments and restores or increases scopolamine-induced decrease of cell proliferation and neuroblast differentiation, but does not lead to adult neurogenesis (maturation of neurons) in the mouse dentate gyrus following scopolamine treatment.

  16. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment.

    Science.gov (United States)

    Feng, Shufang; Shi, Tianyao; Qiu, Jiangxia; Yang, Haihong; Wu, Yan; Zhou, Wenxia; Wang, Wei; Wu, Haitao

    2017-10-01

    It is well known that Notch1 signaling plays a crucial role in embryonic neural development and adult neurogenesis. The latest evidence shows that Notch1 also plays a critical role in synaptic plasticity in mature hippocampal neurons. So far, deeper insights into the function of Notch1 signaling during the different steps of adult neurogenesis are still lacking, and the mechanisms by which Notch1 dysfunction is associated with brain disorders are also poorly understood. In the current study, we found that Notch1 was highly expressed in the adult-born immature neurons in the hippocampal dentate gyrus. Using a genetic approach to selectively ablate Notch1 signaling in late immature precursors in the postnatal hippocampus by cross-breeding doublecortin (DCX) + neuron-specific proopiomelanocortin (POMC)-α Cre mice with floxed Notch1 mice, we demonstrated a previously unreported pivotal role of Notch1 signaling in survival and function of adult newborn neurons in the dentate gyrus. Moreover, behavioral and functional studies demonstrated that POMC-Notch1 -/- mutant mice showed anxiety and depressive-like behavior with impaired synaptic transmission properties in the dentate gyrus. Finally, our mechanistic study showed significantly compromised phosphorylation of cAMP response element-binding protein (CREB) in Notch1 mutants, suggesting that the dysfunction of Notch1 mutants is associated with the disrupted pCREB signaling in postnatally generated immature neurons in the dentate gyrus.-Feng, S., Shi, T., Qiu, J., Yang, H., Wu, Y., Zhou, W., Wang, W., Wu, H. Notch1 deficiency in postnatal neural progenitor cells in the dentate gyrus leads to emotional and cognitive impairment. © FASEB.

  17. 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.

  18. Deficit of Kcnma1 mRNA expression in the dentate gyrus of epileptic rats

    Science.gov (United States)

    Ermolinsky, Boris; Arshadmansab, Massoud F.; Pacheco Otalora, Luis F.; Zarei, Masoud M.; Garrido-Sanabria, Emilio R.

    2008-01-01

    Epileptogenesis in mesial temporal lobe epilepsy is determined by several factors including abnormalities in the expression and function of ion channels. Here, we report a long-lasting deficit in gene expression of Kcnma1 coding for the large-conductance calcium-activated potassium (BK, MaxiK) channel α-subunits after pilocarpine-induced status epilepticus. By using comparative real-time PCR, Taqman gene expression assays, and the delta-delta comparative threshold method we detected a significant reduction in Kcnma1 expression in microdissected dentate gyrus at different intervals after status epilepticus (24 h, 10 days, 1 month, and more than 2 months). BK channels are key regulators of neuronal excitability and transmitter release. Hence, defective Kcnma1 expression may play a critical role in the pathogenesis of mesial temporal lobe epilepsy. PMID:18695509

  19. Axonal transport and axon sprouting in the adult rat dentate gyrus: an autoradiographic study

    International Nuclear Information System (INIS)

    Goldowitz, D.; Cotman, C.W.

    1980-01-01

    In response to an entorhinal lesion, the commissural and associational afferents to the dentate gyrus have been shown to expand beyond their normal terminal zone into the area denervated by the entorhinal lesion. The present study has investigated the axonal transport of [ 3 H]-labeled proteins in the commissural and associational projections following an entorhinal lesion. Injections of [ 3 H]proline, [ 3 H]leucine or [ 3 H)fucose were given in the vicinity of the commissural and associational cells of origin before, immediately subsequent to, or at 5 to 15 days after the entorhinal lesion. The disposition of previously- or newly-synthesized proteins was examined in the commissural and associational terminal field at different times after an entorhinal lesion by light-microscopic autoradiography. (author)

  20. Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus.

    Science.gov (United States)

    Zhang, Tie-Yuan; Keown, Christopher L; Wen, Xianglan; Li, Junhao; Vousden, Dulcie A; Anacker, Christoph; Bhattacharyya, Urvashi; Ryan, Richard; Diorio, Josie; O'Toole, Nicholas; Lerch, Jason P; Mukamel, Eran A; Meaney, Michael J

    2018-01-19

    Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications. Here, we report comprehensive DNA methylome, hydroxymethylome and transcriptome data sets from mouse dorsal and ventral DG. We find genome-wide transcriptional and methylation differences between dorsal and ventral DG, including at key developmental transcriptional factors. Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Enrichment also enhances dorsal-ventral differences in DNA methylation, including at binding sites of the transcription factor NeuroD1, a regulator of adult neurogenesis. These results indicate a dorsal-ventral asymmetry in transcription and methylation that parallels well-known functional and anatomical differences, and that may be enhanced by environmental enrichment.

  1. Loss of perforated synapses in the dentate gyrus: morphological substrate of memory deficit in aged rats.

    Science.gov (United States)

    Geinisman, Y; de Toledo-Morrell, L; Morrell, F

    1986-01-01

    Most, but not all, aged rats exhibit a profound deficit in spatial memory when tested in a radial maze--a task known to depend on the integrity of the hippocampal formation. In this study, animals were divided into three groups based on their spatial memory capacity: young adult rats with good memory, aged rats with impaired memory, and aged rats with good memory. Memory-impaired aged animals showed a loss of perforated axospinous synapses in the dentate gyrus of the hippocampal formation in comparison with either young adults or aged rats with good memory. This finding suggests that the loss of perforated axospinous synapses in the hippocampal formation underlies the age-related deficit in spatial memory. Images PMID:3458260

  2. Protection of Dentate Hilar Cells from Prolonged Stimulation by Intracellular Calcium Chelation

    Science.gov (United States)

    Scharfman, Helen E.; Schwartzkroin, Philip A.

    1989-10-01

    Prolonged afferent stimulation of the rat dentate gyrus in vivo leads to degeneration only of those cells that lack immunoreactivity for the calcium binding proteins parvalbumin and calbindin. In order to test the hypothesis that calcium binding proteins protect against the effects of prolonged stimulation, intracellular recordings were made in hippocampal slices from cells that lack immunoreactivity for calcium binding proteins. Calcium binding protein--negative cells showed electrophysiological signs of deterioration during prolonged stimulation; cells containing calcium binding protein did not. When neurons without calcium binding proteins were impaled with microelectrodes containing the calcium chelator BAPTA, and BAPTA was allowed to diffuse into the cells, these cells showed no deterioration. These results indicate that, in a complex tissue of the central nervous system, an activity-induced increase in intracellular calcium can trigger processes leading to cell deterioration, and that increasing the calcium binding capacity of a cell decreases its vulnerability to damage.

  3. In vivo calcium imaging from dentate granule cells with wide-field fluorescence microscopy.

    Directory of Open Access Journals (Sweden)

    Yuichiro Hayashi

    Full Text Available A combination of genetically-encoded calcium indicators and micro-optics has enabled monitoring of large-scale dynamics of neuronal activity from behaving animals. In these studies, wide-field microscopy is often used to visualize neural activity. However, this method lacks optical sectioning capability, and therefore its axial resolution is generally poor. At present, it is unclear whether wide-field microscopy can visualize activity of densely packed small neurons at cellular resolution. To examine the applicability of wide-field microscopy for small-sized neurons, we recorded calcium activity of dentate granule cells having a small soma diameter of approximately 10 micrometers. Using a combination of high numerical aperture (0.8 objective lens and independent component analysis-based image segmentation technique, activity of putative single granule cell activity was separated from wide-field calcium imaging data. The result encourages wider application of wide-field microscopy in in vivo neurophysiology.

  4. Axonal transport and axon sprouting in the adult rat dentate gyrus: an autoradiographic study

    Energy Technology Data Exchange (ETDEWEB)

    Goldowitz, D; Cotman, C W [California Univ., Irvine (USA)

    1980-12-01

    In response to an entorhinal lesion, the commissural and associational afferents to the dentate gyrus have been shown to expand beyond their normal terminal zone into the area denervated by the entorhinal lesion. The present study has investigated the axonal transport of (/sup 3/H)-labeled proteins in the commissural and associational projections following an entorhinal lesion. Injections of (/sup 3/H)proline, (/sup 3/H)leucine or (/sup 3/H)fucose were given in the vicinity of the commissural and associational cells of origin before, immediately subsequent to, or at 5 to 15 days after the entorhinal lesion. The disposition of previously- or newly-synthesized proteins was examined in the commissural and associational terminal field at different times after an entorhinal lesion by light-microscopic autoradiography.

  5. Effects of developmental hyperserotonemia on the morphology of rat dentate nuclear neurons.

    Science.gov (United States)

    Hough, L H; Segal, S

    2016-05-13

    Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social cognition, disordered communication, restricted interests and repetitive behaviors. Furthermore, abnormalities in basic motor control, skilled motor gestures, and motor learning, are common in ASD. These characteristics have been attributed to a possible defect in the pre- and postnatal development of specific neural networks including the dentate-thalamo-cortical pathway, which is involved in motor learning, automaticity of movements, and higher cognitive functions. The current study utilized custom diolistic labeling and unbiased stereology to characterize morphological alterations in neurons of the dentate nucleus of the cerebellum in developing rat pups exposed to abnormally high levels of the serotonergic agonist 5-methyloxytryptamine (5-MT) pre-and postnatally. Occurring in as many as 30% of autistic subjects, developmental hyperserotonemia (DHS) is the most consistent neurochemical finding reported in autism and has been implicated in the pathophysiology of ASD. This exposure produced dramatic changes in dendritic architecture and synaptic features. We observed changes in the dendritic branching morphology which did not lead to significant differences (p>0.5) in total dendritic length. Instead, DHS groups presented with dendritic trees that display changes in arborescence, that appear to be short reaching with elaborately branched segments, presenting with significantly fewer (p>0.001) dendritic spines and a decrease in numeric density when compared to age-matched controls. These negative changes may be implicated in the neuropathological and functional/behavioral changes observed in ASD, such as delays in motor learning, difficulties in automaticity of movements, and deficits in higher cognitive functions. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  6. The immature dentate gyrus represents a shared phenotype of mouse models of epilepsy and psychiatric disease.

    Science.gov (United States)

    Shin, Rick; Kobayashi, Katsunori; Hagihara, Hideo; Kogan, Jeffrey H; Miyake, Shinichi; Tajinda, Katsunori; Walton, Noah M; Gross, Adam K; Heusner, Carrie L; Chen, Qian; Tamura, Kouichi; Miyakawa, Tsuyoshi; Matsumoto, Mitsuyuki

    2013-06-01

    There is accumulating evidence to suggest psychiatric disorders, such as bipolar disorder and schizophrenia, share common etiologies, pathophysiologies, genetics, and drug responses with many of the epilepsies. Here, we explored overlaps in cellular/molecular, electrophysiological, and behavioral phenotypes between putative mouse models of bipolar disorder/schizophrenia and epilepsy. We tested the hypothesis that an immature dentate gyrus (iDG), whose association with psychosis in patients has recently been reported, represents a common phenotype of both diseases. Behaviors of calcium/calmodulin-dependent protein kinase II alpha (α-CaMKII) heterozygous knock-out (KO) mice, which are a representative bipolar disorder/schizophrenia model displaying iDG, and pilocarpine-treated mice, which are a representative epilepsy model, were tested followed by quantitative polymerase chain reaction (qPCR)/immunohistochemistry for mRNA/protein expression associated with an iDG phenotype. In vitro electrophysiology of dentate gyrus granule cells (DG GCs) was examined in pilocarpine-treated epileptic mice. The two disease models demonstrated similar behavioral deficits, such as hyperactivity, poor working memory performance, and social withdrawal. Significant reductions in mRNA expression and immunoreactivity of the mature neuronal marker calbindin and concomitant increases in mRNA expression and immunoreactivity of the immature neuronal marker calretinin represent iDG signatures that are present in both mice models. Electrophysiologically, we have confirmed that DG GCs from pilocarpine-treated mice represent an immature state. A significant decrease in hippocampal α-CaMKII protein levels was also found in both models. Our data have shown iDG signatures from mouse models of both bipolar disorder/schizophrenia and epilepsy. The evidence suggests that the iDG may, in part, be responsible for the abnormal behavioral phenotype, and that the underlying pathophysiologies in epilepsy

  7. Neurogenesis in the septal and temporal part of the adult rat dentate gyrus.

    Science.gov (United States)

    Bekiari, Chryssa; Giannakopoulou, Aggeliki; Siskos, Nikistratos; Grivas, Ioannis; Tsingotjidou, Anastasia; Michaloudi, Helen; Papadopoulos, Georgios C

    2015-04-01

    Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In this study, BrdU-dated subpopulations of the rat septal and temporal dentate gyrus (coexpressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase-3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21, and 30 days after BrdU administration in order to examine the successive time-frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU(+) cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU-incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid, and less-disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less

  8. Survival of mossy cells of the hippocampal dentate gyrus in humans with mesial temporal lobe epilepsy.

    Science.gov (United States)

    Seress, László; Abrahám, Hajnalka; Horváth, Zsolt; Dóczi, Tamás; Janszky, József; Klemm, Joyce; Byrne, Richard; Bakay, Roy A E

    2009-12-01

    Hippocampal sclerosis can be identified in most patients with mesial temporal lobe epilepsy (TLE). Surgical removal of the sclerotic hippocampus is widely performed to treat patients with drug-resistant mesial TLE. In general, both epilepsy-prone and epilepsy-resistant neurons are believed to be in the hippocampal formation. The hilar mossy cells of the hippocampal dentate gyrus are usually considered one of the most vulnerable types of neurons. The aim of this study was to clarify the fate of mossy cells in the hippocampus in epileptic humans. Of the 19 patients included in this study, 15 underwent temporal lobe resection because of drug-resistant TLE. Four patients were used as controls because they harbored tumors that had not invaded the hippocampus and they had experienced no seizures. Histological evaluation of resected hippocampal tissues was performed using immunohistochemistry. Mossy cells were identified in the control as well as the epileptic hippocampi by using cocaine- and amphetamine-regulated transcript peptide immunohistochemistry. In most cases the number of mossy cells was reduced and thorny excrescences were smaller in the epileptic hippocampi than in controls; however, there was a significant loss of pyramidal cells and a partial loss of granule cells in the same epileptic hippocampi in which mossy cell loss was apparent. The loss of mossy cells could be correlated with the extent of hippocampal sclerosis, patient age at seizure onset, duration of epilepsy, and frequency of seizures. In many cases large numbers of mossy cells were present in the hilus of the dentate gyrus when most pyramidal neurons of the CA1 and CA3 areas of the Ammon's horn were lost, suggesting that mossy cells may not be more vulnerable to epileptic seizures than the hippocampal pyramidal neurons.

  9. Radial glial cells in the adult dentate gyrus: what are they and where do they come from? [version 1; referees: 2 approved

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    Daniel A. Berg

    2018-03-01

    Full Text Available Adult neurogenesis occurs in the dentate gyrus in the mammalian hippocampus. These new neurons arise from neural precursor cells named radial glia-like cells, which are situated in the subgranular zone of the dentate gyrus. Here, we review the emerging topic of precursor heterogeneity in the adult subgranular zone. We also discuss how this heterogeneity may be established during development and focus on the embryonic origin of the dentate gyrus and radial glia-like stem cells. Finally, we discuss recently developed single-cell techniques, which we believe will be critical to comprehensively investigate adult neural stem cell origin and heterogeneity.

  10. Prenatal Alcohol Exposure Increases Histamine H3 Receptor-Mediated Inhibition of Glutamatergic Neurotransmission in Rat Dentate Gyrus.

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    Varaschin, Rafael K; Allen, Nyika A; Rosenberg, Martina J; Valenzuela, C Fernando; Savage, Daniel D

    2018-02-01

    We have reported that prenatal alcohol exposure (PAE)-induced deficits in dentate gyrus, long-term potentiation (LTP), and memory are ameliorated by the histamine H 3 receptor inverse agonist ABT-239. Curiously, ABT-239 did not enhance LTP or memory in control offspring. Here, we initiated an investigation of how PAE alters histaminergic neurotransmission in the dentate gyrus and other brain regions employing combined radiohistochemical and electrophysiological approaches in vitro to examine histamine H 3 receptor number and function. Long-Evans rat dams voluntarily consumed either a 0% or 5% ethanol solution 4 hours each day throughout gestation. This pattern of drinking, which produces a mean peak maternal serum ethanol concentration of 60.8 ± 5.8 mg/dl, did not affect maternal weight gain, litter size, or offspring birthweight. Radiohistochemical studies in adult offspring revealed that specific [ 3 H]-A349821 binding to histamine H 3 receptors was not different in PAE rats compared to controls. However, H 3 receptor-mediated G i /G o protein-effector coupling, as measured by methimepip-stimulated [ 35 S]-GTPγS binding, was significantly increased in cerebral cortex, cerebellum, and dentate gyrus of PAE rats compared to control. A LIGAND analysis of detailed methimepip concentration-response curves in dentate gyrus indicated that PAE significantly elevates receptor-effector coupling by a lower affinity H 3 receptor population without significantly altering the affinities of H 3 receptor subpopulations. In agreement with the [ 35 S]-GTPγS studies, a similar range of methimepip concentrations also inhibited electrically evoked field excitatory postsynaptic potential responses and increased paired-pulse ratio, a measure of decreased glutamate release, to a significantly greater extent in dentate gyrus slices from PAE rats than in controls. These results suggest that a PAE-induced elevation in H 3 receptor-mediated inhibition of glutamate release from

  11. Doublecortin (DCX is not essential for survival and differentiation of newborn neurons in the adult mouse dentate gyrus

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    Jagroop eDhaliwal

    2016-01-01

    Full Text Available In the adult brain, expression of the microtubule-associated protein Doublecortin (DCX is associated with neural progenitor cells (NPCs that give rise to new neurons in the dentate gyrus. Many studies quantify the number of DCX-expressing cells as a proxy for the level of adult neurogenesis, yet no study has determined the effect of removing DCX from adult hippocampal NPCs. Here, we use a retroviral and inducible mouse transgenic approach to either knockdown or knockout DCX from adult NPCs in the dentate gyrus and examine how this affects cell survival and neuronal maturation. Our results demonstrate that shRNA-mediated knockdown of DCX or Cre-mediated recombination in floxed DCX mice does not alter hippocampal neurogenesis and does not change the neuronal fate of the NPCs. Together these findings show that the survival and maturation of adult-generated hippocampal neurons does not require DCX.

  12. Genetic study of Pea (Pisum sativum L.) mutants with changed shape and/or dentation of leaves

    International Nuclear Information System (INIS)

    Naidenova, N.

    2001-01-01

    The purpose of this study is to describe the morphological differences between normal plants and mutants (due to irradiation) with different shape and/or dentation of leaflets and to evaluate their productivity and genetic potential. Dry seeds have been submitted to gamma irradiation with doses 100 Gy, 150 Gy and 200 Gy.The mutants studies in this research introduce an important source for further investigation of genetics of the mutant traits - dentation of leaflets, shape and especially flowering time that is controlled by genetically determined responses to photo period and temperature. Due to the clear phenotypic expression of the shape and leaves in some plants it is considered that the development of the leaves mutants is and important finding for pea genetics making tham valuable morphological markers for genetic investigations

  13. Intra- and interregional cortical interactions related to sharp-wave ripples and dentate spikes.

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    Headley, Drew B; Kanta, Vasiliki; Paré, Denis

    2017-02-01

    The hippocampus generates population events termed sharp-wave ripples (SWRs) and dentate spikes (DSs). While little is known about DSs, SWR-related hippocampal discharges during sleep are thought to replay prior waking activity, reactivating the cortical networks that encoded the initial experience. During slow-wave sleep, such reactivations likely occur during up-states, when most cortical neurons are depolarized. However, most studies have examined the relationship between SWRs and up-states measured in single neocortical regions. As a result, it is currently unclear whether SWRs are associated with particular patterns of widely distributed cortical activity. Additionally, no such investigation has been carried out for DSs. The present study addressed these questions by recording SWRs and DSs from the dorsal hippocampus simultaneously with prefrontal, sensory (visual and auditory), perirhinal, and entorhinal cortices in naturally sleeping rats. We found that SWRs and DSs were associated with up-states in all cortical regions. Up-states coinciding with DSs and SWRs exhibited increased unit activity, power in the gamma band, and intraregional gamma coherence. Unexpectedly, interregional gamma coherence rose much more strongly in relation to DSs than to SWRs. Whereas the increase in gamma coherence was time locked to DSs, that seen in relation to SWRs was not. These observations suggest that SWRs are related to the strength of up-state activation within individual regions throughout the neocortex but not so much to gamma coherence between different regions. Perhaps more importantly, DSs coincided with stronger periods of interregional gamma coherence, suggesting that they play a more important role than previously assumed. Off-line cortico-hippocampal interactions are thought to support memory consolidation. We surveyed the relationship between hippocampal sharp-wave ripples (SWRs) and dentate spikes (DSs) with up-states across multiple cortical regions. SWRs and

  14. Neurons from the adult human dentate nucleus: neural networks in the neuron classification.

    Science.gov (United States)

    Grbatinić, Ivan; Marić, Dušica L; Milošević, Nebojša T

    2015-04-07

    Topological (central vs. border neuron type) and morphological classification of adult human dentate nucleus neurons according to their quantified histomorphological properties using neural networks on real and virtual neuron samples. In the real sample 53.1% and 14.1% of central and border neurons, respectively, are classified correctly with total of 32.8% of misclassified neurons. The most important result present 62.2% of misclassified neurons in border neurons group which is even greater than number of correctly classified neurons (37.8%) in that group, showing obvious failure of network to classify neurons correctly based on computational parameters used in our study. On the virtual sample 97.3% of misclassified neurons in border neurons group which is much greater than number of correctly classified neurons (2.7%) in that group, again confirms obvious failure of network to classify neurons correctly. Statistical analysis shows that there is no statistically significant difference in between central and border neurons for each measured parameter (p>0.05). Total of 96.74% neurons are morphologically classified correctly by neural networks and each one belongs to one of the four histomorphological types: (a) neurons with small soma and short dendrites, (b) neurons with small soma and long dendrites, (c) neuron with large soma and short dendrites, (d) neurons with large soma and long dendrites. Statistical analysis supports these results (pneurons can be classified in four neuron types according to their quantitative histomorphological properties. These neuron types consist of two neuron sets, small and large ones with respect to their perykarions with subtypes differing in dendrite length i.e. neurons with short vs. long dendrites. Besides confirmation of neuron classification on small and large ones, already shown in literature, we found two new subtypes i.e. neurons with small soma and long dendrites and with large soma and short dendrites. These neurons are

  15. Granule cell potentials in the dentate gyrus of the hippocampus: coping behavior and stress ulcers in rats.

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    Henke, P G

    1990-01-01

    Evoked population potentials of the granule cells in the dentate gyrus of the hippocampus were increased in stress-resistant rats and decreased in stress-susceptible rats, as indexed by restraint-induced gastric ulcers. Inescapable, uncontrollable shock stimulation also suppressed granule cell population spikes and interfered with subsequent coping responses when escape was possible, i.e. the so-called helplessness effect. The data were interpreted to indicate that the hippocampus is part of a coping system in stressful situations.

  16. Anthropometrics of mental foramen in dry dentate and edentulous mandibles in Coastal Andhra population of Andhra Pradesh State

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    Srinivas Moogala

    2014-01-01

    Full Text Available Aim: The aim of this study is to determine the morphological features and morphometrics of mental foramen with reference to surrounding anatomical landmarks in Coastal Andhra population of Andhra Pradesh State. Materials and Methods: Two-hundred and nineteen dry dentate and edentulous mandibles are examined in this study. Out of these 127 were dentate and 92 were edentulous. Various morphological and morphometrical parameters were measured by using digital Vernier caliper, metallic wire and metallic scale on both the right and left sides. Results: In the present study, the distance between most anterior margin of mental foramen and posterior border of ramus of the mandible is [MF-PR], MF-PR is 69.61 ± 6.03 mm on the right side and is 69.17 ± 6. 0 mm on left side in dentate mandible. In edentulous type, MF-PR is 68.39 ±6.4 mm on right side and 68.81 ± 6.55 mm on left side. In the present study, the distance between symphysis menti and most anterior margin of mental foramen [MF-SM] in dentate mandible is 28.24 ± 5.09 mm on right side and is 27.45 ± 3.7 mm on left side. In edentulous mandible (MF-SM is 28.51 ± 4.5 mm on right side and on left side is 27.99 ± 4.50 mm. Conclusion: Acquiring the knowledge and importance of anatomy of mental foramen is helpful in avoiding neurovascular complications, during regional anesthesia, peri apical surgeries, nerve repositioning and dental implant placement.

  17. Btg1 is Required to Maintain the Pool of Stem and Progenitor Cells of the Dentate Gyrus and Subventricular Zone

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    Farioli-Vecchioli, Stefano; Micheli, Laura; Saraulli, Daniele; Ceccarelli, Manuela; Cannas, Sara; Scardigli, Raffaella; Leonardi, Luca; Cinà, Irene; Costanzi, Marco; Ciotti, Maria Teresa; Moreira, Pedro; Rouault, Jean-Pierre; Cestari, Vincenzo; Tirone, Felice

    2012-01-01

    Btg1 belongs to a family of cell cycle inhibitory genes. We observed that Btg1 is highly expressed in adult neurogenic niches, i.e., the dentate gyrus and subventricular zone (SVZ). Thus, we generated Btg1 knockout mice to analyze the role of Btg1 in the process of generation of adult new neurons. Ablation of Btg1 causes a transient increase of the proliferating dentate gyrus stem and progenitor cells at post-natal day 7; however, at 2 months of age the number of these proliferating cells, as well as of mature neurons, greatly decreases compared to wild-type controls. Remarkably, adult dentate gyrus stem and progenitor cells of Btg1-null mice exit the cell cycle after completing the S phase, express p53 and p21 at high levels and undergo apoptosis within 5 days. In the SVZ of adult (two-month-old) Btg1-null mice we observed an equivalent decrease, associated to apoptosis, of stem cells, neuroblasts, and neurons; furthermore, neurospheres derived from SVZ stem cells showed an age-dependent decrease of the self-renewal and expansion capacity. We conclude that ablation of Btg1 reduces the pool of dividing adult stem and progenitor cells in the dentate gyrus and SVZ by decreasing their proliferative capacity and inducing apoptosis, probably reflecting impairment of the control of the cell cycle transition from G1 to S phase. As a result, the ability of Btg1-null mice to discriminate among overlapping contextual memories was affected. Btg1 appears, therefore, to be required for maintaining adult stem and progenitor cells quiescence and self-renewal. PMID:22969701

  18. Exercise improves cognitive responses to psychological stress through enhancement of epigenetic mechanisms and gene expression in the dentate gyrus.

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    Andrew Collins

    Full Text Available We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats.Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction.Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons.

  19. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

    Science.gov (United States)

    Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

    2015-01-01

    Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

  20. Factors specifying the development of synapse number in the rat dentate gyrus: effects of partial target loss

    International Nuclear Information System (INIS)

    Lewis, E.R.; Cotman, C.W.

    1980-01-01

    The development of the dentate gyrus has been studied under conditions of partial reduction of granule cell number. Neonatal rats were subjected to X-irradiation, a procedure which reduces the number of granule cells to 20% of control values. In X-irradiated rats, quantitative analyses were performed on cells in the entorhinal cortex which give rise to the perforant path projection to the dentate granule cells, and on the remaining, undamaged dentate granule cells. These residual cells were examined morphologically for possible hyperdevelopment in comparison to granule cells from control animals. Granule cells in X-irradiated animals were similar to granule cells in control animals with respect to dendritic structure and synaptic density. The number of neurons in both the medical and lateral entorhinal cortices in X-irradiated animals appeared normal until day 12, at which time a selective reduction in cell numbers became apparent. By day 30, 25-55% of the cells of origin of the perforant path were absent in X-irradiated animals. It is hypothesized that these cells are subject to retrograde transynaptic degeneration as a result of target removal. Further, it appears that granule cells play an important role in determining the density of their innervation. (Auth.)

  1. Low-Dose Sevoflurane Promotes Hippocampal Neurogenesis and Facilitates the Development of Dentate Gyrus-Dependent Learning in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Chong Chen

    2015-04-01

    Full Text Available Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8% sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4–6 were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.

  2. Persistent discharges in dentate gyrus perisoma-inhibiting interneurons require hyperpolarization-activated cyclic nucleotide-gated channel activation.

    Science.gov (United States)

    Elgueta, Claudio; Köhler, Johannes; Bartos, Marlene

    2015-03-11

    Parvalbumin (PV)-expressing perisoma-inhibiting interneurons (PIIs) of the dentate gyrus integrate rapidly correlated synaptic inputs and generate short-duration action potentials that propagate along the axon to their output synapses, supporting fast inhibitory signaling onto their target cells. Here we show that PV-PIIs in rat and mouse dentate gyrus (DG) integrate their intrinsic activity over time and can turn into a persistent firing mode characterized by the ability to generate long-lasting trains of action potentials at ∼50 Hz in the absence of additional inputs. Persistent firing emerges in the axons remote from the axon initial segment and markedly depends on hyperpolarization-activated cyclic nucleotide-gated channel (HCNC) activation. Persistent firing properties are modulated by intracellular Ca(2+) levels and somatic membrane potential. Detailed computational single-cell PIIs models reveal that HCNC-mediated conductances can contribute to persistent firing during conditions of a shift in their voltage activation curve to more depolarized potentials. Paired recordings from PIIs and their target granule cells show that persistent firing supports strong inhibitory output signaling. Thus, persistent firing may emerge during conditions of intense activation of the network, thereby providing silencing to the circuitry and the maintenance of sparse activity in the dentate gyrus. Copyright © 2015 the authors 0270-6474/15/354131-09$15.00/0.

  3. Effects of butternut squash extract on dentate gyrus cell proliferation and spatial learning in male adult rats

    Institute of Scientific and Technical Information of China (English)

    Mohsen Marzban; Sara Soleimani Asl; Hassan Fallah Huseini; Mahdi Tondar; Samira Choopani; Mehdi Mehdizadeh

    2011-01-01

    Previous studies reported that some plants, including butternut squash, exert positive effects on the brain. However, few studies have examined the effects of butternut squash on learning, memory, and neurogenesis. This study studied the effects of butternut squash extract on spatial learning and cell proliferation in the dentate gyrus of healthy male rats. Thirty-five male Wistar rats were intrap-eritoneally injected with 0, 50, 100, 200 and 400 mg/kg butternut squash extract once daily for 2 months. After the last administration, rat's spatial memory was studied using the Morris water maze. Finally, rats were sacrificed and hippocampal sections were prepared for light microscopy and bromodeoxyuridine immunohistochemistry studies. The results revealed that escape latency and swim distance decreased in all treatment groups compared with the control rats, and that the number of bromodeoxyuridine-positive cells in the dentate gyrus was significantly increased in the treatment groups compared with the controls. These findings suggest that butternut squash extract improves the learning and memory abilities of male rats, and increases the proliferation of dentate gyrus cells.

  4. Smaller Dentate Gyrus and CA2 and CA3 Volumes Are Associated with Kynurenine Metabolites in Collegiate Football Athletes.

    Science.gov (United States)

    Meier, Timothy B; Savitz, Jonathan; Singh, Rashmi; Teague, T Kent; Bellgowan, Patrick S F

    2016-07-15

    An imbalance in kynurenine pathway metabolism is hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism underlying the hippocampal volume loss observed in a variety of neurological disorders. Pre-clinical models suggest that the CA2-3 and dentate gyrus hippocampal subfields are particularly susceptible to excitotoxicity after experimental traumatic brain injury. We tested the hypothesis that smaller hippocampal volumes in collegiate football athletes with (n = 25) and without (n = 24) a concussion history would be most evident in the dentate gyrus and CA2-3 subfields relative to nonfootball healthy controls (n = 27). Further, we investigated whether the concentration of peripheral levels of kynurenine metabolites are altered in football athletes. Football athletes with and without a self-reported concussion history had smaller dentate gyrus (p Football athletes with and without a concussion history had a trend toward lower (p history had greater levels of quinolinic acid compared with athletes without a concussion history (p football athletes with a concussion history (p football athletes without a concussion history (p < 0.05). Our results raise the possibility that abnormalities of the kynurenine metabolic pathway constitute a mechanism for hippocampal volume differences in the context of sports-related brain injury.

  5. Effects of TRPV1 activation on synaptic excitation in the dentate gyrus of a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Bhaskaran, Muthu D; Smith, Bret N

    2010-06-01

    Temporal lobe epilepsy (TLE) is a condition characterized by an imbalance between excitation and inhibition in the temporal lobe. Hallmarks of this change are axon sprouting and accompanying synaptic reorganization in the temporal lobe. Synthetic and endogenous cannabinoids have variable therapeutic potential in treating intractable temporal lobe epilepsy, in part because cannabinoid ligands can bind multiple receptor types. This study utilized in vitro electrophysiological methods to examine the effect of transient receptor potential vanilloid type 1 (TRPV1) activation in dentate gyrus granule cells in a murine model of TLE. Capsaicin, a selective TRPV1 agonist had no measurable effect on overall synaptic input to granule cells in control animals, but significantly enhanced spontaneous and miniature EPSC frequency in mice with TLE. Exogenous application of anandamide, an endogenous cannabinoid that acts at both TRPV1 and cannabinoid type 1 receptors (CB1R), also enhanced glutamate release in the presence of a CB1R antagonist. Anandamide reduced the EPSC frequency when TRPV1 were blocked with capsazepine. Western blot analysis of TRPV1 receptor indicated protein expression was significantly greater in the dentate gyrus of mice with TLE compared with control mice. This study indicates that a prominent cannabinoid agonist can increase excitatory circuit activity in the synaptically reorganized dentate gyrus of mice with TLE by activating TRPV1 receptors, and suggests caution in designing anticonvulsant therapy based on modulating the endocannabinoid system. Copyright (c) 2009 Elsevier Inc. All rights reserved.

  6. Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood.

    Science.gov (United States)

    Daugherty, Ana M; Flinn, Robert; Ofen, Noa

    2017-06-01

    Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution images in a sample of healthy participants (age 8-25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Hippocampal CA3-dentate gyrus volume uniquely linked to improvement in associative memory from childhood to adulthood

    Science.gov (United States)

    Daugherty, Ana M.; Flinn, Robert; Ofen, Noa

    2017-01-01

    Associative memory develops into adulthood and critically depends on the hippocampus. The hippocampus is a complex structure composed of subfields that are functionally-distinct, and anterior-posterior divisions along the length of the hippocampal horizontal axis that may also differ by cognitive correlates. Although each of these aspects has been considered independently, here we evaluate their relative contributions as correlates of age-related improvement in memory. Volumes of hippocampal subfields (subiculum, CA1-2, CA3-dentate gyrus) and anterior-posterior divisions (hippocampal head, body, tail) were manually segmented from high-resolution proton density-weighted images in a sample of healthy participants (age 8–25 years). Adults had smaller CA3-dentate gyrus volume as compared to children, which accounted for 67% of the indirect effect of age predicting better associative memory via hippocampal volumes. Whereas hippocampal body volume demonstrated non-linear age differences, larger hippocampal body volume was weakly related to better associative memory only when accounting for the mutual correlation with subfields measured within that region. Thus, typical development of associative memory was largely explained by age-related differences in CA3-dentate gyrus. PMID:28342999

  8. Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus

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    Farah Chamaa

    2018-05-01

    Full Text Available The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O is an N-methyl-D-aspartic acid (NMDA antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2. Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.

  9. Occurrence and impact of xerostomia among dentate adult New Zealanders: findings from a national survey.

    Science.gov (United States)

    Benn, A M L; Broadbent, J M; Thomson, W M

    2015-09-01

    We investigated the prevalence, associations and impact of xerostomia in a nationally representative sample of dentate adult community-dwelling New Zealanders aged 18 years and over. The data were collected from a representative sample of 2209 adults, as part of the 2009 New Zealand Oral Health Survey (NZOHS). Data were collected using face-to-face interviews, dental examinations and the short-form Oral Health Impact Profile (OHIP-14). Data analysis used appropriate weighting for all procedures to account for the complex survey design. The overall prevalence estimate for xerostomia was 13.1% (95% CI 11.7, 14.7), and it was more common among females. Those in the 75+  and 25-34 age groups were more likely (odds ratios of 6.5 and 4.0, respectively) to have xerostomia. After controlling for sociodemographic characteristics and clinical oral disease, the mean OHIP-14 score among xerostomics was 50% higher than among those who did not have the condition. These data indicate that xerostomia is a common condition which can affect quality of life among people of all ages. © 2015 Australian Dental Association.

  10. Dnmt3a in the dorsal dentate gyrus is a key regulator of fear renewal.

    Science.gov (United States)

    Gong, Zhiting; Zhou, Qiang

    2018-03-23

    Renewal of extinguished fear memory in an altered context is widely believed to be a major limiting issue for exposure therapy in treating various psychiatric diseases. Effective prevention of fear renewal will significantly improve the efficacy of exposure therapy. DNA methyltransferase (DNMTs) mediated epigenetic processes play critical roles in long term memory, but little is known about their functions in fear memory extinction or renewal. Here we investigated whether DNMTs regulate fear renewal after extinction. We found that elevated Dnmt3a level in the dorsal dentate gyrus (dDG) of hippocampus was associated with the absence of fear renewal in an altered context after extinction training. Overexpression and knockdown of Dnmt3a in the dDG regulated the occurrence of fear renewal in a bi-directional manner. In addition, Dnmt3a overexpression was associated with elevated expression of c-Fos in the dDG during extinction training. Furthermore, we found that renewal of remote fear memory can be prevented, and the absence of renewal was concurrent with an elevated Dnmt3a level. Our results indicate that Dnmt3a in the dDG is a key regulator of fear renewal after extinction, and Dnmt3a may play a critical role in controlling fear memory return and thus has therapeutic values.

  11. Vascular pattern of the dentate gyrus is regulated by neural progenitors.

    Science.gov (United States)

    Pombero, Ana; Garcia-Lopez, Raquel; Estirado, Alicia; Martinez, Salvador

    2018-05-01

    Neurogenesis is a vital process that begins during early embryonic development and continues until adulthood, though in the latter case, it is restricted to the subventricular zone and the subgranular zone of the dentate gyrus (DG). In particular, the DG's neurogenic properties are structurally and functionally unique, which may be related to its singular vascular pattern. Neurogenesis and angiogenesis share molecular signals and act synergistically, supporting the concept of a neurogenic niche as a functional unit between neural precursors cells and their environment, in which the blood vessels play an important role. Whereas it is well known that vascular development controls neural proliferation in the embryonary and in the adult brain, by releasing neurotrophic factors; the potential influence of neural cells on vascular components during angiogenesis is largely unknown. We have demonstrated that the reduction of neural progenitors leads to a significant impairment of vascular development. Since VEGF is a potential regulator in the neurogenesis-angiogenesis crosstalk, we were interested in assessing the possible role of this molecule in the hippocampal neurovascular development. Our results showed that VEGF is the molecule involved in the regulation of vascular development by neural progenitor cells in the DG.

  12. Transition Dynamics of a Dentate Gyrus-CA3 Neuronal Network during Temporal Lobe Epilepsy

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    Liyuan Zhang

    2017-07-01

    Full Text Available In temporal lobe epilepsy (TLE, the variation of chemical receptor expression underlies the basis of neural network activity shifts, resulting in neuronal hyperexcitability and epileptiform discharges. However, dynamical mechanisms involved in the transitions of TLE are not fully understood, because of the neuronal diversity and the indeterminacy of network connection. Hence, based on Hodgkin–Huxley (HH type neurons and Pinsky–Rinzel (PR type neurons coupling with glutamatergic and GABAergic synaptic connections respectively, we propose a computational framework which contains dentate gyrus (DG region and CA3 region. By regulating the concentration range of N-methyl-D-aspartate-type glutamate receptor (NMDAR, we demonstrate the pyramidal neuron can generate transitions from interictal to seizure discharges. This suggests that enhanced endogenous activity of NMDAR contributes to excitability in pyramidal neuron. Moreover, we conclude that excitatory discharges in CA3 region vary considerably on account of the excitatory currents produced by the excitatory pyramidal neuron. Interestingly, by changing the backprojection connection, we find that glutamatergic type backprojection can promote the dominant frequency of firings and further motivate excitatory counterpropagation from CA3 region to DG region. However, GABAergic type backprojection can reduce firing rate and block morbid counterpropagation, which may be factored into the terminations of TLE. In addition, neuronal diversity dominated network shows weak correlation with different backprojections. Our modeling and simulation studies provide new insights into the mechanisms of seizures generation and connectionism in local hippocampus, along with the synaptic mechanisms of this disease.

  13. Transcriptional effects of glucocorticoid receptors in the dentate gyrus increase anxiety-related behaviors.

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    Nadège Sarrazin

    Full Text Available The Glucocorticoid Receptor (GR is a transcription factor ubiquitously expressed in the brain. Activation of brain GRs by high levels of glucocorticoid (GC hormones modifies a large variety of physiological and pathological-related behaviors. Unfortunately the specific cellular targets of GR-mediated behavioral effects of GC are still largely unknown. To address this issue, we generated a mutated form of the GR called DeltaGR. DeltaGR is a constitutively transcriptionally active form of the GR that is localized in the nuclei and activates transcription without binding to glucocorticoids. Using the tetracycline-regulated system (Tet-OFF, we developed an inducible transgenic approach that allows the expression of the DeltaGR in specific brain areas. We focused our study on a mouse line that expressed DeltaGR almost selectively in the glutamatergic neurons of the dentate gyrus (DG of the hippocampus. This restricted expression of the DeltaGR increased anxiety-related behaviors without affecting other behaviors that could indirectly influence performance in anxiety-related tests. This behavioral phenotype was also associated with an up-regulation of the MAPK signaling pathway and Egr-1 protein in the DG. These findings identify glutamatergic neurons in the DG as one of the cellular substrate of stress-related pathologies.

  14. Increases in Doublecortin Immunoreactivity in the Dentate Gyrus following Extinction of Heroin-Seeking Behavior

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    Megan P. Hicks

    2012-01-01

    Full Text Available Adult-generated neurons in the dentate gyrus (DG of the hippocampus play a role in various forms of learning and memory. However, adult born neurons in the DG, while still at an immature stage, exhibit unique electrophysiological properties and are also functionally implicated in learning and memory processes. We investigated the effects of extinction of drug-seeking behavior on the formation of immature neurons in the DG as assessed by quantification of doublecortin (DCX immunoreactivity. Rats were allowed to self-administer heroin (0.03 mg/kg/infusion for 12 days and then subjected either to 10 days of extinction training or forced abstinence. We also examined extinction responding patterns following heroin self-administration in glial fibrillary acidic protein thymidine kinase (GFAP-tk transgenic mice, which have been previously demonstrated to show reduced formation of immature and mature neurons in the DG following treatment with ganciclovir (GCV. We found that extinction training increased DCX immunoreactivity in the dorsal DG as compared with animals undergoing forced abstinence, and that GCV-treated GFAP-tk mice displayed impaired extinction learning as compared to saline-treated mice. Our results suggest that extinction of drug-seeking behavior increases the formation of immature neurons in the DG and that these neurons may play a functional role in extinction learning.

  15. The psychostimulant modafinil facilitates water maze performance and augments synaptic potentiation in dentate gyrus.

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    Tsanov, Marian; Lyons, Declan G; Barlow, Sally; González Reyes, Rodrigo E; O'Mara, Shane M

    2010-01-01

    Modafinil is a psychostimulant drug used widely for the treatment of narcolepsy, which also has additional positive effects on cognition. Here, we investigate the effects of modafinil on behavioural performance and synaptic plasticity in rats. Improved acquisition in the water maze task was observed in animals that underwent chronic treatment with modafinil. We found that the distance traveled and escape latency were reduced after the first day in chronically-treated rats, compared to controls. Importantly, swim velocity was similar for both groups, excluding pharmacological effects on motor skills. We also found that modafinil increases synaptic plasticity in the dentate gyrus of urethane-anaesthetized rats; modafinil induced a robust augmentation of the population spike, evident after application of 2 bursts of 200 Hz high-frequency stimulation. Furthermore, the modafinil-dependent enhancement of postsynaptic potentials correlated selectively with theta rhythm augmentation. We propose that modafinil may facilitate hippocampal-associated spatial representation via increased theta-related hippocampal plasticity. Copyright 2010 Elsevier Ltd. All rights reserved.

  16. Impaired neurogenesis of the dentate gyrus is associated with pattern separation deficits: A computational study.

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    Faghihi, Faramarz; Moustafa, Ahmed A

    2016-09-01

    The separation of input patterns received from the entorhinal cortex (EC) by the dentate gyrus (DG) is a well-known critical step of information processing in the hippocampus. Although the role of interneurons in separation pattern efficiency of the DG has been theoretically known, the balance of neurogenesis of excitatory neurons and interneurons as well as its potential role in information processing in the DG is not fully understood. In this work, we study separation efficiency of the DG for different rates of neurogenesis of interneurons and excitatory neurons using a novel computational model in which we assume an increase in the synaptic efficacy between excitatory neurons and interneurons and then its decay over time. Information processing in the EC and DG was simulated as information flow in a two layer feed-forward neural network. The neurogenesis rate was modeled as the percentage of new born neurons added to the neuronal population in each time bin. The results show an important role of an optimal neurogenesis rate of interneurons and excitatory neurons in the DG in efficient separation of inputs from the EC in pattern separation tasks. The model predicts that any deviation of the optimal values of neurogenesis rates leads to different decreased levels of the separation deficits of the DG which influences its function to encode memory.

  17. Ongoing neurogenesis in the adult dentate gyrus mediates behavioral responses to ambiguous threat cues.

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    Lucas R Glover

    2017-04-01

    Full Text Available Fear learning is highly adaptive if utilized in appropriate situations but can lead to generalized anxiety if applied too widely. A role of predictive cues in inhibiting fear generalization has been suggested by stress and fear learning studies, but the effects of partially predictive cues (ambiguous cues and the neuronal populations responsible for linking the predictive ability of cues and generalization of fear responses are unknown. Here, we show that inhibition of adult neurogenesis in the mouse dentate gyrus decreases hippocampal network activation and reduces defensive behavior to ambiguous threat cues but has neither of these effects if the same negative experience is reliably predicted. Additionally, we find that this ambiguity related to negative events determines their effect on fear generalization, that is, how the events affect future behavior under novel conditions. Both new neurons and glucocorticoid hormones are required for the enhancement of fear generalization following an unpredictably cued threat. Thus, adult neurogenesis plays a central role in the adaptive changes resulting from experience involving unpredictable or ambiguous threat cues, optimizing behavior in novel and uncertain situations.

  18. In vivo dentate nucleus MRI relaxometry correlates with previous administration of Gadolinium-based contrast agents

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    Tedeschi, Enrico; Canna, Antonietta; Cocozza, Sirio; Russo, Carmela; Angelini, Valentina; Brunetti, Arturo [University ' ' Federico II' ' , Neuroradiology, Department of Advanced Biomedical Sciences, Naples (Italy); Palma, Giuseppe; Quarantelli, Mario [National Research Council, Institute of Biostructure and Bioimaging, Naples (Italy); Borrelli, Pasquale; Salvatore, Marco [IRCCS SDN, Naples (Italy); Lanzillo, Roberta; Postiglione, Emanuela; Morra, Vincenzo Brescia [University ' ' Federico II' ' , Department of Neurosciences, Reproductive and Odontostomatological Sciences, Naples (Italy)

    2016-12-15

    To evaluate changes in T1 and T2* relaxometry of dentate nuclei (DN) with respect to the number of previous administrations of Gadolinium-based contrast agents (GBCA). In 74 relapsing-remitting multiple sclerosis (RR-MS) patients with variable disease duration (9.8±6.8 years) and severity (Expanded Disability Status Scale scores:3.1±0.9), the DN R1 (1/T1) and R2* (1/T2*) relaxation rates were measured using two unenhanced 3D Dual-Echo spoiled Gradient-Echo sequences with different flip angles. Correlations of the number of previous GBCA administrations with DN R1 and R2* relaxation rates were tested, including gender and age effect, in a multivariate regression analysis. The DN R1 (normalized by brainstem) significantly correlated with the number of GBCA administrations (p<0.001), maintaining the same significance even when including MS-related factors. Instead, the DN R2* values correlated only with age (p=0.003), and not with GBCA administrations (p=0.67). In a subgroup of 35 patients for whom the administered GBCA subtype was known, the effect of GBCA on DN R1 appeared mainly related to linear GBCA. In RR-MS patients, the number of previous GBCA administrations correlates with R1 relaxation rates of DN, while R2* values remain unaffected, suggesting that T1-shortening in these patients is related to the amount of Gadolinium given. (orig.)

