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Sample records for dysbindin regulates hippocampal

  1. Correlated alterations in serotonergic and dopaminergic modulations at the hippocampal mossy fiber synapse in mice lacking dysbindin.

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    Katsunori Kobayashi

    Full Text Available Dysbindin-1 (dystrobrevin-binding protein 1, DTNBP1 is one of the promising schizophrenia susceptibility genes. Dysbindin protein is abundantly expressed in synaptic regions of the hippocampus, including the terminal field of the mossy fibers, and this hippocampal expression of dysbindin is strongly reduced in patients with schizophrenia. In the present study, we examined the functional role of dysbindin in hippocampal mossy fiber-CA3 synaptic transmission and its modulation using the sandy mouse, a spontaneous mutant with deletion in the dysbindin gene. Electrophysiological recordings were made in hippocampal slices prepared from adult male sandy mice and their wild-type littermates. Basic properties of the mossy fiber synaptic transmission in the mutant mice were generally normal except for slightly reduced frequency facilitation. Serotonin and dopamine, two major neuromodulators implicated in the pathophysiology of schizophrenia, can potentiate mossy fiber synaptic transmission probably via an increase in cAMP levels. Synaptic potentiation induced by serotonin and dopamine was very variable in magnitude in the mutant mice, with some mice showing prominent enhancement as compared with the wild-type mice. In addition, the magnitude of potentiation induced by these monoamines significantly correlated with each other in the mutant mice, indicating that a subpopulation of sandy mice has marked hypersensitivity to both serotonin and dopamine. While direct activation of the cAMP cascade by forskolin induced robust synaptic potentiation in both wild-type and mutant mice, this forskolin-induced potentaition correlated in magnitude with the serotonin-induced potentiation only in the mutant mice, suggesting a possible change in coupling of receptor activation to downstream signaling. These results suggest that the dysbindin deficiency could be an essential genetic factor that causes synaptic hypersensitivity to dopamine and serotonin. The altered

  2. MeCP2 regulates the synaptic expression of a Dysbindin-BLOC-1 network component in mouse brain and human induced pluripotent stem cell-derived neurons.

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    Jennifer Larimore

    Full Text Available Clinical, epidemiological, and genetic evidence suggest overlapping pathogenic mechanisms between autism spectrum disorder (ASD and schizophrenia. We tested this hypothesis by asking if mutations in the ASD gene MECP2 which cause Rett syndrome affect the expression of genes encoding the schizophrenia risk factor dysbindin, a subunit of the biogenesis of lysosome-related organelles complex-1 (BLOC-1, and associated interacting proteins. We measured mRNA and protein levels of key components of a dysbindin interaction network by, quantitative real time PCR and quantitative immunohistochemistry in hippocampal samples of wild-type and Mecp2 mutant mice. In addition, we confirmed results by performing immunohistochemistry of normal human hippocampus and quantitative qRT-PCR of human inducible pluripotent stem cells (iPSCs-derived human neurons from Rett syndrome patients. We defined the distribution of the BLOC-1 subunit pallidin in human and mouse hippocampus and contrasted this distribution with that of symptomatic Mecp2 mutant mice. Neurons from mutant mice and Rett syndrome patients displayed selectively reduced levels of pallidin transcript. Pallidin immunoreactivity decreased in the hippocampus of symptomatic Mecp2 mutant mice, a feature most prominent at asymmetric synapses as determined by immunoelectron microcopy. Pallidin immunoreactivity decreased concomitantly with reduced BDNF content in the hippocampus of Mecp2 mice. Similarly, BDNF content was reduced in the hippocampus of BLOC-1 deficient mice suggesting that genetic defects in BLOC-1 are upstream of the BDNF phenotype in Mecp2 deficient mice. Our results demonstrate that the ASD-related gene Mecp2 regulates the expression of components belonging to the dysbindin interactome and these molecular differences may contribute to synaptic phenotypes that characterize Mecp2 deficiencies and ASD.

  3. Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice.