  19. Transition Dynamics of a Dentate Gyrus-CA3 Neuronal Network during Temporal Lobe Epilepsy.

    Science.gov (United States)

    Zhang, Liyuan; Fan, Denggui; Wang, Qingyun

    2017-01-01

    In temporal lobe epilepsy (TLE), the variation of chemical receptor expression underlies the basis of neural network activity shifts, resulting in neuronal hyperexcitability and epileptiform discharges. However, dynamical mechanisms involved in the transitions of TLE are not fully understood, because of the neuronal diversity and the indeterminacy of network connection. Hence, based on Hodgkin-Huxley (HH) type neurons and Pinsky-Rinzel (PR) type neurons coupling with glutamatergic and GABAergic synaptic connections respectively, we propose a computational framework which contains dentate gyrus (DG) region and CA3 region. By regulating the concentration range of N-methyl-D-aspartate-type glutamate receptor (NMDAR), we demonstrate the pyramidal neuron can generate transitions from interictal to seizure discharges. This suggests that enhanced endogenous activity of NMDAR contributes to excitability in pyramidal neuron. Moreover, we conclude that excitatory discharges in CA3 region vary considerably on account of the excitatory currents produced by the excitatory pyramidal neuron. Interestingly, by changing the backprojection connection, we find that glutamatergic type backprojection can promote the dominant frequency of firings and further motivate excitatory counterpropagation from CA3 region to DG region. However, GABAergic type backprojection can reduce firing rate and block morbid counterpropagation, which may be factored into the terminations of TLE. In addition, neuronal diversity dominated network shows weak correlation with different backprojections. Our modeling and simulation studies provide new insights into the mechanisms of seizures generation and connectionism in local hippocampus, along with the synaptic mechanisms of this disease.

  20. Specific radiosensitivy and postnatal neurogenesis of the dentate gyrus of rabbits

    International Nuclear Information System (INIS)

    Gueneau, Gerard.

    1982-09-01

    Adult and young rabbits were delivered a gamma exposure of 4.5 Gy. A light and electron microscope cytological investigation of the hippocampal region in the early hours following the exposure showed the particular radiosensitivity of the dentate gyrus which was demonstrated by: 1) pycnotic cells to be found at the basis of the granular cell layer (subgranular zone) exclusively; 2) a more discrete injury of the granular layer where most nuclei showed a lighter chromatin appearing as ''light spots''. Both radioinduced injuries are described, especially their kinetics, importance, and the effects of dose and age of the animal. The presence of pycnotic cells in the subgranular zone was related to the late postnatal neurogenesis occurring in this zone. The pattern and chronology of this late postnatal neurogenesis was investigated by autoradiography following 3 H thymidine injection. Finally, two series of investigations combining autoradiography and irradiation brought further data on the radiosensitivity and radioresistance of the dental gyrus cells and demonstrated the recovery capacity of the subgranular zone [fr

  1. Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells.

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    Duan, Yuntao; Wang, Shih-Hsiu; Song, Juan; Mironova, Yevgeniya; Ming, Guo-li; Kolodkin, Alex L; Giger, Roman J

    2014-10-14

    Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A-/- GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A-/- mutants, PlexinA2-/- mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A-/- mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders.

  2. Pediatric Patients Demonstrate Progressive T1-Weighted Hyperintensity in the Dentate Nucleus following Multiple Doses of Gadolinium-Based Contrast Agent.

    Science.gov (United States)

    Roberts, D R; Chatterjee, A R; Yazdani, M; Marebwa, B; Brown, T; Collins, H; Bolles, G; Jenrette, J M; Nietert, P J; Zhu, X

    2016-12-01

    While there have been recent reports of brain retention of gadolinium following gadolinium-based contrast agent administration in adults, a retrospective series of pediatric patients has not previously been reported, to our knowledge. We investigated the relationship between the number of prior gadolinium-based contrast agent doses and increasing T1 signal in the dentate nucleus on unenhanced T1-weighted MR imaging. We hypothesized that despite differences in pediatric physiology and the smaller gadolinium-based contrast agent doses that pediatric patients are typically administered based on weighted-adjusted dosing, the pediatric brain would also demonstrate dose-dependent increasing T1 signal in the dentate nucleus. We included children with multiple gadolinium-based contrast agent administrations at our institution. A blinded reader placed ROIs within the dentate nucleus and adjacent cerebellar white matter. To eliminate reader bias, we also performed automated ROI delineation of the dentate nucleus, cerebellar white matter, and pons. Dentate-to-cerebellar white matter and dentate-to pons ratios were compared with the number of gadolinium-based contrast agent administrations. During 20 years at our institution, 280 patients received at least 5 gadolinium-based contrast agent doses, with 1 patient receiving 38 doses. Sixteen patients met the inclusion/exclusion criteria for ROI analysis. Blinded reader dentate-to-cerebellar white matter ratios were significantly associated with gadolinium-based contrast agent doses (r s = 0.77, P = .001). The dentate-to-pons ratio and dentate-to-cerebellar white matter ratios based on automated ROI placement were also significantly correlated with gadolinium-based contrast agent doses (t = 4.98, P contrast agent doses is significantly correlated with progressive T1-weighted dentate hyperintensity. Definitive confirmation of gadolinium deposition requires tissue analysis. Any potential clinical sequelae of gadolinium retention in

  3. 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.

  4. Alpha-CaMKII deficiency causes immature dentate gyrus, a novel candidate endophenotype of psychiatric disorders

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    Yamasaki Nobuyuki

    2008-09-01

    Full Text Available Abstract Elucidating the neural and genetic factors underlying psychiatric illness is hampered by current methods of clinical diagnosis. The identification and investigation of clinical endophenotypes may be one solution, but represents a considerable challenge in human subjects. Here we report that mice heterozygous for a null mutation of the alpha-isoform of calcium/calmodulin-dependent protein kinase II (alpha-CaMKII+/- have profoundly dysregulated behaviours and impaired neuronal development in the dentate gyrus (DG. The behavioral abnormalities include a severe working memory deficit and an exaggerated infradian rhythm, which are similar to symptoms seen in schizophrenia, bipolar mood disorder and other psychiatric disorders. Transcriptome analysis of the hippocampus of these mutants revealed that the expression levels of more than 2000 genes were significantly changed. Strikingly, among the 20 most downregulated genes, 5 had highly selective expression in the DG. Whereas BrdU incorporated cells in the mutant mouse DG was increased by more than 50 percent, the number of mature neurons in the DG was dramatically decreased. Morphological and physiological features of the DG neurons in the mutants were strikingly similar to those of immature DG neurons in normal rodents. Moreover, c-Fos expression in the DG after electric footshock was almost completely and selectively abolished in the mutants. Statistical clustering of human post-mortem brains using 10 genes differentially-expressed in the mutant mice were used to classify individuals into two clusters, one of which contained 16 of 18 schizophrenic patients. Nearly half of the differentially-expressed probes in the schizophrenia-enriched cluster encoded genes that are involved in neurogenesis or in neuronal migration/maturation, including calbindin, a marker for mature DG neurons. Based on these results, we propose that an "immature DG" in adulthood might induce alterations in behavior and

  5. Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking.

    Science.gov (United States)

    Takashima, Yoshio; Fannon, McKenzie J; Galinato, Melissa H; Steiner, Noah L; An, Michelle; Zemljic-Harpf, Alice E; Somkuwar, Sucharita S; Head, Brian P; Mandyam, Chitra D

    2018-02-13

    Abstinence from unregulated methamphetamine self-administration increases hippocampal dependent, context-driven reinstatement of methamphetamine seeking. The current study tested the hypothesis that alterations in the functional properties of granule cell neurons (GCNs) in the dentate gyrus (DG) of the hippocampus in concert with altered expression of synaptic plasticity-related proteins and ultrastructural changes in the DG are associated with enhanced context-driven methamphetamine-seeking behavior. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naïve (controls) and methamphetamine experienced animals (during acute withdrawal, during abstinence, after extinction and after reinstatement). Spontaneous excitatory postsynaptic currents (sEPSCs) and intrinsic excitability were recorded from GCNs. Reinstatement of methamphetamine seeking increased sEPSC frequency and produced larger amplitude responses in GCNs compared to controls and all other groups. Reinstatement of methamphetamine seeking reduced spiking capability in GCNs compared to controls, and all other groups, as indicated by reduced intrinsic spiking elicited by increasing current injections, membrane resistance and fast after hyperpolarization. In rats that reinstated methamphetamine seeking, these altered electrophysiological properties of GCNs were associated with enhanced expression of Fos, GluN2A subunits and PSD95 and reduced expression of GABA A subunits in the DG and enhanced expression of synaptic PSD in the molecular layer. The alterations in functional properties of GCNs and plasticity related proteins in the DG paralleled with no changes in structure of microglial cells in the DG. Taken together, our results demonstrate that enhanced reinstatement of methamphetamine seeking results in alterations in intrinsic spiking and spontaneous glutamatergic synaptic transmission in the GCNs and concomitant increases in neuronal activation of GCNs, and expression

  6. Differential Postnatal Expression of Neuronal Maturation Markers in the Dentate Gyrus of Mice and Rats

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    Tijana Radic

    2017-11-01

    Full Text Available The dentate gyrus (DG is a unique structure of the hippocampus that is distinguished by ongoing neurogenesis throughout the lifetime of an organism. The development of the DG, which begins during late gestation and continues during the postnatal period, comprises the structural formation of the DG as well as the establishment of the adult neurogenic niche in the subgranular zone (SGZ. We investigated the time course of postnatal maturation of the DG in male C57BL/6J mice and male Sprague-Dawley rats based on the distribution patterns of the immature neuronal marker doublecortin (DCX and a marker for mature neurons, calbindin (CB. Our findings demonstrate that the postnatal DG is marked by a substantial maturation with a high number of DCX-positive granule cells (GCs during the first two postnatal weeks followed by a progression toward more mature patterns and increasing numbers of CB-positive GCs within the subsequent 2 weeks. The most substantial shift in maturation of the GC population took place between P7 and P14 in both mice and rats, when young, immature DCX-positive GCs became confined to the innermost part of the GC layer (GCL, indicative of the formation of the SGZ. These results suggest that the first month of postnatal development represents an important transition phase during which DG neurogenesis and the maturation course of the GC population becomes analogous to the process of adult neurogenesis. Therefore, the postnatal DG could serve as an attractive model for studying a growing and functionally maturing neural network. Direct comparisons between mice and rats revealed that the transition from immature DCX-positive to mature CB-positive GCs occurs more rapidly in the rat by approximately 4–6 days. The remarkable species difference in the speed of maturation on the GC population level may have important implications for developmental and neurogenesis research in different rodent species and strains.

  7. Temporal associations for spatial events: the role of the dentate gyrus.

    Science.gov (United States)

    Morris, Andrea M; Curtis, Brian J; Churchwell, John C; Maasberg, David W; Kesner, Raymond P

    2013-11-01

    Previous research suggests that the dorsal dentate gyrus (DG) hippocampal subregion mediates spatial processing functions. However, a novel role for the DG in temporal processing for spatial information has begun to emerge based on the development of a computational model of neurogenesis. According to this model, adult born granule cells in the DG contribute to a temporal associative integration process for events presented closer in time. Currently, there is a paucity of behavioral evidence to support the temporal integration theory. Therefore, we developed a novel behavioral paradigm to investigate the role of the dDG in temporal integration for proximal and distal spatial events. Male Long-Evans rats were randomly assigned to a control group or to receive bilateral intracranial infusions of colchicine into the dDG. Following recovery from surgery, each rat was tested on a cued-recall of sequence paradigm. In this task, animals were allowed to explore identical objects placed in designated spatial locations on a cheeseboard maze across 2 days (e.g., Day 1: A and B; Day 2: C and D). One week later, animals were given a brief cue (A or C) followed by a preference test between spatial location B and D. Control animals had a significant preference for the spatial location previously paired with the cue (the temporal associate) whereas dDG lesioned animals failed to show a preference. These findings suggest that selective colchicine-induced dDG lesions are capable of disrupting the formation of temporal associations between spatial events presented close in time. Copyright © 2013 Elsevier B.V. All rights reserved.

  8. The role of the ventral dentate gyrus in olfactory pattern separation.

    Science.gov (United States)

    Weeden, Christy S S; Hu, Nathan J; Ho, Liana U N; Kesner, Raymond P

    2014-05-01

    Dorsoventral lesion studies of the hippocampus have indicated that the dorsal axis of the hippocampus is important for spatial processing and the ventral axis of the hippocampus is important for olfactory learning and memory and anxiety. There is some evidence to suggest that the ventral CA3 and ventral CA1 conduct parallel processes for pattern completion and temporal processing, respectively. Studies have indicated that the dorsal dentate gyrus (DG) is importantly involved in processes reflecting underlying pattern separation activity for spatial information. However, the ventral DG is less understood. The current study investigated the less-understood role of the ventral DG in olfactory pattern separation. A series of odor stimuli that varied on only one level, number of carbon chains (methyl groups), was used in a matching-to-sample paradigm in order to investigate ventral DG involvement in working memory for similar and less similar odors. Rats with ventral DG lesions were impaired at delays of 60 sec, but not at delays of 15 sec. A memory-based pattern separation effect was observed performance was poorest with only one carbon chain separation between trial odors and was highest for trials with four separations. The present study indicates that the ventral DG plays an important role in olfactory learning and memory processes for highly similar odors. The results also indicate a role for the ventral DG in pattern separation for odor information, which may have further implications for parallel processing across the dorsoventral axis for the DG in spatial (dorsal) and olfactory (ventral) pattern separation. Copyright © 2014 Wiley Periodicals, Inc.

  9. A Computational Model of Pattern Separation Efficiency in the Dentate Gyrus with Implications in Schizophrenia

    Directory of Open Access Journals (Sweden)

    Faramarz eFaghihi

    2015-03-01

    Full Text Available Information processing in the hippocampus begins by transferring spiking activity of the Entorhinal Cortex (EC into the Dentate Gyrus (DG. Activity pattern in the EC is separated by the DG such that it plays an important role in hippocampal functions including memory. The structural and physiological parameters of these neural networks enable the hippocampus to be efficient in encoding a large number of inputs that animals receive and process in their life time. The neural encoding capacity of the DG depends on its single neurons encoding and pattern separation efficiency. In this study, encoding by the DG is modelled such that single neurons and pattern separation efficiency are measured using simulations of different parameter values. For this purpose, a probabilistic model of single neurons efficiency is presented to study the role of structural and physiological parameters. Known neurons number of the EC and the DG is used to construct a neural network by electrophysiological features of neuron in the DG. Separated inputs as activated neurons in the EC with different firing probabilities are presented into the DG. For different connectivity rates between the EC and DG, pattern separation efficiency of the DG is measured. The results show that in the absence of feedback inhibition on the DG neurons, the DG demonstrates low separation efficiency and high firing frequency. Feedback inhibition can increase separation efficiency while resulting in very low single neuron’s encoding efficiency in the DG and very low firing frequency of neurons in the DG (sparse spiking. This work presents a mechanistic explanation for experimental observations in the hippocampus, in combination with theoretical measures. Moreover, the model predicts a critical role for impaired inhibitory neurons in schizophrenia where deficiency in pattern separation of the DG has been observed.

  10. Single K ATP channel opening in response to action potential firing in mouse dentate granule neurons.

    Science.gov (United States)

    Tanner, Geoffrey R; Lutas, Andrew; Martínez-François, Juan Ramón; Yellen, Gary

    2011-06-08

    ATP-sensitive potassium channels (K(ATP) channels) are important sensors of cellular metabolic state that link metabolism and excitability in neuroendocrine cells, but their role in nonglucosensing central neurons is less well understood. To examine a possible role for K(ATP) channels in modulating excitability in hippocampal circuits, we recorded the activity of single K(ATP) channels in cell-attached patches of granule cells in the mouse dentate gyrus during bursts of action potentials generated by antidromic stimulation of the mossy fibers. Ensemble averages of the open probability (p(open)) of single K(ATP) channels over repeated trials of stimulated spike activity showed a transient increase in p(open) in response to action potential firing. Channel currents were identified as K(ATP) channels through blockade with glibenclamide and by comparison with recordings from Kir6.2 knock-out mice. The transient elevation in K(ATP) p(open) may arise from submembrane ATP depletion by the Na(+)-K(+) ATPase, as the pump blocker strophanthidin reduced the magnitude of the elevation. Both the steady-state and stimulus-elevated p(open) of the recorded channels were higher in the presence of the ketone body R-β-hydroxybutyrate, consistent with earlier findings that ketone bodies can affect K(ATP) activity. Using perforated-patch recording, we also found that K(ATP) channels contribute to the slow afterhyperpolarization following an evoked burst of action potentials. We propose that activity-dependent opening of K(ATP) channels may help granule cells act as a seizure gate in the hippocampus and that ketone-body-mediated augmentation of the activity-dependent opening could in part explain the effect of the ketogenic diet in reducing epileptic seizures.

  11. Synaptic properties of SOM- and CCK-expressing cells in dentate gyrus interneuron networks.

    Science.gov (United States)

    Savanthrapadian, Shakuntala; Meyer, Thomas; Elgueta, Claudio; Booker, Sam A; Vida, Imre; Bartos, Marlene

    2014-06-11

    Hippocampal GABAergic cells are highly heterogeneous, but the functional significance of this diversity is not fully understood. By using paired recordings of synaptically connected interneurons in slice preparations of the rat and mouse dentate gyrus (DG), we show that morphologically identified interneurons form complex neuronal networks. Synaptic inhibitory interactions exist between cholecystokinin (CCK)-expressing hilar commissural associational path (HICAP) cells and among somatostatin (SOM)-containing hilar perforant path-associated (HIPP) interneurons. Moreover, both interneuron types inhibit parvalbumin (PV)-expressing perisomatic inhibitory basket cells (BCs), whereas BCs and HICAPs rarely target HIPP cells. HICAP and HIPP cells produce slow, weak, and unreliable inhibition onto postsynaptic interneurons. The time course of inhibitory signaling is defined by the identity of the presynaptic and postsynaptic cell. It is the slowest for HIPP-HIPP, intermediately slow for HICAP-HICAP, but fast for BC-BC synapses. GABA release at interneuron-interneuron synapses also shows cell type-specific short-term dynamics, ranging from multiple-pulse facilitation at HICAP-HICAP, biphasic modulation at HIPP-HIPP to depression at BC-BC synapses. Although dendritic inhibition at HICAP-BC and HIPP-BC synapses appears weak and slow, channelrhodopsin 2-mediated excitation of SOM terminals demonstrates that they effectively control the activity of target interneurons. They markedly reduce the discharge probability but sharpen the temporal precision of action potential generation. Thus, dendritic inhibition seems to play an important role in determining the activity pattern of GABAergic interneuron populations and thereby the flow of information through the DG circuitry. Copyright © 2014 the authors 0270-6474/14/348197-13$15.00/0.

  12. A computational model of pattern separation efficiency in the dentate gyrus with implications in schizophrenia

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    Faghihi, Faramarz; Moustafa, Ahmed A.

    2015-01-01

    Information processing in the hippocampus begins by transferring spiking activity of the entorhinal cortex (EC) into the dentate gyrus (DG). Activity pattern in the EC is separated by the DG such that it plays an important role in hippocampal functions including memory. The structural and physiological parameters of these neural networks enable the hippocampus to be efficient in encoding a large number of inputs that animals receive and process in their life time. The neural encoding capacity of the DG depends on its single neurons encoding and pattern separation efficiency. In this study, encoding by the DG is modeled such that single neurons and pattern separation efficiency are measured using simulations of different parameter values. For this purpose, a probabilistic model of single neurons efficiency is presented to study the role of structural and physiological parameters. Known neurons number of the EC and the DG is used to construct a neural network by electrophysiological features of granule cells of the DG. Separated inputs as activated neurons in the EC with different firing probabilities are presented into the DG. For different connectivity rates between the EC and DG, pattern separation efficiency of the DG is measured. The results show that in the absence of feedback inhibition on the DG neurons, the DG demonstrates low separation efficiency and high firing frequency. Feedback inhibition can increase separation efficiency while resulting in very low single neuron’s encoding efficiency in the DG and very low firing frequency of neurons in the DG (sparse spiking). This work presents a mechanistic explanation for experimental observations in the hippocampus, in combination with theoretical measures. Moreover, the model predicts a critical role for impaired inhibitory neurons in schizophrenia where deficiency in pattern separation of the DG has been observed. PMID:25859189

  13. Synaptic Homeostasis and Allostasis in the Dentate Gyrus Caused by Inflammatory and Neuropathic Pain Conditions

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    Rui-Rui Wang

    2018-01-01

    Full Text Available It has been generally accepted that pain can cause imbalance between excitation and inhibition (homeostasis at the synaptic level. However, it remains poorly understood how this imbalance (allostasis develops in the CNS under different pain conditions. Here, we analyzed the changes in both excitatory and inhibitory synaptic transmission and modulation of the dentate gyrus (DG under two pain conditions with different etiology and duration. First, it was revealed that the functions of the input-output (I/O curves for evoked excitatory postsynaptic currents (eEPSCs following the perforant path (PP stimulation were gained under both acute inflammatory and chronic neuropathic pain conditions relative to the controls. However, the functions of I/O curves for the PP-evoked inhibitory postsynaptic currents (eIPSCs differed between the two conditions, namely it was greatly gained under inflammatory condition, but was reduced under neuropathic condition in reverse. Second, both the frequency and amplitude of miniature IPSCs (mIPSCs were increased under inflammatory condition, however a decrease in frequency of mIPSCs was observed under neuropathic condition. Finally, the spike discharge of the DG granule cells in response to current injection was significantly increased by neuropathic pain condition, however, no different change was found between inflammatory pain condition and the control. These results provide another line of evidence showing homeostatic and allostatic modulation of excitatory synaptic transmission by inhibitory controls under different pathological pain conditions, hence implicating use of different therapeutic approaches to maintain the homeostasis between excitation and inhibition while treating different conditions of pathological pain.

  14. Dentate gyrus neurogenesis ablation via cranial irradiation enhances morphine self-administration and locomotor sensitization.

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    Bulin, Sarah E; Mendoza, Matthew L; Richardson, Devon R; Song, Kwang H; Solberg, Timothy D; Yun, Sanghee; Eisch, Amelia J

    2018-03-01

    Adult dentate gyrus (DG) neurogenesis is important for hippocampal-dependent learning and memory, but the role of new neurons in addiction-relevant learning and memory is unclear. To test the hypothesis that neurogenesis is involved in the vulnerability to morphine addiction, we ablated adult DG neurogenesis and examined morphine self-administration (MSA) and locomotor sensitization. Male Sprague-Dawley rats underwent hippocampal-focused, image-guided X-ray irradiation (IRR) to eliminate new DG neurons or sham treatment (Sham). Six weeks later, rats underwent either MSA (Sham = 16, IRR = 15) or locomotor sensitization (Sham = 12, IRR = 12). Over 21 days of MSA, IRR rats self-administered ~70 percent more morphine than Sham rats. After 28 days of withdrawal, IRR rats pressed the active lever 40 percent more than Sham during extinction. This was not a general enhancement of learning or locomotion, as IRR and Sham groups had similar operant learning and inactive lever presses. For locomotor sensitization, both IRR and Sham rats sensitized, but IRR rats sensitized faster and to a greater extent. Furthermore, dose-response revealed that IRR rats were more sensitive at a lower dose. Importantly, these increases in locomotor activity were not apparent after acute morphine administration and were not a byproduct of irradiation or post-irradiation recovery time. Therefore, these data, along with other previously published data, indicate that reduced hippocampal neurogenesis confers vulnerability for multiple classes of drugs. Thus, therapeutics to specifically increase or stabilize hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. © 2017 Society for the Study of Addiction.

  15. DNA damage and cell cycle events implicate cerebellar dentate nucleus neurons as targets of Alzheimer's disease

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    Yang Yan

    2010-12-01

    Full Text Available Abstract Background Although the cerebellum is considered to be predominantly involved in fine motor control, emerging evidence documents its participation in language, impulsive behavior and higher cognitive functions. While the specific connections of the cerebellar deep nuclei (CDN that are responsible for these functions are still being worked out, their deficiency has been termed "cerebellar cognitive affective syndrome" - a syndrome that bears a striking similarity to many of the symptoms of Alzheimer's disease (AD. Using ectopic cell cycle events and DNA damage markers as indexes of cellular distress, we have explored the neuropathological involvement of the CDN in human AD. Results We examined the human cerebellar dentate nucleus in 22 AD cases and 19 controls for the presence of neuronal cell cycle events and DNA damage using immunohistochemistry and fluorescence in situ hybridization. Both techniques revealed several instances of highly significant correlations. By contrast, neither amyloid plaque nor neurofibrillary tangle pathology was detected in this region, consistent with previous reports of human cerebellar pathology. Five cases of early stage AD were examined and while cell cycle and DNA damage markers were well advanced in the hippocampus of all five, few indicators of either cell cycle events (1 case or a DNA damage response (1 case were found in CDN. This implies that CDN neurons are most likely affected later in the course of AD. Clinical-pathological correlations revealed that cases with moderate to high levels of cell cycle activity in their CDN are highly likely to show deficits in unorthodox cerebellar functions including speech, language and motor planning. Conclusion Our results reveal that the CDN neurons are under cellular stress in AD and suggest that some of the non-motor symptoms found in patients with AD may be partly cerebellar in origin.

  16. Optogenetic stimulation of dentate gyrus engrams restores memory in Alzheimer's disease mice.

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    Perusini, Jennifer N; Cajigas, Stephanie A; Cohensedgh, Omid; Lim, Sean C; Pavlova, Ina P; Donaldson, Zoe R; Denny, Christine A

    2017-10-01

    Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by amyloid-beta (Aβ) plaques and tau neurofibrillary tangles. APPswe/PS1dE9 (APP/PS1) mice have been developed as an AD model and are characterized by plaque formation at 4-6 months of age. Here, we sought to better understand AD-related cognitive decline by characterizing various types of memory. In order to better understand how memory declines with AD, APP/PS1 mice were bred with ArcCreER T2 mice. In this line, neural ensembles activated during memory encoding can be indelibly tagged and directly compared with neural ensembles activated during memory retrieval (i.e., memory traces/engrams). We first administered a battery of tests examining depressive- and anxiety-like behaviors, as well as spatial, social, and cognitive memory to APP/PS1 × ArcCreER T2 × channelrhodopsin (ChR2)-enhanced yellow fluorescent protein (EYFP) mice. Dentate gyrus (DG) neural ensembles were then optogenetically stimulated in these mice to improve memory impairment. AD mice had the most extensive differences in fear memory, as assessed by contextual fear conditioning (CFC), which was accompanied by impaired DG memory traces. Optogenetic stimulation of DG neural ensembles representing a CFC memory increased memory retrieval in the appropriate context in AD mice when compared with control (Ctrl) mice. Moreover, optogenetic stimulation facilitated reactivation of the neural ensembles that were previously activated during memory encoding. These data suggest that activating previously learned DG memory traces can rescue cognitive impairments and point to DG manipulation as a potential target to treat memory loss commonly seen in AD. © 2017 Wiley Periodicals, Inc.

  17. Decrement of GABAA receptor-mediated inhibitory postsynaptic currents in dentate granule cells in epileptic hippocampus.

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    Isokawa, M

    1996-05-01

    1. Inhibitory postsynaptic currents (IPSCs) were studied in hippocampal dentate granule cells (DGCs) in the pilocarpine model and human temporal lobe epilepsy, with the use of the whole cell patch-clamp recording technique in slice preparations. 2. In the pilocarpine model, hippocampal slices were prepared from rats that were allowed to experience spontaneous seizures for 2 mo. Human hippocampal specimens were obtained from epileptic patients who underwent surgical treatment for medically intractable seizures. 3. IPSCs were generated by single perforant path stimulation and recorded at a membrane potential (Vm) of 0 mV near the reversal potential of glutamate excitatory postsynaptic currents in the voltage-clamp recording. IPSCs were pharmacologically identified as gamma-aminobutyric acid-A (GABAA) IPSCs by 10 microM bicuculline methiodide. 4. During low-frequency stimulation, IPSCs were not different in amplitude among non-seizure-experienced rat hippocampi, human nonsclerotic hippocampi, seizure-experienced rat hippocampi, and human sclerotic hippocampi. In the last two groups of DGCs, current-clamp recordings indicated the presence of prolonged excitatory postsynaptic potentials (EPSPs) mediated by the N-methyl-D-aspartate (NMDA) receptor. 5. High-frequency stimulation, administered at Vm = -30 mV to activate NMDA currents, reduced GABAA IPSC amplitude specifically in seizure-experienced rat hippocampi (t = 2.5, P < 0.03) and human sclerotic hippocampi (t = 7.7, P < 0.01). This reduction was blocked by an NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV) (50 microM). The time for GABAA IPSCs to recover to their original amplitude was also shortened by the application of APV. 6. I conclude that, when intensively activated, NMDA receptor-mediated excitatory transmission may interact with GABAergic synaptic inhibition in DGCs in seizure-experienced hippocampus to transiently reduce GABA(A) receptor-channel function. Such interactions may contribute to

  18. R-Modafinil exerts weak effects on spatial memory acquisition and dentate gyrus synaptic plasticity.

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    Bharanidharan Shanmugasundaram

    Full Text Available Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP. Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT, and its phosphorylated form (ph-DAT in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.

  19. Methamphetamine decreases dentate gyrus stem cell self-renewal and shifts the differentiation towards neuronal fate

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    Sofia Baptista

    2014-09-01

    Full Text Available Methamphetamine (METH is a highly addictive psychostimulant drug of abuse that negatively interferes with neurogenesis. In fact, we have previously shown that METH triggers stem/progenitor cell death and decreases neuronal differentiation in the dentate gyrus (DG. Still, little is known regarding its effect on DG stem cell properties. Herein, we investigate the impact of METH on mice DG stem/progenitor cell self-renewal functions. METH (10 nM decreased DG stem cell self-renewal, while 1 nM delayed cell cycle in the G0/G1-to-S phase transition and increased the number of quiescent cells (G0 phase, which correlated with a decrease in cyclin E, pEGFR and pERK1/2 protein levels. Importantly, both drug concentrations (1 or 10 nM did not induce cell death. In accordance with the impairment of self-renewal capacity, METH (10 nM decreased Sox2+/Sox2+ while increased Sox2−/Sox2− pairs of daughter cells. This effect relied on N-methyl-d-aspartate (NMDA signaling, which was prevented by the NMDA receptor antagonist, MK-801 (10 μM. Moreover, METH (10 nM increased doublecortin (DCX protein levels consistent with neuronal differentiation. In conclusion, METH alters DG stem cell properties by delaying cell cycle and decreasing self-renewal capacities, mechanisms that may contribute to DG neurogenesis impairment followed by cognitive deficits verified in METH consumers.

  20. Dentate gyrus network dysfunctions precede the symptomatic phase in a genetic mouse model of seizures

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    Oana eToader

    2013-08-01

    Full Text Available Neuronal circuit disturbances that lead to hyperexcitability in the cortico-hippocampal network are one of the landmarks of temporal lobe epilepsy. The dentate gyrus (DG network plays an important role in regulating the excitability of the entire hippocampus by filtering and integrating information received via the perforant path. Here, we investigated possible epileptogenic abnormalities in the function of the DG neuronal network in the Synapsin II (Syn II knockout mouse (Syn II-/-, a genetic mouse model of epilepsy. Syn II is a presynaptic protein whose deletion in mice reproducibly leads to generalized seizures starting at the age of two months. We made use of a high-resolution microelectrode array (4096 electrodes and patch-clamp recordings, and found that in acute hippocampal slices of young pre-symptomatic (3-6 weeks-old Syn II-/- mice excitatory synaptic output of the mossy fibers is reduced. Moreover, we showed that the main excitatory neurons present in the polymorphic layer of the DG, hilar mossy cells, display a reduced excitability. We also provide evidence of a predominantly inhibitory regulatory output from mossy cells to granule cells, through feed-forward inhibition, and show that the excitatory-inhibitory ratio is increased in both pre-symptomatic and symptomatic Syn II-/- mice. These results support the key role of the hilar mossy neurons in maintaining the normal excitability of the hippocampal network and show that the late epileptic phenotype of the Syn II-/- mice is preceded by neuronal circuitry dysfunctions. Our data provide new insights into the mechanisms of epileptogenesis in the Syn II-/- mice and open the possibility for early diagnosis and therapeutic interventions.

  1. Late maturation of adult-born neurons in the temporal dentate gyrus.

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    Snyder, Jason S; Ferrante, Sarah C; Cameron, Heather A

    2012-01-01

    Hippocampal function varies along its septotemporal axis, with the septal (dorsal) pole more frequently involved in spatial learning and memory and the temporal (ventral) pole playing a greater role in emotional behaviors. One feature that varies across these subregions is adult neurogenesis. New neurons are more numerous in the septal hippocampus but are more active in the temporal hippocampus during water maze training. However, many other aspects of adult neurogenesis remain unexplored in the context of septal versus temporal subregions. In addition, the dentate gyrus contains another functionally important anatomical division along the transverse axis, with the suprapyramidal blade showing greater experience-related activity than the infrapyramidal blade. Here we ask whether new neurons differ in their rates of survival and maturation along the septotemporal and transverse axes. We found that neurogenesis is initially higher in the infrapyramidal than suprapyramidal blade, but these cells are less likely to survive, resulting in similar densities of neurons in the two blades by four weeks. Across the septotemporal axis, neurogenesis was higher in septal than temporal pole, while the survival rate of new neurons did not differ. Maturation was assessed by immunostaining for the neuronal marker, NeuN, which increases in expression level with maturation, and for the immediate-early gene, Arc, which suggests a neuron is capable of undergoing activity-dependent synaptic plasticity. Maturation occurred approximately 1-2 weeks earlier in the septal pole than in the temporal pole. This suggests that septal neurons may contribute to function sooner; however, the prolonged maturation of new temporal neurons may endow them with a longer window of plasticity during which their functions could be distinct from those of the mature granule cell population. These data point to subregional differences in new neuron maturation and suggest that changes in neurogenesis could alter

  2. Nitric oxide facilitates active avoidance learning via enhancement of glutamate levels in the hippocampal dentate gyrus.

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    Wang, Shi; Pan, De-Xi; Wang, Dan; Wan, Peng; Qiu, De-Lai; Jin, Qing-Hua

    2014-09-01

    The hippocampus is a key structure for learning and memory in mammals, and long-term potentiation (LTP) is an important cellular mechanism responsible for learning and memory. Despite a number of studies indicating that nitric oxide (NO) is involved in the formation and maintenance of LTP as a retrograde messenger, few studies have used neurotransmitter release as a visual indicator in awake animals to explore the role of NO in learning-dependent long-term enhancement of synaptic efficiency. Therefore, in the present study, the effects of l-NMMA (a NO synthase inhibitor) and SNP (a NO donor) on extracellular glutamate (Glu) concentrations and amplitudes of field excitatory postsynaptic potential (fEPSP) were measured in the hippocampal dentate gyrus (DG) region during the acquisition and extinction of active-avoidance behavior in freely-moving conscious rats. In the control group, the extracellular concentration of Glu in the DG was significantly increased during the acquisition of active-avoidance behavior and gradually returned to baseline levels following extinction training. In the experimental group, the change in Glu concentration was significantly reduced by local microinjection of l-NMMA, as was the acquisition of the active-avoidance behavior. In contrast, the change in Glu concentration was significantly enhanced by SNP, and the acquisition of the active-avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in extracellular Glu were accompanied by corresponding changes in fEPSP amplitude and active-avoidance behavior. Our results suggest that NO in the hippocampal DG facilitates active avoidance learning via enhancements of glutamate levels and synaptic efficiency in rats. Copyright © 2014 Elsevier B.V. All rights reserved.

  3. DREADD in parvalbumin interneurons of the dentate gyrus modulates anxiety, social interaction and memory extinction.

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    Zou, D; Chen, L; Deng, D; Jiang, D; Dong, F; McSweeney, C; Zhou, Y; Liu, L; Chen, G; Wu, Y; Mao, Y

    2016-01-01

    Parvalbumin (PV)-positive interneurons in the hippocampus play a critical role in animal memory, such as spatial working memory. However, how PV-positive interneurons in the subregions of the hippocampus affect animal behaviors remains poorly defined. Here, we achieved specific and reversible activation of PV-positive interneurons using designer receptors exclusively activated by designer drugs (DREADD) technology. Inducible DREADD expression was demonstrated in vitro in cultured neurons, in which co-transfection of the hM3D-Gq-mCherry vector with a Cre plasmid resulted in a cellular response to hM3Dq ligand clozapine-N-oxide (CNO) stimulation. In addition, the dentate gyrus (DG) of PV-Cre mice received bilateral injection of control lentivirus or lentivirus expressing double floxed hM3D-Gq-mCherry. Selective activation of PV-positive interneurons in the DG did not affect locomotor activity or depression-related behavior in mice. Interestingly, stimulation of PV-positive interneurons induced an anxiolytic effect. Activation of PVpositive interneurons appears to impair social interaction to novelty, but has no effect on social motivation. However, this defect is likely due to the anxiolytic effect as the exploratory behavior of mice expressing hM3DGq is significantly increased. Mice expressing hM3D-Gq did not affect novel object recognition. Activation of PV-positive interneurons in the DG maintains intact cued and contextual fear memory but facilitates fear extinction. Collectively, our results demonstrated that proper control of PV interneurons activity in the DG is critical for regulation of the anxiety, social interaction and fear extinction. These results improve our fundamental understanding of the physiological role of PV-positive interneurons in the hippocampus.

  4. MDMA-induced loss of parvalbumin interneurons within the dentate gyrus is mediated by 5HT2A and NMDA receptors.

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    Collins, Stuart A; Gudelsky, Gary A; Yamamoto, Bryan K

    2015-08-15

    MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation. Copyright © 2015 Elsevier B.V. All rights reserved.

  5. High Signal Intensity in the Dentate Nucleus and Globus Pallidus on Unenhanced T1-Weighted MR Images: Comparison between Gadobutrol and Linear Gadolinium-Based Contrast Agents.

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    Moser, F G; Watterson, C T; Weiss, S; Austin, M; Mirocha, J; Prasad, R; Wang, J

    2018-02-01

    In view of the recent observations that gadolinium deposits in brain tissue after intravenous injection, our aim of this study was to compare signal changes in the globus pallidus and dentate nucleus on unenhanced T1-weighted MR images in patients receiving serial doses of gadobutrol, a macrocyclic gadolinium-based contrast agent, with those seen in patients receiving linear gadolinium-based contrast agents. This was a retrospective analysis of on-site patients with brain tumors. Fifty-nine patients received only gadobutrol, and 60 patients received only linear gadolinium-based contrast agents. Linear gadolinium-based contrast agents included gadoversetamide, gadobenate dimeglumine, and gadodiamide. T1 signal intensity in the globus pallidus, dentate nucleus, and pons was measured on the precontrast portions of patients' first and seventh brain MRIs. Ratios of signal intensity comparing the globus pallidus with the pons (globus pallidus/pons) and dentate nucleus with the pons (dentate nucleus/pons) were calculated. Changes in the above signal intensity ratios were compared within the gadobutrol and linear agent groups, as well as between groups. The dentate nucleus/pons signal ratio increased in the linear gadolinium-based contrast agent group ( t = 4.215, P linear gadolinium-based contrast agent group ( t = 2.931, P linear gadolinium-based contrast agents. © 2018 by American Journal of Neuroradiology.

  6. A septo-temporal molecular gradient of sfrp3 in the dentate gyrus differentially regulates quiescent adult hippocampal neural stem cell activation.

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    Sun, Jiaqi; Bonaguidi, Michael A; Jun, Heechul; Guo, Junjie U; Sun, Gerald J; Will, Brett; Yang, Zhengang; Jang, Mi-Hyeon; Song, Hongjun; Ming, Guo-li; Christian, Kimberly M

    2015-09-04

    A converging body of evidence indicates that levels of adult hippocampal neurogenesis vary along the septo-temporal axis of the dentate gyrus, but the molecular mechanisms underlying this regional heterogeneity are not known. We previously identified a niche mechanism regulating proliferation and neuronal development in the adult mouse dentate gyrus resulting from the activity-regulated expression of secreted frizzled-related protein 3 (sfrp3) by mature neurons, which suppresses activation of radial glia-like neural stem cells (RGLs) through inhibition of Wingless/INT (WNT) protein signaling. Here, we show that activation rates within the quiescent RGL population decrease gradually along the septo-temporal axis in the adult mouse dentate gyrus, as defined by MCM2 expression in RGLs. Using in situ hybridization and quantitative real-time PCR, we identified an inverse septal-to-temporal increase in the expression of sfrp3 that emerges during postnatal development. Elimination of sfrp3 and its molecular gradient leads to increased RGL activation, preferentially in the temporal region of the adult dentate gyrus. Our study identifies a niche mechanism that contributes to the graded distribution of neurogenesis in the adult dentate gyrus and has important implications for understanding functional differences associated with adult hippocampal neurogenesis along the septo-temporal axis.

  7. Dentate network activity is necessary for spatial working memory by supporting CA3 sharp-wave ripple generation and prospective firing of CA3 neurons.

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    Sasaki, Takuya; Piatti, Verónica C; Hwaun, Ernie; Ahmadi, Siavash; Lisman, John E; Leutgeb, Stefan; Leutgeb, Jill K

    2018-02-01

    Complex spatial working memory tasks have been shown to require both hippocampal sharp-wave ripple (SWR) activity and dentate gyrus (DG) neuronal activity. We therefore asked whether DG inputs to CA3 contribute to spatial working memory by promoting SWR generation. Recordings from DG and CA3 while rats performed a dentate-dependent working memory task on an eight-arm radial maze revealed that the activity of dentate neurons and the incidence rate of SWRs both increased during reward consumption. We then found reduced reward-related CA3 SWR generation without direct input from dentate granule neurons. Furthermore, CA3 cells with place fields in not-yet-visited arms preferentially fired during SWRs at reward locations, and these prospective CA3 firing patterns were more pronounced for correct trials and were dentate-dependent. These results indicate that coordination of CA3 neuronal activity patterns by DG is necessary for the generation of neuronal firing patterns that support goal-directed behavior and memory.

  8. Chronic Fluoxetine Induces the Enlargement of Perforant Path-Granule Cell Synapses in the Mouse Dentate Gyrus

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    Kitahara, Yosuke; Ohta, Keisuke; Hasuo, Hiroshi; Shuto, Takahide; Kuroiwa, Mahomi; Sotogaku, Naoki; Togo, Akinobu; Nakamura, Kei-ichiro; Nishi, Akinori

    2016-01-01

    A selective serotonin reuptake inhibitor is the most commonly prescribed antidepressant for the treatment of major depression. However, the mechanisms underlying the actions of selective serotonin reuptake inhibitors are not fully understood. In the dentate gyrus, chronic fluoxetine treatment induces increased excitability of mature granule cells (GCs) as well as neurogenesis. The major input to the dentate gyrus is the perforant path axons (boutons) from the entorhinal cortex (layer II). Through voltage-sensitive dye imaging, we found that the excitatory neurotransmission of the perforant path synapse onto the GCs in the middle molecular layer of the mouse dentate gyrus (perforant path-GC synapse) is enhanced after chronic fluoxetine treatment (15 mg/kg/day, 14 days). Therefore, we further examined whether chronic fluoxetine treatment affects the morphology of the perforant path-GC synapse, using FIB/SEM (focused ion beam/scanning electron microscopy). A three-dimensional reconstruction of dendritic spines revealed the appearance of extremely large-sized spines after chronic fluoxetine treatment. The large-sized spines had a postsynaptic density with a large volume. However, chronic fluoxetine treatment did not affect spine density. The presynaptic boutons that were in contact with the large-sized spines were large in volume, and the volumes of the mitochondria and synaptic vesicles inside the boutons were correlated with the size of the boutons. Thus, the large-sized perforant path-GC synapse induced by chronic fluoxetine treatment contains synaptic components that correlate with the synapse size and that may be involved in enhanced glutamatergic neurotransmission. PMID:26788851

  9. Effects of rapamycin treatment after controlled cortical impact injury on neurogenesis and synaptic reorganization in the mouse dentate gyrus

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    Corwin R Butler

    2015-11-01

    Full Text Available Post-traumatic epilepsy (PTE is one consequence of traumatic brain injury (TBI. A prominent cell signaling pathway activated in animal models of both TBI and epilepsy is the mammalian target of rapamycin (mTOR. Inhibition of mTOR with rapamycin has shown promise as a potential modulator of epileptogenesis in several animal models of epilepsy, but cellular mechanisms linking mTOR expression and epileptogenesis are unclear. In this study, the role of mTOR in modifying functional hippocampal circuit reorganization after focal TBI induced by controlled cortical impact was investigated. Rapamycin (3 or 10 mg/kg, an inhibitor of mTOR signaling, was administered by intraperitoneal injection beginning on the day of injury and continued daily until tissue collection. Relative to controls, rapamycin treatment reduced dentate granule cell area in the hemisphere ipsilateral to the injury two weeks post-injury. Brain injury resulted in a significant increase in doublecortin immunolabeling in the dentate gyrus ipsilateral to the injury, indicating increased neurogenesis shortly after TBI. Rapamycin treatment prevented the increase in doublecortin labeling, with no overall effect on Fluoro-Jade B staining in the ipsilateral hemisphere, suggesting that rapamycin treatment reduced posttraumatic neurogenesis but did not prevent cell loss after injury. At later times post-injury (8-13 weeks, evidence of mossy fiber sprouting and increased recurrent excitation of dentate granule cells was detected, which were attenuated by rapamycin treatment. Rapamycin treatment also diminished seizure prevalence relative to vehicle-treated controls after TBI. Collectively, these results support a role for adult neurogenesis in PTE development and suggest that suppression of epileptogenesis by mTOR inhibition includes effects on post-injury neurogenesis.

  10. Glutamatergic stimulation of the left dentate gyrus abolishes depressive-like behaviors in a rat learned helplessness paradigm.

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    Seo, Jeho; Cho, Hojin; Kim, Gun Tae; Kim, Chul Hoon; Kim, Dong Goo

    2017-10-01

    Episodic experiences of stress have been identified as the leading cause of major depressive disorder (MDD). The occurrence of MDD is profoundly influenced by the individual's coping strategy, rather than the severity of the stress itself. Resting brain activity has been shown to alter in several mental disorders. However, the functional relationship between resting brain activity and coping strategies has not yet been studied. In the present study, we observed different patterns of resting brain activity in rats that had determined either positive (resilient to stress) or negative (vulnerable to stress) coping strategies, and examined whether modulation of the preset resting brain activity could influence the behavioral phenotype associated with negative coping strategy (i.e., depressive-like behaviors). We used a learned helplessness paradigm-a well-established model of MDD-to detect coping strategies. Differences in resting state brain activity between animals with positive and negative coping strategies were assessed using 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Glutamatergic stimulation was used to modulate resting brain activity. After exposure to repeated uncontrollable stress, seven of 23 rats exhibited positive coping strategies, while eight of 23 rats exhibited negative coping strategies. Increased resting brain activity was observed only in the left ventral dentate gyrus of the positive coping rats using FDG-PET. Furthermore, glutamatergic stimulation of the left dentate gyrus abolished depressive-like behaviors in rats with negative coping strategies. Increased resting brain activity in the left ventral dentate gyrus helps animals to select positive coping strategies in response to future stress. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Differential gene expression in dentate granule cells in mesial temporal lobe epilepsy with and without hippocampal sclerosis.

    Science.gov (United States)

    Griffin, Nicole G; Wang, Yu; Hulette, Christine M; Halvorsen, Matt; Cronin, Kenneth D; Walley, Nicole M; Haglund, Michael M; Radtke, Rodney A; Skene, J H Pate; Sinha, Saurabh R; Heinzen, Erin L

    2016-03-01

    Hippocampal sclerosis is the most common neuropathologic finding in cases of medically intractable mesial temporal lobe epilepsy. In this study, we analyzed the gene expression profiles of dentate granule cells of patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis to show that next-generation sequencing methods can produce interpretable genomic data from RNA collected from small homogenous cell populations, and to shed light on the transcriptional changes associated with hippocampal sclerosis. RNA was extracted, and complementary DNA (cDNA) was prepared and amplified from dentate granule cells that had been harvested by laser capture microdissection from surgically resected hippocampi from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis. Sequencing libraries were sequenced, and the resulting sequencing reads were aligned to the reference genome. Differential expression analysis was used to ascertain expression differences between patients with and without hippocampal sclerosis. Greater than 90% of the RNA-Seq reads aligned to the reference. There was high concordance between transcriptional profiles obtained for duplicate samples. Principal component analysis revealed that the presence or absence of hippocampal sclerosis was the main determinant of the variance within the data. Among the genes up-regulated in the hippocampal sclerosis samples, there was significant enrichment for genes involved in oxidative phosphorylation. By analyzing the gene expression profiles of dentate granule cells from surgically resected hippocampal specimens from patients with mesial temporal lobe epilepsy with and without hippocampal sclerosis, we have demonstrated the utility of next-generation sequencing methods for producing biologically relevant results from small populations of homogeneous cells, and have provided insight on the transcriptional changes associated with this pathology. Wiley Periodicals, Inc. © 2016

  12. Lesions of entorhinal cortex produce a calpain-mediated degradation of brain spectrin in dentate gyrus. I. Biochemical studies.

    Science.gov (United States)

    Seubert, P; Ivy, G; Larson, J; Lee, J; Shahi, K; Baudry, M; Lynch, G

    1988-09-06

    Lesions of the rat entorhinal cortex cause extensive synaptic restructuring and perturbation of calcium regulation in the dentate gyrus of hippocampus. Calpain is a calcium-activated protease which has been implicated in degenerative phenomena in muscles and in peripheral nerves. In addition, calpain degrades several major structural neuronal proteins and has been proposed to play a critical role in the morphological changes observed following deafferentation. In this report we present evidence that lesions of the entorhinal cortex produce a marked increase in the breakdown of brain spectrin, a substrate for calpain, in the dentate gyrus. Two lines of evidence indicate that this effect is due to calpain activation: (i) the spectrin breakdown products observed following the lesion are indistinguishable from calpain-generated spectrin fragments in vitro; and (ii) their appearance can be reduced by prior intraventricular in fusion of leupeptin, a calpain inhibitor. Levels of spectrin breakdown products are increased as early as 4 h post-lesion, reach maximal values at 2 days, and remain above normal to some degree for at least 27 days. In addition, a small but significant increase in spectrin proteolysis is also observed in the hippocampus contralateral to the lesioned side in the first week postlesion. At 2 days postlesion the total spectrin immunoreactivity (native polypeptide plus breakdown products) increases by 40%, suggesting that denervation of the dentate gyrus produces not only an increased rate of spectrin degradation but also an increased rate of spectrin synthesis. These results indicate that calpain activation and spectrin degradation are early biochemical events following deafferentation and might well participate in the remodelling of postsynaptic structures. Finally, the magnitude of the observed effects as well as the stable nature of the breakdown products provide a sensitive assay for neuronal pathology.

  13. The effect of a commercial probiotic drink containing Lactobacillus casei strain Shirota on oral health in healthy dentate people

    Directory of Open Access Journals (Sweden)

    Justyna Sutula

    2013-10-01

    Full Text Available Background: In the past decade, the use of probiotic-containing products has been explored as a potential alternative in oral health therapy. A widely available probiotic drink, Yakult, was evaluated for oral health applications in this longitudinal study. Selected oral health parameters, such as levels and composition of salivary and tongue plaque microbiota and of malodorous gases, in dentate healthy individuals were investigated for changes. The persistence of the probiotic strain in the oral cavity was monitored throughout the study period. Methods: A three-phase study (7 weeks was designed to investigate simultaneously the effect of 4-week consumption of the probiotic-containing milk drink Yakult on the microbiota of saliva and dorsum tongue coating in healthy dentate people (n = 22 and levels of volatile sulphur compounds (VSCs in morning breath. Study phases comprised one baseline visit, at which ‘control’ levels of oral parameters were obtained prior to the probiotic product consumption; a 4-week period of daily consumption of one 65 ml bottle of Yakult, each bottle containing a minimum of 6.5×109 viable cells of Lactobacillus casei strain Shirota (LcS; and a 2-week washout period. The microbial viability and composition of saliva and tongue dorsum coating were assessed using a range of solid media. The presence of LcS in the oral cavity was investigated using a novel selective medium, ‘LcS Select’. Portable sulphur monitors Halimeter® and OralChromaTM were used to measure levels of VSCs in morning breath. Results: Utilization of the LcS Select medium revealed a significant (p < 0.05 but temporary and consumption-dependent presence of LcS in saliva and tongue plaque samples from healthy dentate individuals (n = 19 during the probiotic intervention phase. LcS was undetectable with culture after 2 weeks of ceasing its consumption. Morning breath scores measured with Halimeter and OralChroma were not significantly affected

  14. Selection of distinct populations of dentate granule cells in response to inputs as a mechanism for pattern separation in mice

    OpenAIRE

    Deng, Wei; Mayford, Mark; Gage, Fred H

    2013-01-01

    eLife digest Being able to keep memories of similar events separate in your mind is an essential part of remembering. If you use the same carpark every day, recalling where you left your car this morning is challenging, not because you have to remember an event from long ago, but because you have to distinguish between many similar memories. Keeping memories distinct is one of the functions of a subregion of the hippocampus called the dentate gyrus. The process of taking complex memories and ...

  15. Melatonin attenuates scopolamine-induced cognitive impairment via protecting against demyelination through BDNF-TrkB signaling in the mouse dentate gyrus.

    Science.gov (United States)

    Chen, Bai Hui; Park, Joon Ha; Lee, Tae-Kyeong; Song, Minah; Kim, Hyunjung; Lee, Jae Chul; Kim, Young-Myeong; Lee, Choong-Hyun; Hwang, In Koo; Kang, Il Jun; Yan, Bing Chun; Won, Moo-Ho; Ahn, Ji Hyeon

    2018-04-01

    Animal models of scopolamine-induced amnesia are widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies have identified that melatonin improves cognitive dysfunction in animal models. In this study, using a mouse model of scopolamine-induced amnesia, we assessed spatial and short-term memory functions for 4 weeks, investigated the expression of myelin-basic protein (MBP) in the dentate gyrus, and examined whether melatonin and scopolamine cotreatment could keep cognitive function and MBP expression. In addition, to study functions of melatonin for keeping cognitive function and MBP expression, we examined expressions of brain-derived neurotrophic factor (BDNF) and tropomycin receptor kinase B (TrkB) in the mouse dentate gyrus. Scopolamine (1 mg/kg) and melatonin (10 mg/kg) were intraperitoneally treated for 2 and 4 weeks. Two and 4 weeks after scopolamine treatment, mice showed significant cognitive impairment; however, melatonin and scopolamine cotreatment recovered cognitive impairment. Two and 4 weeks of scopolamine treatment, the density of MBP immunoreactive myelinated nerve fibers was significantly decreased in the dentate gyrus; however, scopolamine and melatonin cotreatment significantly increased the scopolamine-induced reduction of MBP expression in the dentate gyrus. Furthermore, the cotreatment of scopolamine and melatonin significantly increased the scopolamine-induced decrease of BDNF and TrKB immunoreactivity in the dentate gyrus. Taken together, our results indicate that melatonin treatment exerts anti-amnesic effect and restores the scopolamine-induced reduction of MBP expression through increasing BDNF and TrkB expressions in the mouse dentate gyrus. Copyright © 2018 Elsevier B.V. All rights reserved.

  16. Preictal activity of subicular, CA1, and dentate gyrus principal neurons in the dorsal hippocampus before spontaneous seizures in a rat model of temporal lobe epilepsy.

    Science.gov (United States)

    Fujita, Satoshi; Toyoda, Izumi; Thamattoor, Ajoy K; Buckmaster, Paul S

    2014-12-10

    Previous studies suggest that spontaneous seizures in patients with temporal lobe epilepsy might be preceded by increased action potential firing of hippocampal neurons. Preictal activity is potentially important because it might provide new opportunities for predicting when a seizure is about to occur and insight into how spontaneous seizures are generated. We evaluated local field potentials and unit activity of single, putative excitatory neurons in the subiculum, CA1, CA3, and dentate gyrus of the dorsal hippocampus in epileptic pilocarpine-treated rats as they experienced spontaneous seizures. Average action potential firing rates of neurons in the subiculum, CA1, and dentate gyrus, but not CA3, increased significantly and progressively beginning 2-4 min before locally recorded spontaneous seizures. In the subiculum, CA1, and dentate gyrus, but not CA3, 41-57% of neurons displayed increased preictal activity with significant consistency across multiple seizures. Much of the increased preictal firing of neurons in the subiculum and CA1 correlated with preictal theta activity, whereas preictal firing of neurons in the dentate gyrus was independent of theta. In addition, some CA1 and dentate gyrus neurons displayed reduced firing rates preictally. These results reveal that different hippocampal subregions exhibit differences in the extent and potential underlying mechanisms of preictal activity. The finding of robust and significantly consistent preictal activity of subicular, CA1, and dentate neurons in the dorsal hippocampus, despite the likelihood that many seizures initiated in other brain regions, suggests the existence of a broader neuronal network whose activity changes minutes before spontaneous seizures initiate. Copyright © 2014 the authors 0270-6474/14/3416671-17$15.00/0.

  17. Trends in annual dental visits among US dentate adults with and without self-reported diabetes and prediabetes, 2004-2014.

    Science.gov (United States)

    Luo, Huabin; Bell, Ronny A; Wright, Wanda; Wu, Qiang; Wu, Bei

    2018-03-31

    The authors assessed the trends of annual dental visits in dentate adults with diabetes or prediabetes or no diabetes, and assessed whether the racial and ethnic disparities in dental visits changed from 2004 through 2014. Data for this analysis came from the Behavioral Risk Factor Surveillance System, a US health survey that looks at behavioral risk factors that was developed by the Centers for Disease Control and Prevention in cooperation with state health departments. Respondents indicated whether they had a dental visit in the past 12 months. Weighted proportions were calculated for annual dental visits in adults by diabetes status, and trends were assessed by racial and ethnic groups. From 2004 through 2014, the proportion of annual dental visits declined from 66.1% to 61.4% (trend P = .02) in the diabetes group, 71.9% to 66.5% (trend P = .01) in the no diabetes group, and 66.0% to 64.9% (trend P = .33) in the prediabetes group. Age, income, and health insurance were moderators of the association between diabetes status and dental visits. Overall, the racial and ethnic disparity in dental visits did not change significantly during the period. Dental visits and services were less frequent in people with diabetes and prediabetes. Racial and ethnic disparities in use of dental services persisted during the observed period. All patients, especially those with diabetes, are encouraged to visit a dentist at least annually. It is important for health care providers, such as primary care physicians and dental care and public health professionals, to make concerted efforts to promote oral health care in diabetes management. Improving access to dental services is vital to achieving this goal. Copyright © 2018 American Dental Association. Published by Elsevier Inc. All rights reserved.

  18. Exposure to Forced Swim Stress Alters Local Circuit Activity and Plasticity in the Dentate Gyrus of the Hippocampus

    Directory of Open Access Journals (Sweden)

    Mouna Maroun

    2008-02-01

    Full Text Available Studies have shown that, depending on its severity and context, stress can affect neural plasticity. Most related studies focused on synaptic plasticity and long-term potentiation (LTP of principle cells. However, evidence suggests that following high-frequency stimulation, which induces LTP in principal cells, modifications also take place at the level of complex interactions with interneurons within the dentate gyrus, that is, at the local circuit level. So far, the possible effects of stress on local circuit activity and plasticity were not studied. Therefore, we set out to examine the possible alterations in local circuit activity and plasticity following exposure to stress. Local circuit activity and plasticity were measured by using frequency dependant inhibition (FDI and commissural modulation protocols following exposure to a 15 minute-forced swim trial. Exposure to stress did not alter FDI. The application of theta-burst stimulation (TBS reduced FDI in both control and stressed rats, but this type of plasticity was greater in stressed rats. Commissural-induced inhibition was significantly higher in stressed rats both before and after applying theta-burst stimulation. These findings indicate that the exposure to acute stress affects aspects of local circuit activity and plasticity in the dentate gyrus. It is possible that these alterations underlie some of the behavioral consequences of the stress experience.

  19. Exposure to Forced Swim Stress Alters Local Circuit Activity and Plasticity in the Dentate Gyrus of the Hippocampus

    Science.gov (United States)

    Yarom, Orli; Maroun, Mouna; Richter-Levin, Gal

    2008-01-01

    Studies have shown that, depending on its severity and context, stress can affect neural plasticity. Most related studies focused on synaptic plasticity and long-term potentiation (LTP) of principle cells. However, evidence suggests that following high-frequency stimulation, which induces LTP in principal cells, modifications also take place at the level of complex interactions with interneurons within the dentate gyrus, that is, at the local circuit level. So far, the possible effects of stress on local circuit activity and plasticity were not studied. Therefore, we set out to examine the possible alterations in local circuit activity and plasticity following exposure to stress. Local circuit activity and plasticity were measured by using frequency dependant inhibition (FDI) and commissural modulation protocols following exposure to a 15 minute-forced swim trial. Exposure to stress did not alter FDI. The application of theta-burst stimulation (TBS) reduced FDI in both control and stressed rats, but this type of plasticity was greater in stressed rats. Commissural-induced inhibition was significantly higher in stressed rats both before and after applying theta-burst stimulation. These findings indicate that the exposure to acute stress affects aspects of local circuit activity and plasticity in the dentate gyrus. It is possible that these alterations underlie some of the behavioral consequences of the stress experience. PMID:18301720

  20. Lipopolysaccharide causes deficits in spatial learning in the watermaze but not in BDNF expression in the rat dentate gyrus.

    Science.gov (United States)

    Shaw, K N; Commins, S; O'Mara, S M

    2001-09-28

    We investigated the effects of a single injection and a daily injection of lipopolysaccharide (LPS) on spatial learning and brain-derived neurotrophic factor (BDNF) expression in the rat dentate gyrus. LPS is derived from the cell wall of Gram-negative bacteria and is a potent endotoxin that causes the release of cytokines such as interleukin-1 and tumour necrosis factor. LPS is thought to activate both the neuroimmune and neuroendocrine systems; it also blocks long-term potentiation in the hippocampus. Here, we examined the effects of LPS on a form of hippocampal-dependent learning-spatial learning in the water maze. Rats were injected with LPS intraperitoneally (100 microg/kg) and trained in the water maze. The first group of rats were injected on day 1 of training, 4 h prior to learning the water maze task. Groups 2 and 3 were injected daily, again 4 h prior to the water-maze task; group 2 with LPS and group 3 with saline. A number of behavioural variables were recorded by a computerised tracking system for each trial. The behavioural results showed a single injection of LPS (group 1) impaired escape latency in both the acquisition and retention phases of the study, whereas a daily injection of LPS did not significantly impair acquisition or retention. BDNF expression was analysed in the dentate gyrus of all animals. No significant differences in BDNF expression were found between the three groups.

  1. Neurofascin Knock Down in the Basolateral Amygdala Mediates Resilience of Memory and Plasticity in the Dorsal Dentate Gyrus Under Stress.

    Science.gov (United States)

    Saha, Rinki; Kriebel, Martin; Volkmer, Hansjürgen; Richter-Levin, Gal; Albrecht, Anne

    2018-02-05

    Activation of the amygdala is one of the hallmarks of acute stress reactions and a central element of the negative impact of stress on hippocampus-dependent memory and cognition. Stress-induced psychopathologies, such as posttraumatic stress disorder, exhibit a sustained hyperactivity of the amygdala, triggered at least in part by deficits in GABAergic inhibition that lead to shifts in amygdalo-hippocampal interaction. Here, we have utilized lentiviral knock down of neurofascin to reduce GABAergic inhibition specifically at the axon initial segment (AIS) of principal neurons within the basolateral amygdala (BLA) of rats. Metaplastic effects of such a BLA modulation on hippocampal synaptic function were assessed using BLA priming prior to the induction of long-term potentiation (LTP) on dentate gyrus synapses in anesthetized rats in vivo. The knock down of neurofascin in the BLA prevented a priming-induced impairment on LTP maintenance in the dentate gyrus. At the behavioral level, a similar effect was observable, with neurofascin knock down preventing the detrimental impact of acute traumatic stress on hippocampus-dependent spatial memory retrieval in a water maze task. These findings suggest that reducing GABAergic inhibition specifically at the AIS synapses of the BLA alters amygdalo-hippocampal interactions such that it attenuates the adverse impact of acute stress exposure on cognition-related hippocampal functions.

  2. Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis.

    Science.gov (United States)

    Nandi, Sayan; Alviña, Karina; Lituma, Pablo J; Castillo, Pablo E; Hébert, Jean M

    2018-01-15

    Dentate granule cells (DGCs) play important roles in cognitive processes. Knowledge about how growth factors such as FGFs and neurotrophins contribute to the maturation and synaptogenesis of DGCs is limited. Here, using brain-specific and germline mouse mutants we show that a module of neurotrophin and FGF signaling, the FGF Receptor Substrate (FRS) family of intracellular adapters, FRS2 and FRS3, are together required for postnatal brain development. In the hippocampus, FRS promotes dentate gyrus morphogenesis and DGC maturation during developmental neurogenesis, similar to previously published functions for both neurotrophins and FGFs. Consistent with a role in DGC maturation, two-photon imaging revealed that Frs2,3-double mutants have reduced numbers of dendritic branches and spines in DGCs. Functional analysis further showed that double-mutant mice exhibit fewer excitatory synaptic inputs onto DGCs. These observations reveal roles for FRS adapters in DGC maturation and synaptogenesis and suggest that FRS proteins may act as an important node for FGF and neurotrophin signaling in postnatal hippocampal development. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Theta and beta oscillatory dynamics in the dentate gyrus reveal a shift in network processing state during cue encounters

    Directory of Open Access Journals (Sweden)

    Lara Maria Rangel

    2015-07-01

    Full Text Available The hippocampus is an important structure for learning and memory processes, and has strong rhythmic activity. Although a large amount of research has been dedicated towards understanding the rhythmic activity in the hippocampus during exploratory behaviors, specifically in the theta (5-10 Hz frequency range, few studies have examined the temporal interplay of theta and other frequencies during the presentation of meaningful cues. We obtained in vivo electrophysiological recordings of local field potentials (LFP in the dentate gyrus (DG of the hippocampus as rats performed three different associative learning tasks. In each task, cue presentations elicited pronounced decrements in theta amplitude in conjunction with increases in beta (15-30Hz amplitude. These changes were often transient but were sustained from the onset of cue encounters until the occurrence of a reward outcome. This oscillatory profile shifted in time to precede cue encounters over the course of the session, and was not present during similar behavior in the absence of task relevant stimuli. The observed decreases in theta amplitude and increases in beta amplitude in the dentate gyrus may thus reflect a shift in processing state that occurs when encountering meaningful cues.

  4. Influence of intra-oral sensory impairment by anaesthesia on food comminution and mixing in dentate subjects.

    Science.gov (United States)

    Yoshida, E; Fueki, K; Wakabayashi, N

    2015-06-01

    Sensory input from sensory receptors regarding food morsels can affect jaw motor behaviours during mastication. The aim was to clarify the effects of intra-oral sensory input on the food-comminuting and food-mixing capacities of dentate subjects. Eleven dentate subjects without sensory dysfunction in their oro-facial region participated in this study. Local anaesthesia was achieved on the periodontal structures and on the oral mucosa of the subjects' preferred chewing side by injecting a lidocaine solution with adrenalin. At baseline (control) and after anaesthesia, data on the subjects' food-comminuting and food-mixing capacities were gathered. The food-comminuting capacity was quantified by measuring the degree of pulverisation of peanuts (objective hardness; 45.3 [Newton, N]) after a prescribed 20 chewing strokes. The food-mixing capacity was measured as the degree of immixture of a two-coloured paraffin wax cube after 10 chewing strokes. Wax cubes of three different hardness levels were used (soft, medium and hard: 20.3, 32.6 and 75.5 [N], respectively) and were chewed in random order. After anaesthesia, the subjects' food-comminuting capacity significantly decreased (P food-mixing capacity for each hardness level of the wax cubes (P food-mixing capacity (P deterioration of the mixing capacity increased as the hardness increased. In conclusion, intra-oral sensory input can affect both food-comminuting and food-mixing capacities. © 2015 John Wiley & Sons Ltd.

  5. Dentate gyrus expression of nestin-immunoreactivity in patients with drug-resistant temporal lobe epilepsy and hippocampal sclerosis.

    Science.gov (United States)

    D'Alessio, L; Konopka, H; Escobar, E; Acuña, A; Oddo, S; Solís, P; Seoane, E; Kochen, S

    2015-04-01

    Granule cells pathology in dentate gyrus, have received considerable attention in terms of understanding the pathophysiology of temporal lobe epilepsy with hippocampal sclerosis. The aim of this study was to determine the nestin (an intermediate filament protein expressed by newly formed cells), immunoreactivity (IR) in granular cells layers of hippocampal tissue extirpated during epilepsy surgical procedure, in patients with drug-resistant epilepsy. Hippocampal sections of 16 patients with hippocampal sclerosis and drug-resistant temporal lobe epilepsy were processed using immunoperoxidase with antibody to nestin. Archival material from 8 normal post-mortem hippocampus, were simultaneously processed. Reactive area for nestin-IR, the total number of positive nestin cells per field (20×), and the MGV (mean gray value) was determined by computerized image analysis (ImageJ), and compared between groups. Student's t test was used for statistical analysis. Nestin-IR cells were found in granule cells layers of both controls and patients. Larger reactive somas (p gyrus may reflect changes in dentate gyrus neuroplasticity associated to chronic temporal epilepsy with hippocampal sclerosis. Further studies are required to determine the clinical implications on memory an emotional alterations such as depression. Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  6. The GAD-given Right of Dentate Gyrus Granule Cells to Become GABAergic

    Science.gov (United States)

    Mody, Istvan

    2002-01-01

    low-affinity neurotrophin receptor p75NTR, perhaps as part of a programmed developmental switch, can convert the phenotype of the sympathetic neuron from noradrenergic to cholinergic 4. Other examples of two fast neurotransmitters released from the same neuron include GABA and glycine in interneurons of the spinal cord 5 and glutamate and dopamine in ventral midbrain dopamine neurons 6. Of all CNS neurons, the granule cells of the dentate gyrus appear to be the champions of neurotransmitter colocalization: glutamate, enkephalin, dynorphin, zinc, and finally GABA 2, 7, 8, 9. With this many transmitters in a single neuron, there are probably different ways in which they can be released. Dynorphin and other opioid peptides can be released directly from the dendrites to inhibit excitatory transmission 8. A similar mechanism may take place for GABA, as described in cortical GABAergic neurons 10. PMID:15309121

  7. Altered expression of the cell cycle regulatory protein cyclin D1 in the rat dentate gyrus after adrenalectomy-induced granular cell lass

    NARCIS (Netherlands)

    Postigo, JA; Van der Werf, YD; Korf, J; Krugers, HJ

    1998-01-01

    The loss of dentate gyrus (DG) granular cells after removal of the rat adrenal glands (ADX) is mediated by a process that is apoptotic in nature. The present study was initiated to compare changes in the immunocytochemical distribution of the cell-cycle regulatory protein cyclin D1, which has been

  8. DEVELOPMENTAL LEAD (PB) EXPOSURE REDUCES THE ABILITY OF THE NNDA ANTAGONIST MK801 TO SUPPRESS LONG-TERM POTENTIATION (LTP) IN THE RAT DENTATE GYRUS, IN VIVO

    Science.gov (United States)

    Chronic developmental lead (Pb) exposure increases the threshold and enhances decay of long-term potentiation (LTP) in the dentate gyrus of the hippocampal formation. MK-801 and other antagonists of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype impair induction of LT...

  9. Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights from In Vivo Recordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts.

    Science.gov (United States)

    Jedlicka, Peter; Muellerleile, Julia; Schwarzacher, Stephan W

    2018-01-01

    The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1) and inhibitory synapses (neuroligin-2 and collybistin). In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

  10. Synaptic Plasticity and Excitation-Inhibition Balance in the Dentate Gyrus: Insights from In Vivo Recordings in Neuroligin-1, Neuroligin-2, and Collybistin Knockouts

    Directory of Open Access Journals (Sweden)

    Peter Jedlicka

    2018-01-01

    Full Text Available The hippocampal dentate gyrus plays a role in spatial learning and memory and is thought to encode differences between similar environments. The integrity of excitatory and inhibitory transmission and a fine balance between them is essential for efficient processing of information. Therefore, identification and functional characterization of crucial molecular players at excitatory and inhibitory inputs is critical for understanding the dentate gyrus function. In this minireview, we discuss recent studies unraveling molecular mechanisms of excitatory/inhibitory synaptic transmission, long-term synaptic plasticity, and dentate granule cell excitability in the hippocampus of live animals. We focus on the role of three major postsynaptic proteins localized at excitatory (neuroligin-1 and inhibitory synapses (neuroligin-2 and collybistin. In vivo recordings of field potentials have the advantage of characterizing the effects of the loss of these proteins on the input-output function of granule cells embedded in a network with intact connectivity. The lack of neuroligin-1 leads to deficient synaptic plasticity and reduced excitation but normal granule cell output, suggesting unaltered excitation-inhibition ratio. In contrast, the lack of neuroligin-2 and collybistin reduces inhibition resulting in a shift towards excitation of the dentate circuitry.

  11. Dentate gyrus and hilus transection blocks seizure propagation and granule cell dispersion in a mouse model for mesial temporal lobe epilepsy.

    Science.gov (United States)

    Pallud, Johan; Häussler, Ute; Langlois, Mélanie; Hamelin, Sophie; Devaux, Bertrand; Deransart, Colin; Depaulis, Antoine

    2011-03-01

    Epilepsy-associated changes of the anatomical organization of the dentate gyrus and hilus may play a critical role in the initiation and propagation of seizures in mesial temporal lobe epilepsy (MTLE). This study evaluated the role of longitudinal projections in the propagation of hippocampal paroxysmal discharges (HPD) in dorsal hippocampus by performing a selective transection in a mouse model for MTLE obtained by a single unilateral intrahippocampal injection of kainic acid (KA). Full transections of the dentate gyrus and hilus were performed in the transverse axis at 22 days after KA injection when spontaneous HPD were fully developed. They: (i) significantly reduced the occurrence of HPD; (ii) increased their duration at the KA injection site; (iii) abolished their spread along the longitudinal axis of the hippocampal formation and; (iv) limited granule cell dispersion (GCD) of the dentate gyrus posterior to the transection. These data suggest that: (i) longitudinal projections through the dentate gyrus and hilus are involved in HPD spread; (ii) distant hippocampal circuits participate in the generation and cessation of HPD and; (iii) GCD requires continuous HPD to develop, even when seizures are established. Our data reveal a critical role for longitudinal projections in the generation and spread of hippocampal seizures. Copyright © 2010 Wiley-Liss, Inc.

  12. Age-dependent role for Ras-GRF1 in the late stages of adult neurogenesis in the dentate gyrus.

    Science.gov (United States)

    Darcy, Michael J; Trouche, Stéphanie; Jin, Shan-Xue; Feig, Larry A

    2014-03-01

    The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RASGRF1(GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis.We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2-month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which

  13. A STEREOLOGICAL ANALYSIS OF THE EFFECT OF EARLY POSTNATAL ETHANOL EXPOSURE ON NEURONAL NUMBERS IN RAT DENTATE GYRUS

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    Takanori Miki

    2011-05-01

    Full Text Available Maternal ethanol ingestion during pregnancy can cause fetal alcohol syndrome (FAS in their offspring. Among the symptoms of FAS, damage to the central nervous system has emerged as one of the most serious problems. We have previously shown that a relatively high dose of ethanol exposure during early postnatal life can cause alterations in spatial learning ability. This ability is controlled, at least in part, by the hippocampal formation. The purpose of the present study was to determine whether exposure of rat pups to ethanol during early postnatal life had effects on the total number of the dentate gyrus neurons. Wistar rats were exposed to a relatively high daily dose of ethanol between postnatal days 10 to 15. Ethanol exposure was achieved by placing rat pups in a chamber containing ethanol vapour for 3 hours a day. The blood ethanol concentration was found to be about 430 mg/dL at the end of the exposure period. Groups of ethanol treated (ET, separation controls (SC and mother reared controls (MRC were anaesthetised and killed at 16-days-of-age by perfusion with phosphate-buffered 2.5% glutaraldehyde. The Cavalieri principle was used to determine the volume of subdivisions of the dentate gyrus, and the physical disector method was used to estimate the numerical densities of neurons within each subdivision. The total number of neurons was calculated by multiplying estimates of the numerical density with the volume. There was, on average, about 421,000 granule cells in all three treatment groups. In the hilus region, ET rats had about 27,000 neuronal cells. This value was significantly smaller than the average of 38,000 such neurons estimated to be present in both MRC and SC animals. It is concluded that neurons in the hilus region of the dentate gyrus may be particularly vulnerable to the effects of a high dose of ethanol exposure during PND 10-15. It is likely that this deficit was due to neuronal death induced by some mechanisms related to

  14. Properties of doublecortin-(DCX-expressing cells in the piriform cortex compared to the neurogenic dentate gyrus of adult mice.

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    Friederike Klempin

    Full Text Available The piriform cortex receives input from the olfactory bulb and (via the entorhinal cortex sends efferents to the hippocampus, thereby connecting the two canonical neurogenic regions of the adult rodent brain. Doublecortin (DCX is a cytoskeleton-associated protein that is expressed transiently in the course of adult neurogenesis. Interestingly, the adult piriform cortex, which is usually considered non-neurogenic (even though some reports exist that state otherwise, also contains an abundant population of DCX-positive cells. We asked how similar these cells would be to DCX-positive cells in the course of adult hippocampal neurogenesis. Using BAC-generated transgenic mice that express GFP under the DCX promoter, we studied DCX-expression and electrophysiological properties of DCX-positive cells in the mouse piriform cortex in comparison with the dentate gyrus. While one class of cells in the piriform cortex indeed showed features similar to newly generated immature granule neurons, the majority of DCX cells in the piriform cortex was mature and revealed large Na+ currents and multiple action potentials. Furthermore, when proliferative activity was assessed, we found that all DCX-expressing cells in the piriform cortex were strictly postmitotic, suggesting that no DCX-positive "neuroblasts" exist here as they do in the dentate gyrus. We conclude that DCX in the piriform cortex marks a unique population of postmitotic neurons with a subpopulation that retains immature characteristics associated with synaptic plasticity. DCX is thus, per se, no marker of neurogenesis but might be associated more broadly with plasticity.

  15. Cultured subventricular zone progenitor cells transduced with neurogenin-2 become mature glutamatergic neurons and integrate into the dentate gyrus.

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    Xia Chen

    Full Text Available We have previously shown that transplantation of immature DCX+/NeuN+/Prox1+ neurons (found in the neonatal DG, but not undifferentiated neuronal progenitor cells (NPCs from ventral subventricular zone (SVZ, results in neuronal maturation in vivo within the dentate niche. Here we investigated whether we could enhance the integration of SVZ NPCs by forced expression of the proneural gene Neurogenin 2 (NEUROG2. NPCs cultured from neonatal GFP-transgenic rat SVZ for 7 days in a non-differentiating medium were transduced with a retrovirus encoding NEUROG2 and DsRed or the DsRed reporter gene alone (control. By 3 days post-transduction, the NEUROG2-transduced cells maintained in culture contained mostly immature neurons (91% DCX+; 76% NeuN+, whereas the control virus-transduced cells remained largely undifferentiated (30% DCX+; <1% NeuN+. At 6 weeks following transplantation into the DG of adult male rats, there were no neurons among the transplanted cells treated with the control virus but the majority of the NEUROG2-transduced DsRed+ SVZ cells became mature neurons (92% NeuN+; DCX-negative. Although the NEUROG2-transduced SVZ cells did not express the dentate granule neuron marker Prox1, most of the NEUROG2-transduced SVZ cells (78% expressed the glutamatergic marker Tbr1, suggesting the acquisition of a glutamatergic phenotype. Moreover, some neurons extended dendrites into the molecular layer, grew axons containing Ankyrin G+ axonal initial segments, and projected into the CA3 region, thus resembling mature DG granule neurons. A proportion of NEUROG2 transduced cells also expressed c-Fos and P-CREB, two markers of neuronal activation. We conclude that NEUROG2-transduction is sufficient to promote neuronal maturation and integration of transplanted NPCs from SVZ into the DG.

  16. Morphologic Integration of Hilar Ectopic Granule Cells into Dentate Gyrus Circuitry in the Pilocarpine Model of Temporal Lobe Epilepsy

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    Cameron, Michael C.; Zhan, Ren-Zhi; Nadler, J. Victor

    2014-01-01

    After pilocarpine-induced status epilepticus, many granule cells born into the postseizure environment migrate aberrantly into the dentate hilus. Hilar ectopic granule cells (HEGCs) are hyperexcitable and may therefore increase circuit excitability. This study determined the distribution of their axons and dendrites. HEGCs and normotopic granule cells were filled with biocytin during whole-cell patch clamp recording in hippocampal slices from pilocarpine-treated rats. The apical dendrite of 86% of the biocytin-labeled HEGCs extended to the outer edge of the dentate molecular layer. The total length and branching of HEGC apical dendrites that penetrated the molecular layer were significantly reduced compared with apical dendrites of normotopic granule cells. HEGCs were much more likely to have a hilar basal dendrite than normotopic granule cells. They were about as likely as normotopic granule cells to project to CA3 pyramidal cells within the slice, but were much more likely to send at least one recurrent mossy fiber into the molecular layer. HEGCs with burst capability had less well-branched apical dendrites than nonbursting HEGCs, their dendrites were more likely to be confined to the hilus, and some exhibited dendritic features similar to those of immature granule cells. HEGCs thus have many paths along which to receive synchronized activity from normotopic granule cells and to transmit their own hyperactivity to both normotopic granule cells and CA3 pyramidal cells. They may therefore contribute to the highly interconnected granule cell hubs that have been proposed as crucial to development of a hyperexcitable, potentially seizure-prone circuit. PMID:21455997

  17. Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

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    Buckmaster, Paul S.; Abrams, Emily; Wen, Xiling

    2018-01-01

    Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31–61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24–36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. PMID:28425097

  18. Priming stimulation of basal but not lateral amygdala affects long-term potentiation in the rat dentate gyrus in vivo.

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    Li, Z; Richter-Levin, G

    2013-08-29

    The amygdaloid complex, or amygdala, has been implicated in assigning emotional significance to sensory information and producing appropriate behavioral responses to external stimuli. The lateral and basal nuclei (lateral and basal amygdala), which are termed together as basolateral amygdala, play a critical role in emotional and motivational learning and memory. It has been established that the basolateral amygdala activation by behavioral manipulations or direct electrical stimulation can modulate hippocampal long-term potentiation (LTP), a putative cellular mechanism of memory. However, the specific functional role of each subnucleus in the modulation of hippocampal LTP has not been studied yet, even though studies have shown cytoarchitectural differences between the basal and lateral amygdala and differences in the connections of each one of them to other brain areas. In this study we have tested the effects of lateral or basal amygdala pre-stimulation on hippocampal dentate gyrus LTP, induced by theta burst stimulation of the perforant path, in anesthetized rats. We found that while priming stimulation of the lateral amygdala did not affect LTP of the dentate gyrus, priming stimulation of the basal amygdala enhanced the LTP response when the priming stimulation was relatively weak, but impaired it when it was relatively strong. These results show that the basal and lateral nuclei of the amygdala, which have been already shown to differ in their anatomy and connectivity, may also have different functional roles. These findings raise the possibility that the lateral and basal amygdala differentially modulate memory processes in the hippocampus under emotional and motivational situations. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

  19. Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy.

    Science.gov (United States)

    Buckmaster, Paul S; Abrams, Emily; Wen, Xiling

    2017-08-01

    Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31-61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24-36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy. © 2017 Wiley Periodicals, Inc.

  20. Dentate gyrus progenitor cell proliferation after the onset of spontaneous seizures in the tetanus toxin model of temporal lobe epilepsy.

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    Jiruska, Premysl; Shtaya, Anan B Y; Bodansky, David M S; Chang, Wei-Chih; Gray, William P; Jefferys, John G R

    2013-06-01

    Temporal lobe epilepsy alters adult neurogenesis. Existing experimental evidence is mainly from chronic models induced by an initial prolonged status epilepticus associated with substantial cell death. In these models, neurogenesis increases after status epilepticus. To test whether status epilepticus is necessary for this increase, we examined precursor cell proliferation and neurogenesis after the onset of spontaneous seizures in a model of temporal lobe epilepsy induced by unilateral intrahippocampal injection of tetanus toxin, which does not cause status or, in most cases, detectable neuronal loss. We found a 4.5 times increase in BrdU labeling (estimating precursor cells proliferating during the 2nd week after injection of toxin and surviving at least up to 7days) in dentate gyri of both injected and contralateral hippocampi of epileptic rats. Radiotelemetry revealed that the rats experienced 112±24 seizures, lasting 88±11s each, over a period of 8.6±1.3days from the first electrographic seizure. On the first day of seizures, their duration was a median of 103s, and the median interictal period was 23min, confirming the absence of experimentally defined status epilepticus. The total increase in cell proliferation/survival was due to significant population expansions of: radial glial-like precursor cells (type I; 7.2×), non-radial type II/III neural precursors in the dentate gyrus stem cell niche (5.6×), and doublecortin-expressing neuroblasts (5.1×). We conclude that repeated spontaneous brief temporal lobe seizures are sufficient to promote increased hippocampal neurogenesis in the absence of status epilepticus. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. The granule cell density of the dentate gyrus following administration of Urtica dioica extract to young diabetic rats.

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    Fazeli, S A; Gharravi, A M; Ghafari, S; Jahanshahi, M; Golalipour, M J

    2008-08-01

    Urtica dioica L. Stinging nettle has long been known worldwide as a medicinal plant. To study the benefits of the nettle in diabetic encephalopathy, the granule cell density of the dentate gyrus of diabetic rats was studied following administration of Urtica dioica extract. A total of 24 male albino Wistar rats were allocated equally to normal, diabetic, preventive and treatment groups. Hyperglycaemia was induced by streptozotocin (80 mg/kg) in the animals of the diabetic and treatment groups. One week after injection of the streptozotocin the animals in the treatment group received a hydroalcoholic extract of Urtica dioica (100 mg/kg/day) for 4 weeks intraperitoneally. The rats of the preventive group received hydroalcoholic extract of U. dioica (100 mg/kg/day) IP for the first 5 days and an injection of streptozotocin (80 mg/kg) on the 6th day. After 5 weeks of study all the rats were sacrificed and coronal sections were taken from the dorsal hippocampal formation of the right cerebral hemispheres and stained with cresyl violet. The area densities of the granule cells were measured and compared in the four groups. The density was lower in the diabetic rats compared with the controls (p > 0.05). The preventive group showed lower cell density than the controls (p > 0.05). The densities in the treated rats were higher than in the diabetic rats (p > 0.05). Furthermore, the control and treated rats showed similar densities (p > 0.05). It seems that U. dioica extract can help compensate for granule cell loss in the diabetic rat dentate gyrus, which can ameliorate cognitive impairment in diabetes. However, preventive use of the extract showed no significant benefit.

  2. The effect of Urtica dioica extract on the number of astrocytes in the dentate gyrus of diabetic rats.

    Science.gov (United States)

    Jahanshahi, M; Golalipour, M J; Afshar, M

    2009-05-01

    Diabetes mellitus is associated with cerebral alterations in both human and animal models of the disease. These alterations include abnormal expression of hypothalamic neuropeptides and hippocampal astrogliosis. Urtica dioica (Nettle) is among several species listed for their use against diabetes in folk medicine. The aim of this study was the evaluation of the astrocyte number in the dentate gyrus of diabetic rats after treatment with nettle. A total of 21 male albino Wistar rats were used in the present study. The animals were divided into three groups: control, nettle-untreated diabetic, and nettle treated diabetic. Hyperglycaemia was induced by streptozotocin (80 mg/kg) in the animals of the diabetic and treatment groups. One week after injection of the streptozotocin, the animals in the treatment group received a hydroalcoholic extract of Urtica dioica (100 mg/kg/day) for 4 weeks intraperitoneally. After a 5-week survival period, all the rats were sacrificed and coronal sections were taken from the dorsal hippocampal formation of the right cerebral hemispheres. The area densities of the astrocytes were measured and compared between the three groups (p < 0.05). The number of astrocytes increased in the diabetic rats (24.06 +/- 9.57) compared with the controls (17.52 +/- 6.66). The densities in the treated rats (19.50 +/- 6.16) were lower than in the diabetic rats. Furthermore, the control and treated rats showed similar densities. We concluded that U. dioica extract helped compensate for astrocytes in the treatment rats dentate gyrus in comparison with diabetic rats.

  3. An Assay for Permeability of the Zebrafish Embryonic Neuroepithelium

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    Chang, Jessica T.; Sive, Hazel

    2012-01-01

    The brain ventricular system is conserved among vertebrates and is composed of a series of interconnected cavities called brain ventricles, which form during the earliest stages of brain development and are maintained throughout the animal's life. The brain ventricular system is found in vertebrates, and the ventricles develop after neural tube formation, when the central lumen fills with cerebrospinal fluid (CSF) 1,2. CSF is a protein rich fluid that is essential for normal brain development...

  4. Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

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    Booker, Sam A; Campbell, Graham R; Mysiak, Karolina S; Brophy, Peter J; Kind, Peter C; Mahad, Don J; Wyllie, David J A

    2017-03-15

    Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function. Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV-deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses

  5. Synaptic Remodeling in the Dentate Gyrus, CA3, CA1, Subiculum, and Entorhinal Cortex of Mice: Effects of Deprived Rearing and Voluntary Running

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    Andrea T. U. Schaefers

    2010-01-01

    Full Text Available Hippocampal cell proliferation is strongly increased and synaptic turnover decreased after rearing under social and physical deprivation in gerbils (Meriones unguiculatus. We examined if a similar epigenetic effect of rearing environment on adult neuroplastic responses can be found in mice (Mus musculus. We examined synaptic turnover rates in the dentate gyrus, CA3, CA1, subiculum, and entorhinal cortex. No direct effects of deprived rearing on rates of synaptic turnover were found in any of the studied regions. However, adult wheel running had the effect of leveling layer-specific differences in synaptic remodeling in the dentate gyrus, CA3, and CA1, but not in the entorhinal cortex and subiculum of animals of both rearing treatments. Epigenetic effects during juvenile development affected adult neural plasticity in mice, but seemed to be less pronounced than in gerbils.

  6. Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction.

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    Bernier, Brian E; Lacagnina, Anthony F; Ayoub, Adam; Shue, Francis; Zemelman, Boris V; Krasne, Franklin B; Drew, Michael R

    2017-06-28

    Dentate gyrus (DG) is widely thought to provide a teaching signal that enables hippocampal encoding of memories, but its role during retrieval is poorly understood. Some data and models suggest that DG plays no role in retrieval; others encourage the opposite conclusion. To resolve this controversy, we evaluated the effects of optogenetic inhibition of dorsal DG during context fear conditioning, recall, generalization, and extinction in male mice. We found that (1) inhibition during training impaired context fear acquisition; (2) inhibition during recall did not impair fear expression in the training context, unless mice had to distinguish between similar feared and neutral contexts; (3) inhibition increased generalization of fear to an unfamiliar context that was similar to a feared one and impaired fear expression in the conditioned context when it was similar to a neutral one; and (4) inhibition impaired fear extinction. These effects, as well as several seemingly contradictory published findings, could be reproduced by BACON (Bayesian Context Fear Algorithm), a physiologically realistic hippocampal model positing that acquisition and retrieval both involve coordinated activity in DG and CA3. Our findings thus suggest that DG contributes to retrieval and extinction, as well as to the initial establishment of context fear. SIGNIFICANCE STATEMENT Despite abundant evidence that the hippocampal dentate gyrus (DG) plays a critical role in memory, it remains unclear whether the role of DG relates to memory acquisition or retrieval. Using contextual fear conditioning and optogenetic inhibition, we show that DG contributes to both of these processes. Using computational simulations, we identify specific mechanisms through which the suppression of DG affects memory performance. Finally, we show that DG contributes to fear extinction learning, a process in which learned fear is attenuated through exposures to a fearful context in the absence of threat. Our data resolve a

  7. Effects of Environmental Enrichment on Doublecortin and BDNF Expression along the Dorso-Ventral Axis of the Dentate Gyrus.

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    Gualtieri, Fabio; Brégère, Catherine; Laws, Grace C; Armstrong, Elena A; Wylie, Nicholas J; Moxham, Theo T; Guzman, Raphael; Boswell, Timothy; Smulders, Tom V

    2017-01-01

    Adult hippocampal neurogenesis (AHN) in the dentate gyrus is known to respond to environmental enrichment, chronic stress, and many other factors. The function of AHN may vary across the septo-temporal axis of the hippocampus, as different subdivisions are responsible for different functions. The dorsal pole regulates cognitive-related behaviors, while the ventral pole mediates mood-related responses through the hypothalamic-pituitary-adrenal (HPA) axis. In this study, we investigate different methods of quantifying the effect of environmental enrichment on AHN in the dorsal and ventral parts of the dentate gyrus (dDG and vDG). To this purpose, 11-week-old female CD-1 mice were assigned for 8 days to one of two conditions: the Environmental Enrichment (E) group received (i) running wheels, (ii) larger cages, (iii) plastic tunnels, and (iv) bedding with male urine, while the Control (C) group received standard housing. Dorsal CA ( Cornu Ammonis ) and DG regions were larger in the E than the C animals. Distance run linearly predicted the volume of the dorsal hippocampus, as well as of the intermediate and ventral CA regions. In the dDG, the amount of Doublecortin (DCX) immunoreactivity was significantly higher in E than in C mice. Surprisingly, this pattern was the opposite in the vDG (C > E). Real-time PCR measurement of Dcx mRNA and DCX protein analysis using ELISA showed the same pattern. Brain Derived Neurotrophic Factor (BDNF) immunoreactivity and mRNA displayed no difference between E and C, suggesting that upregulation of DCX was not caused by changes in BDNF levels. BDNF levels were higher in vDG than in dDG, as measured by both methods. Bdnf expression in vDG correlated positively with the distance run by individual E mice. The similarity in the patterns of immunoreactivity, mRNA and protein for differential DCX expression and for BDNF distribution suggests that the latter two methods might be effective tools for more rapid quantification of AHN.

  8. Effects of Environmental Enrichment on Doublecortin and BDNF Expression along the Dorso-Ventral Axis of the Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Fabio Gualtieri

    2017-09-01

    Full Text Available Adult hippocampal neurogenesis (AHN in the dentate gyrus is known to respond to environmental enrichment, chronic stress, and many other factors. The function of AHN may vary across the septo-temporal axis of the hippocampus, as different subdivisions are responsible for different functions. The dorsal pole regulates cognitive-related behaviors, while the ventral pole mediates mood-related responses through the hypothalamic-pituitary-adrenal (HPA axis. In this study, we investigate different methods of quantifying the effect of environmental enrichment on AHN in the dorsal and ventral parts of the dentate gyrus (dDG and vDG. To this purpose, 11-week-old female CD-1 mice were assigned for 8 days to one of two conditions: the Environmental Enrichment (E group received (i running wheels, (ii larger cages, (iii plastic tunnels, and (iv bedding with male urine, while the Control (C group received standard housing. Dorsal CA (Cornu Ammonis and DG regions were larger in the E than the C animals. Distance run linearly predicted the volume of the dorsal hippocampus, as well as of the intermediate and ventral CA regions. In the dDG, the amount of Doublecortin (DCX immunoreactivity was significantly higher in E than in C mice. Surprisingly, this pattern was the opposite in the vDG (C > E. Real-time PCR measurement of Dcx mRNA and DCX protein analysis using ELISA showed the same pattern. Brain Derived Neurotrophic Factor (BDNF immunoreactivity and mRNA displayed no difference between E and C, suggesting that upregulation of DCX was not caused by changes in BDNF levels. BDNF levels were higher in vDG than in dDG, as measured by both methods. Bdnf expression in vDG correlated positively with the distance run by individual E mice. The similarity in the patterns of immunoreactivity, mRNA and protein for differential DCX expression and for BDNF distribution suggests that the latter two methods might be effective tools for more rapid quantification of AHN.

  9. Stress-induced gene expression and behavior are controlled by DNA methylation and methyl donor availability in the dentate gyrus

    Science.gov (United States)

    Saunderson, Emily A.; Spiers, Helen; Gutierrez-Mecinas, Maria; Trollope, Alexandra F.; Shaikh, Abeera; Mill, Jonathan; Reul, Johannes M. H. M.

    2016-01-01

    Stressful events evoke long-term changes in behavioral responses; however, the underlying mechanisms in the brain are not well understood. Previous work has shown that epigenetic changes and immediate-early gene (IEG) induction in stress-activated dentate gyrus (DG) granule neurons play a crucial role in these behavioral responses. Here, we show that an acute stressful challenge [i.e., forced swimming (FS)] results in DNA demethylation at specific CpG (5′-cytosine–phosphate–guanine-3′) sites close to the c-Fos (FBJ murine osteosarcoma viral oncogene homolog) transcriptional start site and within the gene promoter region of Egr-1 (early growth response protein 1) specifically in the DG. Administration of the (endogenous) methyl donor S-adenosyl methionine (SAM) did not affect CpG methylation and IEG gene expression at baseline. However, administration of SAM before the FS challenge resulted in an enhanced CpG methylation at the IEG loci and suppression of IEG induction specifically in the DG and an impaired behavioral immobility response 24 h later. The stressor also specifically increased the expression of the de novo DNA methyltransferase Dnmt3a [DNA (cytosine-5-)-methyltransferase 3 alpha] in this hippocampus region. Moreover, stress resulted in an increased association of Dnmt3a enzyme with the affected CpG loci within the IEG genes. No effects of SAM were observed on stress-evoked histone modifications, including H3S10p-K14ac (histone H3, phosphorylated serine 10 and acetylated lysine-14), H3K4me3 (histone H3, trimethylated lysine-4), H3K9me3 (histone H3, trimethylated lysine-9), and H3K27me3 (histone H3, trimethylated lysine-27). We conclude that the DNA methylation status of IEGs plays a crucial role in FS-induced IEG induction in DG granule neurons and associated behavioral responses. In addition, the concentration of available methyl donor, possibly in conjunction with Dnmt3a, is critical for the responsiveness of dentate neurons to environmental

  10. Interleukin-1β increases neuronal death in the hippocampal dentate gyrus associated with status epilepticus in the developing rat.