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    Sanjeev K Bhardwaj

    2015-03-01

    Full Text Available The expression of dysbindin-1, a protein coded by the risk gene dtnbp1, is reduced in the brains of schizophrenia patients. Evidence indicates a role of dysbindin-1 in dopaminergic and glutamatergic transmission. Glutamatergic transmission and plasticity at excitatory synapses is critically regulated by G-protein coupled metabotropic glutamate receptor (mGluR family members, that have been implicated in schizophrenia. Here, we report a role of dysbindin-1 in hippocampal group 1 mGluR (mGluRI function in mice. In hippocampal synaptoneurosomal preparations from sandy (sdy mice, that have a loss of function mutation in dysbindin-1 gene, we observed a striking reduction in mGluRI agonist [(S-3,5-dihydroxyphenylglycine] (DHPG-induced phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2. This mGluR-ERK1/2 deficit occurred in the absence of significant changes in protein levels of the two members of the mGluRI family (i.e., mGluR1 and mGluR5 or in another mGluRI signaling pathway, i.e., protein kinase C (PKC. Aberrant mGluRI-ERK1/2 signaling affected hippocampal synaptic plasticity in the sdy mutants as DHPG-induced long-term depression (LTD at CA1 excitatory synapses was significantly reduced. Behavioral data suggest that the mGluRI hypofunction may underlie some of the cognitive abnormalities described in sdy mice as the administration of CDPPB (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl benzamide, a positive allosteric modulator of mGluR5, rescued short-term object recognition and spatial learning and memory deficits in these mice. Taken together, our data suggest a novel role of dysbindin-1 in regulating mGluRI functions.

  4. Oxidative stress reduces levels of dysbindin-1A via its PEST domain.

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    Yap, Mei-Yi Alicia; Lo, Yew-Long; Talbot, Konrad; Ong, Wei-Yi

    2014-12-01

    Oxidative stress resulting from the generation of reactive oxygen species has been proposed as an etiological factor in schizophrenia. The present study tests the hypothesis that oxidative stress can affect levels of dysbindin-1A, encoded by Dtnbp1, a genetic risk factor for schizophrenia, via its PEST domain. In vitro studies on SH-SY5Y cells indicate that oxidative stress triggers proteasomal degradation of dysbindin-1A, and that this requires interactions with its PEST domain, which may be a TRIM32 target. We specifically found (a) that oxidative stress induced in SH-SY5Y cells by 500 µM hydrogen peroxide reduced levels of full-length dysbindin-1, but did not reduce levels of that protein lacking its PEST domain and (b) that levels of full-length dysbindin-1, but not dysbindin-1 lacking its PEST domain, were higher in cells treated with the proteasome inhibitor MG132. Oxidative stress thus emerges as the first known cellular factor regulating dysbindin-1 isoforms with PEST domains. These findings are consistent with the previously noted fact that phosphorylation of PEST domains often marks proteins for proteasomal degradation, and raises the possibility that treatments reducing oxidative stress in the brain, especially during development, may lower schizophrenia risk.

  5. Dysbindin-Containing Complexes and their Proposed Functions in Brain: From Zero to (too Many in a Decade

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    Cristina A Ghiani

    2011-04-01

    Full Text Available Dysbindin (also known as dysbindin–1 or dystrobrevin-binding protein 1 was identified 10 years ago as a ubiquitously expressed protein of unknown function. In the following years, the protein and its encoding gene, DTNBP1, have become the focus of intensive research owing to genetic and histopathological evidence suggesting a potential role in the pathogenesis of schizophrenia. In this review, we discuss published results demonstrating that dysbindin function is required for normal physiology of the mammalian central nervous system. In tissues other than brain and in non-neuronal cell types, the protein has been characterized as a stable component of a multi-subunit complex, named BLOC–1 (biogenesis of lysosome-related organelles complex–1, which has been implicated in intracellular protein trafficking and the biogenesis of specialized organelles of the endosomal–lysosomal system. In the brain, however, dysbindin has been proposed to associate into multiple complexes with alternative binding partners, and to play a surprisingly wide variety of functions including transcriptional regulation, neurite and dendritic spine formation, synaptic vesicle biogenesis and exocytosis, and trafficking of glutamate and dopamine receptors. This puzzling array of molecular and functional properties ascribed to the dysbindin protein from brain underscores the need of further research aimed at ascertaining its biological significance in health and disease.

  6. Wnt signaling in the regulation of adult hippocampal neurogenesis

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    Lorena eVarela-Nallar

    2013-06-01

    Full Text Available In the adult brain new neurons are continuously generated mainly in two regions, the subventricular zone of the lateral ventricles and the subgranular zone (SGZ in the hippocampal dentate gyrus. In the SGZ, radial neural stem cells give rise to granule cells that integrate into the hippocampal circuitry and are relevant for the plasticity of the hippocampus. Loss of neurogenesis impairs learning and memory, suggesting that this process is important for adult hippocampal function. Adult neurogenesis is tightly regulated by multiple signaling pathways, including the canonical Wnt/beta-catenin pathway. This pathway plays important roles during the development of neuronal circuits and in the adult brain it modulates synaptic transmission and plasticity. Here, we review current knowledge on the regulation of adult hippocampal neurogenesis by the Wnt/beta-catenin signaling cascade and the potential mechanisms involved in this regulation. Also we discuss the evidence supporting that the canonical Wnt pathway is part of the signaling mechanisms involved in the regulation of neurogenesis in different physiological conditions. Finally, some unsolved questions regarding the Wnt-mediated regulation of neurogenesis are discussed.