    Science.gov (United States)

    Rincón-López, C; Tlapa-Pale, A; Medel-Matus, J-S; Martínez-Quiroz, J; Rodríguez-Landa, J F; López-Meraz, M-L

    Interleukin-1β (IL-1β) increases necrotic neuronal cell death in the CA1 area after induced status epilepticus (SE) in developing rats. However, it remains uncertain whether IL-1β has a similar effect on the hippocampal dentate gyrus (DG). In this study, we analysed the effects of IL-1β on 14-day-old Wistar rats experiencing DG neuronal death induced by SE. SE was induced with lithium-pilocarpine. Six hours after SE onset, a group of pups was injected with IL-1β (at 0, 0.3, 3, 30, or 300ng/μL) in the right ventricle; another group was injected with IL-1β receptor (IL-1R1) antagonist (IL-1Ra, at 30ng/μL) of IL-1RI antagonist (IL-1Ra) alone, and additional group with 30ng/μL of IL-1Ra plus 3ng/μL of IL-1β. Twenty-four hours after SE onset, neuronal cell death in the dentate gyrus of the dorsal hippocampus was assessed using haematoxylin-eosin staining. Dead cells showed eosinophilic cytoplasm and condensed and fragmented nuclei. We observed an increased number of eosinophilic cells in the hippocampal DG ipsilateral to the site of injection of 3ng/μL and 300ng/μL of IL-1β in comparison with the vehicle group. A similar effect was observed in the hippocampal DG contralateral to the site of injection of 3ng/μL of IL-1β. Administration of both of IL-1β and IL-1Ra failed to prevent an increase in the number of eosinophilic cells. Our data suggest that IL-1β increases apoptotic neuronal cell death caused by SE in the hippocampal GD, which is a mechanism independent of IL-1RI activation. Copyright © 2016 Sociedad Española de Neurología. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Evidence for proteolytic cleavage of brevican by the ADAMTSs in the dentate gyrus after excitotoxic lesion of the mouse entorhinal cortex

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    Gottschall Paul E

    2005-08-01

    Full Text Available Abstract Background Brevican is a member of the lectican family of aggregating extracellular matrix (ECM proteoglycans that bear chondroitin sulfate (CS chains. It is highly expressed in the central nervous system (CNS and is thought to stabilize synapses and inhibit neural plasticity and as such, neuritic or synaptic remodeling would be less likely to occur in regions with intact and abundant, lectican-containing, ECM complexes. Neural plasticity may occur more readily when these ECM complexes are broken down by endogenous proteases, the ADAMTSs (adisintegrin and metalloproteinase with thrombospondin motifs, that selectively cleave the lecticans. The purpose of these experiments was to determine whether the production of brevican or the ADAMTS-cleaved fragments of brevican were altered after deafferentation and reinnervation of the dentate gyrus via entorhinal cortex lesion (ECL. Results In the C57Bl6J mouse, synaptic density in the molecular layer of the dentate gyrus, as measured by synaptophysin levels in ELISA, was significantly attenuated 2 days (nearly 50% of contralateral and 7 days after lesion and returned to levels not different from the contralateral region at 30 days. Immunoreactive brevican in immunoblot was elevated 2 days after lesion, whereas there was a significant increase in the proteolytic product at 7, but not 30 days post-lesion. ADAMTS activity, estimated using the ratio of the specific ADAMTS-derived brevican fragment and intact brevican levels was increased at 7 days, but was not different from the contralateral side at 2 or 30 days after deafferentation. Conclusion These findings indicate that ADAMTS activity in the dentate outer molecular layer (OML is elevated during the initial synaptic reinnervation period (7 days after lesion. Therefore, proteolytic processing of brevican appears to be a significant extracellular event in the remodeling of the dentate after EC lesion, and may modulate the process of sprouting and

  12. Diffusion tensor MRI shows progressive changes in the hippocampus and dentate gyrus after status epilepticus in rat - histological validation with Fourier-based analysis.

    Science.gov (United States)

    Salo, Raimo A; Miettinen, Tuukka; Laitinen, Teemu; Gröhn, Olli; Sierra, Alejandra

    2017-05-15

    Imaging markers for monitoring disease progression, recovery, and treatment efficacy are a major unmet need for many neurological diseases, including epilepsy. Recent evidence suggests that diffusion tensor imaging (DTI) provides high microstructural contrast even outside major white matter tracts. We hypothesized that in vivo DTI could detect progressive microstructural changes in the dentate gyrus and the hippocampal CA3bc in the rat brain after status epilepticus (SE). To test this hypothesis, we induced SE with systemic kainic acid or pilocarpine in adult male Wistar rats and subsequently scanned them using in vivo DTI at five time-points: prior to SE, and 10, 20, 34, and 79 days post SE. In order to tie the DTI findings to changes in the tissue microstructure, myelin- and glial fibrillary acidic protein (GFAP)-stained sections from the same animals underwent Fourier analysis. We compared the Fourier analysis parameters, anisotropy index and angle of myelinated axons or astrocyte processes, to corresponding DTI parameters, fractional anisotropy (FA) and the orientation angle of the principal eigenvector. We found progressive detectable changes in DTI parameters in both the dentate gyrus (FA, axial diffusivity [D || ], linear anisotropy [CL] and spherical anisotropy [CS], pFourier analysis revealed that both myelinated axons and astrocyte processes played a role in the water diffusion anisotropy changes detected by DTI in individual portions of the dentate gyrus (suprapyramidal blade, mid-portion, and infrapyramidal blade). In the whole dentate gyrus, myelinated axons markedly contributed to the water diffusion changes. In CA3bc as well as in CA3b and CA3c, both myelinated axons and astrocyte processes contributed to water diffusion anisotropy and orientation. Our study revealed that DTI is a promising method for noninvasive detection of microstructural alterations in the hippocampus proper. These alterations may be potential imaging markers for epileptogenesis

  13. The roles of BDNF, pCREB and Wnt3a in the latent period preceding activation of progenitor cell mitosis in the adult dentate gyrus by fluoxetine.

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    Scarlett B Pinnock

    2010-10-01

    Full Text Available The formation of new neurons continues into adult life in the dentate gyrus of the rat hippocampus, as in many other species. Neurogenesis itself turns out to be highly labile, and is regulated by a number of factors. One of these is the serotoninergic system: treatment with drugs (such as the SSRI fluoxetine markedly stimulates mitosis in the progenitor cells of the dentate gyrus. But this process has one remarkable feature: it takes at least 14 days of continuous treatment to be effective. This is despite the fact that the pharmacological action of fluoxetine occurs within an hour or so of first administration. This paper explores the role of BDNF in this process, using the effect of a Trk antagonist (K252a on the labelling of progenitor cells with the mitosis marker Ki67 and the associated expression of pCREB and Wnt3a. These experiments show that (i Fluoxetine increased Ki67 counts, as well as pCREB and Wnt3a expression in the dentate gyrus. The action of fluoxetine on the progenitor cells and on pCREB (but not Wnt3a depends upon Trk receptor activation, since it was prevented by icv infusion of K252a. (ii These receptors are required for both the first 7 days of fluoxetine action, during which no apparent change in progenitor mitosis occurs, as well as the second 7 days. Increased pCREB was always associated with progenitor cell mitosis, but Wnt3a expression may be necessary but not sufficient for increased progenitor cell proliferation. These results shed new light on the action of fluoxetine on neurogenesis in the adult dentate gyrus, and have both clinical and experimental interest.

  14. Local injection of d-lys-3-GHRP-6 in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation.

    Science.gov (United States)

    Beheshti, Siamak; Aslani, Neda

    2018-02-01

    It is well known that the hormone ghrelin affects learning and memory in different experimental models of learning. Though, the effect of antagonism of ghrelin receptor type 1a (GHS-R1a) in various regions of the brain and on different stages of learning has not been examined. In this study the effect of injection of a GHS-R1a selective antagonist (d-Lys-3-GHRP-6) into the basolateral amygdala, dentate gyrus or ventral tegmental area was examined on memory consolidation in the passive avoidance task. Adult male Wistar rats weighing 230-280g were used. Animals underwent stereotaxic surgery and cannulated in their amygdala, dentate gyrus or ventral tegmental area. One week after surgery, the rats received different doses of d-Lys-3-GHRP-6 (0.08, 0.8, and 8nM), immediately after training. The control groups received solvent of the drug. Twenty four hours later in the test day, memory retrieval was assessed. In all groups, post-training injection of d-Lys-3-GHRP-6 decreased step-through latency and increased entries into the dark compartment and time spent in the dark compartment, significantly and in a dose-dependent manner. The results indicate that antagonism of the GHS-R1a in the rat amygdala, dentate gyrus or ventral tegmental area impairs memory consolidation and show that the ghrelin signaling has a widespread influence on cognitive performance. Copyright © 2017. Published by Elsevier Ltd.

  15. Evaluation of the protective effects of tocotrienol-rich fraction from palm oil on the dentate gyrus following chronic restraint stress in rats

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    Saiful Bhari Talip

    2013-06-01

    Full Text Available Exposure to chronic restraint stress has been shown to cause a number of morphological changes in the hippocampal formation of rats. Tocotrienol, an isoform of vitamin E, exhibits numerous health benefits, different from those of tocopherol. Recent studies have demonstrated that tocotrienol prevents stress-induced changes in the gastric mucosa, thus indicating that it may also protect other organs such as the brain from the damaging effects of stress. Therefore, the aim of the present study was to investigate the protective effect of tocotrienol-rich fraction (TRF extracted from palm oil on the dentate gyrus of rats following exposure to chronic restraint stress. Thirty-six male Sprague Dawley rats were divided into four groups: control, stress, tocotrienol and combination of stress and tocotrienol. Animals were stressed by restraining them for 5 hours every day for 21 consecutive days. TRF was administered via oral gavage at a dose of 200 mg/kg body weight. Our results showed that the plasma corticosterone level was significantly increased in response to stress, compared to the control. The results confirmed previous findings that chronic restraint stress suppresses cellular proliferation and reduces granule cell number in the dentate gyrus. However, TRF supplementation failed to prevent or minimize these stress-induced changes. Therefore, we conclude that TRF at the current dosage is not effective in preventing the morphological changes in the dentate gyrus induced by chronic restraint stress.

  16. Effects of unpredictable chronic stress on behavior and brain-derived neurotrophic factor expression in CA3 subfield and dentate gyrus of the hippocampus in different aged rats.

    Science.gov (United States)

    Li, Ying; Ji, Yong-juan; Jiang, Hong; Liu, De-xiang; Zhang, Qian; Fan, Shu-jian; Pan, Fang

    2009-07-05

    Brain-derived neurotrophic factor (BDNF) is a stress-responsive intercellular messenger modifying hypothalamic-pituitary-adrenal (HPA) axis activity. The interaction between stress and age in BDNF expression is currently not fully understood. This study was conducted to observe unpredictable stress effect on behavior and BDNF expression in CA3 subfield (CA3) and dentate gyrus of hippocampus in different aged rats. Forty-eight Wistar rats of two different ages (2 months and 15 months) were randomly assigned to six groups: two control groups and four stress groups. The rats in the stress group received three weeks of unpredictable mild stress. The depression state and the stress level of the animals were determined by sucrose preference test and observation of exploratory behavior in an open field (OF) test. The expressions of BDNF in CA3 and dentate gyrus of the hippocampus were measured using immunohistochemistry. Age and stress had different effects on the behavior of different aged animals (age: F = 6.173, P BDNF expression in the CA3 and dentate gyrus regions of the hippocampus following stress in both age groups (P BDNF (F = 9.408, P BDNF expression compared to the young stressed group at every testing time point. Stress has age-dependent effects on behavioral responses and hippocampal BDNF expression in rats.

  17. Kindling-induced potentiation of excitatory and inhibitory inputs to hippocampal dentate granule cells. II. Effects of the NMDA antagonist MK-801.

    LENUS (Irish Health Repository)

    Robinson, G B

    1991-10-18

    The effect of the non-competitive N-methyl-D-aspartate antagonist MK-801 on the early development of kindling-induced potentiation was examined in the rabbit hippocampal dentate gyrus. MK-801 (0.5 mg\\/kg) was administered 2 h before each daily kindling stimulation was applied to the perforant path. This treatment continued for the first 10 days of kindling. MK-801 depressed the growth of the afterdischarge duration and suppressed development of behavioral seizures. MK-801 did not block kindling-induced potentiation of either the perforant path-dentate granule cell population spike or excitatory postsynaptic potential. Random impulse train stimulation and non-linear systems analytic techniques were used to examine kindling-induced potentiation of presumed GABAergic recurrent inhibitory circuits. Both the magnitude and duration of kindling-induced response inhibition, to the second of each pair of impulses within the train, were reduced in rabbits pretreated with MK-801. These results suggest that MK-801 differentially affects kindling-induced potentiation of excitatory and inhibitory circuits within the rabbit hippocampal dentate gyrus.

  18. Uhrf2 deletion impairs the formation of hippocampus-dependent memory by changing the structure of the dentate gyrus.

    Science.gov (United States)

    Chen, Xiao-Rong; Sun, Shi-Cheng; Teng, Shuai-Wen; Li, Liang; Bie, Yi-Fan; Yu, Hui; Li, Da-Li; Chen, Zhe-Yu; Wang, Yue

    2018-03-01

    Ubiquitin-like with PHD and ring finger domains 2 (Uhrf2) is distributed in many brain regions, including the cortex and hippocampus. Decreased Uhrf2 expression is involved in neurodegenerative disease. A recent study showed Uhrf2 deletion impaired spatial memory; however, the mechanism remains elusive. In our study, we determined that Uhrf2 +/- and Uhrf2 -/- mice had significant learning and memory deficiencies in contextual fear conditioning (CFC) and the novel place recognition test but not in the novel object recognition test. Interestingly, there were no changes in the Uhrf2 protein levels in the hippocampus of C57BL6 mice after CFC training, which suggests Uhrf2 in adult mice may not be related to the formation of CFC long-term memory. Based on Nissl staining, Uhrf2 deletion caused neuropathological changes specifically in the crest of the dentate gyrus (DG), such as cell swelling, a vague outline and confused boundary; however, no changes were identified in the medial prefrontal cortex (mPFC). Transmission electron microscope assay further indicated a series of abnormal ultrastructure changes in neurons and glia in the DG crest. These results suggested that Uhrf2 deletion selectively blocked the development of the DG crest and impaired hippocampus-dependent learning and memory. Our study will facilitate a better understanding of the role of Uhrf2 protein in the central nervous system.

  19. Fatty acid synthase as a factor required for exercise-induced cognitive enhancement and dentate gyrus cellular proliferation.

    Directory of Open Access Journals (Sweden)

    Nataliya E Chorna

    Full Text Available Voluntary running is a robust inducer of adult hippocampal neurogenesis. Given that fatty acid synthase (FASN, the key enzyme for de novo fatty acid biosynthesis, is critically involved in proliferation of embryonic and adult neural stem cells, we hypothesized that FASN could mediate both exercise-induced cell proliferation in the subgranular zone (SGZ of the dentate gyrus (DG and enhancement of spatial learning and memory. In 20 week-old male mice, voluntary running-induced hippocampal-specific upregulation of FASN was accompanied also by hippocampal-specific accumulation of palmitate and stearate saturated fatty acids. In experiments addressing the functional role of FASN in our experimental model, chronic intracerebroventricular (i.c.v. microinfusions of C75, an irreversible FASN inhibitor, and significantly impaired exercise-mediated improvements in spatial learning and memory in the Barnes maze. Unlike the vehicle-injected mice, the C75 group adopted a non-spatial serial escape strategy and displayed delayed escape latencies during acquisition and memory tests. Furthermore, pharmacologic blockade of FASN function with C75 resulted in a significant reduction, compared to vehicle treated controls, of the number of proliferative cells in the DG of running mice as measured by immunoreactive to Ki-67 in the SGZ. Taken together, our data suggest that FASN plays an important role in exercise-mediated cognitive enhancement, which might be associated to its role in modulating exercise-induced stimulation of neurogenesis.

  20. Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse.

    Science.gov (United States)

    Cai, Yulong; Tang, Xiaotong; Chen, Xi; Li, Xin; Wang, Ying; Bao, Xiaohang; Wang, Lian; Sun, Dayu; Zhao, Jinghui; Xing, Yan; Warner, Margaret; Xu, Haiwei; Gustafsson, Jan-Åke; Fan, Xiaotang

    2018-03-20

    The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

  1. CXCL12-mediated feedback from granule neurons regulates generation and positioning of new neurons in the dentate gyrus.

    Science.gov (United States)

    Abe, Philipp; Wüst, Hannah M; Arnold, Sebastian J; van de Pavert, Serge A; Stumm, Ralf

    2018-03-14

    Adult hippocampal neurogenesis is implicated in learning and memory processing. It is tightly controlled at several levels including progenitor proliferation as well as migration, differentiation and integration of new neurons. Hippocampal progenitors and immature neurons reside in the subgranular zone (SGZ) and are equipped with the CXCL12-receptor CXCR4 which contributes to defining the SGZ as neurogenic niche. The atypical CXCL12-receptor CXCR7 functions primarily by sequestering extracellular CXCL12 but whether CXCR7 is involved in adult neurogenesis has not been assessed. We report that granule neurons (GN) upregulate CXCL12 and CXCR7 during dentate gyrus maturation in the second postnatal week. To test whether GN-derived CXCL12 regulates neurogenesis and if neuronal CXCR7 receptors influence this process, we conditionally deleted Cxcl12 and Cxcr7 from the granule cell layer. Cxcl12 deletion resulted in lower numbers, increased dispersion and abnormal dendritic growth of immature GN and reduced neurogenesis. Cxcr7 ablation caused an increase in progenitor proliferation and progenitor numbers and reduced dispersion of immature GN. Thus, we provide a new mechanism where CXCL12-signals from GN prevent dispersion and support maturation of newborn GN. CXCR7 receptors of GN modulate the CXCL12-mediated feedback from GN to the neurogenic niche. © 2018 Wiley Periodicals, Inc.

  2. Replacement of asymmetric synaptic profiles in the molecular layer of dentate gyrus following cycloheximide in the pilocarpine model in rats.

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    Simone eBittencourt

    2015-11-01

    Full Text Available Mossy fiber sprouting is among the best-studied forms of post-lesional synaptic plasticity and is regarded by many as contributory to seizures in both humans and animal models of epilepsy. It is not known whether mossy fiber sprouting increases the number of synapses in the molecular layer or merely replaces lost contacts. Using the pilocarpine model of status epilepticus to induce mossy fiber sprouting, and cycloheximide to block this sprouting, we evaluated at the ultrastructural level the number and type of asymmetric synaptic contacts in the molecular layer of the dentate gyrus. As expected, whereas pilocarpine-treated rats had dense silver grain deposits in the inner molecular layer (reflecting mossy fiber sprouting, pilocarpine+cycloheximide-treated animals did not differ from controls. Both groups of treated rats (Pilo group and CHX+Pilo group had reduced density of asymmetric synaptic profiles (putative excitatory synaptic contacts, which was greater for cycloheximide-treated animals. For both treated groups the loss of excitatory synaptic contacts was even greater in the outer molecular layer than in the best studied inner molecular layer (in which mossy fiber sprouting occurs. These results indicate that mossy fiber sprouting tends to replace lost synaptic contacts rather than increase the absolute number of contacts. We speculate that the overall result is more consistent with restored rather than with increased excitability.

  3. Effect of Aggregated β-Amyloid (1-42 on Synaptic Plasticity of Hippocampal Dentate Gyrus Granule Cells in Vivo

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    Shirin Babri

    2012-12-01

    Full Text Available Introduction: Alzheimer’s disease (AD is a common neurodegenerative disorder in elderly people with an impairment of cognitive decline and memory loss. β-amyloid (Aβ as a potent neurotoxic peptide has a pivotal role in the pathogenesis of AD. This disease begins with impairment in synaptic functions before developing into later neuro­degeneration and neuronal loss. The aim of this study was to evaluate the synaptic plasticity and electrophysiological function of granule cells in hippocampal dentate gyrus (DG after intracerebroventricular (i.c.v. administration of aggregated Aβ (1-42 peptide in vivo. Methods: Animals were divided to control and Aβ (1-42 groups. Long-term potentia­tion (LTP in perforant path-DG synapses was assessed in order to investigate the effect of aggregated Aβ (1-42 on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP slope and population spike (PS amplitude were measured. Results: Administration of Aβ (1-42 significantly decreased fEPSP slope and PS amplitude in Aβ (1-42 group comparing with the control group and had no effect on baseline activity of neurons. Conclusion: The present study indicates that administration of aggregated form of Aβ (1-42 into the lateral ventricle effectively inhibits LTP in granular cells of the DG in hippocampus in vivo.

  4. Basic fibroblast growth factor enhances cell proliferation in the dentate gyrus of neonatal rats following hypoxic-ischemic brain damage.

    Science.gov (United States)

    Zhu, Huan; Qiao, Lixing; Sun, Yao; Yin, Liping; Huang, Li; Jiang, Li; Li, Jiaqing

    2018-04-23

    Perinatal hypoxic-ischemic insult is considered a major contributor to child mortality and morbidity and leads to neurological deficits in newborn infants. There has been a lack of promising neurotherapeutic interventions for hypoxic-ischemic brain damage (HIBD) for clinical application in infants. The present study aimed to investigate the correlation between neurogenesis and basic fibroblast growth factor (bFGF) in the hippocampal dentate gyrus (DG) region in neonatal rats following HIBD. Cell proliferation was examined by detecting BrdU signals, and the role of bFGF in cell proliferation in the DG region following neonatal HIBD was investigated. Cell proliferation was induced by HIBD in the hippocampal DG of neonatal rats. Furthermore, bFGF gene expression was upregulated in the hippocampus in neonatal rats, particularly between 7 and 14 days after HIBD. Moreover, intraperitoneal injection of exogenous bFGF enhanced cell proliferation in the hippocampal DG following neonatal HIBD. Taken together, these data indicate that cell proliferation in the DG could be induced by neonatal HIBD, and bFGF promotes proliferation following neonatal HIBD. Copyright © 2018 Elsevier B.V. All rights reserved.

  5. GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

    Energy Technology Data Exchange (ETDEWEB)

    Boku, Shuken, E-mail: shuboku@med.hokudai.ac.jp [Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo (Japan); Nakagawa, Shin [Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo (Japan); Takamura, Naoki [Pharmaceutical Laboratories, Dainippon Sumitomo Pharma Co. Ltd., Osaka (Japan); Kato, Akiko [Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo (Japan); Takebayashi, Minoru [Department of Psychiatry, National Hospital Organization Kure Medical Center, Kure (Japan); Hisaoka-Nakashima, Kazue [Department of Pharmacology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima (Japan); Omiya, Yuki; Inoue, Takeshi; Kusumi, Ichiro [Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo (Japan)

    2013-05-17

    Highlights: •GDNF has no effect on ADP proliferation and apoptosis. •GDNF increases ADP differentiation into astrocyte. •A specific inhibitor of STAT3 decreases the astrogliogenic effect of GDNF. •STAT3 knockdown by lentiviral shRNA vector also decreases the astrogliogenic effect of GDNF. •GDNF increases the phosphorylation of STAT3. -- Abstract: While the pro-neurogenic actions of antidepressants in the adult hippocampal dentate gyrus (DG) are thought to be one of the mechanisms through which antidepressants exert their therapeutic actions, antidepressants do not increase proliferation of neural precursor cells derived from the adult DG. Because previous studies showed that antidepressants increase the expression and secretion of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells derived from rat astrocytes and GDNF increases neurogenesis in adult DG in vivo, we investigated the effects of GDNF on the proliferation, differentiation and apoptosis of cultured neural precursor cells derived from the adult DG. Data showed that GDNF facilitated the differentiation of neural precursor cells into astrocytes but had no effect on their proliferation or apoptosis. Moreover, GDNF increased the phosphorylation of STAT3, and both a specific inhibitor of STAT3 and lentiviral shRNA for STAT3 decreased their differentiation into astrocytes. Taken together, our findings suggest that GDNF facilitates astrogliogenesis from neural precursor cells in adult DG through activating STAT3 and that this action might indirectly affect neurogenesis.

  6. Gadolinium deposition within the dentate nucleus and globus pallidus after repeated administrations of gadolinium-based contrast agents - current status

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan [University of Nis, Faculty of Medicine, Nis (Serbia); Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Center for Radiology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-05-15

    Gadolinium-based contrast agents (GBCAs) have been used clinically since 1988 for contrast-enhanced magnetic resonance imaging (CE-MRI). Generally, GBCAs are considered to have an excellent safety profile. However, GBCA administration has been associated with increased occurrence of nephrogenic systemic fibrosis (NSF) in patients with severely compromised renal function, and several studies have shown evidence of gadolinium deposition in specific brain structures, the globus pallidus and dentate nucleus, in patients with normal renal function. Gadolinium deposition in the brain following repeated CE-MRI scans has been demonstrated in patients using T1-weighted unenhanced MRI and inductively coupled plasma mass spectroscopy. Additionally, rodent studies with controlled GBCA administration also resulted in neural gadolinium deposits. Repeated GBCA use is associated with gadolinium deposition in the brain. This is especially true with the use of less-stable, linear GBCAs. In spite of increasing evidence of gadolinium deposits in the brains of patients after multiple GBCA administrations, the clinical significance of these deposits continues to be unclear. Here, we discuss the current state of scientific evidence surrounding gadolinium deposition in the brain following GBCA use, and the potential clinical significance of gadolinium deposition. There is considerable need for further research, both to understand the mechanism by which gadolinium deposition in the brain occurs and how it affects the patients in which it occurs. (orig.)

  7. Somatostatin-positive interneurons in the dentate gyrus of mice provide local- and long-range septal synaptic inhibition.

    Science.gov (United States)

    Yuan, Mei; Meyer, Thomas; Benkowitz, Christoph; Savanthrapadian, Shakuntala; Ansel-Bollepalli, Laura; Foggetti, Angelica; Wulff, Peer; Alcami, Pepe; Elgueta, Claudio; Bartos, Marlene

    2017-04-03

    Somatostatin-expressing-interneurons (SOMIs) in the dentate gyrus (DG) control formation of granule cell (GC) assemblies during memory acquisition. Hilar-perforant-path-associated interneurons (HIPP cells) have been considered to be synonymous for DG-SOMIs. Deviating from this assumption, we show two functionally contrasting DG-SOMI-types. The classical feedback-inhibitory HIPPs distribute axon fibers in the molecular layer. They are engaged by converging GC-inputs and provide dendritic inhibition to the DG circuitry. In contrast, SOMIs with axon in the hilus, termed hilar interneurons (HILs), provide perisomatic inhibition onto GABAergic cells in the DG and project to the medial septum. Repetitive activation of glutamatergic inputs onto HIPP cells induces long-lasting-depression (LTD) of synaptic transmission but long-term-potentiation (LTP) of synaptic signals in HIL cells. Thus, LTD in HIPPs may assist flow of spatial information from the entorhinal cortex to the DG, whereas LTP in HILs may facilitate the temporal coordination of GCs with activity patterns governed by the medial septum.

  8. The effects of a reminder of underwater trauma on behaviour and memory-related mechanisms in the rat dentate gyrus.

    Science.gov (United States)

    Ardi, Ziv; Ritov, Gilad; Lucas, Morgan; Richter-Levin, Gal

    2014-04-01

    Intrusive re-experiencing is a core symptom in post-traumatic stress disorder (PTSD), often triggered by contextual cues associated with the trauma. It is not yet clear if intrusive re-experiencing is only the result, or whether it may contribute to the establishment of PTSD following acute stress. This study aimed at examining the impact of an underwater trauma (UWT) reminder on anxiety-like behaviour and on neuronal activity and plasticity in the hippocampus and the amygdala. Sprague-Dawley rats were exposed to UWT and 24 h later were re-exposed to the context. The effects on behaviour, activation of the amygdala (BLA) and dentate gyrus (DG), and on long-term potentiation (LTP) and local circuit activity (frequency-dependent inhibition (FDI) and paired-pulse inhibition (PPI)) in the DG were assessed. The exposure to UWT by itself resulted in increased anxiety behaviour in the open field, together with increased PPI. Upon exposure to the UWT reminder, an additional increase in anxiety was also observed in the EPM and in FDI. Moreover, reminder exposure resulted in impaired DG LTP and a significant BLA extracellular-signal-regulated kinases (ERK) 2 activation. In conclusion, these observed effects of exposure to a trauma reminder, following the exposure to the initial trauma, might be associated with the progression of trauma-related pathologies and the development of related disorders.

  9. Effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus of hippocampal formation in rats

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    Ghasem Zarei

    2014-01-01

    Full Text Available Background: Several studies have been shown that antidepressant drugs have contradictory effects on cognitive processes. Therefore, the aim of this study was to investigate the effects of amitriptyline and fluoxetine on synaptic plasticity in the dentate gyrus (DG of the hippocampal formation in rat. Materials and Methods: Experimental groups were the control, the fluoxetine, and amitriptyline. The rats were treated for 21 days and then, paired pulse facilitation/inhibition (PPF/I and long-term potentiation (LTP in perforant path-DG synapses were assessed (by 400 Hz tetanization. Field excitatory post-synaptic potential (fEPSP slope and population spike (PS amplitude were measured. Results: The results of PPF/I showed that PS amplitude ratios were increased in 10-70 ms inter-stimulus intervals in the amitriptyline group compared to the control group. In the fluoxetine group, EPSP slope ratios were decreased in intervals 30, 40, and 50 ms inter-stimulus intervals compared to the control group. The PS-LTP was significantly lower in the fluoxetine and the amitriptyline groups with respect to the control group. Conclusion: The results showed that fluoxetine and amitriptyline affect synaptic plasticity in the hippocampus and these effects is probably due to the impact on the number of active neurons.

  10. GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

    International Nuclear Information System (INIS)

    Boku, Shuken; Nakagawa, Shin; Takamura, Naoki; Kato, Akiko; Takebayashi, Minoru; Hisaoka-Nakashima, Kazue; Omiya, Yuki; Inoue, Takeshi; Kusumi, Ichiro

    2013-01-01

    Highlights: •GDNF has no effect on ADP proliferation and apoptosis. •GDNF increases ADP differentiation into astrocyte. •A specific inhibitor of STAT3 decreases the astrogliogenic effect of GDNF. •STAT3 knockdown by lentiviral shRNA vector also decreases the astrogliogenic effect of GDNF. •GDNF increases the phosphorylation of STAT3. -- Abstract: While the pro-neurogenic actions of antidepressants in the adult hippocampal dentate gyrus (DG) are thought to be one of the mechanisms through which antidepressants exert their therapeutic actions, antidepressants do not increase proliferation of neural precursor cells derived from the adult DG. Because previous studies showed that antidepressants increase the expression and secretion of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells derived from rat astrocytes and GDNF increases neurogenesis in adult DG in vivo, we investigated the effects of GDNF on the proliferation, differentiation and apoptosis of cultured neural precursor cells derived from the adult DG. Data showed that GDNF facilitated the differentiation of neural precursor cells into astrocytes but had no effect on their proliferation or apoptosis. Moreover, GDNF increased the phosphorylation of STAT3, and both a specific inhibitor of STAT3 and lentiviral shRNA for STAT3 decreased their differentiation into astrocytes. Taken together, our findings suggest that GDNF facilitates astrogliogenesis from neural precursor cells in adult DG through activating STAT3 and that this action might indirectly affect neurogenesis

  11. Glucagon-Like Peptide-1 as Predictor of Body Mass Index and Dentate Gyrus Neurogenesis: Neuroplasticity and the Metabolic Milieu

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    Jeremy D. Coplan

    2014-01-01

    Full Text Available Glucagon-like peptide-1 (GLP-1 regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1, and body mass index (BMI in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues.

  12. Blockade of intracellular Zn2+ signaling in the basolateral amygdala affects object recognition memory via attenuation of dentate gyrus LTP.

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    Fujise, Yuki; Kubota, Mitsuyasu; Suzuki, Miki; Tamano, Haruna; Takeda, Atsushi

    2017-09-01

    Hippocampus-dependent memory is modulated by the amygdala. However, it is unknown whether intracellular Zn 2+ signaling in the amygdala is involved in hippocampus-dependent memory. On the basis of the evidence that intracellular Zn 2+ signaling in dentate granule cells (DGC) is necessary for object recognition memory via LTP at medial perforant pathway (PP)-DGC synapses, the present study examined whether intracellular Zn 2+ signaling in the amygdala influences object recognition memory via modulation of LTP at medial PP-DGC synapses. When ZnAF-2DA (100 μM, 2 μl) was injected into the basolateral amygdala (BLA), intracellular ZnAF-2 locally chelated intracellular Zn 2+ in the amygdala. Recognition memory was affected when training of object recognition test was performed 20 min after ZnAF-2DA injection into the BLA. Twenty minutes after injection of ZnAF-2DA into the BLA, LTP induction at medial PP-DGC synapses was attenuated, while LTP induction at PP-BLA synapses was potentiated and LTP induction at BLA-DGC synapses was attenuated. These results suggest that intracellular Zn 2+ signaling in the BLA is involved in BLA-associated LTP and modulates LTP at medial PP-DGC synapses, followed by modulation of object recognition memory. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. A natural form of learning can increase and decrease the survival of new neurons in the dentate gyrus.

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    Olariu, Ana; Cleaver, Kathryn M; Shore, Lauren E; Brewer, Michelle D; Cameron, Heather A

    2005-01-01

    Granule cells born in the adult dentate gyrus undergo a 4-week developmental period characterized by high susceptibility to cell death. Two forms of hippocampus-dependent learning have been shown to rescue many of the new neurons during this critical period. Here, we show that a natural form of associative learning, social transmission of food preference (STFP), can either increase or decrease the survival of young granule cells in adult rats. Increased numbers of pyknotic as well as phospho-Akt-expressing BrdU-labeled cells were seen 1 day after STFP training, indicating that training rapidly induces both cell death and active suppression of cell death in different subsets. A single day of training for STFP increased the survival of 8-day-old BrdU-labeled cells when examined 1 week later. In contrast, 2 days of training decreased the survival of BrdU-labeled cells and the density of immature neurons, identified with crmp-4. This change from increased to decreased survival could not be accounted for by the ages of the cells. Instead, we propose that training may initially increase young granule cell survival, then, if continued, cause them to die. This complex regulation of cell death could potentially serve to maintain granule cells that are actively involved in memory consolidation, while rapidly using and discarding young granule cells whose training is complete to make space for new naïve neurons. Published 2005 Wiley-Liss, Inc.

  14. Reward memory relieves anxiety-related behavior through synaptic strengthening and protein kinase C in dentate gyrus.

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    Lei, Zhuofan; Liu, Bei; Wang, Jin-Hui

    2016-04-01

    Anxiety disorders are presumably associated with negative memory. Psychological therapies are widely used to treat this mental deficit in human beings based on the view that positive memory competes with negative memory and relieves anxiety status. Cellular and molecular processes underlying psychological therapies remain elusive. Therefore, we have investigated its mechanisms based on a mouse model in which food reward at one open-arm of the elevated plus-maze was used for training mice to form reward memory and challenge the open arms. Mice with the reward training showed increased entries and stay time in reward open-arm versus neutral open-arm as well as in open-arms versus closed-arms. Accompanying with reward memory formation and anxiety relief, glutamatergic synaptic transmission in dentate gyrus in vivo and dendritic spines in granule cells became upregulated. This synaptic up-regulation was accompanied by the expression of more protein kinase C (PKC) in the dendritic spines. The inhibition of PKC by chelerythrine impaired the formation of reward memory, the relief of anxiety-related behavior and the up-regulation of glutamate synapses. Our results suggest that reward-induced positive memory relieves mouse anxiety-related behavior by strengthening synaptic efficacy and PKC in the hippocampus, which imply the underlying cellular and molecular processes involved in the beneficial effects of psychological therapies treating anxiety disorders. © 2015 Wiley Periodicals, Inc.

  15. Naringin attenuates granule cell dispersion in the dentate gyrus in a mouse model of temporal lobe epilepsy.

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    Jang, Hannah; Jeong, Kyoung Hoon; Kim, Sang Ryong

    2016-07-01

    Morphological abnormalities of the dentate gyrus (DG) are an important phenotype in the hippocampus of patients with temporal lobe epilepsy. We recently reported that naringin, a bioflavonoid in grapefruit and citrus fruits, exerts beneficial effects in the kainic acid (KA) mouse model of epilepsy. We found that naringin treatment reduced seizure activities and decreased autophagic stress and neuroinflammation in the hippocampus following in vivo lesion with KA. However, it remains unclear whether naringin may also attenuate seizure-induced morphological changes in the DG, collectively known as granule cell dispersion (GCD). To clarify whether naringin treatment reduces GCD, we evaluated the effects of intraperitoneal injection of naringin on GCD and activation of mammalian target of rapamycin complex 1 (mTORC1), an important regulator of GCD, following intrahippocampal injection of KA. Our results showed that naringin treatment significantly reduced KA-induced GCD and mTORC1 activation, which was confirmed by assessing the phosphorylated form of the mTORC1 substrate, 4E-BP1, in the hippocampus. These results suggest that naringin treatment may help prevent epilepsy-induced hippocampal injury by inhibiting mTORC1 activation and thereby reducing GCD in the hippocampus in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Naringenin ameliorates kainic acid-induced morphological alterations in the dentate gyrus in a mouse model of temporal lobe epilepsy.

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    Park, Jungha; Jeong, Kyoung Hoon; Shin, Won-Ho; Bae, Young-Seuk; Jung, Un Ju; Kim, Sang Ryong

    2016-10-19

    Granule cell dispersion (GCD) in the dentate gyrus (DG) of the hippocampus is a morphological alteration characteristic of temporal lobe epilepsy. Recently, we reported that treatment with naringin, a flavonoid found in grapefruit and citrus fruits, reduced spontaneous recurrent seizures by inhibiting kainic acid (KA)-induced GCD and neuronal cell death in mouse hippocampus, suggesting that naringin might have beneficial effects for preventing epileptic events in the adult brain. However, it is still unclear whether the beneficial effects of naringin treatment are mediated by the metabolism of naringin into naringenin in the KA-treated hippocampus. To investigate this possibility, we evaluated whether intraperitoneal injections of naringenin could mimic naringin-induced effects against GCD caused by intrahippocampal KA injections in mice. Our results showed that treatment with naringenin delayed the onset of KA-induced seizures and attenuated KA-induced GCD by inhibiting activation of the mammalian target of rapamycin complex 1 in both neurons and reactive astrocytes in the DG. In addition, its administration attenuated the production of proinflammatory cytokines such as tumor necrosis tumor necrosis factor-α (TNFα) and interleukin-1β (IL-1β) from microglial activation in the DG following KA treatment. These results suggest that naringenin may be an active metabolite of naringin and help prevent the progression of epileptic insults in the hippocampus in vivo; therefore, naringenin may be a beneficial metabolite of naringin for the treatment of epilepsy.

  17. Hearing assessment during deep brain stimulation of the central nucleus of the inferior colliculus and dentate cerebellar nucleus in rat

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    Jasper V. Smit

    2017-10-01

    Full Text Available Background Recently it has been shown in animal studies that deep brain stimulation (DBS of auditory structures was able to reduce tinnitus-like behavior. However, the question arises whether hearing might be impaired when interfering in auditory-related network loops with DBS. Methods The auditory brainstem response (ABR was measured in rats during high frequency stimulation (HFS and low frequency stimulation (LFS in the central nucleus of the inferior colliculus (CIC, n = 5 or dentate cerebellar nucleus (DCBN, n = 5. Besides hearing thresholds using ABR, relative measures of latency and amplitude can be extracted from the ABR. In this study ABR thresholds, interpeak latencies (I–III, III–V, I–V and V/I amplitude ratio were measured during off-stimulation state and during LFS and HFS. Results In both the CIC and the CNBN groups, no significant differences were observed for all outcome measures. Discussion DBS in both the CIC and the CNBN did not have adverse effects on hearing measurements. These findings suggest that DBS does not hamper physiological processing in the auditory circuitry.

  18. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb

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    Deshpande, Aditi; Bergami, Matteo; Ghanem, Alexander; Conzelmann, Karl-Klaus; Lepier, Alexandra; Götz, Magdalena; Berninger, Benedikt

    2013-01-01

    Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple types of GABAergic interneurons before long-range projections become established, such as those originating from cortical areas. Interestingly, despite fundamental similarities in the overall pattern of evolution of presynaptic connectivity, there were notable differences with regard to the development of cortical projections: although DG granule neuron input originating from the entorhinal cortex could be traced starting only from 3 to 5 wk on, newly generated neurons in the OB received input from the anterior olfactory nucleus and piriform cortex already by the second week. This early glutamatergic input onto newly generated interneurons in the OB was matched in time by the equally early innervations of DG granule neurons by glutamatergic mossy cells. The development of connectivity revealed by our study may suggest common principles for incorporating newly generated neurons into a preexisting circuit. PMID:23487772

  19. Ectopic Expression of α6 and δ GABAA Receptor Subunits in Hilar Somatostatin Neurons Increases Tonic Inhibition and Alters Network Activity in the Dentate Gyrus

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    Tong, Xiaoping; Peng, Zechun; Zhang, Nianhui; Cetina, Yliana; Huang, Christine S.; Wallner, Martin; Otis, Thomas S.

    2015-01-01

    The role of GABAA receptor (GABAAR)-mediated tonic inhibition in interneurons remains unclear and may vary among subgroups. Somatostatin (SOM) interneurons in the hilus of the dentate gyrus show negligible expression of nonsynaptic GABAAR subunits and very low tonic inhibition. To determine the effects of ectopic expression of tonic GABAAR subtypes in these neurons, Cre-dependent viral vectors were used to express GFP-tagged GABAAR subunits (α6 and δ) selectively in hilar SOM neurons in SOM-Cre mice. In single-transfected animals, immunohistochemistry demonstrated strong expression of either the α6 or δ subunit; in cotransfected animals, both subunits were consistently expressed in the same neurons. Electrophysiology revealed a robust increase of tonic current, with progressively larger increases following transfection of δ, α6, and α6/δ subunits, respectively, indicating formation of functional receptors in all conditions and likely coassembly of the subunits in the same receptor following cotransfection. An in vitro model of repetitive bursting was used to determine the effects of increased tonic inhibition in hilar SOM interneurons on circuit activity in the dentate gyrus. Upon cotransfection, the frequency of GABAAR-mediated bursting in granule cells was reduced, consistent with a reduction in synchronous firing among hilar SOM interneurons. Moreover, in vivo studies of Fos expression demonstrated reduced activation of α6/δ-cotransfected neurons following acute seizure induction by pentylenetetrazole. The findings demonstrate that increasing tonic inhibition in hilar SOM interneurons can alter dentate gyrus circuit activity during strong stimulation and suggest that tonic inhibition of interneurons could play a role in regulating excessive synchrony within the network. SIGNIFICANCE STATEMENT In contrast to many hippocampal interneurons, somatostatin (SOM) neurons in the hilus of the dentate gyrus have very low levels of nonsynaptic GABAARs and exhibit

  20. Amenorrhea - primary

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    ... of periods - primary Images Primary amenorrhea Normal uterine anatomy (cut section) Absence of menstruation (amenorrhea) References Bulun SE. The physiology and pathology of the female reproductive axis. In: ...

  1. Combined role of seizure-induced dendritic morphology alterations and spine loss in newborn granule cells with mossy fiber sprouting on the hyperexcitability of a computer model of the dentate gyrus.

    Science.gov (United States)

    Tejada, Julian; Garcia-Cairasco, Norberto; Roque, Antonio C

    2014-05-01

    Temporal lobe epilepsy strongly affects hippocampal dentate gyrus granule cells morphology. These cells exhibit seizure-induced anatomical alterations including mossy fiber sprouting, changes in the apical and basal dendritic tree and suffer substantial dendritic spine loss. The effect of some of these changes on the hyperexcitability of the dentate gyrus has been widely studied. For example, mossy fiber sprouting increases the excitability of the circuit while dendritic spine loss may have the opposite effect. However, the effect of the interplay of these different morphological alterations on the hyperexcitability of the dentate gyrus is still unknown. Here we adapted an existing computational model of the dentate gyrus by replacing the reduced granule cell models with morphologically detailed models coming from three-dimensional reconstructions of mature cells. The model simulates a network with 10% of the mossy fiber sprouting observed in the pilocarpine (PILO) model of epilepsy. Different fractions of the mature granule cell models were replaced by morphologically reconstructed models of newborn dentate granule cells from animals with PILO-induced Status Epilepticus, which have apical dendritic alterations and spine loss, and control animals, which do not have these alterations. This complex arrangement of cells and processes allowed us to study the combined effect of mossy fiber sprouting, altered apical dendritic tree and dendritic spine loss in newborn granule cells on the excitability of the dentate gyrus model. Our simulations suggest that alterations in the apical dendritic tree and dendritic spine loss in newborn granule cells have opposing effects on the excitability of the dentate gyrus after Status Epilepticus. Apical dendritic alterations potentiate the increase of excitability provoked by mossy fiber sprouting while spine loss curtails this increase.

  2. The ethanol metabolite acetaldehyde inhibits the induction of long-term potentiation in the rat dentate gyrus in vivo

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    Abe, Kazuho; Yamaguchi, Shinichi; Sugiura, Minoru; Saito, Hiroshi

    1999-01-01

    Ethanol has been reported to inhibit the induction of long-term potentiation (LTP) in the hippocampus. However, the correlation between the effects of ethanol in vivo and in vitro remained unclear. In addition, previous works have little considered the possibility that the effect of ethanol is mediated by its metabolites. To solve these problems, we investigated the effects of ethanol and acetaldehyde, the first metabolite in the metabolism of ethanol, on the induction of LTP at medial perforant path-granule cell synapses in the dentate gyrus of anaesthetized rats in vivo.Oral administration of 1 g kg−1 ethanol significantly inhibited the induction of LTP, confirming the effectiveness of ethanol in vivo.A lower dose of ethanol (0.5 g kg−1) failed to inhibit the induction of LTP in intact rats, but significantly inhibited LTP in rats treated with disulfiram, an inhibitor of aldehyde dehydrogenase, demonstrating that LTP is inhibited by acetaldehyde accumulation following ethanol administration.Intravenous injection of acetaldehyde (0.06 g kg−1) significantly inhibited the induction of LTP.The inhibitory effect of acetaldehyde on LTP induction was also observed when it was injected into the cerebroventricules, suggesting that acetaldehyde has a direct effect on the brain. The intracerebroventricular dose of acetaldehyde effective in inhibiting LTP induction (0.1–0.15 mg brain−1) was approximately 10 fold lower than that of ethanol (1.0–1.5 mg brain−1).It is possible that acetaldehyde is partly responsible for memory impairments induced by ethanol intoxication. PMID:10482910

  3. Strain-dependent variations in spatial learning and in hippocampal synaptic plasticity in the dentate gyrus of freely behaving rats

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    Denise eManahan-Vaughan

    2011-03-01

    Full Text Available Hippocampal synaptic plasticity is believed to comprise the cellular basis for spatial learning. Strain-dependent differences in synaptic plasticity in the CA1 region have been reported. However, it is not known whether these differences extend to other synapses within the trisynaptic circuit, although there is evidence for morphological variations within that path. We investigated whether Wistar and Hooded Lister (HL rat strains express differences in synaptic plasticity in the dentate gyrus in vivo. We also explored whether they exhibit differences in the ability to engage in spatial learning in an 8-arm radial maze. Basal synaptic transmission was stable over a 24h period in both rat strains, and the input-output relationship of both strains was not significantly different. Paired-pulse analysis revealed significantly less paired-pulse facilitation in the Hooded Lister strain when pulses were given 40-100 msec apart. Low frequency stimulation at 1Hz evoked long-term depression (>24h in Wistar and short-term depression (<2h in HL rats; 200Hz stimulation induced long-term potentiation (>24h in Wistar, and a transient, significantly smaller potentiation (<1h in HL rats, suggesting that HL rats have higher thresholds for expression of persistent synaptic plasticity. Training for 10d in an 8-arm radial maze revealed that HL rats master the working memory task faster than Wistar rats, although both strains show an equivalent performance by the end of the trial period. HL rats also perform more efficiently in a double working and reference memory task. On the other hand, Wistar rats show better reference memory performance on the final (8-10 days of training. Wistar rats were less active and more anxious than HL rats.These data suggest that strain-dependent variations in hippocampal synaptic plasticity occur in different hippocampal synapses. A clear correlation with differences in spatial learning is not evident however.

  4. Inducing a long-term potentiation in the dentate gyrus is sufficient to produce rapid antidepressant-like effects.

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    Kanzari, A; Bourcier-Lucas, C; Freyssin, A; Abrous, D N; Haddjeri, N; Lucas, G

    2018-03-01

    Recent hypotheses propose that one prerequisite to obtain a rapid antidepressant (AD) effect would reside in processes of synaptic reinforcement occurring within the dentate gyrus (DG) of the hippocampus independently from neurogenesis. However, to date no relationship has been established between an increased DG synaptic plasticity, and rapid AD-like action. To the best of our knowledge, this study shows for the first time that inducing a long-term potentiation (LTP) within the DG by stimulating the perforant pathway (PP) is sufficient to induce such effects. Thus, Sprague-Dawley rats having undergone a successful LTP displayed a significant reduction of immobility when passed acutely 3 days thereafter in the forced swimming test (FST). Further, in a longitudinal paradigm using the pseudo-depressed Wistar-Kyoto rat strain, LTP elicited a decrease of FST immobility after only 2 days, whereas the AD desipramine was not effective before 16 days. In both models, the influence of LTP was transient, as it was no more observed after 8-9 days. No effects were observed on the locomotor activity or on anxiety-related behavior. Theta-burst stimulation of a brain region anatomically adjacent to the PP remained ineffective in the FST. Immunoreactivity of DG cells for phosphorylated histone H3 and doublecortin were not modified three days after LTP, indicating a lack of effect on both cell proliferation and neurogenesis. Finally, depleting brain serotonin contents reduced the success rate of LTP but did not affect its subsequent AD-like effects. These results confirm the 'plastic DG' theory of rapid AD efficacy. Beyond, they point out stimulations of the entorhinal cortex, from which the PP originates, as putative new approaches in AD research.

  5. Neural androgen receptors affect the number of surviving new neurones in the adult dentate gyrus of male mice.

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    Swift-Gallant, A; Duarte-Guterman, P; Hamson, D K; Ibrahim, M; Monks, D A; Galea, L A M

    2018-04-01

    Adult hippocampal neurogenesis occurs in many mammalian species. In rats, the survival of new neurones within the hippocampus is modulated by the action of androgen via the androgen receptor (AR); however, it is not known whether this holds true in mice. Furthermore, the evidence is mixed regarding whether androgens act in neural tissue or via peripheral non-neural targets to promote new neurone survival in the hippocampus. We evaluated whether the action of androgen via AR underlies the survival of new neurones in mice, and investigated whether increasing AR selectively in neural tissue would increase new neurone survival in the hippocampus. We used the cre-loxP system to overexpress AR only in neural tissues (Nestin-AR). These males were compared with wild-type males, as well as control males with 1 of the 2 mutations required for overexpression. Mice were gonadectomised and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU) and for 37 days (following BrdU injection), mice were treated with oil or dihydrotestosterone (DHT). Using immunohistochemistry, proliferation (Ki67) and survival (BrdU) of new neurones were both evaluated in the dorsal and ventral dentate gyrus. Dihydrotestosterone treatment increased the survival of new neurones in the entire hippocampus in wild-type mice and control mice that only have 1 of 2 necessary mutations for transgenic expression. However, DHT treatment did not increase the survival of new neurones in mice that overexpressed AR in neural tissue. Cell proliferation (Ki67) and cell death (pyknotic cells) were not affected by DHT treatment in wild-type or transgenic males. These results suggest that androgens act via neural AR to affect hippocampal neurogenesis by promoting cell survival; however, the relationship between androgen dose and new neurone survival is nonlinear. © 2018 British Society for Neuroendocrinology.

  6. Memory retrieval-induced activation of adult-born neurons generated in response to damage to the dentate gyrus.

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    Aguilar-Arredondo, Andrea; Zepeda, Angélica

    2018-04-16

    The dentate gyrus (DG) is a neurogenic structure that exhibits functional and structural reorganization after injury. Neurogenesis and functional recovery occur after brain damage, and the possible relation between both processes is a matter of study. We explored whether neurogenesis and the activation of new neurons correlated with DG recovery over time. We induced a DG lesion in young adult rats through the intrahippocampal injection of kainic acid and analyzed functional recovery and the activation of new neurons after animals performed a contextual fear memory task (CFM) or a control spatial exploratory task. We analyzed the number of BrdU+ cells that co-localized with doublecortin (DCX) or with NeuN within the damaged DG and evaluated the number of cells in each population that were labelled with the activity marker c-fos after either task. At 10 days post-lesion (dpl), a region of the granular cell layer was devoid of cells, evidencing the damaged area, whereas at 30 dpl this region was significantly smaller. At 10 dpl, the number of BrdU+/DCX+/c-fos positive cells was increased compared to the sham-lesion group, but CFM was impaired. At 30 dpl, a significantly greater number of BrdU+/NeuN+/c-fos positive cells was observed than at 10 dpl, and activation correlated with CFM recovery. Performance in the spatial exploratory task induced marginal c-fos immunoreactivity in the BrdU+/NeuN+ population. We demonstrate that neurons born after the DG was damaged survive and are activated in a time- and task-dependent manner and that activation of new neurons occurs along functional recovery.

  7. Reduced Levels of the Synaptic Functional Regulator FMRP in Dentate Gyrus of the Aging Sprague-Dawley Rat

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    Roman Smidak

    2017-11-01

    Full Text Available Fragile X mental retardation protein (FMRP encoded by Fragile X mental retardation 1 (FMR1 gene is a RNA-binding regulator of mRNA translation, transport and stability with multiple targets responsible for proper synaptic function. Epigenetic silencing of FMR1 gene expression leads to the development of Fragile X syndrome (FXS that is characterized by intellectual disability and other behavioral problems including autism. In the rat FXS model, the lack of FMRP caused a deficit in hippocampal-dependent memory. However, the hippocampal changes of FMRP in aging rats are not fully elucidated. The current study addresses the changes in FMRP levels in dentate gyrus (DG from young (17 weeks and aging (22 months Sprague – Dawley rats. The aging animal group showed significant decline in spatial reference memory. Protein samples from five rats per each group were analyzed by quantitative proteomic analysis resulting in 153 significantly changed proteins. FMRP showed significant reduction in aging animals which was confirmed by immunoblotting and immunofluorescence microscopy. Furthermore, bioinformatic analysis of the differential protein dataset revealed several functionally related protein groups with individual interactions with FMRP. These include high representation of the RNA translation and processing machinery connected to FMRP and other RNA-binding regulators including CAPRIN1, the members of Pumilio (PUM and CUG-BP, Elav-like (CELF family, and YTH N(6-methyladenosine RNA-binding proteins (YTHDF. The results of the current study point to the important role of FMRP and regulation of RNA processing in the rat DG and memory decline during the aging process.

  8. Acute restraint stress decreases c-fos immunoreactivity in hilar mossy cells of the adult dentate gyrus

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    Moretto, Jillian N.; Duffy, Áine M.

    2017-01-01

    Although a great deal of information is available about the circuitry of the mossy cells (MCs) of the dentate gyrus (DG) hilus, their activity in vivo is not clear. The immediate early gene c-fos can be used to gain insight into the activity of MCs in vivo, because c-fos protein expression reflects increased neuronal activity. In prior work, it was identified that control rats that were perfusion-fixed after removal from their home cage exhibited c-fos immunoreactivity (ir) in the DG in a spatially stereotyped pattern: ventral MCs and dorsal granule cells (GCs) expressed c-fos protein (Duffy et al., Hippocampus 23:649–655, 2013). In this study, we hypothesized that restraint stress would alter c-fos-ir, because MCs express glucocorticoid type 2 receptors and the DG is considered to be involved in behaviors related to stress or anxiety. We show that acute restraint using a transparent nose cone for just 10 min led to reduced c-fos-ir in ventral MCs compared to control rats. In these comparisons, c-fos-ir was evaluated 30 min after the 10 min-long period of restraint, and if evaluation was later than 30 min c-fos-ir was no longer suppressed. Granule cells (GCs) also showed suppressed c-fos-ir after acute restraint, but it was different than MCs, because the suppression persisted for over 30 min after the restraint. We conclude that c-fos protein expression is rapidly and transiently reduced in ventral hilar MCs after a brief period of restraint, and suppressed longer in dorsal GCs. PMID:28190104

  9. Intrinsic neurophysiological properties of hilar ectopic and normotopic dentate granule cells in human temporal lobe epilepsy and a rat model.

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    Althaus, A L; Sagher, O; Parent, J M; Murphy, G G

    2015-02-15

    Hilar ectopic dentate granule cells (DGCs) are a salient feature of aberrant plasticity in human temporal lobe epilepsy (TLE) and most rodent models of the disease. Recent evidence from rodent TLE models suggests that hilar ectopic DGCs contribute to hyperexcitability within the epileptic hippocampal network. Here we investigate the intrinsic excitability of DGCs from humans with TLE and the rat pilocarpine TLE model with the objective of comparing the neurophysiology of hilar ectopic DGCs to their normotopic counterparts in the granule cell layer (GCL). We recorded from 36 GCL and 7 hilar DGCs from human TLE tissue. Compared with GCL DGCs, hilar DGCs in patient tissue exhibited lower action potential (AP) firing rates, more depolarized AP threshold, and differed in single AP waveform, consistent with an overall decrease in excitability. To evaluate the intrinsic neurophysiology of hilar ectopic DGCs, we made recordings from retrovirus-birthdated, adult-born DGCs 2-4 mo after pilocarpine-induced status epilepticus or sham treatment in rats. Hilar DGCs from epileptic rats exhibited higher AP firing rates than normotopic DGCs from epileptic or control animals. They also displayed more depolarized resting membrane potential and wider AP waveforms, indicating an overall increase in excitability. The contrasting findings between disease and disease model may reflect differences between the late-stage disease tissue available from human surgical specimens and the earlier disease stage examined in the rat TLE model. These data represent the first neurophysiological characterization of ectopic DGCs from human hippocampus and prospectively birthdated ectopic DGCs in a rodent TLE model. Copyright © 2015 the American Physiological Society.

  10. Different patterns of amygdala priming differentially affect dentate gyrus plasticity and corticosterone, but not CA1 plasticity.

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    Rose-Marie eVouimba

    2013-05-01

    Full Text Available Stress-induced activation of the amygdala is involved in the modulation of memory processes in the hippocampus. However, stress effects on amygdala and memory remain complex. The activation of the basolateral amygdala (BLA was found to modulate plasticity in other brain areas, including the hippocampus. We previously demonstrated a differential effect of BLA priming on LTP in the CA1 and the dentate gyrus (DG. While BLA priming suppressed long term potentiation (LTP in CA1, it was found to enhance it in the DG. However, since the amygdala itself is amenable to experience-induced plasticity it is thus conceivable that when activity within the amygdala is modified this will have impact on the way the amygdala modulates activity and plasticity in other brain areas. In the current study we examined the effects of different patterns of BLA activation on the modulation of LTP in the DG and CA1, as well as on serum corticosterone (CORT. In CA1, BLA priming impaired LTP induction as was reported before. In contrast, in the DG, varying BLA stimulation intensity and frequency resulted in differential effects on LTP, ranging from no effect to strong impairment or enhancement. Varying BLA stimulation patterns resulted in also differential alterations in Serum CORT, leading to higher CORT levels being positively correlated with LTP magnitude in DG but not in CA1.The results support the notion of a differential role for the DG in aspects of memory, and add to this view the possibility that DG-associated aspects of memory will be enhanced under more emotional or stressful conditions. It is interesting to think of BLA patterns of activation and the differential levels of circulating CORT as two arms of the emotional and stress response that attempt to synchronize brain activity to best meet the challenge. It is foreseeable to think of abnormal such synchronization under extreme conditions, which would lead to the development of maladaptive behavior.

  11. Pathological evaluation of ganglion cells in biopsies from upper side of the dentate line in patients with perianal problems

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    Marjan Joudi

    2014-07-01

    Full Text Available Introduction: Constipation is one of the most common complaints of individuals, which may present with complication like hemorrhoid and fissure. Hirschsprung is a disease presenting with chronic constipation and its diagnosis may be delayed until adulthood. It is diagnosed by biopsies from anorectal transitional zone. This study aimed to evaluate the association between Hirschsprung and anorectal problems. Method: Sixty three patients with anorectal problems who underwent surgery enrolled in this study. Some consecutive biopsies were obtained from anal canal at 2, 4 and 6 cm above the dentate line. Biopsies were assessed for ganglion cells changes. Patients' data and biopsies results were analyzed with SPSS version18. Results: Out of 63 patients 29 (46 % patients were female and 34 (54 % were male with the mean of 32.65 ± 13.73 years. Fifty six (73 % patients complained from constipation with the mean time of 57.65 ± 45.21 months. Aganglionic zone were reported in six patients with the mean length of 43.33 mm. There was not any relation between anal ganglion cells pathology and constipation (p=0.363, but there was a significant relation between duration of constipation and pathologic changes (p=0.001. The ratio of constipation duration to age was related to anal ganglion cell pathology (p=0.001. Hemorrhoid degree was also affected anal ganglion cells pathology (p=0.037. Conclusion: The relation between Hirschsprung's disease and anorectal problems in adults were significant. The pathologic findings were more presented in younger patients, and those with longer history of constipation and lower degree hemorrhoids. Key words: Anal ganglion cells, Hemorrhoids, Constipation  

  12. Adiponectin regulates contextual fear extinction and intrinsic excitability of dentate gyrus granule neurons through AdipoR2 receptors.

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    Zhang, D; Wang, X; Wang, B; Garza, J C; Fang, X; Wang, J; Scherer, P E; Brenner, R; Zhang, W; Lu, X-Y

    2017-07-01

    Post-traumatic stress disorder (PTSD) is characterized by exaggerated fear expression and impaired fear extinction. The underlying molecular and cellular mechanisms of PTSD are largely unknown. The current pharmacological and non-pharmacological treatments for PTSD are either ineffective or temporary with high relapse rates. Here we report that adiponectin-deficient mice exhibited normal contextual fear conditioning but displayed slower extinction learning. Infusions of adiponectin into the dentate gyrus (DG) of the hippocampus in fear-conditioned mice facilitated extinction of contextual fear. Whole-cell patch-clamp recordings in brain slices revealed that intrinsic excitability of DG granule neurons was enhanced by adiponectin deficiency and suppressed after treatment with the adiponectin mimetic AdipoRon, which were associated with increased input resistance and hyperpolarized resting membrane potential, respectively. Moreover, deletion of AdipoR2, but not AdipoR1 in the DG, resulted in augmented fear expression and reduced extinction, accompanied by intrinsic hyperexcitability of DG granule neurons. Adiponectin and AdipoRon failed to induce facilitation of fear extinction and elicit inhibition of intrinsic excitability of DG neurons in AdipoR2 knockout mice. These results indicated that adiponectin action via AdipoR2 was both necessary and sufficient for extinction of contextual fear and intrinsic excitability of DG granule neurons, implying that enhancing or dampening DG neuronal excitability may cause resistance to or facilitation of extinction. Therefore, our findings provide a functional link between adiponectin/AdipoR2 activation, DG neuronal excitability and contextual fear extinction, and suggest that targeting adiponectin/AdipoR2 may be used to strengthen extinction-based exposure therapies for PTSD.

  13. Activation of β-adrenoceptor facilitates active avoidance learning through enhancement of glutamate levels in the hippocampal dentate gyrus.

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    Lv, Jing; Feng, Hao; Chen, Ling; Wang, Wei-Yao; Yue, Xue-Ling; Jin, Qing-Hua

    2017-10-18

    Long-term potentiation (LTP) is widely accepted as the best studied model for neurophysiological mechanisms that could underlie learning and memory formation. Despite a number of studies indicating that β-adrenoceptors in the hippocampal dentate gyrus (DG) is involved in the modulation of learning and memory as well as LTP, few studies have used glutamate release as a visual indicator in awake animals to explore the role of β-adrenoceptors in learning-dependent LTP. Therefore, in the present study, the effects of propranolol (an antagonist of β-adrenoceptor) and isoproterenol (an agonist of β-adrenoceptor) on extracellular concentrations of glutamate and amplitudes of field excitatory postsynaptic potential were measured in the DG region during active avoidance learning in freely moving conscious rats. In the control group, the glutamate level in the DG was significantly increased during the acquisition of active avoidance behavior and returned to basal level following extinction training. In propranolol group, antagonism of β-adrenoceptors in the DG significantly reduced the change in glutamate level, and the acquisition of the active avoidance behavior was significantly inhibited. In contrast, the change in glutamate level was significantly enhanced by isoproterenol, and the acquisition of the active avoidance behavior was significantly accelerated. Furthermore, in all groups, the changes in glutamate level were accompanied by corresponding changes in field excitatory postsynaptic potential amplitude and active avoidance behavior. Our results suggest that activation of β-adrenoceptors in the hippocampal DG facilitates active avoidance learning by modulations of glutamate level and synaptic efficiency in rats.

  14. Aberrant Epigenetic Gene Regulation in GABAergic Interneuron Subpopulations in the Hippocampal Dentate Gyrus of Mouse Offspring Following Developmental Exposure to Hexachlorophene.

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    Watanabe, Yousuke; Abe, Hajime; Nakajima, Kota; Ideta-Otsuka, Maky; Igarashi, Katsuhide; Woo, Gye-Hyeong; Yoshida, Toshinori; Shibutani, Makoto

    2018-05-01

    Maternal hexachlorophene (HCP) exposure causes transient disruption of hippocampal neurogenesis in mouse offspring. We examined epigenetically hypermethylated and downregulated genes related to this HCP-induced disrupted neurogenesis. Mated female mice were dietary exposed to 0 or 100 ppm HCP from gestational day 6 to postnatal day (PND) 21 on weaning. The hippocampal dentate gyrus of male offspring was subjected to methyl-capture sequencing and real-time reverse transcription-polymerase chain reaction analyses on PND 21. Validation analyses on methylation identified three genes, Dlx4, Dmrt1, and Plcb4, showing promoter-region hypermethylation. Immunohistochemically, DLX4+, DMRT1+, and PLCB4+ cells in the dentate hilus co-expressed GAD67, a γ-aminobutyric acid (GABA)ergic neuron marker. HCP decreased all of three subpopulations as well as GAD67+ cells on PND 21. PLCB4+ cells also co-expressed the metabotropic glutamate receptor, GRM1. HCP also decreased transcript level of synaptic plasticity-related genes in the dentate gyrus and immunoreactive granule cells for synaptic plasticity-related ARC. On PND 77, all immunohistochemical cellular density changes were reversed, whereas the transcript expression of the synaptic plasticity-related genes fluctuated. Thus, HCP-exposed offspring transiently reduced the number of GABAergic interneurons. Among them, subpopulations expressing DLX4, DMRT1, or PLCB4 were transiently reduced in number through an epigenetic mechanism. Considering the role of the Dlx gene family in GABAergic interneuron migration and differentiation, the decreased number of DLX4+ cells may be responsible for reducing those GABAergic interneurons regulating neurogenesis. The effect on granule cell synaptic plasticity was sustained until the adult stage, and reduced GABAergic interneurons active in GRM1-PLCB4 signaling may be responsible for the suppression on weaning.

  15. Comparison of functionally orientated tooth replacement and removable partial dentures on the nutritional status of partially dentate older patients: a randomised controlled clinical trial.

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    McKenna, Gerald; Allen, P Finbarr; O'Mahony, Denis; Flynn, Albert; Cronin, Michael; DaMata, Cristiane; Woods, Noel

    2014-06-01

    The aims of this study were to conduct a randomised controlled clinical trial (RCT) of partially dentate older adults comparing functionally orientated treatment based on the SDA concept with conventional treatment using RPDs to replace missing natural teeth. The two treatment strategies were evaluated according to their impact on nutritional status measured using haematological biomarkers. A randomised controlled clinical trial (RCT) was conducted of partially dentate patients aged 65 years and older (Trial Registration no. ISRCTN26302774). Each patient provided haematological samples which were screened for biochemical markers of nutritional status. Each sample was tested in Cork University Hospital for serum Albumin, serum Cholesterol, Ferritin, Folate, Vitamin B12 and 25-hydroxycholecalciferol (Vitamin D). A mixed model analysis of covariance (ANCOVA) indicated that for Vitamin B12 (p=0.9392), serum Folate (p=0.5827), Ferritin (p=0.6964), Albumin (p=0.8179), Serum Total Cholesterol (p=0.3670) and Vitamin D (p=0.7666) there were no statistically significant differences recorded between the two treatment groups. According to the mixed model analysis of covariance (ANCOVA) for Vitamin D there was a significant difference between levels recorded at post-operative time points after treatment intervention (p=0.0470). There was an increase of 7% in 25-hydroxycholecalciferol levels recorded at 6 months compared to baseline (p=0.0172). There was no further change in recorded levels at 12 months (p=0.6482) and these increases were similar within the two treatment groups (p>0.05). The only measure which illustrated consistent significant improvements in nutritional status for either group were Vitamin D levels. However no significant difference was recorded between the two treatment groups. Functionally orientated prosthodontic rehabilitation for partially dentate older patients was no worse than conventional removable partial dentures in terms of impact on nutritional

  16. Endoscopic submucosal dissection for anorectal tumor with hemorrhoids close to the dentate line: a multicenter study of Hiroshima GI Endoscopy Study Group.

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    Tamaru, Yuzuru; Oka, Shiro; Tanaka, Shinji; Hiraga, Yuko; Kunihiro, Masaki; Nagata, Shinji; Furudoi, Akira; Ninomiya, Yuki; Asayama, Naoki; Shigita, Kenjiro; Nishiyama, Soki; Hayashi, Nana; Chayama, Kazuaki

    2016-10-01

    The lower rectum close to the dentate line has distinct characteristics, making endoscopic submucosal dissection (ESD) of tumors challenging. We assessed clinical outcomes of ESD for such patients with hemorrhoids. Sixty-four patients (mean age, 68 years) underwent ESD for anorectal tumors close to the dentate line. We divided patients into those with (Group A, 45 patients) and without hemorrhoids (Group B, 19 patients). We examined en bloc and histological en bloc resection rates, procedure time, complication rates, and postoperative prognosis after ESD. The mean tumor size was 43 mm. Histologic diagnoses were adenoma (42 %, 27/64), carcinoma in situ (44 %, 28/64), and T1 carcinoma (14 %, 9/64). There was no significant difference in en bloc resection (93 %, 42/45 vs. 95 %, 18/19) or postoperative bleeding rates (16 %, 7/45 vs. 11 %, 2/19) between Groups A and B, respectively. The mean procedural durations were 120 and 124 min, respectively, in Groups A and B. No perforations occurred. There was no significant difference in postoperative anal pain rate between Groups A (18 %, 8/45) and B (16 %, 3/19), and it resolved within a few days in all cases. There was one case of stricture in Group B. Two patients with T1 carcinoma underwent additional surgery, one underwent chemotherapy, and five had no additional treatment. No recurrence occurred during the follow-up period of 38 months. ESD is safe and effective for anorectal tumors close to the dentate line in patients with hemorrhoids.

  17. Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy.

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    Maisano, Xu; Litvina, Elizabeth; Tagliatela, Stephanie; Aaron, Gloster B; Grabel, Laura B; Naegele, Janice R

    2012-01-04

    Cell therapies for neurological disorders require an extensive knowledge of disease-associated neuropathology and procedures for generating neurons for transplantation. In many patients with severe acquired temporal lobe epilepsy (TLE), the dentate gyrus exhibits sclerosis and GABAergic interneuron degeneration. Mounting evidence suggests that therapeutic benefits can be obtained by transplanting fetal GABAergic progenitors into the dentate gyrus in rodents with TLE, but the scarcity of human fetal cells limits applicability in patient populations. In contrast, virtually limitless quantities of neural progenitors can be obtained from embryonic stem (ES) cells. ES cell-based therapies for neurological repair in TLE require evidence that the transplanted neurons integrate functionally and replace cell types that degenerate. To address these issues, we transplanted mouse ES cell-derived neural progenitors (ESNPs) with ventral forebrain identities into the hilus of the dentate gyrus of mice with TLE and evaluated graft differentiation, mossy fiber sprouting, cellular morphology, and electrophysiological properties of the transplanted neurons. In addition, we compared electrophysiological properties of the transplanted neurons with endogenous hilar interneurons in mice without TLE. The majority of transplanted ESNPs differentiated into GABAergic interneuron subtypes expressing calcium-binding proteins parvalbumin, calbindin, or calretinin. Global suppression of mossy fiber sprouting was not observed; however, ESNP-derived neurons formed dense axonal arborizations in the inner molecular layer and throughout the hilus. Whole-cell hippocampal slice electrophysiological recordings and morphological analyses of the transplanted neurons identified five basic types; most with strong after-hyperpolarizations and smooth or sparsely spiny dendritic morphologies resembling endogenous hippocampal interneurons. Moreover, intracellular recordings of spontaneous EPSCs indicated that

  18. Effects of treadmill running on extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats

    Science.gov (United States)

    Reisi, Parham; Alaei, Hojjatallah; Babri, Shirin; Sharifi, Mohammad Reza; Mohaddes, Gisue; Soleimannejad, Elaheh; Rashidi, Bahman

    2010-01-01

    BACKGROUND: The present study evaluated the effects of treadmill running on extracellular basal levels of glutamate and GABA at dentate gyrus of streptozotocin-induced diabetic rats. METHODS: After 12 weeks of diabetes induction and exercise period, extracellular levels of glutamate and GABA were investigated. RESULTS: The results showed that glutamate levels were significantly decreased in diabetes-rest group comparing to the control-rest and the diabetes-exercise groups. CONCLUSIONS: The findings support the possibility that treadmill running is helpful in alleviating neurotransmitter homeostasis and alterations in transmission in diabetes mellitus. PMID:21526077

  19. A cell adhesion molecule mimetic, FGL peptide, induces alterations in synapse and dendritic spine structure in the dentate gyrus of aged rats: a three-dimensional ultrastructural study

    DEFF Research Database (Denmark)

    Popov, Victor I; Medvedev, Nikolay I; Kraev, Igor V

    2008-01-01

    pits. Three-dimensional analysis showed a significant decrease in both post-synaptic density and apposition zone curvature of mushroom spines following FGL treatment, whereas for thin spines the convexity of the apposition zone increased. These data indicate that FGL induces large changes in the fine...... 100 serial ultrathin sections. FGL affected neither hippocampal volume nor spine or synaptic density in the middle molecular layer of the dentate gyrus. However, it increased the ratio of mushroom to thin spines, number of multivesicular bodies and also increased the frequency of appearance of coated...... structure of synapses and dendritic spines in hippocampus of aged rats, complementing data showing its effect on cognitive processes....

  20. Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways

    OpenAIRE

    Yujing Tian; Mengwen Qi; Zhouqing Wang; Chunfeng Wu; Zhen Sun; Yingchun Li; Sha Sha; Yimei Du; Lei Chen; Lei Chen; Ling Chen

    2017-01-01

    Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i). Transient receptor potential vanilloid 4 (TRPV4) is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG). The present study aimed to examine the effect of TRPV4 activati...

  1. Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome.

    Science.gov (United States)

    Zhang, Nianhui; Peng, Zechun; Tong, Xiaoping; Lindemeyer, A Kerstin; Cetina, Yliana; Huang, Christine S; Olsen, Richard W; Otis, Thomas S; Houser, Carolyn R

    2017-11-01

    While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABA A receptors (GABA A Rs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABA A R, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABA A Rs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with

  2. Potassium conductances mediate bidirectional state-dependent modulation of action potential evoked dendritic calcium signals in dentate gyrus granule cells

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    János Brunner

    2014-03-01

    Full Text Available Backpropagating action potentials (bAPs and local calcium signals that they trigger are fundamental for dendritic functions. Here we addressed the question what extent the changes of local dendritic membrane properties can contribute to the shaping of the coupling between dendritic action potentials and the local calcium responses. Using a combination of in vitro electrophysiological and confocal imaging techniques we found that activation of dendritic GIRK channels via mGlu2 or GABAB receptors enhanced the bAP¬-triggered calcium signals in the dendrites of dentate gyrus granule cells (GCs. The enhancement of calcium signals was significant only in those dendritic regions, where these receptors are predominantly expressed. Similarly to GIRK channel activation, somatic hyperpolarization by DC current injection (from -64 mV to -77 mV, significantly increased bAP-associated calcium signals in the proximal dendrites. The hyperpolarization was associated with a decrease in the input resistance due to the rectification of the membrane potential of GCs. The effect of hyperpolarization on the calcium signals was maintained when T-type calcium currents were blocked but it decreased when GIRK channels were inhibited. Simultaneous dual somato-dendritic recordings from GCs showed that somatic hyperpolarization accelerated the repolarization phase of dendritic bAP in the proximal region whereas the rising phase and peak amplitude was not affected. We hypothesize that the larger driving force for calcium ions during the faster repolarization can contribute to the increasing in calcium signals. Employment of previously recorded dendritic bAP waveforms from hyperpolarized membrane potential as voltage command evoked larger calcium currents in nucleated patches compared to bAP waveform from the same recording at depolarized membrane potential. Furthermore, addition of native, high-voltage activated, inactivating potassium conductance by somatic dynamic clamp

  3. Alterations in the Interplay between Neurons, Astrocytes and Microglia in the Rat Dentate Gyrus in Experimental Models of Neurodegeneration

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    Daniele Lana

    2017-09-01

    Full Text Available The hippocampus is negatively affected by aging and neurodegenerative diseases leading to impaired learning and memory abilities. A diverse series of progressive modifications in the intercellular communication among neurons, astrocytes and microglia occur in the hippocampus during aging or inflammation. A detailed understanding of the neurobiological modifications that contribute to hippocampal dysfunction may reveal new targets for therapeutic intervention. The current study focussed on the interplay between neurons and astroglia in the Granule Layer (GL and the Polymorphic Layer (PL of the Dentate Gyrus (DG of adult, aged and LPS-treated rats. In GL and PL of aged and LPS-treated rats, astrocytes were less numerous than in adult rats. In GL of LPS-treated rats, astrocytes acquired morphological features of reactive astrocytes, such as longer branches than was observed in adult rats. Total and activated microglia increased in the aged and LPS-treated rats, as compared to adult rats. In the GL of aged and LPS-treated rats many neurons were apoptotic. Neurons decreased significantly in GL and PL of aged but not in rats treated with LPS. In PL of aged and LPS-treated rats many damaged neurons were embraced by microglia cells and were infiltrated by branches of astrocyte, which appeared to be bisecting the cell body, forming triads. Reactive microglia had a scavenging activity of dying neurons, as shown by the presence of neuronal debris within their cytoplasm. The levels of the chemokine fractalkine (CX3CL1 increased in hippocampal homogenates of aged rats and rats treated with LPS, and CX3CL1 immunoreactivity colocalized with activated microglia cells. Here we demonstrated that in the DG of aged and LPS-treated rats, astrocytes and microglia cooperate and participate in phagocytosis/phagoptosis of apoptotic granular neurons. The differential expression/activation of astroglia and the alteration of their intercommunication may be responsible for

  4. The Coexpression of Reelin and Neuronal Nitric Oxide Synthase in a Subpopulation of Dentate Gyrus Neurons Is Downregulated in Heterozygous Reeler Mice

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    Raquel Romay-Tallón

    2010-01-01

    Full Text Available Reelin is an extracellular matrix protein expressed in several interneuron subtypes in the hippocampus and dentate gyrus. Neuronal nitric oxide synthase (nNOS is also expressed by interneurons in these areas. We investigated whether reelin and nNOS are co-localized in the same population of hippocampal interneurons, and whether this colocalization is altered in the heterozygous reeler mouse. We found colocalization of nNOS in reelin-positive cells in the CA1 stratum radiatum and lacunosum moleculare, the CA3 stratum radiatum, and the dentate gyrus subgranular zone, molecular layer, and hilus. In heterozygous reeler mice, the colocalization of nNOS in reelin-positive cells was significantly decreased only in the subgranular zone and molecular layer. The coexpression of reelin and nNOS in several hippocampal regions suggests that reelin and nNOS may work synergistically to promote glutamatergic function, and the loss of this coexpression in heterozygous reeler mice may underlie some of the behavioral deficits observed in these animals.

  5. Visualization by high resolution immunoelectron microscopy of the transient receptor potential vanilloid-1 at inhibitory synapses of the mouse dentate gyrus.

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    Miren-Josune Canduela

    Full Text Available We have recently shown that the transient receptor potential vanilloid type 1 (TRPV1, a non-selective cation channel in the peripheral and central nervous system, is localized at postsynaptic sites of the excitatory perforant path synapses in the hippocampal dentate molecular layer (ML. In the present work, we have studied the distribution of TRPV1 at inhibitory synapses in the ML. With this aim, a preembedding immunogold method for high resolution electron microscopy was applied to mouse hippocampus. About 30% of the inhibitory synapses in the ML are TRPV1 immunopositive, which is mostly localized perisynaptically (∼60% of total immunoparticles at postsynaptic dendritic membranes receiving symmetric synapses in the inner 1/3 of the layer. This TRPV1 pattern distribution is not observed in the ML of TRPV1 knock-out mice. These findings extend the knowledge of the subcellular localization of TRPV1 to inhibitory synapses of the dentate molecular layer where the channel, in addition to excitatory synapses, is present.

  6. Bcl-2 over-expression fails to prevent age-related loss of calretinin positive neurons in the mouse dentate gyrus

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    Han Mingbo

    2006-08-01

    Full Text Available Abstract Background Cognitive performance declines with increasing age. Possible cellular mechanisms underlying this age-related functional decline remain incompletely understood. Early studies attributed this functional decline to age-related neuronal loss. Subsequent studies using unbiased stereological techniques found little or no neuronal loss during aging. However, studies using specific cellular markers found age-related loss of specific neuronal types. To test whether there is age-related loss of specific neuronal populations in the hippocampus, and subsequently, whether over-expression of the B-cell lymphoma protein-2 (Bcl-2 in these neurons could delay possible age-related neuronal loss, we examined calretinin (CR positive neurons in the mouse dentate gyrus during aging. Result In normal mice, there was an age-related loss of CR positive cells in the dentate gyrus. At the same region, there was no significant decrease of total numbers of neurons, which suggested that age-related loss of CR positive cells was due to the decrease of CR expression in these cells instead of cell death. In the transgenic mouse line over-expressing Bcl-2 in neurons, there was an age-related loss of CR positive cells. Interestingly, there was also an age-related neuronal loss in this transgenic mouse line. Conclusion These data suggest an age-related loss of CR positive neurons but not total neuronal loss in normal mice and this age-related neuronal change is not prevented by Bcl-2 over-expression.

  7. Redistribution of ionotropic glutamate receptors detected by laser microdissection of the rat dentate gyrus 48 h following LTP induction in vivo.

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    Jeremy T T Kennard

    Full Text Available The persistence and input specificity of long-term potentiation (LTP make it attractive as a mechanism of information storage. In its initial phase, both in vivo and in vitro studies have shown that LTP is associated with increased membrane localization of AMPA receptor subunits, but the molecular basis of LTP maintenance over the long-term is still unclear. We have previously shown that expression of AMPA and NMDA receptor subunits is elevated in whole homogenates prepared from dentate gyrus 48 h after LTP induction in vivo. In the present study, we utilized laser microdissection (LMD techniques to determine whether AMPA and NMDA receptor upregulation occurs specifically in the stimulated regions of the dentate gyrus dendritic arbor. Receptor proteins GluN1, GluA1 and GluA2, as well as postsynaptic density protein of 95 kDa and tubulin were detected by Western blot analysis in microdissected samples. Gradients of expression were observed for GluN1 and GluA2, decreasing from the inner to the outer zones of the molecular layer, and were independent of LTP. When induced at medial perforant path synapses, LTP was associated with an apparent specific redistribution of GluA1 and GluN1 to the middle molecular layer that contains these synapses. These data indicate that glutamate receptor proteins are delivered specifically to dendritic regions possessing LTP-expressing synapses, and that these changes are preserved for at least 48 h.

  8. Two-Stage Translational Control of Dentate Gyrus LTP Consolidation Is Mediated by Sustained BDNF-TrkB Signaling to MNK

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    Debabrata Panja

    2014-11-01

    Full Text Available BDNF signaling contributes to protein-synthesis-dependent synaptic plasticity, but the dynamics of TrkB signaling and mechanisms of translation have not been defined. Here, we show that long-term potentiation (LTP consolidation in the dentate gyrus of live rodents requires sustained (hours BDNF-TrkB signaling. Surprisingly, this sustained activation maintains an otherwise labile signaling pathway from TrkB to MAP-kinase-interacting kinase (MNK. MNK activity promotes eIF4F translation initiation complex formation and protein synthesis in mechanistically distinct early and late stages. In early-stage translation, MNK triggers release of the CYFIP1/FMRP repressor complex from the 5′-mRNA cap. In late-stage translation, MNK regulates the canonical translational repressor 4E-BP2 in a synapse-compartment-specific manner. This late stage is coupled to MNK-dependent enhanced dendritic mRNA translation. We conclude that LTP consolidation in the dentate gyrus is mediated by sustained BDNF signaling to MNK and MNK-dependent regulation of translation in two functionally and mechanistically distinct stages.

  9. Neurons in the hippocampal CA1 region, but not the dentate gyrus, are susceptible to oxidative stress in rats with streptozotocin-induced type 1 diabetes

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    Sang Gun Lee

    2015-01-01

    Full Text Available In this study, we investigated the effects of streptozotocin-induced type 1 diabetes on antioxidant-like protein-1 immunoreactivity, protein carbonyl levels, and malondialdehyde formation, a marker for lipid peroxidation, in the hippocampus. For this study, streptozotocin (75 mg/kg was intraperitoneally injected into adult rats to induce type 1 diabetes. The three experimental parameters were determined at 2, 3, 4 weeks after streptozotocin treatment. Fasting blood glucose levels significantly increased by 20.7-21.9 mM after streptozotocin treatment. The number of antioxidant-like protein-1 immunoreactive neurons significantly decreased in the hippocampal CA1 region, but not the dentate gyrus, 3 weeks after streptozotocin treatment compared to the control group. Malondialdehyde and protein carbonyl levels, which are modified by oxidative stress, significantly increased with a peak at 3 weeks after malondialdehyde treatment, and then decreased 4 weeks after malondialdehyde treatment. These results suggest that neurons in the hippocampal CA1 region, but not the dentate gyrus, are susceptible to oxidative stress 3 weeks after malondialdehyde treatment.

  10. Neuronal apoptosis and synaptic density in the dentate gyrus of ischemic rats' response to chronic mild stress and the effects of Notch signaling.

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    Shaohua Wang

    Full Text Available Our previous research highlighted an inconsistency with Notch1 signaling-related compensatory neurogenesis after chronic mild stress (CMS in rodents suffering from cerebral ischemia, which continue to display post-stroke depressive symptoms. Here, we hypothesize that CMS aggrandized ischemia-related apoptosis injury and worsened synaptic integrity via gamma secretase-meditated Notch1 signaling. Adult rats were exposed to a CMS paradigm after left middle cerebral artery occlusion (MCAO. Open-field and sucrose consumption testing were employed to assess depression-like behavior. Gene expression of pro-apoptotic Bax, anti-apoptotic Bcl-2, and synaptic density-related synaptophysin were measured by western blotting and real-time PCR on Day 28 after MCAO surgery. CMS induced depressive behaviors in ischemic rats, which was accompanied by an elevation in Bax/bcl-2 ratio, TUNEL staining in neurons and reduced synaptophysin expression in the dentate gyrus. These collective effects were reversed by the gamma-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl-L-alanyl]-S-phenyl-glycine t-butyl ester. We found that post-stroke stressors made neurons in the dentate gyrus vulnerable to apoptosis, which supports a putative role for Notch signaling in neural integrity, potentially in newborn cells' synaptic deficit with regard to preexisting cells. These findings suggest that post-stroke depression therapeutically benefits from blocking gamma secretase mediated Notch signaling, and whether this signaling pathway could be a therapeutic target needs to be further investigated.

  11. Synaptic plasticity and the analysis of the field-EPSP as well as the population spike using separate recording electrodes in the dentate gyrus in freely moving rats.

    Science.gov (United States)

    Frey, Sabine; Frey, Julietta U

    2009-10-30

    Commonly, synaptic plasticity events such as long-term potentiation (LTP) are investigated by using a stimulation electrode and a single, monopolar field recording electrode in the dentate gyrus in intact, freely moving rats. The recording electrode is mostly positioned in the granular cell layer, or the hilar region of the dentate gyrus, i.e. far away from the place of generation of monosynaptic postsynaptic excitatory potentials (EPSP). Since LTP is a synaptic phenomenon and field recordings far away from the activated synapses do not guarantee a specific interpretation of the overlaid, mixture of complex potentials of several different electrical fields it is often difficult or even impossible to interpret the data obtained by such a single recording electrode. Therefore, at least a separate or two recording electrodes should be used to record the EPSP as well as the spike, respectively, ideally at their places of generation. Here, we describe a method by implanting a chronic bipolar recording electrode which fulfils the above requirements by recording the field-EPSP as well as the population spike at their places of generation and describe the time course of LTP measured using this "double-recording" electrode. We show that different tetanization protocols resulted in EPSP- or population spike-LTP but only if the potentials were recorded by electrodes positioned within adequate places of potential generation. Interestingly, the commonly used recording in the hilus of a distinct part of a potential, mistakenly analyzed as an "EPSP" did not reveal any LTP.

  12. Primary explosives

    Energy Technology Data Exchange (ETDEWEB)

    Matyas, Robert; Pachman, Jiri [Pardubice Univ. (Czech Republic). Faculty of Chemical Technology

    2013-06-01

    The first chapter provides background such as the basics of initiation and differences between requirements on primary explosives used in detonators and igniters. The authors then clarify the influence of physical characteristics on explosive properties, focusing on those properties required for primary explosives. Furthermore, the issue of sensitivity is discussed. All the chapters on particular groups of primary explosives are structured in the same way, including introduction, physical and chemical properties, explosive properties, preparation and documented use.

  13. Primary fibromyalgia

    DEFF Research Database (Denmark)

    Jacobsen, S; Jensen, L T; Foldager, M

    1990-01-01

    Serum concentrations of procollagen type III aminoterminal peptide have previously been reported to be low in some patients with primary fibromyalgia and the aim of this study was to determine if such patients differ clinically from primary fibromyalgia patients with normal levels of procollagen...... type III aminoterminal peptide. Subjective symptoms, tender points and dynamic muscle strength in 45 women with primary fibromyalgia were related to serum concentrations of procollagen type III aminoterminal peptide. Patients with low serum concentrations of procollagen type III aminoterminal peptide...... concentrations of procollagen type III aminoterminal peptide of primary fibromyalgia patients are connected to the disease impact....

  14. Increasing signal intensity within the dentate nucleus and globus pallidus on unenhanced T1W magnetic resonance images in patients with relapsing-remitting multiple sclerosis: correlation with cumulative dose of a macrocyclic gadolinium-based contrast agent, gadobutrol

    Energy Technology Data Exchange (ETDEWEB)

    Stojanov, Dragan A. [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Center for Radiology, Nis (Serbia); Aracki-Trenkic, Aleksandra [Clinical Center Nis, Center for Radiology, Nis (Serbia); Vojinovic, Slobodan; Ljubisavljevic, Srdjan [University of Nis, Faculty of Medicine, Nis (Serbia); Clinical Center Nis, Clinic for Neurology, Nis (Serbia); Benedeto-Stojanov, Daniela [University of Nis, Faculty of Medicine, Nis (Serbia)

    2016-03-15

    To evaluate correlation between cumulative dose of gadobutrol and signal intensity (SI) within dentate nucleus and globus pallidus on unenhanced T1-weighted images in patients with relapsing-remitting multiple sclerosis (RRMS). Dentate nucleus-to-pons and globus pallidus-to-thalamus SI ratios, and renal and liver functions, were evaluated after multiple intravenous administrations of 0.1 mmol/kg gadobutrol at 27, 96-98, and 168 weeks. We compared SI ratios based on the number of administrations, total amount of gadobutrol administered, and time between injections. Globus pallidus-to-thalamus (p = 0.025) and dentate nucleus-to-pons (p < 0.001) SI ratios increased after multiple gadobutrol administrations, correlated with the number of administrations (ρ = 0.263, p = 0.046, respectively) and depended on the length of administration (p = 0.017, p = 0.037, respectively). Patients receiving gadobutrol at 27 weeks showed the greatest increase in both SI ratios (p = 0.006; p = 0.014, respectively, versus 96-98 weeks). GGT increased at the end of the study (p = 0.004). In patients with RRMS, SI within the dentate nucleus and globus pallidus increased on unenhanced T1-weighted images after multiple gadobutrol injections. Administration of the same total amount of gadobutrol over a shorter period caused greater SI increase. (orig.)

  15. Neurotoxic Doses of Chronic Methamphetamine  Trigger Retrotransposition of the Identifier Element  in Rat Dorsal Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Anna Moszczynska

    2017-03-01

    Full Text Available Short interspersed elements (SINEs are typically silenced by DNA hypermethylation in somatic cells, but can retrotranspose in proliferating cells during adult neurogenesis. Hypomethylation caused by disease pathology or genotoxic stress leads to genomic instability of SINEs. The goal of the present investigation was to determine whether neurotoxic doses of binge or chronic methamphetamine (METH trigger retrotransposition of the identifier (ID element, a member of the rat SINE family, in the dentate gyrus genomic DNA. Adult male Sprague‐Dawley rats were treated with saline or high doses of binge or chronic METH and sacrificed at three different time points thereafter. DNA methylation analysis, immunohistochemistry and next‐generation sequencing (NGS were performed on the dorsal dentate gyrus samples. Binge METH triggered hypomethylation, while chronic METH triggered hypermethylation of the CpG‐2 site. Both METH regimens were associated with increased intensities in poly(A‐binding protein 1 (PABP1, a SINE regulatory protein‐like immunohistochemical staining in the dentate gyrus. The amplification of several ID element sequences was significantly higher in the chronic METH group than in the control group a week after METH, and they mapped to genes coding for proteins regulating cell growth and proliferation, transcription, protein function as well as for a variety of transporters. The results suggest that chronic METH induces ID element retrotransposition in the dorsal dentate gyrus and may affect hippocampal neurogenesis.

  16. Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats

    International Nuclear Information System (INIS)

    Abe, Hajime; Saito, Fumiyo; Tanaka, Takeshi; Mizukami, Sayaka; Hasegawa-Baba, Yasuko; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2016-01-01

    Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region-specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at ≥ 0.1% or 0.4% on PND 21. CPZ at 0.4% decreased immunostaining intensity for 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) and CNPase + and OLIG2 + oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho + oligodendrocytes were detected in the corpus callosum at ≥ 0.1%. In the dentate gyrus, CPZ at ≥ 0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1 + and GRIN2A + hilar γ-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2 + granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells. - Highlights: • We examined developmental cuprizone (CPZ) neurotoxicity in maternally exposed rats. • Multiple brain region-specific global gene expression profiling was performed. • CPZ decreased

  17. Developmental cuprizone exposure impairs oligodendrocyte lineages differentially in cortical and white matter tissues and suppresses glutamatergic neurogenesis signals and synaptic plasticity in the hippocampal dentate gyrus of rats

    Energy Technology Data Exchange (ETDEWEB)

    Abe, Hajime [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Saito, Fumiyo [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Tanaka, Takeshi; Mizukami, Sayaka [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193 (Japan); Hasegawa-Baba, Yasuko [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Imatanaka, Nobuya; Akahori, Yumi [Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004 (Japan); Yoshida, Toshinori [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan); Shibutani, Makoto, E-mail: mshibuta@cc.tuat.ac.jp [Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509 (Japan)

    2016-01-01

    Developmental cuprizone (CPZ) exposure impairs rat hippocampal neurogenesis. Here, we captured the developmental neurotoxicity profile of CPZ using a region-specific expression microarray analysis in the hippocampal dentate gyrus, corpus callosum, cerebral cortex and cerebellar vermis of rat offspring exposed to 0, 0.1, or 0.4% CPZ in the maternal diet from gestation day 6 to postnatal day (PND) 21. Transcripts of those genes identified as altered were subjected to immunohistochemical analysis on PNDs 21 and 77. Our results showed that transcripts for myelinogenesis-related genes, including Cnp, were selectively downregulated in the cerebral cortex by CPZ at ≥ 0.1% or 0.4% on PND 21. CPZ at 0.4% decreased immunostaining intensity for 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) and CNPase{sup +} and OLIG2{sup +} oligodendrocyte densities in the cerebral cortex, whereas CNPase immunostaining intensity alone was decreased in the corpus callosum. By contrast, a striking transcript upregulation for Klotho gene and an increased density of Klotho{sup +} oligodendrocytes were detected in the corpus callosum at ≥ 0.1%. In the dentate gyrus, CPZ at ≥ 0.1% or 0.4% decreased the transcript levels for Gria1, Grin2a and Ptgs2, genes related to the synapse and synaptic transmission, and the number of GRIA1{sup +} and GRIN2A{sup +} hilar γ-aminobutyric acid (GABA)-ergic interneurons and cyclooxygenase-2{sup +} granule cells. All changes were reversed at PND 77. Thus, developmental CPZ exposure reversibly decreased mature oligodendrocytes in both cortical and white matter tissues, and Klotho protected white matter oligodendrocyte growth. CPZ also reversibly targeted glutamatergic signals of GABAergic interneuron to affect dentate gyrus neurogenesis and synaptic plasticity in granule cells. - Highlights: • We examined developmental cuprizone (CPZ) neurotoxicity in maternally exposed rats. • Multiple brain region-specific global gene expression profiling

  18. Primary productivity

    Digital Repository Service at National Institute of Oceanography (India)

    Verlecar, X.N.; Parulekar, A.H.

    Photosynthetic production in the oceans in relation to light, nutrients and mixing processes is discussed. Primary productivity in the estuarine region is reported to be high in comparison to coastal and oceanic waters. Upwelling phenomenon...

  19. Primary Hyperparathyroidism

    Science.gov (United States)

    ... Neoplasia Type 1 Thyroid Disease & Pregnancy Primary Hyperparathyroidism Prolactinoma National Hormone and Pituitary Program (NHPP): Information for ... qualified health care provider nearby. Eating, Diet, and Nutrition Eating, diet, and nutrition have not been shown ...