  7. Wnt signaling in the regulation of adult hippocampal neurogenesis

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    Varela-Nallar, Lorena; Inestrosa, Nibaldo C.

    2013-01-01

    In the adult brain new neurons are continuously generated mainly in two regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) in the hippocampal dentate gyrus. In the SGZ, radial neural stem cells (NSCs) give rise to granule cells that integrate into the hippocampal circuitry and are relevant for the plasticity of the hippocampus. Loss of neurogenesis impairs learning and memory, suggesting that this process is important for adult hippocampal function. Adult neurogenesis is tightly regulated by multiple signaling pathways, including the canonical Wnt/β-catenin pathway. This pathway plays important roles during the development of neuronal circuits and in the adult brain it modulates synaptic transmission and plasticity. Here, we review current knowledge on the regulation of adult hippocampal neurogenesis by the Wnt/β-catenin signaling cascade and the potential mechanisms involved in this regulation. Also we discuss the evidence supporting that the canonical Wnt pathway is part of the signaling mechanisms involved in the regulation of neurogenesis in different physiological conditions. Finally, some unsolved questions regarding the Wnt-mediated regulation of neurogenesis are discussed. PMID:23805076

  8. Dendrosomatic Sonic Hedgehog Signaling in Hippocampal Neurons Regulates Axon Elongation

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    Petralia, Ronald S.; Ott, Carolyn; Wang, Ya-Xian; Lippincott-Schwartz, Jennifer; Mattson, Mark P.

    2015-01-01

    The presence of Sonic Hedgehog (Shh) and its signaling components in the neurons of the hippocampus raises a question about what role the Shh signaling pathway may play in these neurons. We show here that activation of the Shh signaling pathway stimulates axon elongation in rat hippocampal neurons. This Shh-induced effect depends on the pathway transducer Smoothened (Smo) and the transcription factor Gli1. The axon itself does not respond directly to Shh; instead, the Shh signal transduction originates from the somatodendritic region of the neurons and occurs in neurons with and without detectable primary cilia. Upon Shh stimulation, Smo localization to dendrites increases significantly. Shh pathway activation results in increased levels of profilin1 (Pfn1), an actin-binding protein. Mutations in Pfn1's actin-binding sites or reduction of Pfn1 eliminate the Shh-induced axon elongation. These findings indicate that Shh can regulate axon growth, which may be critical for development of hippocampal neurons. SIGNIFICANCE STATEMENT Although numerous signaling mechanisms have been identified that act directly on axons to regulate their outgrowth, it is not known whether signals transduced in dendrites may also affect axon outgrowth. We describe here a transcellular signaling pathway in embryonic hippocampal neurons in which activation of Sonic Hedgehog (Shh) receptors in dendrites stimulates axon growth. The pathway involves the dendritic-membrane-associated Shh signal transducer Smoothened (Smo) and the transcription factor Gli, which induces the expression of the gene encoding the actin-binding protein profilin 1. Our findings suggest scenarios in which stimulation of Shh in dendrites results in accelerated outgrowth of the axon, which therefore reaches its presumptive postsynaptic target cell more quickly. By this mechanism, Shh may play critical roles in the development of hippocampal neuronal circuits. PMID:26658865

  9. Dysbindin Deficiency Modifies the Expression of GABA Neuron and Ion Permeation Transcripts in the Developing Hippocampus

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    Larimore, Jennifer; Zlatic, Stephanie A.; Arnold, Miranda; Singleton, Kaela S.; Cross, Rebecca; Rudolph, Hannah; Bruegge, Martha V.; Sweetman, Andrea; Garza, Cecilia; Whisnant, Eli; Faundez, Victor

    2017-01-01

    The neurodevelopmental factor dysbindin is required for synapse function and GABA interneuron development. Dysbindin protein levels are reduced in the hippocampus of schizophrenia patients. Mouse dysbindin genetic defects and other mouse models of neurodevelopmental disorders share defective GABAergic neurotransmission and, in several instances, a loss of parvalbumin-positive interneuron phenotypes. This suggests that mechanisms downstream of dysbindin deficiency, such as those affecting GABA interneurons, could inform pathways contributing to or ameliorating diverse neurodevelopmental disorders. Here we define the transcriptome of developing wild type and dysbindin null Bloc1s8sdy/sdy mouse hippocampus in order to identify mechanisms downstream dysbindin defects. The dysbindin mutant transcriptome revealed previously reported GABA parvalbumin interneuron defects. However, the Bloc1s8sdy/sdy transcriptome additionally uncovered changes in the expression of molecules controlling cellular excitability such as the cation-chloride cotransporters NKCC1, KCC2, and NCKX2 as well as the potassium channel subunits Kcne2 and Kcnj13. Our results suggest that dysbindin deficiency phenotypes, such as GABAergic defects, are modulated by the expression of molecules controlling the magnitude and cadence of neuronal excitability.