  20. Primary Myelofibrosis

    Science.gov (United States)

    ... attack is higher. Patients also have an increased risk of acute myeloid leukemia or primary myelofibrosis . Symptoms of polycythemia vera include headaches and a feeling of fullness below the ribs on the left ...

  1. Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

    Directory of Open Access Journals (Sweden)

    Wang-shu Xu

    2016-01-01

    Full Text Available Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia.

  2. Excitotoxic median raphe lesions aggravate working memory storage performance deficits caused by scopolamine infusion into the dentate gyrus of the hippocampus in the inhibitory avoidance task in rats

    Directory of Open Access Journals (Sweden)

    Babar E.

    2002-01-01

    Full Text Available The interactions between the median raphe nucleus (MRN serotonergic system and the septohippocampal muscarinic cholinergic system in the modulation of immediate working memory storage performance were investigated. Rats with sham or ibotenic acid lesions of the MRN were bilaterally implanted with cannulae in the dentate gyrus of the hippocampus and tested in a light/dark step-through inhibitory avoidance task in which response latency to enter the dark compartment immediately after the shock served as a measure of immediate working memory storage. MRN lesion per se did not alter response latency. Post-training intrahippocampal scopolamine infusion (2 and 4 µg/side produced a more marked reduction in response latencies in the lesioned animals compared to the sham-lesioned rats. Results suggest that the immediate working memory storage performance is modulated by synergistic interactions between serotonergic projections of the MRN and the muscarinic cholinergic system of the hippocampus.

  3. A Voltage-Based STDP Rule Combined with Fast BCM-Like Metaplasticity Accounts for LTP and Concurrent "Heterosynaptic" LTD in the Dentate Gyrus In Vivo.

    Directory of Open Access Journals (Sweden)

    Peter Jedlicka

    2015-11-01

    Full Text Available Long-term potentiation (LTP and long-term depression (LTD are widely accepted to be synaptic mechanisms involved in learning and memory. It remains uncertain, however, which particular activity rules are utilized by hippocampal neurons to induce LTP and LTD in behaving animals. Recent experiments in the dentate gyrus of freely moving rats revealed an unexpected pattern of LTP and LTD from high-frequency perforant path stimulation. While 400 Hz theta-burst stimulation (400-TBS and 400 Hz delta-burst stimulation (400-DBS elicited substantial LTP of the tetanized medial path input and, concurrently, LTD of the non-tetanized lateral path input, 100 Hz theta-burst stimulation (100-TBS, a normally efficient LTP protocol for in vitro preparations produced only weak LTP and concurrent LTD. Here we show in a biophysically realistic compartmental granule cell model that this pattern of results can be accounted for by a voltage-based spike-timing-dependent plasticity (STDP rule combined with a relatively fast Bienenstock-Cooper-Munro (BCM-like homeostatic metaplasticity rule, all on a background of ongoing spontaneous activity in the input fibers. Our results suggest that, at least for dentate granule cells, the interplay of STDP-BCM plasticity rules and ongoing pre- and postsynaptic background activity determines not only the degree of input-specific LTP elicited by various plasticity-inducing protocols, but also the degree of associated LTD in neighboring non-tetanized inputs, as generated by the ongoing constitutive activity at these synapses.

  4. 3β-Methyl-Neurosteroid Analogs are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic δGABA-A Receptors in the Hippocampus Dentate Gyrus Subfield.

    Science.gov (United States)

    Chuang, Shu-Hui; Reddy, Doodipala Samba

    2018-03-30

    Neurosteroids are powerful modulators of GABA-A receptors. Ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor-mediated phasic currents. Concentration-response profiles of GX were determined in two cell types: δ-containing dentate gyrus granule cells (DGGCs) and γ2-containing CA1 pyramidal cells (CA1PCs). GX produced significantly greater potentiation of the GABA-A receptor-activated chloride currents in DGGCs (500%) than CA1PCs (200%). In the absence of GABA, GX evoked 2-fold greater inward currents in DGGCs than CA1PCs, which were 2-fold greater than AP within DGGCs. In hippocampus slices, GX potentiated and directly activated tonic currents in DGGCs. These responses were significantly diminished in DGGCs from δ-subunit knockout (δKO) mice, confirming GX's selectivity for δGABA-A receptors. Like AP, GX potentiation of tonic currents was prevented by protein kinase C inhibition. Furthermore, GX's protection against hippocampus kindled seizures was significantly diminished in δKO mice. GX analogs exhibited greater potency and efficacy than GX on δGABA-A receptor-mediated tonic inhibition. In summary, these results provide strong evidence that GX and its analogs are preferential allosteric modulators and direct activators of extrasynaptic δGABA-A receptors regulating network inhibition and seizures in the dentate gyrus. Therefore, these findings provide a mechanistic rationale for the clinical use of synthetic neurosteroids in epilepsy and seizure disorders. The American Society for Pharmacology and Experimental Therapeutics.

  5. Mnemonic Discrimination Deficits in First-Episode Psychosis and a Ketamine Model Suggests Dentate Gyrus Pathology Linked to N-Methyl-D-Aspartate Receptor Hypofunction.

    Science.gov (United States)

    Kraguljac, Nina Vanessa; Carle, Matthew; Frölich, Michael A; Tran, Steve; Yassa, Michael A; White, David Matthew; Reddy, Abhishek; Lahti, Adrienne Carol

    2018-03-01

    Converging evidence from neuroimaging and postmortem studies suggests that hippocampal subfields are differentially affected in schizophrenia. Recent studies report dentate gyrus dysfunction in chronic schizophrenia, but the underlying mechanisms remain to be elucidated. Here we sought to examine if this deficit is already present in first-episode psychosis, and if N-methyl-D-aspartate receptor hypofunction, a putative central pathophysiological mechanism in schizophrenia, experimentally induced by ketamine, would result in a similar abnormality. We applied a mnemonic discrimination task selectively taxing pattern separation in two experiments: 1) a group of 23 first-episode psychosis patients and 23 matched healthy volunteers and 2) a group of 19 healthy volunteers before and during a ketamine challenge (0.27 mg/kg over 10 minutes, then 0.25 mg/kg/hour for 50 minutes, 0.01 mL/s). We calculated response bias-corrected pattern separation and recognition scores. We also examined the relationships between task performance and symptom severity as well as ketamine levels. We report a deficit in pattern separation but not recognition performance in first-episode psychosis patients compared with healthy volunteers (p = .04) and in volunteers during the ketamine challenge compared with baseline (p = .003). Exploratory analyses revealed no correlation between task performance and Repeatable Battery for the Assessment of Neuropsychological Status total scores or positive symptoms in first-episode psychosis patients, or with ketamine serum levels. We observed a mnemonic discrimination deficit but intact recognition in both datasets. Our findings suggest a tentative mechanistic link between dentate gyrus dysfunction in first-episode psychosis and N-methyl-D-aspartate receptor hypofunction. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. Involvement of over-expressed BMP4 in pentylenetetrazol kindling-induced cell proliferation in the dentate gyrus of adult rats

    International Nuclear Information System (INIS)

    Yin Jinbo; Ma Yuxin; Yin Qing; Xu Haiwei; An Ning; Liu Shiyong; Fan Xiaotang; Yang Hui

    2007-01-01

    The dentate gyrus (DG) of the hippocampus is one of a few regions in the adult mammalian brain characterized by ongoing neurogenesis. Proliferation of neural precursors in the granule cell layer of the DG has been identified in pentylenetetrazol (PTZ) kindling epilepsy model, however, little is known about the molecular mechanism. We previously reported that the expression pattern of bone morphogenetic proteins-4 (BMP4) mRNA in the hippocampus was developmentally regulated and mainly localized in the DG of the adult. To explore the role of BMP4 in epileptic activity, we detected BMP4 expression in the DG during PTZ kindling process and explore its correlation with cell proliferation combined with bromodeoxyuridine (BrdU) labeling technique. We found that dynamic changes in BMP4 level and BrdU labeled cells dependent on the kindling stage of PTZ induced seizure-prone state. The number of BMP4 mRNA-positive cells and BrdU labeled cells reached the top level 1 day after PTZ kindled, then declined to base level 2 months later. Furthermore, there was a significant correlation between increased BMP4 mRNA expression and increased number of BrdU labeled cells. After effectively blocked expression of BMP4 with antisense oligodeoxynucleotides(ASODN), the BrdU labeled cells in the dentate gyrus subgranular zone(DG-SGZ) and hilus were significantly decreased 16d after First PTZ injection and 1, 3, 7, 14d after kindled respectively. These findings suggest that increased proliferation in the DG of the hippocampus resulted from kindling epilepsy elicited by PTZ maybe be modulated by BMP4 over-expression

  7. Overexpression of Mineralocorticoid Receptors in the Mouse Forebrain Partly Alleviates the Effects of Chronic Early Life Stress on Spatial Memory, Neurogenesis and Synaptic Function in the Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Sofia Kanatsou

    2017-05-01

    Full Text Available Evidence from human studies suggests that high expression of brain mineralocorticoid receptors (MR may promote resilience against negative consequences of stress exposure, including childhood trauma. We examined, in mice, whether brain MR overexpression can alleviate the effects of chronic early life stress (ELS on contextual memory formation under low and high stress conditions, and neurogenesis and synaptic function of dentate gyrus granular cells. Male mice were exposed to ELS by housing the dam with limited nesting and bedding material from postnatal day (PND 2 to 9. We investigated the moderating role of MRs by using forebrain-specific transgenic MR overexpression (MR-tg mice. Low-stress contextual (i.e., object relocation memory formation was hampered by ELS in wildtype but not MR-tg mice. Anxiety like behavior and high-stress contextual (i.e., fear memory formation were unaffected by ELS and/or MR expression level. At the cellular level, an interaction effect was observed between ELS and MR overexpression on the number of doublecortin-positive cells, with a significant difference between the wildtype ELS and MR-tg ELS groups. No interaction was found regarding Ki-67 and BrdU staining. A significant interaction between ELS and MR expression was further observed with regard to mEPSCs and mIPSC frequency. The ratio of evoked EPSC/IPSC or NMDA/AMPA responses was unaffected. Overall, these results suggest that ELS affects contextual memory formation under low stress conditions as well as neurogenesis and synaptic transmission in dentate granule cells, an effect that can be alleviated by MR-overexpression.

  8. Increased signal intensities in the dentate nucleus and globus pallidus on unenhanced T1-weighted images: evidence in children undergoing multiple gadolinium MRI exams

    Energy Technology Data Exchange (ETDEWEB)

    Hu, Houchun H.; Pokorney, Amber; Towbin, Richard B.; Miller, Jeffrey H. [Phoenix Children' s Hospital, Department of Medical Imaging and Radiology, Phoenix, AZ (United States)

    2016-10-15

    Recent reports have suggested residual gadolinium deposition in the brain in subjects undergoing multiple contrast-enhanced MRI exams. These findings have raised some concerns regarding gadolinium-based contrast agent (GBCA) usage and retention in brain tissues. To summarize findings of hyperintense brain structures on precontrast T1-weighted images in 21 children undergoing multiple GBCA MRI exams. This retrospective study involved 21 patients, each of whom received multiple MRI examinations (range: 5-37 exams) with GBCA over the course of their medical treatment (duration from first to most recent exam: 1.2-12.9 years). The patients were between 0.9 and 14.4 years of age at the time of their first GBCA exam. Regions of interest were drawn in the dentate nucleus and the globus pallidus on 2-D fast spin echo images acquired at 1.5 T. The signal intensities of these two structures were normalized by that of the corpus callosum genu. Signal intensity ratios from these patients were compared to control patients of similar ages who have never received GBCA. Signal intensity ratios increased between the first and the most recent MRI exam in all 21 patients receiving GBCA, with an increase of 18.6%±12.7% (range: 0.5% to 47.5%) for the dentate nucleus and 12.4%±7.4% (range: -1.2% to 33.7%) for the globus pallidus (P<0.0001). Signal intensity ratios were also higher in GBCA patients than in controls (P<0.01). The degree of signal intensity enhancement did not correlate with statistical significance to the cumulative number or volume of GBCA administrations each patient received, the patient's age or the elapsed time between the first and most recent GBCA MRI exams. These results in children are consistent with recent findings in adults, suggesting possible gadolinium deposition in the brain. (orig.)

  9. Effect of 12-month weekly professional oral hygiene care on the composition of the oral flora in dentate, dependent elderly residents: A prospective study.

    Science.gov (United States)

    Wikström, Maude; Kareem, Kawa L; Almståhl, Annica; Palmgren, Erika; Lingström, Peter; Wårdh, Inger

    2017-06-01

    To study the effect of weekly professional oral hygiene care on the proportion of micro-organisms associated with good oral health, caries, and periodontal and soft tissue diseases in oral biofilms in dentate, dependent elderly residents. Assisted oral hygiene care reduces the plaque score and number of micro-organisms in the oral biofilms in elderly residents. Less is known about the effect on the quality/composition of the remaining oral flora. Participants comprised 33 residents in the study and 35 in the control group. Dental status (≥10 natural teeth and no removable dentures to be included), plaque score, salivary secretion rate and prescription medicines were recorded. Duplicate samples, collected from supragingival plaque and tongue, were analysed using cultivation technique. Differences between and within groups were analysed using one-way and two-way ANOVA, respectively. At the baseline, the number of teeth in the participants (mean age, 83.7 ± 7.4 years) was 22.0 ± 4.5. The number of prescription medicines was 9.4 ± 4.5. Seventy-six per cent had low salivary secretion rate. Fifty per cent had "visible thick" supragingival plaque. At the 12-month registration, "no visible" or "visible but thin" plaque was recorded in 92% in the study group. The proportions of bacteria associated with good oral health and periodontal diseases were decreased over time, while the frequency and proportions of micro-organisms associated with caries and soft tissue infection were unaffected or increased. The results indicate that assisted oral hygiene care alone is not sufficient to regain an oral microbial flora associated with good oral health in dentate, dependent elderly residents. © 2016 John Wiley & Sons A/S and The Gerodontology Association. Published by John Wiley & Sons Ltd.

  10. Defective synaptic transmission and structure in the dentate gyrus and selective fear memory impairment in the Rsk2 mutant mouse model of Coffin-Lowry syndrome.

    Science.gov (United States)

    Morice, Elise; Farley, Séverine; Poirier, Roseline; Dallerac, Glenn; Chagneau, Carine; Pannetier, Solange; Hanauer, André; Davis, Sabrina; Vaillend, Cyrille; Laroche, Serge

    2013-10-01

    The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined the performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicates altered synapse ultrastructure. These findings show that RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Effects of chronic alcohol consumption, withdrawal and nerve growth factor on neuropeptide Y expression and cholinergic innervation of the rat dentate hilus.

    Science.gov (United States)

    Pereira, Pedro A; Rocha, João P; Cardoso, Armando; Vilela, Manuel; Sousa, Sérgio; Madeira, M Dulce

    2016-05-01

    Several studies have demonstrated the vulnerability of the hippocampal formation (HF) to chronic alcohol consumption and withdrawal. Among the brain systems that appear to be particularly vulnerable to the effects of these conditions are the neuropeptide Y (NPY)-ergic and the cholinergic systems. Because these two systems seem to closely interact in the HF, we sought to study the effects of chronic alcohol consumption (6months) and subsequent withdrawal (2months) on the expression of NPY and on the cholinergic innervation of the rat dentate hilus. As such, we have estimated the areal density and the somatic volume of NPY-immunoreactive neurons, and the density of the cholinergic varicosities. In addition, because alcohol consumption and withdrawal are associated with impaired nerve growth factor (NGF) trophic support and the administration of exogenous NGF alters the effects of those conditions on various cholinergic markers, we have also estimated the same morphological parameters in withdrawn rats infused intracerebroventricularly with NGF. NPY expression increased after withdrawal and returned to control values after NGF treatment. Conversely, the somatic volume of these neurons did not differ among all groups. On other hand, the expression of vesicular acetylcholine transporter (VAChT) was reduced by 24% in ethanol-treated rats and by 46% in withdrawn rats. The administration of NGF to withdrawn rats increased the VAChT expression to values above control levels. These results show that the effects of prolonged alcohol intake and protracted withdrawal on the hilar NPY expression differ from those induced by shorter exposures to ethanol and by abrupt withdrawal. They also suggest that the normalizing effect of NGF on NPY expression might rely on the NGF-induced improvement of cholinergic neurotransmission in the dentate hilus. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. High pressure and [Ca2+] produce an inverse modulation of synaptic input strength, network excitability and frequency response in the rat dentate gyrus

    Directory of Open Access Journals (Sweden)

    Thomas I Talpalar

    2016-09-01

    Full Text Available Hyperbaric environments induce the high pressure neurological syndrome (HPNS characterized by hyperexcitability of the central nervous system and memory impairment. Human divers and other animals experience the HPNS at pressures beyond 1.1 MPa. High pressure depresses synaptic transmission and alters its dynamics in various animal models. Medial perforant path (MPP synapses connecting the medial entorhinal cortex with the hippocampal formation are suppressed by 50% at 10.1MPa. Reduction of synaptic inputs is paradoxically associated with enhanced ability of dentate gyrus’ granule cells to generate spikes at high pressure. This mechanism allows MPP inputs to elicit standard granule cell outputs at 0.1 -25 Hz frequencies under hyperbaric conditions. An increased postsynaptic gain of MPP inputs probably allows diving animals to perform in hyperbaric environments, but makes them vulnerable to high intensity/frequency stimuli producing hyperexcitability. Increasing extracellular Ca2+ (Ca2+o partially reverted pressure-mediated depression of MPP inputs and increased MPP’s low-pass filter properties. We postulated that raising Ca2+o in addition to increase synaptic inputs may reduce network excitability in the dentate gyrus potentially improving its function and reducing sensitivity to high intensity and pathologic stimuli. For this matter, we activated the MPP with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions, while assessing the granule cell’s output under various conditions of pressure and Ca2+o. Our results reveal that pressure and Ca2+o produce an inverse modulation on synaptic input strength and network excitability. These coincident phenomena suggest a potential general mechanism of networks that adjusts gain as an inverse function of synaptic inputs’ strength. Such mechanism may serve for adaptation to variable pressure and other physiological and pathological conditions and may explain the

  13. [Hypertension: once primary, always primary?

    NARCIS (Netherlands)

    Braam, R.L.; Pieters, G.F.F.M.; Thien, Th.

    2002-01-01

    Three patients diagnosed with primary hypertension suddenly developed hard-to-treat blood pressure after several years of stable blood pressure. One patient, a man aged 48 years, had developed a renal artery stenosis, which had not been present five years earlier. The other two patients, a man aged

  14. Hyperthyroidism (primary)

    OpenAIRE

    Nygaard, Birte

    2010-01-01

    Hyperthyroidism is characterised by high levels of serum thyroxine and triiodothyronine, and low levels of thyroid-stimulating hormone (TSH). Thyrotoxicosis is the clinical effect of high levels of thyroid hormones, whether or not the thyroid gland is the primary source.The main causes of hyperthyroidism are Graves' disease, toxic multinodular goitre, and toxic adenoma.About 20 times more women than men have hyperthyroidism.

  15. The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

    Science.gov (United States)

    Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

    2016-02-01

    Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

  16. Signal intensity at unenhanced T1-weighted magnetic resonance in the globus pallidus and dentate nucleus after serial administrations of a macrocyclic gadolinium-based contrast agent in children

    Energy Technology Data Exchange (ETDEWEB)

    Rossi Espagnet, Maria Camilla; Bernardi, Bruno; Figa-Talamanca, Lorenzo [Ospedale Pediatrico Bambino Gesu, IRCCS, Neuroradiology Unit, Imaging Department, Rome (Italy); Pasquini, Luca [Ospedale Pediatrico Bambino Gesu, IRCCS, Neuroradiology Unit, Imaging Department, Rome (Italy); University Sapienza, Neuroradiology Unit, Azienda Ospedaliera Sant' Andrea, Rome (Italy); Toma, Paolo [Ospedale Pediatrico Bambino Gesu, IRCCS, Department of Imaging, Rome (Italy); Napolitano, Antonio [Ospedale Pediatrico Bambino Gesu, IRCCS, Enterprise Risk Management, Medical Physics Department, Rome (Italy)

    2017-09-15

    Few studies have been conducted on the relations between T1-weighted signal intensity changes in the pediatric brain following gadolinium-based contrast agent (GBCA) exposure. The purpose of this study is to investigate the effect of multiple administrations of a macrocyclic GBCA on signal intensity in the globus pallidus and dentate nucleus of the pediatric brain on unenhanced T1-weighted MR images. This retrospective study included 50 patients, mean age: 8 years (standard deviation: 4.8 years), with normal renal function exposed to ≥6 administrations of the same macrocyclic GBCA (gadoterate meglumine) and a control group of 59 age-matched GBCA-naive patients. The globus pallidus-to-thalamus signal intensity ratio and dentate nucleus-to-pons signal intensity ratio were calculated from unenhanced T1-weighted images for both patients and controls. A mixed linear model was used to evaluate the effects on signal intensity ratios of the number of GBCA administrations, the time interval between administrations, age, radiotherapy and chemotherapy. T-test analyses were performed to compare signal intensity ratio differences between successive administrations and baseline MR signal intensity ratios in patients compared to controls. P-values were considered significant if <0.05. A significant effect of the number of GBCA administrations on relative signal intensities globus pallidus-to-thalamus (F[8]=3.09; P=0.002) and dentate nucleus-to-pons (F[8]=2.36; P=0.021) was found. The relative signal intensities were higher at last MR examination than at baseline (P<0.001). Quantitative analysis evaluation of globus pallidus:thalamus and dentate nucleus:pons of the pediatric brain demonstrated an increase after serial administrations of macrocyclic GBCA. Further research is necessary to fully understand GBCA pharmacokinetic in children. (orig.)

  17. Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

    Institute of Scientific and Technical Information of China (English)

    Lin CHEN; Shan GONG; Li-Dong SHAN; Wei-Ping XU; Yue-Jin ZHANG; Shi-Yu GUO; Tadashi Hisamitsu; Qi-Zhang YIN; Xing-Hong JIANG

    2006-01-01

    Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test,while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.

  18. Behavior-driven arc expression is reduced in all ventral hippocampal subfields compared to CA1, CA3, and dentate gyrus in rat dorsal hippocampus.

    Science.gov (United States)

    Chawla, M K; Sutherland, V L; Olson, K; McNaughton, B L; Barnes, C A

    2018-02-01

    Anatomical connectivity and lesion studies reveal distinct functional heterogeneity along the dorsal-ventral axis of the hippocampus. The immediate early gene Arc is known to be involved in neural plasticity and memory and can be used as a marker for cell activity that occurs, for example, when hippocampal place cells fire. We report here, that Arc is expressed in a greater proportion of cells in dorsal CA1, CA3, and dentate gyrus (DG), following spatial behavioral experiences compared to ventral hippocampal subregions (dorsal CA1 = 33%; ventral CA1 = 13%; dorsal CA3 = 23%; ventral CA3 = 8%; and dorsal DG = 2.5%; ventral DG = 1.2%). The technique used here to obtain estimates of numbers of behavior-driven cells across the dorsal-ventral axis, however, corresponds quite well with samples from available single unit recording studies. Several explanations for the two- to-threefold reduction in spatial behavior-driven cell activity in the ventral hippocampus can be offered. These include anatomical connectivity differences, differential gain of the self-motion signals that appear to alter the scale of place fields and the proportion of active cells, and possibly variations in the neuronal responses to non-spatial information within the hippocampus along its dorso-ventral axis. © 2017 Wiley Periodicals, Inc.

  19. Characterization of calcium signals in human induced pluripotent stem cell-derived dentate gyrus neuronal progenitors and mature neurons, stably expressing an advanced calcium indicator protein.

    Science.gov (United States)

    Vőfély, Gergő; Berecz, Tünde; Szabó, Eszter; Szebényi, Kornélia; Hathy, Edit; Orbán, Tamás I; Sarkadi, Balázs; Homolya, László; Marchetto, Maria C; Réthelyi, János M; Apáti, Ágota

    2018-04-01

    Pluripotent stem cell derived human neuronal progenitor cells (hPSC-NPCs) and their mature neuronal cell culture derivatives may efficiently be used for central nervous system (CNS) drug screening, including the investigation of ligand-induced calcium signalization. We have established hippocampal NPC cultures derived from human induced PSCs, which were previously generated by non-integrating Sendai virus reprogramming. Using established protocols these NPCs were differentiated into hippocampal dentate gyrus neurons. In order to study calcium signaling without the need of dye loading, we have stably expressed an advanced calcium indicator protein (GCaMP6fast) in the NPCs using the Sleeping Beauty transposon system. We observed no significant effects of the long-term GCaMP6 expression on NPC morphology, gene expression pattern or neural differentiation capacity. In order to compare the functional properties of GCaMP6-expressing neural cells and the corresponding parental cells loaded with calcium indicator dye Fluo-4, a detailed characterization of calcium signals was performed. We found that the calcium signals induced by ATP, glutamate, LPA, or proteases - were similar in these two systems. Moreover, the presence of the calcium indicator protein allowed for a sensitive, repeatable detection of changes in calcium signaling during the process of neurogenesis and neuronal maturation. Copyright © 2018 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    Masayuki Tanaka

    2016-07-01

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

  1. Ensemble place codes in hippocampus: CA1, CA3, and dentate gyrus place cells have multiple place fields in large environments.

    Directory of Open Access Journals (Sweden)

    Eunhye Park

    Full Text Available Previously we reported that the hippocampus place code must be an ensemble code because place cells in the CA1 region of hippocampus have multiple place fields in a more natural, larger-than-standard enclosure with stairs that permitted movements in 3-D. Here, we further investigated the nature of hippocampal place codes by characterizing the spatial firing properties of place cells in the CA1, CA3, and dentate gyrus (DG hippocampal subdivisions as rats foraged in a standard 76-cm cylinder as well as a larger-than-standard box (1.8 m×1.4 m that did not have stairs or any internal structure to permit movements in 3-D. The rats were trained to forage continuously for 1 hour using computer-controlled food delivery. We confirmed that most place cells have single place fields in the standard cylinder and that the positional firing pattern remapped between the cylinder and the large enclosure. Importantly, place cells in the CA1, CA3 and DG areas all characteristically had multiple place fields that were irregularly spaced, as we had reported previously for CA1. We conclude that multiple place fields are a fundamental characteristic of hippocampal place cells that simplifies to a single field in sufficiently small spaces. An ensemble place code is compatible with these observations, which contradict any dedicated coding scheme.

  2. Distribution of peptidergic populations in the human dentate gyrus (somatostatin [SOM-28, SOM-12] and neuropeptide Y [NPY]) during postnatal development.

    Science.gov (United States)

    Cebada-Sánchez, S; Insausti, R; González-Fuentes, J; Arroyo-Jiménez, M M; Rivas-Infante, E; Lagartos, M J; Martínez-Ruiz, J; Lozano, G; Marcos, P

    2014-10-01

    The postnatal development of the human hippocampal formation establishes the time and place at which we start autobiographical memories. However, data concerning the maturation of the neurochemical phenotypes characteristic of interneurons in the human hippocampus are scarce. We have studied the perinatal and postnatal changes of the dentate gyrus (DG) interneuron populations at three rostrocaudal levels. Immunohistochemically identified neurons and fibers for somatostatin (SOM-12 and SOM-28) and neuropeptide Y (NPY) and the co-localization of SOM-28 and NPY were analyzed. In total, 13 cases were investigated from late pregnancy (1 case), perinatal period (6 cases), first year (1 case), early infancy (3 cases), and late infancy (2 cases). Overall, the pattern of distribution of these peptides in the DG was similar to that of the adult. The distribution of cells was charted, and the cell density (number of positive cells/mm(2)) was calculated. The highest density corresponded to the polymorphic cell layer and was higher at pre- and perinatal periods. At increasing ages, neuron density modifications revealed a decrease from 5 postnatal months onward. In contrast, by late infancy, two immunoreactive bands for SOM-28 and NPY in the molecular layer were much better defined. Double-immunohistochemistry showed that NPY-positive neurons co-localized with SOM-28, whereas some fibers contained only one or other of the neuropeptides. Thus, this peptidergic population, presumably inhibitory, probably has a role in DG maturation and its subsequent functional activity in memory processing.

  3. Signal intensity change on unenhanced T1-weighted images in dentate nucleus and globus pallidus after multiple administrations of gadoxetate disodium: an intraindividual comparative study

    Energy Technology Data Exchange (ETDEWEB)

    Conte, Giorgio; Minotti, Marta; De Piano, Francesca [Universita degli Studi di Milano, Postgraduation School in Radiodiagnostics, Milan (Italy); Preda, Lorenzo [Universita degli Studi di Pavia, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, Pavia (Italy); National Center of Oncological Hadrontherapy (CNAO Foundation), Division of Radiology, Pavia (Italy); Cocorocchio, Emilia; Ferrucci, Pier Francesco [European Institute of Oncology, Melanoma and Sarcoma Medical Oncology Division, Milan (Italy); Raimondi, Sara [European Institute of Oncology, Division of Epidemiology and Biostatistics, Milan (Italy); Giannitto, Caterina; Petralia, Giuseppe [European Institute of Oncology, Division of Radiology, Milan (Italy); Bellomi, Massimo [European Institute of Oncology, Division of Radiology, Milan (Italy); Universita degli Studi di Milano, Oncology and Haematology/Oncology Department, Milan (Italy)

    2017-10-15

    To investigate whether there is an increased signal intensity (SI) of dentate nucleus (DN) and globus pallidus (GP) on unenhanced T1-weighted magnetic resonance imaging (MRI), in patients who had undergone multiple administrations of gadoxetate disodium. We retrospectively included stage III melanoma patients, who had been previously enrolled in a trial of adjuvant therapy and who had undergone whole-body contrast-enhanced MRIs with gadoxetate disodium every three months for their follow-up. The SI ratios of DN-to-pons and GP-to-thalamus on unenhanced T1-weighted images were calculated. The difference in SI ratios between the first and the last MRI examinations was assessed and a linear mixed model was performed to detect how SI ratios varied with the number of administrations. Eighteen patients were included in our study. The number of gadoxetate disodium administrations ranged from 2 to 18. Paired t-test did not show any significant difference in DN-to-pons (p=0.21) and GP-to-thalamus (p=0.09) SI ratios by the end of the study. DN-to-pons SI ratio and GP-to-thalamus SI ratio did not significantly increase with increasing the number of administrations (p=0.14 and p=0.06, respectively). Multiple administrations of gadoxetate disodium are not associated with increased SI in DN and GP in the brain. (orig.)

  4. Preventing effect of L-type calcium channel blockade on electrophysiological alterations in dentate gyrus granule cells induced by entorhinal amyloid pathology.

    Directory of Open Access Journals (Sweden)

    Hamid Gholami Pourbadie

    Full Text Available The entorhinal cortex (EC is one of the earliest affected brain regions in Alzheimer's disease (AD. EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs, nimodipine and isradipine, were investigated. The amyloid beta (Aβ 1-42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days, almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer's disease.

  5. Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APP(swe)/PS1(dE9) transgenic mice

    DEFF Research Database (Denmark)

    Olesen, Louise Orum; Sivasaravanaparan, Mithula; Severino, Maurizio

    2017-01-01

    Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the...... working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory....... the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APPswe/PS1dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis......Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess...

  6. Signal intensity change on unenhanced T1-weighted images in dentate nucleus following gadobenate dimeglumine in patients with and without previous multiple administrations of gadodiamide

    Energy Technology Data Exchange (ETDEWEB)

    Ramalho, Joana [University of North Carolina Hospital, Chapel Hill, NC (United States); Centro Hospitalar de Lisboa Central, Lisbon (Portugal); Semelka, Richard C.; Castillo, Mauricio [University of North Carolina Hospital, Chapel Hill, NC (United States); AlObaidy, Mamdoh [University of North Carolina Hospital, Chapel Hill, NC (United States); King Faisal Specialist Hospital and Research Center, Riyadh (Saudi Arabia); Ramalho, Miguel [University of North Carolina Hospital, Chapel Hill, NC (United States); Hospital Garcia de Orta, Almada (Portugal); Nunes, Renato H. [University of North Carolina Hospital, Chapel Hill, NC (United States); Santa Casa de Misericordia de Sao Paulo, Sao Paulo (Brazil)

    2016-11-15

    To evaluate the impact of previous administration of gadodiamide and neural tissue gadolinium deposition in patients who received gadobenate dimeglumine. Our population included 62 patients who underwent at least three administrations of gadobenate dimeglumine, plus an additional contrast-enhanced last MRI for reference, divided into two groups: group 1, patients who in addition to gadobenate dimeglumine administrations had prior exposure to multiple doses of gadodiamide; group 2, patients without previous exposure to other gadolinium-based contrast agent (GBCAs). Quantitative analysis was performed on the first and last gadobenate dimeglumine MRIs in both groups. Dentate nucleus-to-middle cerebellar peduncle signal intensity ratios (DN/MCP) and relative change (RC) in signal over time were calculated and compared between groups using generalized additive model. Group 1 showed significant increase in baseline and follow-up DN/MCP compared to group 2 (p < 0.0001). The RC DN/MCP showed a non-statistically significant trend towards an increase in patients who underwent previous gadodiamide (p = 0.0735). There is increased T1 signal change over time in patients who underwent gadobenate dimeglumine and had received prior gadodiamide compared to those without known exposure to previous gadodiamide. A potentiating effect from prior gadodiamide on subsequent administered gadobenate dimeglumine may occur. (orig.)

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

    International Nuclear Information System (INIS)

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

    2012-01-01

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

  8. MicroRNA profiling in the dentate gyrus in epileptic rats: The role of miR-187-3p.

    Science.gov (United States)

    Zhang, Suya; Kou, Yubin; Hu, Chunmei; Han, Yan

    2017-06-01

    This study aimed to explore the role of aberrant miRNA expression in epilepsy and to identify more potential genes associated with epileptogenesis.The miRNA expression profile of GSE49850, which included 20 samples from the rat epileptic dentate gyrus at 7, 14, 30, and 90 days after electrical stimulation and 20 additional samples from sham time-matched controls, was downloaded from the Gene Expression Omnibus database. The significantly differentially expressed miRNAs were identified in stimulated samples at each time point compared to time-matched controls, respectively. The target genes of consistently differentially expressed miRNAs were screened from miRDB and microRNA.org databases, followed by Gene Ontology (GO) and pathway enrichment analysis and regulatory network construction. The overlapping target genes for consistently differentially expressed miRNAs were also identified from these 2 databases. Furthermore, the potential binding sites of miRNAs and their target genes were analyzed.Rno-miR-187-3p was consistently downregulated in stimulated groups compared with time-matched controls. The predicted target genes of rno-miR-187-3p were enriched in different GO terms and pathways. In addition, 7 overlapping target genes of rno-miR-187-3p were identified, including NFS1, PAQR4, CAND1, DCLK1, PRKAR2A, AKAP3, and KCNK10. These 7 overlapping target genes were determined to have a different number of matched binding sites with rno-miR-187-3p.Our study suggests that miR-187-3p may play an important role in epilepsy development and progression via regulating numerous target genes, such as NFS1, CAND1, DCLK1, AKAP3, and KCNK10. Determining the underlying mechanism of the role of miR-187-3p in epilepsy may make it a potential therapeutic option.

  9. RNA-Sequencing Reveals Unique Transcriptional Signatures of Running and Running-Independent Environmental Enrichment in the Adult Mouse Dentate Gyrus

    Directory of Open Access Journals (Sweden)

    Catherine-Alexandra Grégoire

    2018-04-01

    Full Text Available Environmental enrichment (EE is a powerful stimulus of brain plasticity and is among the most accessible treatment options for brain disease. In rodents, EE is modeled using multi-factorial environments that include running, social interactions, and/or complex surroundings. Here, we show that running and running-independent EE differentially affect the hippocampal dentate gyrus (DG, a brain region critical for learning and memory. Outbred male CD1 mice housed individually with a voluntary running disk showed improved spatial memory in the radial arm maze compared to individually- or socially-housed mice with a locked disk. We therefore used RNA sequencing to perform an unbiased interrogation of DG gene expression in mice exposed to either a voluntary running disk (RUN, a locked disk (LD, or a locked disk plus social enrichment and tunnels [i.e., a running-independent complex environment (CE]. RNA sequencing revealed that RUN and CE mice showed distinct, non-overlapping patterns of transcriptomic changes versus the LD control. Bio-informatics uncovered that the RUN and CE environments modulate separate transcriptional networks, biological processes, cellular compartments and molecular pathways, with RUN preferentially regulating synaptic and growth-related pathways and CE altering extracellular matrix-related functions. Within the RUN group, high-distance runners also showed selective stress pathway alterations that correlated with a drastic decline in overall transcriptional changes, suggesting that excess running causes a stress-induced suppression of running’s genetic effects. Our findings reveal stimulus-dependent transcriptional signatures of EE on the DG, and provide a resource for generating unbiased, data-driven hypotheses for novel mediators of EE-induced cognitive changes.

  10. A Transient Upregulation of Glutamine Synthetase in the Dentate Gyrus Is Involved in Epileptogenesis Induced by Amygdala Kindling in the Rat.

    Directory of Open Access Journals (Sweden)

    Hong-Liu Sun

    Full Text Available Reduction of glutamine synthetase (GS function is closely related to established epilepsy, but little is known regarding its role in epileptogenesis. The present study aimed to elucidate the functional changes of GS in the brain and its involvement in epileptogenesis using the amygdala kindling model of epilepsy induced by daily electrical stimulation of basolateral amygdala in rats. Both expression and activity of GS in the ipsilateral dentate gyrus (DG were upregulated when kindled seizures progressed to stage 4. A single dose of L-methionine sulfoximine (MSO, in 2 µl, a selective GS inhibitor, was administered into the ipsilateral DG on the third day following the first stage 3 seizure (just before GS was upregulated. It was found that low doses of MSO (5 or 10 µg significantly and dose-dependently reduced the severity of and susceptibility to evoked seizures, whereas MSO at a high dose (20 µg aggravated kindled seizures. In animals that seizure acquisition had been successfully suppressed with 10 µg MSO, GS upregulation reoccurred when seizures re-progressed to stage 4 and re-administration of 10 µg MSO consistently reduced the seizures. GLN at a dose of 1.5 µg abolished the alleviative effect of 10 µg MSO and deleterious effect of 20 µg MSO on kindled seizures. Moreover, appropriate artificial microRNA interference (1 and 1.5×10(6 TU/2 µl of GS expression in the ipsilateral DG also inhibited seizure progression. In addition, a transient increase of GS expression and activity in the cortex was also observed during epileptogenesis evoked by pentylenetetrazole kindling. These results strongly suggest that a transient and region-specific upregulation of GS function occurs when epilepsy develops into a certain stage and eventually promotes the process of epileptogenesis. Inhibition of GS to an adequate degree and at an appropriate timing may be a potential therapeutic approach to interrupting epileptogenesis.

  11. Stimulation of the sigma-1 receptor by DHEA enhances synaptic efficacy and neurogenesis in the hippocampal dentate gyrus of olfactory bulbectomized mice.

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    Shigeki Moriguchi

    Full Text Available Dehydroepiandrosterone (DHEA is the most abundant neurosteroid synthesized de novo in the central nervous system. We previously reported that stimulation of the sigma-1 receptor by DHEA improves cognitive function by activating calcium/calmodulin-dependent protein kinase II (CaMKII, protein kinase C and extracellular signal-regulated kinase in the hippocampus in olfactory bulbectomized (OBX mice. Here, we asked whether DHEA enhances neurogenesis in the subgranular zone of the hippocampal dentate gyrus (DG and improves depressive-like behaviors observed in OBX mice. Chronic treatment with DHEA at 30 or 60 mg/kg p.o. for 14 days significantly improved hippocampal LTP impaired in OBX mice concomitant with increased CaMKII autophosphorylation and GluR1 (Ser-831 phosphorylation in the DG. Chronic DHEA treatment also ameliorated depressive-like behaviors in OBX mice, as assessed by tail suspension and forced swim tests, while a single DHEA treatment had no affect. DHEA treatment also significantly increased the number of BrdU-positive neurons in the subgranular zone of the DG of OBX mice, an increase inhibited by treatment with NE-100, a sigma-1 receptor antagonist. DHEA treatment also significantly increased phosphorylation of Akt (Ser-473, Akt (Ser-308 and ERK in the DG. Furthermore, GSK-3β (Ser-9 phosphorylation increased in the DG of OBX mice possibly accounting for increased neurogenesis through Akt activation. Finally, we confirmed that DHEA treatment of OBX mice increases the number of BrdU-positive neurons co-expressing β-catenin, a downstream GSK-3βtarget. Overall, we conclude that sigma-1 receptor stimulation by DHEA ameliorates OBX-induced depressive-like behaviors by increasing neurogenesis in the DG through activation of the Akt/GSK-3β/β-catenin pathway.

  12. The effects of soy and tamoxifen on apoptosis in the hippocampus and dentate gyrus in a pentylenetetrazole-induced seizure model of ovariectomized rats.

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    Ebrahimzadeh-Bideskan, Ali Reza; Mansouri, Somaieh; Ataei, Mariam Lale; Jahanshahi, Mehrdad; Hosseini, Mahmoud

    2018-03-01

    The effects of tamoxifen and soy on apoptosis of the hippocampus and dentate gyrus of ovariectomized rats after repeated seizures were investigated. Female rats were divided into: (1) Control, (2) Sham, (3) Sham-Tamoxifen (Sham-T), (4) Ovariectomized (OVX), (5) OVX-Tamoxifen (OVX-T), (6)OVX-Soy(OVX-S) and (7) OVX-S-T. The animals in the OVX-S, OVX-T and OVX-S-T groups received soy extract (60 mg/kg; i.p.), tamoxifen (10 mg/kg) or both for 2 weeks before induction of seizures. The animals in these groups additionally received the mentioned treatments before each injection of pentylenetetrazole (PTZ; 40 mg/kg) for 6 days. The animals in the Sham and OVX groups received a vehicle of tamoxifen and soy. A significant decrease in the seizure score and TUNEL-positive neurons was seen in the OVX group compared to the Sham (P < 0.001). The animals in both the OVX-T and OVX-S groups had a significantly higher seizure score as well as number of TUNEL-positive neurons compared to the OVX group (P < 0.01-P < 0.001). Co-treatment of the OVX rats by the extract and tamoxifen decreased the seizure score and number of TUNEL-positive neurons compared to OVX-S (P < 0.001). Treatment of the OVX rats by either soy or tamoxifen increased the seizure score as well as the number of TUNEL-positive neurons in the hippocampal formation. Co-administration of tamoxifen and soy extract inhibited the effects of the soy extract and tamoxifen when they were administered alone. It might be suggested that both soy and tamoxifen have agonistic effects on estrogen receptors by changing the seizure severity.

  13. RNA-Sequencing Reveals Unique Transcriptional Signatures of Running and Running-Independent Environmental Enrichment in the Adult Mouse Dentate Gyrus.

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    Grégoire, Catherine-Alexandra; Tobin, Stephanie; Goldenstein, Brianna L; Samarut, Éric; Leclerc, Andréanne; Aumont, Anne; Drapeau, Pierre; Fulton, Stephanie; Fernandes, Karl J L

    2018-01-01

    Environmental enrichment (EE) is a powerful stimulus of brain plasticity and is among the most accessible treatment options for brain disease. In rodents, EE is modeled using multi-factorial environments that include running, social interactions, and/or complex surroundings. Here, we show that running and running-independent EE differentially affect the hippocampal dentate gyrus (DG), a brain region critical for learning and memory. Outbred male CD1 mice housed individually with a voluntary running disk showed improved spatial memory in the radial arm maze compared to individually- or socially-housed mice with a locked disk. We therefore used RNA sequencing to perform an unbiased interrogation of DG gene expression in mice exposed to either a voluntary running disk (RUN), a locked disk (LD), or a locked disk plus social enrichment and tunnels [i.e., a running-independent complex environment (CE)]. RNA sequencing revealed that RUN and CE mice showed distinct, non-overlapping patterns of transcriptomic changes versus the LD control. Bio-informatics uncovered that the RUN and CE environments modulate separate transcriptional networks, biological processes, cellular compartments and molecular pathways, with RUN preferentially regulating synaptic and growth-related pathways and CE altering extracellular matrix-related functions. Within the RUN group, high-distance runners also showed selective stress pathway alterations that correlated with a drastic decline in overall transcriptional changes, suggesting that excess running causes a stress-induced suppression of running's genetic effects. Our findings reveal stimulus-dependent transcriptional signatures of EE on the DG, and provide a resource for generating unbiased, data-driven hypotheses for novel mediators of EE-induced cognitive changes.

  14. Repeated Neck Restraint Stress Bidirectionally Modulates Excitatory Transmission in the Dentate Gyrus and Performance in a Hippocampus-dependent Memory Task.

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    Spyrka, Jadwiga; Hess, Grzegorz

    2018-05-21

    The consequences of stress depend on characteristics of the stressor, including the duration of exposure, severity, and predictability. Exposure of mice to repeated neck restraint has been shown to bidirectionally modulate the potential for long-term potentiation (LTP) in the dentate gyrus (DG) in a manner dependent on the number of restraint repetitions, but the influence of repeated brief neck restraint on electrophysiology of single DG neurons has not yet been investigated. Here, we aimed at finding the effects of 1, 3, 7, 14, or 21 daily neck restraint sessions lasting 10 min on electrophysiological characteristics of DG granule cells as well as excitatory and inhibitory synaptic inputs to these neurons. While the excitability of DG granule cells and inhibitory synaptic transmission were unchanged, neck restraint decreased the frequency of spontaneous excitatory currents after three repetitions but enhanced it after 14 and 21 repetitions. The consequences of repeated neck restraint on hippocampus-dependent memory were investigated using the object location test (OLT). Neck restraint stress impaired cognitive performance in the OLT after three repetitions but improved it after 14 and 21 repetitions. Mice subjected to three neck restraint sessions displayed an increase in the measures of depressive and anxiety-like behaviors, however, prolongation of the exposure to neck restraint resulted in a gradual decline in the intensity of these measures. These data indicate that stress imposed by an increasing number of repeated neck restraint episodes bidirectionally modulates both excitatory synaptic transmission in the DG and cognitive performance in the object location memory task. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

  15. Prenatal nicotine and maternal deprivation stress de-regulate the development of CA1, CA3, and dentate gyrus neurons in hippocampus of infant rats.

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    Hong Wang

    Full Text Available Adverse experiences by the developing fetus and in early childhood are associated with profound effects on learning, emotional behavior, and cognition as a whole. In this study we investigated the effects of prenatal nicotine exposure (NIC, postnatal maternal deprivation (MD or the combination of the two (NIC+MD to determine if hippocampal neuron development is modulated by exposure to drugs of abuse and/or stress. Growth of rat offspring exposed to MD alone or NIC+MD was repressed until after weaning. In CA1 but not CA3 of postnatal day 14 (P14 pups, MD increased pyramidal neurons, however, in dentate gyrus (DG, decreased granule neurons. NIC had no effect on neuron number in CA1, CA3 or DG. Unexpectedly, NIC plus MD combined caused a synergistic increase in the number of CA1 or CA3 neurons. Neuron density in CA regions was unaffected by treatment, but in the DG, granule neurons had a looser packing density after NIC, MD or NIC+MD exposure. When septotemporal axes were analyzed, the synergism of stress and drug exposure in CA1 and CA3 was associated with rostral, whereas MD effects were predominantly associated with caudal neurons. TUNEL labeling suggests no active apoptosis at P14, and doublecortin positive neurons and mossy fibers were diminished in NIC+MD relative to controls. The laterality of the effect of nicotine and/or maternal deprivation in right versus left hippocampus was also analyzed and found to be insiginificant. We report for the first time that early life stressors such as postnatal MD and prenatal NIC exposure, when combined, may exhibit synergistic consequences for CA1 and CA3 pyramidal neuron development, and a potential antagonistic influence on developing DG neurons. These results suggest that early stressors may modulate neurogenesis, apoptosis, or maturation of glutamatergic neurons in the hippocampus in a region-specific manner during critical periods of neurodevelopment.

  16. Synergistic Effects of Psychosocial Stress and Mild Peripheral Infection on Inducing Microglial Activation in the Hippocampal Dentate Gyrus and Long-Lasting Deficits in Hippocampus-Related Memory.

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    Tzeng, Wen-Yu; Su, Chien-Chou; Sun, Li-Han; Cherng, Chianfang G.; Yu, Lung

    2018-04-30

    Lipopolysaccharide (LPS) treatment and stress may cause immune activation in the brain, an event which has been thought to play a role in mediating stress-induced cognitive dysfunction. However, the enduring impact of psychosocial stress on brain immune activation or cognitive deficits has not been well investigated. Likewise, it remains unexplored whether there exist synergistic effects of psychosocial stress and a weak systemic LPS treatment on brain immune activation and/or cognitive function. In this work, a 10-day social defeat regimen was used to model psychosocial stress and the number and density of ionized calcium-binding adaptor molecule 1 (Iba1)-stained microglia was used to reveal brain immune activation in male Balb/C mice. The social defeat regimen did not cause observable microglial activation in dentate gyrus (DG) 24 h after the conclusion of the regimen. Microglial activation peaked in DG 24 h following a single 1 mg/kg intra-peritoneal LPS injection. At this time point, DG microglial activation was not evident providing 0.125 mg/kg or lower of LPS was used, this dose of LPS was, thus, regarded as the “sub-threshold” in this study. Twenty-four h after the conclusion of the defeat regimen, mice received a social interaction test to determine their defeat stress susceptibility and a “sub-threshold” LPS injection. DG microglial activation was observed in the defeat-stress susceptible, but not in the resilient, mice. Furthermore, the stress-susceptible mice showed impairment in object location and Y maze tasks 24 and 72 h after the “sub-threshold” LPS injection. These results suggest that psychosocial stress, when combined with a negligible peripheral infection, may induce long-lasting hippocampus-related memory deficits exclusively in subjects susceptible to psychosocial stresses.

  17. Is Arc mRNA Unique: A Search for mRNAs That Localize to the Distal Dendrites of Dentate Gyrus Granule Cells Following Neural Activity

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    Christopher A. de Solis

    2017-10-01

    Full Text Available There have been several attempts to identify which RNAs are localized to dendrites; however, no study has determined which RNAs localize to the dendrites following the induction of synaptic activity. We sought to identify all RNA transcripts that localize to the distal dendrites of dentate gyrus granule cells following unilateral high frequency stimulation of the perforant pathway (pp-HFS using Sprague Dawley rats. We then utilized laser microdissection (LMD to very accurately dissect out the distal 2/3rds of the molecular layer (ML, which contains these dendrites, without contamination from the granule cell layer, 2 and 4 h post pp-HFS. Next, we purified and amplified RNA from the ML and performed an unbiased screen for 27,000 RNA transcripts using Affymetrix microarrays. We determined that Activity Regulated Cytoskeletal Protein (Arc/Arg3.1 mRNA, exhibited the greatest fold increase in the ML at both timepoints (2 and 4 h. In total, we identified 31 transcripts that increased their levels within the ML following pp-HFS across the two timepoints. Of particular interest is that one of these identified transcripts was an unprocessed micro-RNA (pri-miR132. Fluorescent in situ hybridization and qRT-PCR were used to confirm some of these candidate transcripts. Our data indicate Arc is a unique activity dependent gene, due to the magnitude that its activity dependent transcript localizes to the dendrites. Our study determined other activity dependent transcripts likely localize to the dendrites following neural activity, but do so with lower efficiency compared to Arc.

  18. Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

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    Täuber Martin G

    2003-09-01

    Full Text Available Abstract Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S-alpha-(4-hydroxyphenyl-beta-methyl-4-(phenylmethyl-1-piperid inepropanol (RO 25-6981. Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28 or 3.75 mg (150 mg/kg; n = 15 every 3 h or an equal volume of sterile saline (250 μl; n = 40 starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures.

  19. α1-Adrenoceptors in the hippocampal dentate gyrus involved in learning-dependent long-term potentiation during active-avoidance learning in rats.

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    Lv, Jing; Zhan, Su-Yang; Li, Guang-Xie; Wang, Dan; Li, Ying-Shun; Jin, Qing-Hua

    2016-11-09

    The hippocampus is the key structure for learning and memory in mammals and long-term potentiation (LTP) is an important cellular mechanism responsible for learning and memory. The influences of norepinephrine (NE) on the modulation of learning and memory, as well as LTP, through β-adrenoceptors are well documented, whereas the role of α1-adrenoceptors in learning-dependent LTP is not yet clear. In the present study, we measured extracellular concentrations of NE in the hippocampal dentate gyrus (DG) region using an in-vivo brain microdialysis and high-performance liquid chromatography techniques during the acquisition and extinction of active-avoidance behavior in freely moving conscious rats. Next, the effects of prazosin (an antagonist of α1-adrenoceptor) and phenylephrine (an agonist of the α1-adrenoceptor) on amplitudes of field excitatory postsynaptic potential were measured in the DG region during the active-avoidance behavior. Our results showed that the extracellular concentration of NE in the DG was significantly increased during the acquisition of active-avoidance behavior and gradually returned to the baseline level following extinction training. A local microinjection of prazosin into the DG significantly accelerated the acquisition of the active-avoidance behavior, whereas a local microinjection of phenylephrine retarded the acquisition of the active-avoidance behavior. Furthermore, in all groups, the changes in field excitatory postsynaptic potential amplitude were accompanied by corresponding changes in active-avoidance behavior. Our results suggest that NE activation of α1-adrenoceptors in the hippocampal DG inhibits active-avoidance learning by modulation of synaptic efficiency in rats.

  20. Dehydroepiandrosterone increases the number and dendrite maturation of doublecortin cells in the dentate gyrus of middle age male Wistar rats exposed to chronic mild stress.

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    Herrera-Pérez, J J; Martínez-Mota, L; Jiménez-Rubio, G; Ortiz-López, L; Cabrera-Muñoz, E A; Galindo-Sevilla, N; Zambrano, E; Hernández-Luis, F; Ramírez-Rodríguez, G B; Flores-Ramos, M

    2017-03-15

    Aging increases the vulnerability to stress and risk of developing depression. These changes have been related to a reduction of dehydroepiandrosterone (DHEA) levels, an adrenal steroid with anti-stress effects. Also, adult hippocampal neurogenesis decreases during aging and its alteration or impaired is related to the development of depression. Besides, it has been hypothesized that DHEA increases the formation of new neurons. However, it is unknown whether treatment with DHEA in aging may stimulate the dendrite maturation of newborn neurons and reversing depressive-like signs evoked by chronic stress exposure. Here aged male rats (14 months old) were subjected to a scheme of chronic mild stress (CMS) during six weeks, received a treatment with DHEA from the third week of CMS. Changes in body weight and sucrose preference (SP) were measured once a week. DHEA levels were measured in serum, identification of doublecortin-(DCX)-, BrdU- and BrdU/NeuN-labeled cells was done in the dentate gyrus of the hippocampus. CMS produced a gradual reduction in the body weight, but no changes in the SP were observed. Treatment enhanced levels of DHEA, but lack of recovery on body weight of stressed rats. Aging reduced the number of DCX-, BrdU- and BrdU/NeuN- cells but DHEA just significantly increased the number of DCX-cells in rats under CMS and controls, reaching levels of young non-stressed rats (used here as a reference of an optimal status of health). In rats under CMS, DHEA facilitated dendritic maturation of immature new neurons. Our results reveal that DHEA improves neural plasticity even in conditions of CMS in middle age rats. Thus, this hormone reverted the decrement of DCX-cells caused during normal aging. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Blockade of NMDA receptor subtype NR2B prevents seizures but not apoptosis of dentate gyrus neurons in bacterial meningitis in infant rats

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    Kolarova, Anna; Ringer, Ralph; Täuber, Martin G; Leib, Stephen L

    2003-01-01

    Background Excitotoxic neuronal injury by action of the glutamate receptors of the N-methyl-d-aspartate (NMDA) subtype have been implicated in the pathogenesis of brain damage as a consequence of bacterial meningitis. The most potent and selective blocker of NMDA receptors containing the NR2B subunit is (R,S)-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperid inepropanol (RO 25-6981). Here we evaluated the effect of RO 25-6981 on hippocampal neuronal apoptosis in an infant rat model of meningitis due to Streptococcus pneumoniae. Animals were randomized for treatment with RO 25-6981 at a dosage of either 0.375 mg (15 mg/kg; n = 28) or 3.75 mg (150 mg/kg; n = 15) every 3 h or an equal volume of sterile saline (250 μl; n = 40) starting at 12 h after infection. Eighteen hours after infection, animals were assessed clinically and seizures were observed for a period of 2 h. At 24 h after infection animals were sacrificed and brains were examined for apoptotic injury to the dentate granule cell layer of the hippocampus. Results Treatment with RO 25-6981 had no effect on clinical scores, but the incidence of seizures was reduced (P < 0.05 for all RO 25-6981 treated animals combined). The extent of apoptosis was not affected by low or high doses of RO 25-6981. Number of apoptotic cells (median [range]) was 12.76 [3.16–25.3] in animals treated with low dose RO 25-6981 (control animals 13.8 [2.60–31.8]; (P = NS) and 9.8 [1.7–27.3] (controls: 10.5 [2.4–21.75]) in animals treated with high dose RO 25-6981 (P = NS). Conclusions Treatment with a highly selective blocker of NMDA receptors containing the NR2B subunit failed to protect hippocampal neurons from injury in this model of pneumococcal meningitis, while it had some beneficial effect on the incidence of seizures. PMID:13129439

  2. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ

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    Guoxi Li

    2015-12-01

    Full Text Available The seipin gene (BSCL2 was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2. Neuronal seipin-knockout (seipin-nKO mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ. The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi. In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1 and neurogenic differentiation 1 (NeuroD1 mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705 was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice.

  3. Activation of Transient Receptor Potential Vanilloid 4 Impairs the Dendritic Arborization of Newborn Neurons in the Hippocampal Dentate Gyrus through the AMPK and Akt Signaling Pathways

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    Yujing Tian

    2017-06-01

    Full Text Available Neurite growth is an important process for the adult hippocampal neurogenesis which is regulated by a specific range of the intracellular free Ca2+ concentration ([Ca2+]i. Transient receptor potential vanilloid 4 (TRPV4 is a calcium-permeable channel and activation of it causes an increase in [Ca2+]i. We recently reported that TRPV4 activation promotes the proliferation of stem cells in the adult hippocampal dentate gyrus (DG. The present study aimed to examine the effect of TRPV4 activation on the dendrite morphology of newborn neurons in the adult hippocampal DG. Here, we report that intracerebroventricular injection of the TRPV4 agonist GSK1016790A for 5 days (GSK1016790A-injected mice reduced the number of doublecortin immunopositive (DCX+ cells and DCX+ fibers in the hippocampal DG, showing the impaired dendritic arborization of newborn neurons. The phosphorylated AMP-activated protein kinase (p-AMPK protein level increased from 30 min to 2 h, and then decreased from 1 to 5 days after GSK1016790A injection. The phosphorylated protein kinase B (p-Akt protein level decreased from 30 min to 5 days after GSK1016790A injection; this decrease was markedly attenuated by the AMPK antagonist compound C (CC, but not by the AMPK agonist AICAR. Moreover, the phosphorylated mammalian target of rapamycin (mTOR and p70 ribosomal S6 kinase (p70S6k protein levels were decreased by GSK1016790A; these changes were sensitive to 740 Y-P and CC. The phosphorylation of glycogen synthase kinase 3β (GSK3β at Y216 was increased by GSK1016790A, and this change was accompanied by increased phosphorylation of microtubule-associated protein 2 (MAP2 and collapsin response mediator protein-2 (CRMP-2. These changes were markedly blocked by 740 Y-P and CC. Finally, GSK1016790A-induced decrease of DCX+ cells and DCX+ fibers was markedly attenuated by 740 Y-P and CC, but was unaffected by AICAR. We conclude that TRPV4 activation impairs the dendritic arborization of newborn

  4. Hilar granule cells of the mouse dentate gyrus: effects of age, septotemporal location, strain, and selective deletion of the proapoptotic gene BAX.

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    Bermudez-Hernandez, Keria; Lu, Yi-Ling; Moretto, Jillian; Jain, Swati; LaFrancois, John J; Duffy, Aine M; Scharfman, Helen E

    2017-09-01

    The dentate gyrus (DG) principal cells are glutamatergic granule cells (GCs), and they are located in a compact cell layer. However, GCs are also present in the adjacent hilar region, but have been described in only a few studies. Therefore, we used the transcription factor prospero homeobox 1 (Prox1) to quantify GCs at postnatal day (PND) 16, 30, and 60 in a common mouse strain, C57BL/6J mice. At PND16, there was a large population of Prox1-immunoreactive (ir) hilar cells, with more in the septal than temporal hippocampus. At PND30 and 60, the size of the hilar Prox1-ir cell population was reduced. Similar numbers of hilar Prox1-expressing cells were observed in PND30 and 60 Swiss Webster mice. Prox1 is usually considered to be a marker of postmitotic GCs. However, many Prox1-ir hilar cells, especially at PND16, were not double-labeled with NeuN, a marker typically found in mature neurons. Most hilar Prox1-positive cells at PND16 co-expressed doublecortin (DCX) and calretinin, markers of immature GCs. Double-labeling with a marker of actively dividing cells, Ki67, was not detected. These results suggest that, surprisingly, a large population of cells in the hilus at PND16 are immature GCs (Type 2b and Type 3 cells). We also asked whether hilar Prox1-ir cell numbers are modifiable. To examine this issue, we conditionally deleted the proapoptotic gene BAX in Nestin-expressing cells at a time when there are numerous immature GCs in the hilus, PND2-8. When these mice were examined at PND60, the numbers of Prox1-ir hilar cells were significantly increased compared to control mice. However, deletion of BAX did not appear to change the proportion that co-expressed NeuN, suggesting that the size of the hilar Prox1-expressing population is modifiable. However, deleting BAX, a major developmental disruption, does not appear to change the proportion that ultimately becomes neurons.

  5. Sex Differences in Stress and Group Housing Effects on the Number of Newly Proliferated Cells and Neuroblasts in Middle-Aged Dentate Gyrus.

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    Tzeng, Wen-Yu; Wu, Hsin-Hua; Wang, Ching-Yi; Chen, Jin-Chung; Yu, Lung; Cherng, Chianfang G

    2016-01-01

    Sex differences in stress and coping responses have been frequently documented in aged people, while whether such differences in aged people may appear at the middle age are unknown. This study was undertaken to study the impact of acute stress and social interaction on early neurogenesis in the dentate gyrus (DG) and hippocampus-related memory in two sexes of middle-aged mice. The number of newly proliferated cells, neuroblasts in DG, the object recognition and location memory in 9-month-old male and female C57BL/6N mice were assessed under baseline conditions as well as following an acute stressor regimen and group housing. Three conspecific companions, serving as "the housing group," were used to model the social interaction throughout the stressor regimen. Males had lower numbers of newly proliferated cells and neuroblasts under baseline conditions as compared to females. The stressor regimen caused rapid decreases in the number of newly proliferated cells and neuroblasts in female DG but no obvious changes were observed in male DG. Group housing, regardless of companions' age, prevented the stress-induced decreases in the number of newly proliferated cells and neuroblasts in female DG. In contrast, the presence of young or age-matched companions potentiated the stress effect in males by decreasing the number of newly proliferated cells and neuroblasts. Finally, neither the stressor regimen nor group housing affected mouse performances in the object recognition and location memory in either sex. These findings, taken together, provide evidence to support a notion that middle-aged females appear to demonstrate more stress susceptibility on early neurogenesis in DG as compared to middle-aged males, although the hippocampus-related memory performances are comparable and not affected by stress in these males and females. Experiencing stress, middle-aged females are more prone to benefit from social interaction as compared to middle-aged males in this regard. We

  6. The involvement of CRF1 receptor within the basolateral amygdala and dentate gyrus in the naloxone-induced conditioned place aversion in morphine-dependent mice.

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    Valero, E; Gómez-Milanés, I; Almela, P; Ribeiro Do Couto, B; Laorden, M L; Milanés, M V; Núñez, C

    2018-06-08

    Drug withdrawal-associated aversive memories trigger relapse to drug-seeking behavior. Corticotrophin-releasing factor (CRF) is an important mediator of the reinforcing properties of drugs of abuse. However, the involvement of CRF1 receptor (CRF1R) in aversive memory induced by opiate withdrawal has yet to be elucidated. We used the conditioned-place aversion (CPA) paradigm to evaluate the role of CRF1R on opiate withdrawal memory acquisition, along with plasticity-related processes that occur after CPA within the basolateral amygdala (BLA) and dentate gyrus (DG). Male mice were rendered dependent on morphine and injected acutely with naloxone before paired to confinement in a naloxone-associated compartment. The CPA scores as well as the number of TH-positive neurons (in the NTS-A2 noradrenergic cell group), and the expression of the transcription factors Arc and pCREB (in the BLA and DG) were measured with and without CRF1R blockade. Mice subjected to conditioned naloxone-induced morphine withdrawal robustly expressed CPA. Pre-treatment with the selective CRF1R antagonist CP-154,526 before naloxone conditioning session impaired morphine withdrawal-induced aversive memory acquisition. CP-154,526 also antagonized the enhanced number of TH-positive neurons in the NTS-A2 that was seen after CPA. Increased Arc expression and Arc-pCREB co-localization were seen in the BLA after CPA, which was not modified by CP-154,526. In the DG, CPA was accompanied by a decrease of Arc expression and no changes in Arc-pCREB co-localization, whereas pre-treatment with CP-154,526 induced an increase in both parameters. These results indicate that CRF-CRF1R pathway could be a critical factor governing opiate withdrawal memory storage and retrieval and might suggest a role for TH-NA pathway in the effects of withdrawal on memory. Our results might indicate that the blockade of CRF1R could represent a promising pharmacological treatment strategy approach for the attenuation of the relapse

  7. Repeating Spatial-Temporal Motifs of CA3 Activity Dependent on Engineered Inputs from Dentate Gyrus Neurons in Live Hippocampal Networks.

    Science.gov (United States)

    Bhattacharya, Aparajita; Desai, Harsh; DeMarse, Thomas B; Wheeler, Bruce C; Brewer, Gregory J

    2016-01-01

    Anatomical and behavioral studies, and in vivo and slice electrophysiology of the hippocampus suggest specific functions of the dentate gyrus (DG) and the CA3 subregions, but the underlying activity dynamics and repeatability of information processing remains poorly understood. To approach this problem, we engineered separate living networks of the DG and CA3 neurons that develop connections through 51 tunnels for axonal communication. Growing these networks on top of an electrode array enabled us to determine whether the subregion dynamics were separable and repeatable. We found spontaneous development of polarized propagation of 80% of the activity in the native direction from DG to CA3 and different spike and burst dynamics for these subregions. Spatial-temporal differences emerged when the relationships of target CA3 activity were categorized with to the number and timing of inputs from the apposing network. Compared to times of CA3 activity when there was no recorded tunnel input, DG input led to CA3 activity bursts that were 7× more frequent, increased in amplitude and extended in temporal envelope. Logistic regression indicated that a high number of tunnel inputs predict CA3 activity with 90% sensitivity and 70% specificity. Compared to no tunnel input, patterns of >80% tunnel inputs from DG specified different patterns of first-to-fire neurons in the CA3 target well. Clustering dendrograms revealed repeating motifs of three or more patterns at up to 17 sites in CA3 that were importantly associated with specific spatial-temporal patterns of tunnel activity. The number of these motifs recorded in 3 min was significantly higher than shuffled spike activity and not seen above chance in control networks in which CA3 was apposed to CA3 or DG to DG. Together, these results demonstrate spontaneous input-dependent repeatable coding of distributed activity in CA3 networks driven by engineered inputs from DG networks. These functional configurations at measured times

  8. Dentate gyrus supports slope recognition memory, shades of grey-context pattern separation and recognition memory, and CA3 supports pattern completion for object memory.

    Science.gov (United States)

    Kesner, Raymond P; Kirk, Ryan A; Yu, Zhenghui; Polansky, Caitlin; Musso, Nick D

    2016-03-01

    In order to examine the role of the dorsal dentate gyrus (dDG) in slope (vertical space) recognition and possible pattern separation, various slope (vertical space) degrees were used in a novel exploratory paradigm to measure novelty detection for changes in slope (vertical space) recognition memory and slope memory pattern separation in Experiment 1. The results of the experiment indicate that control rats displayed a slope recognition memory function with a pattern separation process for slope memory that is dependent upon the magnitude of change in slope between study and test phases. In contrast, the dDG lesioned rats displayed an impairment in slope recognition memory, though because there was no significant interaction between the two groups and slope memory, a reliable pattern separation impairment for slope could not be firmly established in the DG lesioned rats. In Experiment 2, in order to determine whether, the dDG plays a role in shades of grey spatial context recognition and possible pattern separation, shades of grey were used in a novel exploratory paradigm to measure novelty detection for changes in the shades of grey context environment. The results of the experiment indicate that control rats displayed a shades of grey-context pattern separation effect across levels of separation of context (shades of grey). In contrast, the DG lesioned rats displayed a significant interaction between the two groups and levels of shades of grey suggesting impairment in a pattern separation function for levels of shades of grey. In Experiment 3 in order to determine whether the dorsal CA3 (dCA3) plays a role in object pattern completion, a new task requiring less training and using a choice that was based on choosing the correct set of objects on a two-choice discrimination task was used. The results indicated that control rats displayed a pattern completion function based on the availability of one, two, three or four cues. In contrast, the dCA3 lesioned rats

  9. Orexin 1 and orexin 2 receptor antagonism in the basolateral amygdala modulate long-term potentiation of the population spike in the perforant path-dentate gyrus-evoked field potential in rats.

    Science.gov (United States)

    Ardeshiri, Motahareh Rouhi; Hosseinmardi, Narges; Akbari, Esmaeil

    2018-03-01

    Involvement of amygdalo-hippocampal substructures in patients with narcolepsy due to deficiencies in the orexinergic system, and the presence of hippocampus-dependent memory impairments in this disorder, have led us to investigate the effects of orexin 1 and 2 receptor antagonism in the basolateral amygdala (BLA) on long-term potentiation (LTP) of dentate gyrus (DG) granular cells. We used a 200-Hz high-frequency stimulation protocol in anesthetized rats. We studied the long-term synaptic plasticity of perforant path-dentate gyrus granule cells following the inactivation of orexin receptors before and after tetanic stimulation. LTP of the DG population spike was attenuated in the presence of orexin 1 and 2 receptor antagonism (treatment with SB-334867-A and TCS-OX2-29, respectively) in the BLA when compared to that observed following treatment with dimethyl sulfoxide (DMSO). However, the population excitatory post-synaptic potentials were not affected. Moreover, when orexin 1 and 2 receptors in the BLA were blocked after LTP induction, there were no differences between the DMSO and treatment groups. Our findings suggest that the orexinergic system of the BLA plays a modulatory role in the regulation of hippocampal plasticity in rats. Copyright © 2018 Elsevier Inc. All rights reserved.

  10. Rufinamide, an antiepileptic drug, improves cognition and increases neurogenesis in the aged gerbil hippocampal dentate gyrus via increasing expressions of IGF-1, IGF-1R and p-CREB.

    Science.gov (United States)

    Chen, Bai Hui; Ahn, Ji Hyeon; Park, Joon Ha; Song, Minah; Kim, Hyunjung; Lee, Tae-Kyeong; Lee, Jae Chul; Kim, Young-Myeong; Hwang, In Koo; Kim, Dae Won; Lee, Choong-Hyun; Yan, Bing Chun; Kang, Il Jun; Won, Moo-Ho

    2018-04-25

    Rufinamide is a novel antiepileptic drug and commonly used in the treatment of Lennox-Gastaut syndrome. In the present study, we investigated effects of rufinamide on cognitive function using passive avoidance test and neurogenesis in the hippocampal dentate gyrus using Ki-67 (a marker for cell proliferation), doublecortin (DCX, a marker for neuroblast) and BrdU/NeuN (markers for newly generated mature neurons) immunohistochemistry in aged gerbils. Aged gerbils (24-month old) were treated with 1 mg/kg and 3 mg/kg rufinamide for 4 weeks. Treatment with 3 mg/kg rufinamide, not 1 mg/kg rufinamide, significantly improved cognitive function and increased neurogenesis, showing that proliferating cells (Ki-67-immunoreactive cells), differentiating neuroblasts (DCX-immunoreactive neuroblasts) and mature neurons (BrdU/NeuN-immunoreactive cells) in the aged dentate gyrus compared with those in the control group. When we examined its mechanisms, rufinamide significantly increased immunoreactivities of insulin-like growth factor-1 (IGF-1), its receptor (IGF-1R), and phosphorylated cAMP response element binding protein (p-CREB). However, rufinamide did not show any increase in immunoreactivities of brain-derived neurotrophic factor and its receptor. Therefore, our results indicate that rufinamide can improve cognitive function and increase neurogenesis in the hippocampus of the aged gerbil via increasing expressions of IGF-1, IGF-1R and p-CREB. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. The forced swimming-induced behavioural immobility response involves histone H3 phospho-acetylation and c-Fos induction in dentate gyrus granule neurons via activation of the N-methyl-D-aspartate/extracellular signal-regulated kinase/mitogen- and stress-activated kinase signalling pathway.

    Science.gov (United States)

    Chandramohan, Yalini; Droste, Susanne K; Arthur, J Simon C; Reul, Johannes M H M

    2008-05-01

    The hippocampus is involved in learning and memory. Previously, we have shown that the acquisition of the behavioural immobility response after a forced swim experience is associated with chromatin modifications and transcriptional induction in dentate gyrus granule neurons. Given that both N-methyl-D-aspartate (NMDA) receptors and the extracellular signal-regulated kinases (ERK) 1/2 signalling pathway are involved in neuroplasticity processes underlying learning and memory, we investigated in rats and mice whether these signalling pathways regulate chromatin modifications and transcriptional events participating in the acquisition of the immobility response. We found that: (i) forced swimming evoked a transient increase in the number of phospho-acetylated histone H3-positive [P(Ser10)-Ac(Lys14)-H3(+)] neurons specifically in the middle and superficial aspects of the dentate gyrus granule cell layer; (ii) antagonism of NMDA receptors and inhibition of ERK1/2 signalling blocked forced swimming-induced histone H3 phospho-acetylation and the acquisition of the behavioural immobility response; (iii) double knockout (DKO) of the histone H3 kinase mitogen- and stress-activated kinases (MSK) 1/2 in mice completely abolished the forced swimming-induced increases in histone H3 phospho-acetylation and c-Fos induction in dentate granule neurons and the behavioural immobility response; (iv) blocking mineralocorticoid receptors, known not to be involved in behavioural immobility in the forced swim test, did not affect forced swimming-evoked histone H3 phospho-acetylation in dentate neurons; and (v) the pharmacological manipulations and gene deletions did not affect behaviour in the initial forced swim test. We conclude that the forced swimming-induced behavioural immobility response requires histone H3 phospho-acetylation and c-Fos induction in distinct dentate granule neurons through recruitment of the NMDA/ERK/MSK 1/2 pathway.

  12. Primary Progressive Aphasia

    Science.gov (United States)

    ... which cause different symptoms. Semantic variant primary progressive aphasia Symptoms include these difficulties: Comprehending spoken or written ... word meanings Naming objects Logopenic variant primary progressive aphasia Symptoms include: Having difficulty retrieving words Frequently pausing ...

  13. Brain tumor - primary - adults

    Science.gov (United States)

    ... Vestibular schwannoma (acoustic neuroma) - adults; Meningioma - adults; Cancer - brain tumor (adults) ... Primary brain tumors include any tumor that starts in the brain. Primary brain tumors can start from brain cells, ...

  14. Primary ovarian malignant melanoma

    Directory of Open Access Journals (Sweden)

    Kostov Miloš

    2010-01-01

    Full Text Available Background. Primary ovarian malignant melanoma is extremely rare. It usually appears in the wall of a dermoid cyst or is associated with another teratomatous component. Metastatic primary malignant melanoma to ovary from a primary melanoma elsewhere is well known and has been often reported especially in autopsy studies. Case report. We presented a case of primary ovarian malignant melanoma in a 45- year old woman, with no evidence of extraovarian primary melanoma nor teratomatous component. The tumor was unilateral, macroscopically on section presented as solid mass, dark brown to black color. Microscopically, tumor cells showed positive immunohistochemical reaction for HMB-45, melan-A and S-100 protein, and negative immunoreactivity for estrogen and progesteron receptors. Conclusion. Differentiate metastatic melanoma from rare primary ovarian malignant melanoma, in some of cases may be a histopathological diagnostic problem. Histopathological diagnosis of primary ovarian malignant melanoma should be confirmed by immunohistochemical analyses and detailed clinical search for an occult primary tumor.

  15. Investigating Primary Source Literacy

    Science.gov (United States)

    Archer, Joanne; Hanlon, Ann M.; Levine, Jennie A.

    2009-01-01

    Primary source research requires students to acquire specialized research skills. This paper presents results from a user study testing the effectiveness of a Web guide designed to convey the concepts behind "primary source literacy". The study also evaluated students' strengths and weaknesses when conducting primary source research. (Contains 3…

  16. Primary Hyperparathyroidism: An Overview

    Directory of Open Access Journals (Sweden)

    Jessica MacKenzie-Feder

    2011-01-01

    Full Text Available Primary hyperparathyroidism is a common condition that affects 0.3% of the general population. Primary and tertiary care specialists can encounter patients with primary hyperparathyroidism, and prompt recognition and treatment can greatly reduce morbidity and mortality from this disease. In this paper we will review the basic physiology of calcium homeostasis and then consider genetic associations as well as common etiologies and presentations of primary hyperparathyroidism. We will consider emerging trends in detection and measurement of parathyroid hormone as well as available imaging modalities for the parathyroid glands. Surgical indications and approach will be reviewed as well as medical management of primary hyperparathyroidism with bisphosphonates and calcimimetics.

  17. Normocalcemic Primary Hyperparathyroidism

    Science.gov (United States)

    Cusano, Natalie E.; Silverberg, Shonni J.; Bilezikian, John P.

    2013-01-01

    Primary hyperparathyroidism, a common endocrine disorder, is traditionally defined by hypercalcemia and elevated levels of parathyroid hormone (PTH). A newer presentation of primary hyperparathyroidism has been described over the past decade, in which PTH is elevated but serum calcium is consistently normal, in the absence of secondary causes of hyperparathyroidism, such as renal disease or vitamin D deficiency. Recognition of this phenotype of primary hyperparathyroidism, normocalcemic primary hyperparathyroidism, supports a biphasic chronological time course in some individuals in which PTH levels are first elevated but serum calcium is normal, followed by the development of frank hypercalcemia. This review focuses on the available literature regarding this newly described phenotype of primary hyperparathyroidism. PMID:23374739

  18. Multiple primary cancer

    International Nuclear Information System (INIS)

    Jung, Gyu Sik; Lee, Ouk; Kim, So Sun; Kim, Ho Joon; Chun, Byung Hee; Joh, Young Duck

    1989-01-01

    It is rare for one human being to be afflicted with more than one cancer. However with further advances in therapeutic regimens, histopathologic observation, diagnostic modalities, and increased curiosity, there are increasing number of case reports of multiple primary cancer. The present study evaluates 25 histologically confirmed cases of multiple primary cancer from 1974 to 1988 at Kosin Medical Center. The most frequent site of the first primary cancer in male was stomach and in female, uterine cervix. The first primary cancer in female occurred in endocrine-related organs (breast, uterus and thyroid) in 63.6 percent. Synchronous cancers are diagnosed simultaneously or within an interval of about six months and synchronous cancers were 16 out of 25 cases. Metachronous cancers are diagnosed at interval of more than six months. There were 9 metachronous cancers and average interval between the first and second primary cancer was 22.8 months. The incidence of multiple primary cancer was 0.11 percent. The average age was 51.9 years at the time of the first primary cancer (53.1 years in male and 50.3 years in female). CT scan was most helpful in early detection of multiple primary cancers facilitating biopsy and surgery. Multiple primary cancers are beyond the medical curiosity. Early diagnosis of the disease and careful follow-up study, based on an awareness of the possibility of second cancers, will substantially increase the survival of these patients

  19. Aquisição de uma tarefa temporal (DRL por ratos submetidos a lesão seletiva do giro denteado The acquisition of a temporal task (DRL by dentate gyrus-selective colchicine lesioned rats

    Directory of Open Access Journals (Sweden)

    José Lino Oliveira Bueno

    2006-01-01

    Full Text Available A lesão seletiva do giro denteado (DG reduz a eficiência do desempenho de ratos treinados pré-operatoriamente em um esquema de reforçamento diferencial de baixas taxas (DRL; embora os animais lesados sejam capazes de suprimir a resposta de pressão na barra por determinado intervalo de tempo após a resposta anterior, eles subestimam esse intervalo, resultando em um desempenho menos eficiente. Como os animais tinham recebido treinamento pré-operatório, não ficou claro se a lesão interfere na aquisição da discriminação temporal. Este estudo avaliou o efeito da lesão do DG na aquisição de uma tarefa de DRL-20 s. Ratos foram submetidos à neurocirurgia e então ao treino na tarefa de DRL-20 s. Os resultados mostraram que embora os animais lesados se beneficiem do treinamento na tarefa, sua aquisição não é tão eficiente quanto a exibida pelos animais controle. Os resultados sugerem ainda que a lesão do giro denteado interfere na acuidade da discriminação temporal.Previous studies have shown that dentate gyrus damage render rats less efficient than sham-operated controls in the performance of a differential reinforcement of low rates of responding (DRL-20 s task acquired prior to the lesion; even though the lesioned rats were able to postpone their responses after a previous bar press, they seem to underestimate time relative to sham-operated controls, which interferes with their performance. This study investigated the effects of multiplesite, intradentate, colchicine injections on the acquisition and performance of a DRL-20 s task in rats not exposed to preoperatory training, i.e., trained after the lesion. Results showed that the lesioned rats improved along repetitive training in the DRL-20 s task; however, relative to the sham-operated controls, their acquisition rate was slower and the level of proficiency achieved was poorer, indicating that damage to the dentate gyrus interferes with temporal discrimination.

  20. Using Primary Source Documents.

    Science.gov (United States)

    Mintz, Steven

    2003-01-01

    Explores the use of primary sources when teaching about U.S. slavery. Includes primary sources from the Gilder Lehrman Documents Collection (New York Historical Society) to teach about the role of slaves in the Revolutionary War, such as a proclamation from Lord Dunmore offering freedom to slaves who joined his army. (CMK)

  1. Medics in Primary School

    Science.gov (United States)

    Press, Colin

    2003-01-01

    Some time ago a flyer on "Medics in Primary School" came the author's way. It described a programme for making placements in primary schools available to medical students. The benefits of the program to medical students and participating schools were highlighted, including opportunities to develop communication skills and demystify…

  2. Daily oral intake of theanine prevents the decline of 5-bromo-2′-deoxyuridine incorporation in hippocampal dentate gyrus with concomitant alleviation of behavioral abnormalities in adult mice with severe traumatic stress

    Directory of Open Access Journals (Sweden)

    Takeshi Takarada

    2015-03-01

    Full Text Available Posttraumatic stress disorder is a long-lasting psychiatric disease with the consequence of hippocampal atrophy in humans exposed to severe fatal stress. We demonstrated a positive correlation between the transient decline of 5-bromo-2′-deoxyuridine (BrdU incorporation in the hippocampal dentate gyrus (DG and long-lasting behavioral abnormalities in mice with traumatic stress. Here, we investigated pharmacological properties of theanine on the declined BrdU incorporation and abnormal behaviors in mice with traumatic stress. Prior daily oral administration of theanine at 50–500 mg/kg for 5 days significantly prevented the decline of BrdU incorporation, while theanine significantly prevented the decline in the DG even when administered for 5 days after stress. Consecutive daily administration of theanine significantly inhibited the prolonged immobility in mice with stress in forced swimming test seen 14 days later. Although traumatic stress significantly increased spontaneous locomotor activity over 30 min even when determined 14 days later, the increased total locomotion was significantly ameliorated following the administration of theanine at 50 mg/kg for 14 days after stress. These results suggest that theanine alleviates behavioral abnormalities together with prevention of the transient decline of BrdU incorporation in the hippocampal DG in adult mice with severe traumatic stress.

  3. Vanillin and 4-hydroxybenzyl alcohol promotes cell proliferation and neuroblast differentiation in the dentate gyrus of mice via the increase of brain-derived neurotrophic factor and tropomyosin-related kinase B.

    Science.gov (United States)

    Cho, Jeong-Hwi; Park, Joon Ha; Ahn, Ji Hyeon; Lee, Jae-Chul; Hwang, In Koo; Park, Seung Min; Ahn, Ji Yun; Kim, Dong Won; Cho, Jun Hwi; Kim, Jong-Dai; Kim, Young-Myeong; Won, Moo-Ho; Kang, Il-Jun

    2016-04-01

    4-Hydroxy‑3-methoxybenzaldehyde (vanillin) and 4-hydroxybenzyl alcohol (4-HBA) are well‑known phenolic compounds, which possess various therapeutic properties and are widely found in a variety of plants. In the present study, the effects of vanillin and 4‑HBA were first investigated on cell proliferation, as well as neuronal differentiation and integration of granule cells in the dentate gyrus (DG) of adolescent mice using Ki‑67, doublecortin (DCX) immunohistochemistry and 5‑bromo‑2'‑deoxyuridine (BrdU)/feminizing Locus on X 3 (NeuN) double immunofluorescence. In both the vanillin and 4‑HBA groups, the number of Ki‑67+ cells, DCX+ neuroblasts and BrdU+/NeuN+ neurons were significantly increased in the subgranular zone of the DG, as compared with the vehicle group. In addition, the levels of brain‑derived neurotrophic factor (BDNF) and tropomyosin‑related kinase B (TrkB), a BDNF receptor, were significantly increased in the DG in the vanillin and 4‑HBA groups compared with the vehicle group. These results indicated that vanillin and 4‑HBA enhanced cell proliferation, neuroblast differentiation and integration of granule cells in the DG of adolescent mice . These neurogenic effects of vanillin and 4‑HBA may be closely associated with increases in BDNF and TrkB.

  4. The effect of acute swim stress and training in the water maze on hippocampal synaptic activity as well as plasticity in the dentate gyrus of freely moving rats: revisiting swim-induced LTP reinforcement.

    Science.gov (United States)

    Tabassum, Heena; Frey, Julietta U

    2013-12-01

    Hippocampal long-term potentiation (LTP) is a cellular model of learning and memory. An early form of LTP (E-LTP) can be reinforced into its late form (L-LTP) by various behavioral interactions within a specific time window ("behavioral LTP-reinforcement"). Depending on the type and procedure used, various studies have shown that stress differentially affects synaptic plasticity. Under low stress, such as novelty detection or mild foot shocks, E-LTP can be transformed into L-LTP in the rat dentate gyrus (DG). A reinforcing effect of a 2-min swim, however, has only been shown in (Korz and Frey (2003) J Neurosci 23:7281-7287; Korz and Frey (2005) J Neurosci 25:7393-7400; Ahmed et al. (2006) J Neurosci 26:3951-3958; Sajikumar et al., (2007) J Physiol 584.2:389-400) so far. We have reinvestigated these studies using the same as well as an improved recording technique which allowed the recording of field excitatory postsynaptic potentials (fEPSP) and the population spike amplitude (PSA) at their places of generation in freely moving rats. We show that acute swim stress led to a long-term depression (LTD) in baseline values of PSA and partially fEPSP. In contrast to earlier studies a LTP-reinforcement by swimming could never be reproduced. Our results indicate that 2-min swim stress influenced synaptic potentials as well as E-LTP negatively. Copyright © 2013 Wiley Periodicals, Inc.

  5. Neuron and neuroblast numbers and cytogenesis in the dentate gyrus of aged APPswe/PS1dE9 transgenic mice: Effect of long-term treatment with paroxetine.

    Science.gov (United States)

    Olesen, Louise Ørum; Sivasaravanaparan, Mithula; Severino, Maurizio; Babcock, Alicia A; Bouzinova, Elena V; West, Mark J; Wiborg, Ove; Finsen, Bente

    2017-08-01

    Altered neurogenesis may influence hippocampal functions such as learning and memory in Alzheimer's disease. Selective serotonin reuptake inhibitors enhance neurogenesis and have been reported to reduce cerebral amyloidosis in both humans and transgenic mice. We have used stereology to assess the longitudinal changes in the number of doublecortin-expressing neuroblasts and number of granular neurons in the dentate gyrus of APP swe /PS1 dE9 transgenic mice. Furthermore, we investigated the effect of long-term paroxetine treatment on the number of neuroblasts and granular neurons, hippocampal amyloidosis, and spontaneous alternation behaviour, a measure of spatial working memory, in transgenic mice. We observed no difference in granular neurons between transgenic and wild type mice up till 18months of age, and no differences with age in wild type mice. The number of neuroblasts and the performance in the spontaneous alternation task was reduced in aged transgenic mice. Paroxetine treatment from 9 to 18months of age reduced hippocampal amyloidosis without affecting the number of neuroblasts or granular neurons. These findings suggest that the amyloidosis affects the differentiation of neuroblasts and spatial working memory, independent of changes in total granular neurons. Furthermore, while long-term paroxetine treatment may be able to reduce hippocampal amyloidosis, it appears to have no effect on total number of granular neurons or spatial working memory. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Primary Sclerosing Cholangitis (PSC)

    Science.gov (United States)

    ... Legacy Society Make Gifts of Stock Donate Your Car Personal Fundraising Partnership & Support Share Your Story Spread the Word Give While You Shop Contact Us Donate Now Primary Sclerosing Cholangitis Back ...

  7. Primary cultures of astrocytes

    DEFF Research Database (Denmark)

    Lange, Sofie C; Bak, Lasse Kristoffer; Waagepetersen, Helle S

    2012-01-01

    During the past few decades of astrocyte research it has become increasingly clear that astrocytes have taken a central position in all central nervous system activities. Much of our new understanding of astrocytes has been derived from studies conducted with primary cultures of astrocytes...... subsequently found in vivo. Nevertheless, primary cultures of astrocytes are an in vitro model that does not fully mimic the complex events occurring in vivo. Here we present an overview of the numerous contributions generated by the use of primary astrocyte cultures to uncover the diverse functions...... of astrocytes. Many of these discoveries would not have been possible to achieve without the use of astrocyte cultures. Additionally, we address and discuss the concerns that have been raised regarding the use of primary cultures of astrocytes as an experimental model system....

  8. Primary Meningeal Rhabdomyosarcoma

    Science.gov (United States)

    Palta, Manisha; Riedel, Richard F.; Vredenburgh, James J.; Cummings, Thomas J.; Green, Scott; Chang, Zheng; Kirkpatrick, John P.

    2011-01-01

    Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy. PMID:21772793

  9. Primary Meningeal Rhabdomyosarcoma

    Directory of Open Access Journals (Sweden)

    Manisha Palta

    2011-01-01

    Full Text Available Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13. Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC systemic therapy.

  10. Primary meningeal rhabdomyosarcoma.

    Science.gov (United States)

    Palta, Manisha; Riedel, Richard F; Vredenburgh, James J; Cummings, Thomas J; Green, Scott; Chang, Zheng; Kirkpatrick, John P

    2011-01-01

    Primary meningeal rhabdomyosarcoma is a rare primary brain malignancy, with scant case reports. While most reports of primary intracranial rhabdomyosarcoma occur in pediatric patients, a handful of cases in adult patients have been reported in the medical literature. We report the case of a 44-year-old male who developed primary meningeal rhabdomyosarcoma. After developing episodes of right lower extremity weakness, word finding difficulty, and headaches, a brain magnetic resonance imaging (MRI) demonstrated a vertex lesion with radiographic appearance of a meningeal-derived tumor. Subtotal surgical resection was performed due to sagittal sinus invasion and initial pathology was interpreted as an anaplastic meningioma. Re-review of pathology demonstrated rhabdomyosarcoma negative for alveolar translocation t(2;13). Staging studies revealed no evidence of disseminated disease. He was treated with stereotactic radiotherapy with concurrent temozolamide to be followed by vincristine, actinomycin-D, and cyclophosphamide (VAC) systemic therapy.

  11. Primary Nurse - Role Evolution

    Science.gov (United States)

    Mundinger, Mary O'Neil

    1973-01-01

    Primary nursing means that each patient has an individual nurse who is responsible for assessing his nursing needs and planning and evaluating his nursing care. The article describes the advantages and problems connected with this approach to patient care. (AG)

  12. Multiple Primary Tumors

    African Journals Online (AJOL)

    2017-12-05

    Dec 5, 2017 ... Multiple primary tumors occur in clinical practice causing diagnostic dilemma. It is not very .... was estrogen receptor negative, progesterone receptor negative, and ... cervical, ovarian, and urinary bladder cancers. Multiple.

  13. Primary infertility (image)

    Science.gov (United States)

    Primary infertility is a term used to describe a couple that has never been able to conceive a pregnancy ... to do so through unprotected intercourse. Causes of infertility include a wide range of physical as well ...

  14. Primary Intraorbital Ectopic Meningioma

    Science.gov (United States)

    Yokoyama, Tetsuo; Nishizawa, Shigeru; Sugiyama, Kenji; Yokota, Noki; Ohta, Seiji; Uemura, Kenichi; Hinokuma, Kaoru; Inenaga, Chikanori

    1999-01-01

    We report a case of intraorbital meningioma. Operative findings and histopathological examination revealed the tumoc to be meningothelial meningloma and to be located entirely outside the optic dura. This case demonstrates the occurrence of primary intraorbital ectopic meningioma, and the tumor was removed through a modified Dolenc approach. The primary intraorbital ectopic meningioma is discussed and the surgical approach to the orbital apex region is reviewed. ImagesFigure 1Figure 2Figure 4Figure 5 PMID:17171081

  15. Primary leiomyosarcoma of epididymis

    Directory of Open Access Journals (Sweden)

    Dillip Kumar Muduly

    2012-01-01

    Full Text Available Primary leiomyosarcomas rarely arise from epididymis. But they are the most common histopathological types of sarcoma arising from the epididymis. Primary epididymal leiomyosarcoma occurs usually in older patients. We report a young patient of 35 years presenting with leiomyosarcoma of left epididymis. He did not have any metastasis and underwent left high inguinal orchiectomy. He is on regular follow-up and disease free for last two years.

  16. Primary care ... where?

    Science.gov (United States)

    Adcock, G B

    1999-07-01

    Corporate-based nurse managed centers are not the national norm. More prevalent is the use of an occupational health or physician-directed medical model of care. The author describes how a 14-year-old primary care center at a North Carolina computer software company is just "business as usual" when viewed in the context of the company's philosophy, goals, and culture. Included are considerations for nurse practitioners interested in the successful transplantation of this primary care model to other settings.

  17. Other primary headaches

    Directory of Open Access Journals (Sweden)

    Anish Bahra

    2012-01-01

    Full Text Available The ′Other Primary Headaches′ include eight recognised benign headache disorders. Primary stabbing headache is a generally benign disorder which often co-exists with other primary headache disorders such as migraine and cluster headache. Primary cough headache is headache precipitated by valsalva; secondary cough has been reported particularly in association with posterior fossa pathology. Primary exertional headache can occur with sudden or gradual onset during, or immediately after, exercise. Similarly headache associated with sexual activity can occur with gradual evolution or sudden onset. Secondary headache is more likely with both exertional and sexual headache of sudden onset. Sudden onset headache, with maximum intensity reached within a minute, is termed thunderclap headache. A benign form of thunderclap headache exists. However, isolated primary and secondary thunderclap headache cannot be clinically differentiated. Therefore all headache of thunderclap onset should be investigated. The primary forms of the aforementioned paroxysmal headaches appear to be Indomethacin sensitive disorders. Hypnic headache is a rare disorder which is termed ′alarm clock headache′, exclusively waking patients from sleep. The disorder can be Indomethacin responsive, but can also respond to Lithium and caffeine. New daily persistent headache is a rare and often intractable headache which starts one day and persists daily thereafter for at least 3 months. The clinical syndrome more often has migrainous features or is otherwise has a chronic tension-type headache phenotype. Management is that of the clinical syndrome. Hemicrania continua straddles the disorders of migraine and the trigeminal autonomic cephalalgias and is not dealt with in this review.

  18. Primary Ectopic Ethmoidal Craniopharyngioma.

    Science.gov (United States)

    Preti, Andrea; Karligkiotis, Apostolos; Facco, Carla; Ottini, Giorgia; Volpi, Luca; Castelnuovo, Paolo

    2017-06-01

    Craniopharyngiomas are benign but aggressive epithelial tumors usually originating in the anterior lobe of the pituitary gland from squamous remnants of an incompletely involuted craniopharingeal duct developing from the Rathke pouch. To the authors' knowledge only 1 patient of a primary isolated ethmoidal craniopharyngioma has been reported in the literature.The authors report the case of a 17-year-old boy with a primary extracranial ethmoidal craniopharyngioma. An endoscopic endonasal approach was employed to resect the tumor. After 2 years of clinical and radiological follow-up no recurrence of disease was observed.Primary ethmoidal craniopharyngiomas are rare entities and biopsy is necessary for diagnosis. However, a preoperative assessment by means of nasal endoscopy, computed tomography scan, and enhanced magnetic resonance imaging is mandatory to better evaluate the extension and characteristics of the tumor. The endoscopic endonasal technique is a safe and effective approach for the treatment of these lesions.

  19. Primary renal synovial sarcoma

    Directory of Open Access Journals (Sweden)

    Girish D. Bakhshi

    2012-03-01

    Full Text Available Primary Renal Sarcoma is rare tumor comprising only 1% of all renal tumours. Synovial sarcomas are generally deep-seated tumors arising in the proximity of large joints of adolescents and young adults and account for 5-10% of all soft tissue tumours. Primary synovial sarcoma of kidney is rare and has poor prognosis. It can only be diagnosed by immunohistochemistry. It should be considered as a differential in sarcomatoid and spindle cell tumours. We present a case of 33-year-old female, who underwent left sided radical nephrectomy for renal tumour. Histopathology and genetic analysis diagnosed it to be primary renal synovial sarcoma. Patient underwent radiation therapy and 2 years follow up is uneventful. A brief case report with review of literature is presented.

  20. Primary headaches in children

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Pan

    2015-01-01

    Full Text Available Headache is a widespread clinical problem; the prevalence is high in all age groups, from which children and teenagers are not spared. It has been reported that, as many as 75% of school-age children may experience headache infrequently, among them 10% have recurrent headaches. [1],[2] The vast majority of headaches are primary and classified as migraine, tension-type headache (TTH, cluster headache, and other trigeminal autonomic cephalgias. The type of primary headaches could usually be diagnosed by a thorough and careful history taking, and physical examination. Once the diagnosis of migraine is established and appropriate reassurance provided, a balanced and individually tailored treatment plan can be instituted. The goal of treatment includes abortive or acute pain treatment, preventive long-term treatment, and biobehavioral therapy. Knowledge of precise impact of primary headaches on child′s quality of life helps to design a proper comprehensive treatment plan.

  1. Normocalcemic primary hyperparathyroidism

    Science.gov (United States)

    Bilezikian, John P.; Silverberg, Shonni J.

    2011-01-01

    SUMMARY Primary hyperparathyroidism is a common disorder of mineral metabolism characterized by incompletely regulated, excessive secretion of parathyroid hormone from one or more of the parathyroid glands. The historical view of this disease describes two distinct entities marked by two eras. When primary hyperparathyroidism was first discovered about 80 years ago, it was always symptomatic with kidney stones, bone disease and marked hypercalcemia. With the advent of the multichannel autoanalyzer about 40 years ago, the clinical phenotype changed to a disorder characterized by mild hypercalcemia and the absence of classical other features of the disease. We may now be entering a 3rd era in the history of this disease in which patients are being discovered with normal total and ionized serum calcium concentrations but with parathyroid hormone levels that are consistently elevated. In this article, we describe this new entity, normocalcemic primary hyperparathyroidism, a forme fruste of the disease. PMID:20485897

  2. [Primary care in Ireland].

    Science.gov (United States)

    Sánchez-Sagrado, T

    Spanish doctors are still leaving the country to look for quality work. Ireland is not a country with many Spanish professionals but it is interesting to know its particular Health care system. Ireland is one of the countries with a national health care system, although it has a mixture of private health care insurance schemes. People have a right to health care if they have been living in Ireland at least for a year. Access to the primary care health system depends on age and income: free of charge for Category 1 and co-payments for the rest. This division generates great inequalities among the population. Primary Care doctors are self-employed, and they work independently. However, since 2001 they have tended to work in multidisciplinary teams in order to strengthen the Primary Care practice. Salary is gained from a combination of public and private incomes which are not differentiated. The role of the General Practitioner consists in the treatment of acute and chronic diseases, minor surgery, child care, etc. There is no coordination between Primary and Secondary care. Access to specialised medicine is regulated by the price of consultation. Primary Care doctors are not gatekeepers. To be able to work here, doctors must have three years of training after medical school. After that, Continuing Medical Education is compulsory, and the college of general practitioners monitors it annually. The Irish health care system does not fit into the European model. Lack of a clear separation between public and private health care generates great inequalities. The non-existence of coordination between primary and specialised care leads to inefficiencies, which Ireland cannot allow itself after a decade of economic crisis. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  3. Thoughts on primary care.

    Science.gov (United States)

    Raskin, Lynne

    2010-01-01

    The uptake of family health teams in Ontario has been tremendous. And the creation of group practices in primary care has taken root in other provinces as well. For many people, being involved with something new is exciting. At the same time, once they are committed, they discover the challenges that can be simultaneously exhilarating and frustrating. This issue of Healthcare Quarterly offers two articles that provide interesting reflections on what has been learned so far from the perspectives of both team leadership and the team members themselves within a transforming primary care system.

  4. Primary lymphoma of the brain

    Science.gov (United States)

    Brain lymphoma; Cerebral lymphoma; Primary lymphoma of the central nervous system; Lymphoma - brain ... The cause of primary brain lymphoma is not known. People with a weakened immune system are at high risk for primary lymphoma of the brain. ...

  5. Reliability of a digital image method for measuring medial mandibular flexure in dentate subjects Confiabilidade de um método de imagem digital para medição de deflexão mandibular medial em adultos dentados

    Directory of Open Access Journals (Sweden)

    Rosemary Sadami Arai Shinkai

    2004-12-01

    Full Text Available Medial mandibular flexure (MMF is the functional approximation of hemi-mandibles in jaw opening and protrusion, which may affect conventional or implant-supported arch prostheses. OBJECTIVE: This study evaluated the intra- and inter-rater reliability of a digital image method for linear measurement of MMF in dentate subjects. MATERIAL AND METHODS: Mandibular occlusal impressions in vinyl polysiloxane during rest and maximum opening were obtained from seven adult volunteers. Each impression and the Mitutoyo digital calipers with a 10mm opening were scanned at a 200% magnification. The images were processed using Adobe Photoshop software to get reference points on contralateral first molars. Linear intermolar measurements were taken using the Image Tool software (UTHSCSA, which was calibrated with the standard opening of the digital calipers. Intermolar distance was measured in triplicate for each image by two independent examiners. MMF was calculated by subtracting the intermolar distance in maximum opening (or protrusion from the distance in rest position. Data were analyzed by intraclass correlation (ICC tests for estimating intra- and inter-rater reliability. RESULTS: MMF values ranged from -0.21 to 0.44mm. Intra-rater ICCs were 0.982 and 0.993, and inter-rater ICC was 0.696. CONCLUSION: The present results show excellent intra-rater and good inter-rater reliability of this digital image method for measuring MMF in dentate subjects.A deflexão mandibular medial (MMF é uma deformação funcional que ocorre com a aproximação das hemi-mandíbulas em abertura e protrusão, podendo afetar próteses convencionais e implanto-suportadas em arco. OBJETIVOS: Este trabalho avaliou a confiabilidade intra- e inter-examinador de um método de imagem digital para aferição linear da MMF. MATERIAL E MÉTODOS: Foram selecionados sete voluntários adultos dentados, obtendo-se registros oclusais inferiores de silicona de adição em repouso, abertura e

  6. Surgery of Primary Melanomas

    Directory of Open Access Journals (Sweden)

    Piotr Rutkowski

    2010-05-01

    Full Text Available Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

  7. Surgery of Primary Melanomas

    Energy Technology Data Exchange (ETDEWEB)

    Rutkowski, Piotr, E-mail: rutkowskip@coi.waw.pl; Zdzienicki, Marcin; Nowecki, Zbigniew I. [Soft Tissue/Bone Sarcoma and Melanoma Department, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw (Poland); Akkooi, Alexander C. J. van [Erasmus University Medical Center-Daniel den Hoed Cancer Center, Rotterdam (Netherlands)

    2010-05-11

    Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas.

  8. Surgery of Primary Melanomas

    International Nuclear Information System (INIS)

    Rutkowski, Piotr; Zdzienicki, Marcin; Nowecki, Zbigniew I.; Akkooi, Alexander C. J. van

    2010-01-01

    Surgery remains the mainstay of melanoma therapy, regardless of the tumor site. Only the early diagnosis combined with proper surgical therapy currently gives patients affected by this malignancy the chance for a full cure. The main goal of surgical therapy is to provide the local control of the disease and to secure long-term survival of the patient without reasonable functional and esthetic impairment. The recommended method of biopsy—excisional biopsy, as an initial diagnostic and, to some extent, therapeutic procedure—is performed under local anesthesia as an elliptical incision with visual clear margins of 1–3 mm and with some mm of subcutaneous tissue. The extent of radical excision of the primary tumor (or scar after excisional biopsy) is based on the histopathologic characteristics of the primary tumor and usually consists of 1–2 cm margins with primary closure. The philosophy behind conducted randomized clinical trials has been to find the most conservative surgical approach that is able to guarantee the same results as more demolitive treatment. This has been the background of the trials designed to define the correct margins of excision around a primary cutaneous melanoma. Much less definition can be dedicated to the surgical management of patients with non-cutaneous melanomas

  9. Primary intestinal lymphangiectasia.

    Science.gov (United States)

    Suresh, N; Ganesh, R; Sankar, Janani; Sathiyasekaran, Malathi

    2009-10-01

    Primary intestinal lymphangiectasia (PIL) is a rare disease of intestinal lymphatics presenting with hypoproteinemia, bilateral lower limb edema, ascites, and protein losing enteropathy. We report a series of 4 children from Chennai, India presenting with anasarca, recurrent diarrhea, hypoproteinemia and confirmatory features of PIL on endoscopy and histopathology.

  10. Healthcare is primary

    Directory of Open Access Journals (Sweden)

    Raman Kumar

    2015-01-01

    Full Text Available India is undergoing a rapid transformation in terms of governance, administrative reforms, newer policy develoment, and social movements. India is also considered one of the most vibrant economies in the world. The current discourse in public space is dominated by issues such as economic development, security, corruption free governance, gender equity, and women safety. Healthcare though remains a pressing need of population; seems to have taken a backseat. In the era of decreasing subsidies and cautious investment in social sectors, the 2 nd National Conference on Family Medicine and Primary Care 2015 (FMPC brought a focus on "healthcare" in India. The theme of this conference was "Healthcare is Primary." The conference participants discussed on the theme of why healthcare should be a national priority and why strong primary care should remain at the center of healthcare delivery system. The experts recommended that India needs to strengthen the "general health system" instead of focusing on disease based vertical programs. Public health system should have capacity and skill pool to be able to deliver person centered comprehensive health services to the community. Proactive implementation of policies towards human resource in health is the need of the hour. As the draft National Health Policy 2015 is being debated, "family medicine" (academic primary care, the unfinished agenda of National Health Policy 2002, remains a priority area of implementation.

  11. Multiple Primary Tumors

    African Journals Online (AJOL)

    2018-02-07

    Feb 7, 2018 ... breast and ascending colon. KEYWORDS: Carcinoid, colorectal cancer, metachronous, synchronous. Multiple Primary Tumors. MA Adeyanju, AA Ilori. Address for correspondence: Dr. MA Adeyanju,. Department of Surgery, Federal Medical Centre, Ebute Metta,. Lagos, Nigeria. E-mail: mbadeyanju@yahoo.

  12. Primary malignant intramedullary lymphoma

    International Nuclear Information System (INIS)

    Orrego P, E.; Heinicke Y, H.; Arbaiza A, D.; Yepez R, V.

    1999-01-01

    A case of primary malignant intramedullary lymphoma, localized in the dorsal part of the spinal cord is presented. The clinical symptoms were associated with motor and sensitive deficit. Clinical investigations excluded the presence of lymphoma in other locations in the central nervous system and the extra neural organs. Postoperative radiotherapy and chemotherapy improved relict neurological symptoms. (authors)

  13. Primary black holes

    International Nuclear Information System (INIS)

    Novikov, I.; Polnarev, A.

    1981-01-01

    Proves are searched for of the formation of the so-called primary black holes at the very origin of the universe. The black holes would weigh less than 10 13 kg. The formation of a primary black hole is conditional on strong fluctuations of the gravitational field corresponding roughly to a half of the fluctuation maximally permissible by the general relativity theory. Only big fluctuations of the gravitational field can overcome the forces of the hot gas pressure and compress the originally expanding matter into a black hole. Low-mass black holes have a temperature exceeding that of the black holes formed from stars. A quantum process of particle formation, the so-called evaporation takes place in the strong gravitational field of a black hole. The lower the mass of the black hole, the shorter the evaporation time. The analyses of processes taking place during the evaporation of low-mass primary black holes show that only a very small proportion of the total mass of the matter in the universe could turn into primary black holes. (M.D.)

  14. Familial primary hyperparathyroidism

    International Nuclear Information System (INIS)

    Iqbal, P.; Javed, R.

    2007-01-01

    A case of primary hyperparathyroidism in a 17 years old female is described. Patient presented with severe abdominal and pelvic pains associate with discomfort. Diagnostic testing revealed multiple upper and lower limb fractures and renal stones. Case was self limiting. Patient's condition resolved on parathyroidectomy for adenoma and partial thyroidectomy. Follow-up showed familial links. (author)

  15. Multiple Primary Cancer Monograph

    Science.gov (United States)

    To identify groups of cancer survivors that are at increased risk for multiple primary cancers, investigators led an effort to provide the first comprehensive population-based analysis of the risk of subsequent cancer in the U.S., resulting in a monograph.

  16. Primary cosmic ray flux

    Energy Technology Data Exchange (ETDEWEB)

    Stanev, Todor

    2001-05-01

    We discuss the primary cosmic ray flux from the point of view of particle interactions and production of atmospheric neutrinos. The overall normalization of the cosmic ray flux and its time variations and site dependence are major ingredients of the atmospheric neutrino predictions and the basis for the derivation of the neutrino oscillation parameters.

  17. in primary care

    African Journals Online (AJOL)

    Claire van Deventer

    Keywords: child HIV, doctor involvement, primary health care, quality improvement ... expertise increased, PHC facilities are now expected to be able to .... organised patient documentation were revisited. .... Review: what can we learn from quality ... South Pacific: Review of evidence and lessons from an innovative.

  18. [Primary and secondary encopresis].

    Science.gov (United States)

    Lang-Langer, Ellen

    2007-01-01

    While the difficulty of the child to part with its faeces in primary encopresis is linked to the incapability to experience the object as separated and independent from himself, secondary encopresis is a progressed psychical state of development. In this case we have to deal with regression caused by conflict. Two case-studies show clearly the differences.

  19. Spirometry in primary care

    Science.gov (United States)

    Coates, Allan L; Graham, Brian L; McFadden, Robin G; McParland, Colm; Moosa, Dilshad; Provencher, Steeve; Road, Jeremy

    2013-01-01

    Canadian Thoracic Society (CTS) clinical guidelines for asthma and chronic obstructive pulmonary disease (COPD) specify that spirometry should be used to diagnose these diseases. Given the burden of asthma and COPD, most people with these diseases will be diagnosed in the primary care setting. The present CTS position statement was developed to provide guidance on key factors affecting the quality of spirometry testing in the primary care setting. The present statement may also be used to inform and guide the accreditation process for spirometry in each province. Although many of the principles discussed are equally applicable to pulmonary function laboratories and interpretation of tests by respirologists, they are held to a higher standard and are outside the scope of the present statement. PMID:23457669

  20. Cancer of unknown primary

    DEFF Research Database (Denmark)

    Dyrvig, Anne-Kirstine; Yderstræde, Knud Bonnet; Gerke, Oke

    2017-01-01

    210 (38.7%) had a CUP diagnosis confirmed. Within the cohort, 347 patients (64.0%) had a registration in CR matching with the NPR registration. Exposure to diagnostic procedures included biopsy (n = 439, 81.0%) and image modalities (n = 532, 98.2%). Survival was poor with 67 (12.4%) individuals alive...... after 4 years.The validity of a CUP diagnosis in NPR was low when using data from CR as reference. More than half the suspected CUP patients had a previous cancer diagnosis with CUP being the most frequent. Patients were diagnosed in compliance with guidelines indicating high external validity, but less...... than 1 quarter had their primary identified and the 1-year survival was approximately 20%. Research is needed to develop efficacious methods for primary detection....

  1. Primary omental pregnancy

    International Nuclear Information System (INIS)

    Yildizhan, R.; Kurdoglu, M.; Kolusari, A.; Erten, R.

    2008-01-01

    Omental pregnancy is a rare form of ectopic pregnancy and can be seen primarily or secondary to a tubal pregnancy. A 25-yeal-old woman presented with abdominal distention with pain and anemia without vaginal bleeding. After a provisional diagnosis of ruptured ectopic pregnancy, laparotomy was performed. On surgical exploration, the bilateral tubes and ovaries were intact, however, an omental pregnancy was detected as the cause of hemoperitoneum. Partial omentectomy was performed. Although most cases are secondary, presented here is an additional case of primary omental pregnancy at 12 weeks according to Studdiford's criteria. Histological evidence of neovascularization into the supporting tissue confirmed our diagnosis. A primary omental pregnancy should always be considered as a possible explanation for severe hemoperitoneum in ectopic pregnancies presenting with acute abdomen and with intact adnexes on surgical exploration. (author)

  2. Basics of primary immunodeficiencies

    Directory of Open Access Journals (Sweden)

    Claudia Hernández-Martínez

    2016-05-01

    Full Text Available Primary immunodeficiencies (PID are a heterogeneous group of inherited disorders, the etiology are the defects in the development or function of the immune system. The principal PID manifestations are the infections in early age, malignancy and diseases of immune dysregulation as autoimmunity and allergy. PIDs are genetics disorders and most of them are inherited as autosomal recessive, also this group of diseases is more prevalent in males and in childhood. The antibody immunodeficiency is the PID more common in adults. The more frequent disorders are the infections in the respiratory tract, abscesses, candidiasis, diarrhea, BCGosis etc. Initial approach included a complete blood count and quantification of immunoglobulins. The delay in diagnosis could be explained due to a perception that the recurrent infections are normal process or think that they are exclusively of childhood. The early diagnosis of PID by primary care physicians is important to opportune treatment and better prognosis.

  3. [Primary care in France].

    Science.gov (United States)

    Sánchez-Sagrado, T

    2016-01-01

    The poor planning of health care professionals in Spain has led to an exodus of doctors leaving the country. France is one of the chosen countries for Spanish doctors to develop their professional career. The French health care system belongs to the Bismarck model. In this model, health care system is financed jointly by workers and employers through payroll deduction. The right to health care is linked to the job, and provision of services is done by sickness-funds controlled by the Government. Primary care in France is quite different from Spanish primary care. General practitioners are independent workers who have the right to set up a practice anywhere in France. This lack of regulation has generated a great problem of "medical desertification" with problems of health care access and inequalities in health. French doctors do not want to work in rural areas or outside cities because "they are not value for money". Medical salary is linked to professional activity. The role of doctors is to give punctual care. Team work team does not exist, and coordination between primary and secondary care is lacking. Access to diagnostic tests, hospitals and specialists is unlimited. Duplicity of services, adverse events and inefficiencies are the norm. Patients can freely choose their doctor, and they have a co-payment for visits and hospital care settings. Two years training is required to become a general practitioner. After that, continuing medical education is compulsory, but it is not regulated. Although the French medical Health System was named by the WHO in 2000 as the best health care system in the world, is it not that good. While primary care in Spain has room for improvement, there is a long way for France to be like Spain. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  4. [Primary care in Italy].

    Science.gov (United States)

    Sánchez-Sagrado, T

    Italy is not a country where Spanish doctors emigrate, as there is an over-supply of health care professionals. The Italian Servizio Sanitario Nazionale has some differences compared to the Spanish National Health System. The Servizio Sanitario Nazionale is financed by national and regional taxes and co-payments. There are taxes earmarked for health, and Primary Care receives 50% of the total funds. Italian citizens and residents in Italy have the right to free health cover. However, there are co-payments for laboratory and imaging tests, pharmaceuticals, specialist ambulatory services, and emergencies. Co-payments vary in the different regions. The provision of services is regional, and thus fragmentation and major inequities are the norm. Doctors in Primary Care are self-employed and from 2000 onwards, there are incentives to work in multidisciplinary teams. Salary is regulated by a national contract and it is the sum of per-capita payments and extra resources for specific activities. Responsibilities are similar to those of Spanish professionals. However, medical care is more personal. Relationships between Primary Care and specialised care depend on the doctors' relationships. Primary Care doctors are gatekeepers for specialised care, except for gynaecology, obstetrics and paediatrics. Specialised training is compulsory in order to work as general practitioner. The Italian Health Care System is a national health system like the Spanish one. However, health care professionals are self-employed, and there are co-payments. In spite of co-payments, Italians have one of the highest average life expectancy, and they support a universal and publicly funded health-care system. Copyright © 2017 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S.L.U. All rights reserved.

  5. Primary Tunnel Junction Thermometry

    International Nuclear Information System (INIS)

    Pekola, Jukka P.; Holmqvist, Tommy; Meschke, Matthias

    2008-01-01

    We describe the concept and experimental demonstration of primary thermometry based on a four-probe measurement of a single tunnel junction embedded within four arrays of junctions. We show that in this configuration random sample specific and environment-related errors can be avoided. This method relates temperature directly to Boltzmann constant, which will form the basis of the definition of temperature and realization of official temperature scales in the future

  6. Primary stabbing headache.

    Science.gov (United States)

    Pareja, Juan A; Sjaastad, Ottar

    2010-01-01

    Primary stabbing headache is characterized by transient, cephalic ultrashort stabs of pain. It is a frequent complaint with a prevalence of 35.2%, a female preponderance, and a mean age of onset of 28 years (Vågå study). Attacks are generally characterized by moderate to severe, jabbing or stabbing pain, lasting from a fraction of a second to 3s. Attack frequency is generally low, with one or a few attacks per day. The paroxysms generally occur spontaneously, during daytime. Most patients exhibit a sporadic pattern, with an erratic, unpredictable alternation between symptomatic and non-symptomatic periods. Paroxysms are almost invariably unilateral. Temporal and fronto-ocular areas are most frequently affected. Attacks tend to move from one area to another, in either the same or the opposite hemicranium. Jabs may be accompanied by a shock-like feeling and even by head movement - "jolts" -or vocalization. On rare occasions, conjunctival hemorrhage and monocular vision loss have been described as associated features. Primary stabbing headache may concur, synchronously or independently, with other primary headaches. In contrast to what is the case in adults, in childhood it is not usually associated with other headaches. Treatment is rarely necessary. Indomethacin, 75-150 mg daily, may seem to be of some avail. Celecoxib, nifedipine, melatonin, and gabapentin have been reported to be effective in isolated cases and small series of patients. The drug studies need corroboration. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. [Primary headache and depression].

    Science.gov (United States)

    Gesztelyi, Gyöngyi

    2004-11-28

    Primary headaches--mainly tension-type headache and migraine--affect a significant portion of the population. Depression is also highly prevalent. The co-existence of a primary headache and depression in the same patient therefore might be a coincidence due to the high prevalence of these conditions, but there might be a causal relationship between them, or headaches and depression might have a common background. This review of the literature summarizes the features of the relationship between primary headaches and depression. Depression is more prevalent in headache patients than in the headache-free population. Prospective epidemiological studies suggest a common genetic, biochemical or environmental background behind primary headaches and depression. This theory is supported by the role of the same neurotransmitter systems (mostly serotonin and dopamine) in headaches as well as in depression. Comorbid depression is associated with female gender, higher age, and higher frequency of headaches. Most depression inventories--questionnaires used to screen for the severity of depressive symptoms--contain transdiagnostic items, therefore their use in their original form is limited in organic diseases: due to the somatic items they might overestimate the severity of depression. When examining a headache patient special attention should be paid to the recognition of comorbid depression. The diagnosis of suspected mood disorder could be supported by using simple screening methods, such as the original or the abbreviated versions of standard depression inventories, but the final diagnosis of major depression needs psychiatric evaluation. Quality of life of the headache patient is affected not only by the characteristics of pain (frequency, duration, severity) but also by the disability caused by headache and the associating mood disorder. Recognizing coexisting mood disorder and disability helps to make the best treatment choice for the acute and preventive treatment of

  8. Efficient adenoviral vector directed expression of a foreign gene to neurons and sustentacular cells in the mouse olfactory neuroepithelium

    NARCIS (Netherlands)

    Gispen, W.H.; Holtmaat, A.J.G.D.; Hermens, W.T.J.M.C.; Oestreicher, A.B.; Kaplitt, M.G.; Verhaagen, J.

    1996-01-01

    Replication deficient recombinant adenoviral vectors are efficient gene transfer agents for postmitotic cells, including neurons and glial cells. In this paper we have examined the effectiveness of adenoviral vector-mediated gene transfer to the olfactory epithelium of adult mice. We show that

  9. Efficient adenoviral vector-directed expression of a foreign gene to neurons and sustentacular cells in the mouse olfactory neuroepithelium

    NARCIS (Netherlands)

    Holtmaat, Anthony J D G; Hermens, W.T.J.M.C.; Oestreicher, A B; Gispen, Willem Hendrik; Kaplitt, M G; Verhaagen, J

    1996-01-01

    Replication deficient recombinant adenoviral vectors are efficient gene transfer agents for postmitotic cells, including neurons and glial cells. In this paper we have examined the effectiveness of adenoviral vector-mediated gene transfer to the olfactory epithelium of adult mice. We show that

  10. Visualizing Metal Content and Intracellular Distribution in Primary Hippocampal Neurons with Synchrotron X-Ray Fluorescence.

    Directory of Open Access Journals (Sweden)

    Robert A Colvin

    Full Text Available Increasing evidence suggests that metal dyshomeostasis plays an important role in human neurodegenerative diseases. Although distinctive metal distributions are described for mature hippocampus and cortex, much less is known about metal levels and intracellular distribution in individual hippocampal neuronal somata. To solve this problem, we conducted quantitative metal analyses utilizing synchrotron radiation X-Ray fluorescence on frozen hydrated primary cultured neurons derived from rat embryonic cortex (CTX and two regions of the hippocampus: dentate gyrus (DG and CA1. Comparing average metal contents showed that the most abundant metals were calcium, iron, and zinc, whereas metals such as copper and manganese were less than 10% of zinc. Average metal contents were generally similar when compared across neurons cultured from CTX, DG, and CA1, except for manganese that was larger in CA1. However, each metal showed a characteristic spatial distribution in individual neuronal somata. Zinc was uniformly distributed throughout the cytosol, with no evidence for the existence of previously identified zinc-enriched organelles, zincosomes. Calcium showed a peri-nuclear distribution consistent with accumulation in endoplasmic reticulum and/or mitochondria. Iron showed 2-3 distinct highly concentrated puncta only in peri-nuclear locations. Notwithstanding the small sample size, these analyses demonstrate that primary cultured neurons show characteristic metal signatures. The iron puncta probably represent iron-accumulating organelles, siderosomes. Thus, the metal distributions observed in mature brain structures are likely the result of both intrinsic neuronal factors that control cellular metal content and extrinsic factors related to the synaptic organization, function, and contacts formed and maintained in each region.

  11. Localization of primary aldosteronism

    International Nuclear Information System (INIS)

    Pagny, J.Y.; Chatellier, G.; Raynaud, A.; Plouin, P.F.; Corvol, P.

    1988-01-01

    After diagnosis of primary aldosteronism on the basis of biochemical evidence, the detection of the tumour is of crucial importance in the management of the disease. The efficacy of CT-Scan, Iodo-Cholesterol Scintigraphy, digitalized phlebography, adrenal vein sampling for steroid measurements (AVS), and Nuclear Magnetic Resonance (NMR) in 160 hypertensive patients with primary aldosteronism was reviewed. Diagnosis of Conn's adenoma (n=96) or Adrenal Hyperplasia (n=40) was confirmed by surgery or at least two concordant tumour localization tests. Scintigraphy gave a correct diagnosis in 53% of the 51 exams, CT-Scan in 82% of the 85 exams, and phlebography in 79% of 61 exams. Plasma Aldosterone/ Cortisol ratio was 5 times higher on the side of adenoma in 55% of the 47 cases but this ratio was also present in 23% of 22 patients with adrenal hyperplasia. Each procedure exhibited few false positive and false negative cases. NMR performed in 15 patients with Conn's adenoma identified all the cases. But tumours displayed a signal close to the liver signal and identical to the normal adrenal. These results and the risk of invasive procedure (failure of catheterization of the right adrenal vein (n=6) and adrenal haematoma (n=2) lead to propose a schema of exploration of patients with primary aldosteronism. The CT-Scan could be performed at the first step once the biological diagnosis confirmed. Phlebography and AVS will be performed only if tumour was less than 1 cm at the CT-Scan despite important biological abnormalities. This schema requires to be validated by a prospective evaluation [fr

  12. Teacher of primary English

    CERN Multimedia

    2003-01-01

    Part-time teacher of primary English needed for September 2003 to teach English National Curriculum (KS2) and NLS to mother tongue or good second language English-speakers aged 7-10. 4 hours contact time per week, team planning, marking and meetings. Candidates should be English mother tongue qualified teachers, confident, flexible classroom practitioners and team players. For further details and how to apply see http://enpferney.org/staff_vacancies.htm English National Programme, Lycée International, Ferney-Voltaire (http://enpferney.org/)

  13. Primary isolated hepatic tuberculosis

    International Nuclear Information System (INIS)

    Sheikh, A.S.F.; Qureshi, I.H.; Saba, K.; Bukhari, M.H.

    2013-01-01

    Isolated hepatic tuberculosis without pulmonary or bowel involvement is a diagnostic challenge and can cause considerable morbidity. A young lady from Lahore presented with fever, pain in right hypochondria, nausea and weight loss. CT scan of abdomen showed multiple small hypodense non-enhancing lesions and a heterogeneous texture of liver. Biopsy confirmed the diagnosis of hepatic tuberculosis. It was concluded a case of isolated hepatic tuberculosis without evidence of other primary sites involvement. It is important to consider tuberculosis in the differential diagnosis when suspecting lymphoproliferative or metastatic diseases in a patient with vague symptoms and abnormal hepatic texture on CT. (author)

  14. PRIMARY CARIES: AN OVERVIEW

    Directory of Open Access Journals (Sweden)

    Gaurav Solanki

    2012-01-01

    Full Text Available Primary caries is an initial lesions produced by direct extension from an external surface. Dental caries is called as tooth decay or a cavity is a disease in which bacterial processes changes carbohydrate to acid which than dematerializes the hard tooth structure like enamel, dentin and cementum. Streptococcus mutans and Lactobacillus are the bacteria responsible for the dental caries by acid production. This article throws light on the dental caries disease, its sign and symptoms, treatment and prevention of it. A review of some patents on dental caries is also provided that summarizes the recent technical advancements taken place in this area.

  15. Primary cutaneous lymphoma

    International Nuclear Information System (INIS)

    Nguyen, M. Connie; Cleary, Sean F.; Hoppe, Richard T.

    1995-01-01

    Purpose: A retrospective review analyzed the survival and freedom from relapse of patients with stage IE or IIE primary cutaneous lymphoma (non mycosis fungoides) after treatments with radiation therapy alone (XRT), chemotherapy alone (RX) or combined modality therapy (CMT). Methods and Materials: Fifty two patients with stage IE-IIE cutaneous lymphoma treated at Stanford University Hospital were reviewed. The median age was 57, with a range of 26 to 94 and a male to female ratio of 1.21:1. Patients were staged according to the Ann Arbor System. Pathology was classified according to the Working Formulation. Treatment outcomes were compared using Kaplan-Meier survival curves with a Gehan p-value test. Results: The follow up range was 6 months to 22 years (median 7 years.) Twenty one percent of patients had low grade, 63% had intermediate grade and 15% had high grade lymphoma. The most common histologic subtype was diffuse large cell lymphoma Thirty two patients received radiation alone as initial treatment and sixteen patients received combined modality as initial treatment. Four patients received chemotherapy alone. The only significant prognostic factor for survival was the stage at diagnosis. Patients with stage IE disease had a longer actuarial survival (5-yr=79%, 10-yr=71%), as compared to those with stage IIE (5-yr=49%, 10-yr=33%), (p=0.029). The only significant prognostic factor for freedom from relapse was the initial treatment. Initial combined modality treatment lead to a longer freedom from relapse compared to patients treated with radiation alone (p=0.002), (median 5 years vs. 1.2 years). Despite this, the actuarial overall survival in the combined modality group and the radiation alone group are similar (median survival 7.7 and 8 years). The efficacy of either radiation or chemotherapy as salvage treatment after radiation failure was equivalent and both salvage treatments lead to equally long survival and freedom from second relapse. Conclusion

  16. Bellefonte primary containment structure

    International Nuclear Information System (INIS)

    Olyniec, J.H.

    1981-01-01

    Construction of the reactor building primary containment structure at the Bellefonte Nuclear Plant involved several specialized construction techniques. This two unit plant is one of the nine nuclear units at six different sites now under construction by the Tennessee Valley Authority (TVA). The post-Tensioned, cast-in-place interior steel lined containment structure is unique within TVA. Problems during construction were identified at weekly planning meetings, and options were discussed. Close coordination between craft supervisors and on-site engineering personnel drew together ''hands-on''experience and technical background. Details of the construction techniques, problems, and solutions are presented

  17. Primary Carnitine Deficiency

    DEFF Research Database (Denmark)

    Rasmussen, Jan; Hougaard, David M; Sandhu, Noreen

    2017-01-01

    Primary carnitine deficiency (PCD) causes low levels of carnitine in patients potentially leading to metabolic and cardiac symptoms. Newborn screening for PCD is now routine in many countries by measuring carnitine levels in infants. In this study we report Apgar scores, length and weight...... scores, length and weight compared to controls. Newborns with PCD and newborns born to mothers with PCD had significantly lower levels of free carnitine (fC0) than controls. Screening algorithms focusing only on fC0 had a high rate of detection of newborns with PCD. Sample collection 4-9 days after birth...

  18. Aspirin for Primary Prevention.

    Science.gov (United States)

    Richman, Ilana B; Owens, Douglas K

    2017-07-01

    Aspirin reduces the risk of nonfatal myocardial infarction and stroke, and the risk of colorectal cancer. Aspirin increases the risk of gastrointestinal and intracranial bleeding. The best available evidence supports initiating aspirin in select populations. In 2016, the US Preventive Services Task Force recommended initiating aspirin for the primary prevention of both cardiovascular disease and colorectal cancer among adults ages 50 to 59 who are at increased risk for cardiovascular disease. Adults 60 to 69 who are at increased cardiovascular disease risk may also benefit. There remains considerable uncertainty about whether younger and older patients may benefit. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Primary cutaneous lymphoma

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, M Connie; Cleary, Sean F; Hoppe, Richard T

    1995-07-01

    Purpose: A retrospective review analyzed the survival and freedom from relapse of patients with stage IE or IIE primary cutaneous lymphoma (non mycosis fungoides) after treatments with radiation therapy alone (XRT), chemotherapy alone (RX) or combined modality therapy (CMT). Methods and Materials: Fifty two patients with stage IE-IIE cutaneous lymphoma treated at Stanford University Hospital were reviewed. The median age was 57, with a range of 26 to 94 and a male to female ratio of 1.21:1. Patients were staged according to the Ann Arbor System. Pathology was classified according to the Working Formulation. Treatment outcomes were compared using Kaplan-Meier survival curves with a Gehan p-value test. Results: The follow up range was 6 months to 22 years (median 7 years.) Twenty one percent of patients had low grade, 63% had intermediate grade and 15% had high grade lymphoma. The most common histologic subtype was diffuse large cell lymphoma Thirty two patients received radiation alone as initial treatment and sixteen patients received combined modality as initial treatment. Four patients received chemotherapy alone. The only significant prognostic factor for survival was the stage at diagnosis. Patients with stage IE disease had a longer actuarial survival (5-yr=79%, 10-yr=71%), as compared to those with stage IIE (5-yr=49%, 10-yr=33%), (p=0.029). The only significant prognostic factor for freedom from relapse was the initial treatment. Initial combined modality treatment lead to a longer freedom from relapse compared to patients treated with radiation alone (p=0.002), (median 5 years vs. 1.2 years). Despite this, the actuarial overall survival in the combined modality group and the radiation alone group are similar (median survival 7.7 and 8 years). The efficacy of either radiation or chemotherapy as salvage treatment after radiation failure was equivalent and both salvage treatments lead to equally long survival and freedom from second relapse. Conclusion

  20. PRIMARY SCHOOL TEACHER

    CERN Multimedia

    Madeleine Dittus

    2002-01-01

    For January 2003, the A.P.E.G. has an opening for a primary school teacher in the German national language program. The position requires one afternoon of teaching (13:30 till 16:30) every Tuesday at the Collège in Prévessin. The candidate should be a native speaker of German and have some knowledge of French. If you are interested, please send your CV, a copy of your diploma, and a short letter of motivation, until December 9th, to the following address. Madeleine Dittus Présidente A.P.E.G. 5, La vie Destraz 01630 St. Genis-Pouilly (France)

  1. Pattern of Primary Nocturnal Enuresis in Primary School Children ...

    African Journals Online (AJOL)

    Pattern of Primary Nocturnal Enuresis in Primary School Children (First Grade) in ... The control group consisting of 100 age-matched non-enuretic children ... was insignificantly associated with a positive family history, family size or birth rank.

  2. Glehnia littoralis Extract Promotes Neurogenesis in the Hippocampal Dentate Gyrus of the Adult Mouse through Increasing Expressions of Brain-Derived Neurotrophic Factor and Tropomyosin-Related Kinase B.

    Science.gov (United States)

    Park, Joon Ha; Shin, Bich Na; Ahn, Ji Hyeon; Cho, Jeong Hwi; Lee, Tae-Kyeong; Lee, Jae-Chul; Jeon, Yong Hwan; Kang, Il Jun; Yoo, Ki-Yeon; Hwang, In Koo; Lee, Choong Hyun; Noh, Yoo Hun; Kim, Sung-Su; Won, Moo-Ho; Kim, Jong Dai

    2018-03-20

    Glehnia littoralis has been used for traditional Asian medicine, which has diverse therapeutic activities. However, studies regarding neurogenic effects of G. littoralis have not yet been considered. Therefore, in this study, we examined effects of G. littoralis extract on cell proliferation, neuroblast differentiation, and the maturation of newborn neurons in the hippocampus of adult mice. A total of 39 male ICR mice (12 weeks old) were randomly assigned to vehicle-treated and 100 and 200 mg/kg G. littoralis extract-treated groups (n = 13 in each group). Vehicle and G. littoralis extract were orally administrated for 28 days. To examine neurogenic effects of G. littoralis extract, we performed immunohistochemistry for 5-bromo-2-deoxyuridine (BrdU, an indicator for cell proliferation) and doublecortin (DCX, an immature neuronal marker) and double immunofluorescence staining for BrdU and neuronal nuclear antigen (NeuN, a mature neuronal marker). In addition, we examined expressional changes of brain-derived neurotrophic factor (BDNF) and its major receptor tropomyosin-related kinase B (TrkB) using Western blotting analysis. Treatment with 200 mg/kg, not 100 mg/kg, significantly increased number of BrdU-immunoreactive ( + ) and DCX + cells (48.0 ± 3.1 and 72.0 ± 3.8 cells/section, respectively) in the subgranular zone (SGZ) of the dentate gyrus (DG) and BrdU + /NeuN + cells (17.0 ± 1.5 cells/section) in the granule cell layer as well as in the SGZ. In addition, protein levels of BDNF and TrkB (about 232% and 244% of the vehicle-treated group, respectively) were significantly increased in the DG of the mice treated with 200 mg/kg of G. littoralis extract. G. littoralis extract promots cell proliferation, neuroblast differentiation, and neuronal maturation in the hippocampal DG, and neurogenic effects might be closely related to increases of BDNF and TrkB proteins by G. littoralis extract treatment.

  3. Deficits in synaptic function occur at medial perforant path-dentate granule cell synapses prior to Schaffer collateral-CA1 pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat Model.

    Science.gov (United States)

    Smith, Lindsey A; McMahon, Lori L

    2018-02-01

    Alzheimer's disease (AD) pathology begins decades prior to onset of clinical symptoms, and the entorhinal cortex and hippocampus are among the first and most extensively impacted brain regions. The TgF344-AD rat model, which more fully recapitulates human AD pathology in an age-dependent manner, is a next generation preclinical rodent model for understanding pathophysiological processes underlying the earliest stages of AD (Cohen et al., 2013). Whether synaptic alterations occur in hippocampus prior to reported learning and memory deficit is not known. Furthermore, it is not known if specific hippocampal synapses are differentially affected by progressing AD pathology, or if synaptic deficits begin to appear at the same age in males and females in this preclinical model. Here, we investigated the time-course of synaptic changes in basal transmission, paired-pulse ratio, as an indirect measure of presynaptic release probability, long-term potentiation (LTP), and dendritic spine density at two hippocampal synapses in male and ovariectomized female TgF344-AD rats and wildtype littermates, prior to reported behavioral deficits. Decreased basal synaptic transmission begins at medial perforant path-dentate granule cell (MPP-DGC) synapses prior to Schaffer-collateral-CA1 (CA3-CA1) synapses, in the absence of a change in paired-pulse ratio (PPR) or dendritic spine density. N-methyl-d-aspartate receptor (NMDAR)-dependent LTP magnitude is unaffected at CA3-CA1 synapses at 6, 9, and 12months of age, but is significantly increased at MPP-DGC synapses in TgF344-AD rats at 6months only. Sex differences were only observed at CA3-CA1 synapses where the decrease in basal transmission occurs at a younger age in males versus females. These are the first studies to define presymptomatic alterations in hippocampal synaptic transmission in the TgF344-AD rat model. The time course of altered synaptic transmission mimics the spread of pathology through hippocampus in human AD and provides

  4. The selective antagonism of P2X7 and P2Y1 receptors prevents synaptic failure and affects cell proliferation induced by oxygen and glucose deprivation in rat dentate gyrus.

    Directory of Open Access Journals (Sweden)

    Giovanna Maraula

    Full Text Available Purinergic P2X and P2Y receptors are broadly expressed on both neurons and glial cells in the central nervous system (CNS, including dentate gyrus (DG. The aim of this research was to determine the synaptic and proliferative response of the DG to severe oxygen and glucose deprivation (OGD in acute rat hippocampal slices and to investigate the contribution of P2X7 and P2Y1 receptor antagonism to recovery of synaptic activity after OGD. Extracellular field excitatory post-synaptic potentials (fEPSPs in granule cells of the DG were recorded from rat hippocampal slices. Nine-min OGD elicited an irreversible loss of fEPSP and was invariably followed by the appearance of anoxic depolarization (AD. Application of MRS2179 (selective antagonist of P2Y1 receptor and BBG (selective antagonist of P2X7 receptor, before and during OGD, prevented AD appearance and allowed a significant recovery of neurotransmission after 9-min OGD. The effects of 9-min OGD on proliferation and maturation of cells localized in the subgranular zone (SGZ of slices prepared from rats treated with 5-Bromo-2'-deoxyuridine (BrdU were investigated. Slices were further incubated with an immature neuron marker, doublecortin (DCX. The number of BrdU+ cells in the SGZ was significantly decreased 6 hours after OGD. This effect was antagonized by BBG, but not by MRS2179. Twenty-four hours after 9-min OGD, the number of BrdU+ cells returned to control values and a significant increase of DCX immunofluorescence was observed. This phenomenon was still evident when BBG, but not MRS2179, was applied during OGD. Furthermore, the P2Y1 antagonist reduced the number of BrdU+ cells at this time. The data demonstrate that P2X7 and P2Y1 activation contributes to early damage induced by OGD in the DG. At later stages after the insult, P2Y1 receptors might play an additional and different role in promoting cell proliferation and maturation in the DG.

  5. Primary iris leiomyoma.

    Science.gov (United States)

    Yeaney, Gabrielle A; Platt, Sean; Singh, Arun D

    Intraocular leiomyomas are uncommon and usually occur in the ciliary body. Primary leiomyoma of the iris is both rare and a difficult diagnosis to make, given melanocytic tumors are more common and may be amelanotic. The somewhat controversial diagnosis of iris leiomyoma requires further confirmation by immunohistochemistry and electron microscopy. Herein, we describe a 58-year-old man with a 2-mm round translucent pink lesion of the iris. The tumor was excised by sector iridectomy. Immunohistochemistry showed positivity for both smooth muscle actin and desmin and negativity for S-100, HMB45, SOX10, MelanA, CD31, CD34, and h-caldesmon. Epstein-Barr virus-associated smooth muscle tumor was excluded by chromogenic in situ hybridization-Epstein-Barr virus-encoded RNA. Ultrastructural analysis showed cytoplasmic myofilaments with focal fusiform densities and micropinocytotic vesicles. Our review of previous literature confirmed the unusual nature of this tumor. Primary iris leiomyoma should be considered in the differential of an amelanotic S-100-immunonegative iris tumor. Copyright © 2016 Elsevier Inc. All rights reserved.

  6. Imaging in primary osteosarcomas

    International Nuclear Information System (INIS)

    Davies, A.M.

    1998-01-01

    Osteosarcoma is the most common primary malignant bone tumour with the exception of myeloma. The majority of osteosarcoma cases arise within bone and are called conventional osteosarcoma. Intraosseous variants include telangiectatic, small-cell, low-grade intraosseous and cortical osteosarcoma. Less than 10% of osteosarcomas arise on the surface of bone and are subdivided into periosteal, high-grade surface and parosteal varieties. The imaging features of these subtypes of osteosarcoma are described and the impact on diagnosis highlighted. Using material from over 750 osteosarcomas treated at the author's centre, this article reviews the role of imaging in the management of this condition. Detection still relies principally on the conventional radiograph with bone scintigraphy and MR imaging useful in occult tumours. Establishing the radiological diagnosis depends on careful analysis of the radiographs, with particular attention paid to the nature and extent of bone destruction, periosteal new bone formation and matrix mineralization. The prudent radiologist will be wary of those bone conditions, such as stress fractures and osteomyelitis, which are frequently mistaken for osteosarcoma. Appropriate surgical staging requires MR imaging of the primary tumour to show the bony and soft tissue extent of the lesion and to confirm/exclude skip metastases and local lymph-node involvement. Staging should also include bone scintigraphy to confirm/exclude multiple lesions and chest CT to confirm/exclude pulmonary metastases. Following definitive surgery, imaging is used in the follow-up to monitor potential local recurrence and the development of pulmonary or osseous metastases. (orig.) [de

  7. [Normocalcemic primary hyperparathyroidism].

    Science.gov (United States)

    Spivacow, Francisco R; Sapag Durán, Ana; Zanchetta, María B

    2014-01-01

    This report shows our conclusions on the clinical, biochemical and densitometry characteristics of 35 normocalcemic primary hyperparathyroidism (PHPT) patients. This condition is defined by a high level of intact parathyroid hormone (iPTHI) with persistently normal serum and ionized calcium in the absence of secondary hyperparathyroidism. Our selection consisted of 30 women (90%) and 5 men (10%). The control group of 55 hypercalcemic patients with primary hyperparathyroidism included 51 women (93%) and 4 men (7%). The average age at diagnosis of normocalcemic PHPT was 61.4 ± 11.7 years and 56.4 ± 11.3 years in hypercalcemic PHPT. Besides the expected differences in serum calcium, ionized calcium, phosphorus and 24 h urinary calcium, we found no significant changes in other biochemical variables, and no differences in densitometry evaluations such as the presence of osteopenia or osteoporosis and the number of fractures in the two types of PHPT. But there was a significant difference in the presence of renal lithiasis between normocalcemic PHPT (11.4%) and clasic PHPT (49.1%) p < 0.0005, to some extent associated to the presence of hypercalciuria in classic PHPT. Two of the 35 patients with normocalcemic PHPT became classic hypercalcemic PHPT over a 4 year follow-up period. Our findings support the hypothesis that the normocalcemic PHPT could be an early stage of the classic PHPT, both having similar clinical effects to metabolic renal and bone levels.

  8. Asymptomatic Primary Hyperparathyroidism

    Science.gov (United States)

    Silverberg, Shonni J.; Walker, Marcella D.; Bilezikian, John P.

    2014-01-01

    The clinical profile of primary hyperparathyroidism (PHPT) as it is seen in the United States and most Western countries has evolved significantly over the past half century. The introduction of the multichannel serum autoanalyzer in the 1970s led to the recognition of a cohort of individuals with asymptomatic hypercalcemia, in whom evaluation led to the diagnosis of PHPT. The term “asymptomatic primary hyperparathyroidism” was introduced to describe patients who lack obvious signs and symptoms referable to either excess calcium or parathyroid hormone. Although it was expected that asymptomatic patients would eventually develop classical symptoms of PHPT, observational data suggest that most patients do not evolve over time to become overtly symptomatic. In most parts of the world, the asymptomatic phenotype of PHPT has replaced classical PHPT. This report is a selective review of data on asymptomatic PHPT: its demographic features, presentation and natural history, as well as biochemical, skeletal, neuromuscular, psychological, and cardiovascular manifestations. In addition, we will summarize available information on treatment indications and options for those with asymptomatic disease. PMID:23374736

  9. COMMUNITY MEDICINE & PRIMARY HEALTH CARE

    African Journals Online (AJOL)

    Journal of Community Medicine and Primary Health Care. ... Ladoke Akintola University of Technology, PMB 4400, Osogbo, Osun State. ... weak management and poor adherence to the basic infrastructure e.g. primary, secondary and tertiary.

  10. Bezafibrate for primary biliary cirrhosis

    DEFF Research Database (Denmark)

    Rudic, Jelena S; Poropat, Goran; Krstic, Miodrag N

    2012-01-01

    Treatment of primary biliary cirrhosis is complicated. There are studies suggesting that bezafibrate, alone or in combination with ursodeoxycholic acid (UDCA), is effective in the treatment of primary biliary cirrhosis, but no systematic review has summarised the evidence yet....

  11. BR-5 primary circuit decontamination

    International Nuclear Information System (INIS)

    Efimov, I.A.; Nikulin, M.P.; Smirnov-Averin, A.P.; Tymosh, B.S.; Shereshkov, V.S.

    1976-01-01

    Results and methodology of steam-water and acid decontamination of the primary coolant circuit SBR-5 reactor in 1971 are discussed. Regeneration process in a cold trap of the primary coolant circuit is discussed

  12. Primary Prevention With Statins

    DEFF Research Database (Denmark)

    Mortensen, Martin B; Afzal, Shoaib; Nordestgaard, Børge G

    2015-01-01

    BACKGROUND: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility. OBJECTIVES: This study...... the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin......-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC...

  13. Primary care guidelines

    DEFF Research Database (Denmark)

    Ijäs, Jarja; Alanen, Seija; Kaila, Minna

    2009-01-01

    OBJECTIVE: To describe the adoption of the national Hypertension Guideline in primary care and to evaluate the co