  10. Propagation of dysbindin-1B aggregates: exosome-mediated transmission of neurotoxic deposits.

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    Zhu, C-Y; Shen, Y; Xu, Q

    2015-04-16

    Given the detection of aggregated deposits in chronic mental diseases (CMD), the disturbance of proteostasis in those diseases is receiving increasing attention. The study of aggregated proteins can contribute to our understanding of the chronic and progressive condition of such diseases. Dysbindin, encoded by the schizophrenia susceptibility gene DTNBP1, has been reported to co-aggregate with DISC1. However, there has been no evidence to date on the aggregation tendency of dysbindin. Therefore, we investigated the isoform-specific aggregation of dysbindin. We found that dysbindin-1B aggregated into cell-invasive deposits in mice. Because of the efficient propagation of dysbindin-1B, we further studied the mechanism of propagation and identified it as exosome-mediated transmission of the aggregates. In addition, aggregates of dysbindin-1B were toxic. Through exosome-mediated propagation, the deposits of dysbindin-1B exerted toxic effects on recipient neurons a long distance away from the initial aggregation site in mice brain. The rapid long distance propagation of neurotoxic deposits of dysbindin-1B in affected neuronal circuitry indicates a possible mechanism for the progressive deterioration of neurons and cognitive function in CMD.

  11. Kinase/phosphatase overexpression reveals pathways regulating hippocampal neuron morphology.

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    Buchser, William J; Slepak, Tatiana I; Gutierrez-Arenas, Omar; Bixby, John L; Lemmon, Vance P

    2010-07-01

    Development and regeneration of the nervous system requires the precise formation of axons and dendrites. Kinases and phosphatases are pervasive regulators of cellular function and have been implicated in controlling axodendritic development and regeneration. We undertook a gain-of-function analysis to determine the functions of kinases and phosphatases in the regulation of neuron morphology. Over 300 kinases and 124 esterases and phosphatases were studied by high-content analysis of rat hippocampal neurons. Proteins previously implicated in neurite growth, such as ERK1, GSK3, EphA8, FGFR, PI3K, PKC, p38, and PP1a, were confirmed to have effects in our functional assays. We also identified novel positive and negative neurite growth regulators. These include neuronal-developmentally regulated kinases such as the activin receptor, interferon regulatory factor 6 (IRF6) and neural leucine-rich repeat 1 (LRRN1). The protein kinase N2 (PKN2) and choline kinase alpha (CHKA) kinases, and the phosphatases PPEF2 and SMPD1, have little or no established functions in neuronal function, but were sufficient to promote neurite growth. In addition, pathway analysis revealed that members of signaling pathways involved in cancer progression and axis formation enhanced neurite outgrowth, whereas cytokine-related pathways significantly inhibited neurite formation.

  12. Pannexin 1 regulates bidirectional hippocampal synaptic plasticity in adult mice

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    Ardiles, Alvaro O.; Flores-Muñoz, Carolina; Toro-Ayala, Gabriela; Cárdenas, Ana M.; Palacios, Adrian G.; Muñoz, Pablo; Fuenzalida, Marco; Sáez, Juan C.; Martínez, Agustín D.

    2014-01-01

    The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory. PMID:25360084

  13. Regulation of hippocampal synaptic strength by glial xCT.

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    Williams, Leena E; Featherstone, David E

    2014-11-26

    Most extracellular glutamate in the brain is released by xCT, a glial antiporter that exports glutamate and imports cystine. The function of xCT, and extracellular glutamate in general, remains unclear. Several lines of evidence suggest that glutamate from xCT could act in a paracrine fashion to suppress glutamatergic synapse strength by triggering removal of postsynaptic glutamate receptors. To test this idea, we used whole-cell patch-clamp electrophysiology and immunohistochemistry to quantify receptor number and synapse function in xCT knock-out mouse hippocampal CA3-CA1 synapses. Consistent with the hypothesis that xCT suppresses glutamate receptor number and synapse strength, xCT knock-out synapses showed increased AMPA receptor abundance with concomitant large enhancements of spontaneous and evoked synaptic transmission. We saw no evidence for changes in GABA receptor abundance or the overall number of glutamatergic synapses. The xCT knock-out phenotype was replicated by incubating slices in the xCT inhibitor (S)-4-carboxyphenylglycine, and consistent with the idea that xCT works by regulating extracellular glutamate, the xCT knock-out phenotype could be reproduced in controls by incubating the slices in glutamate-free aCSF. We conclude that glutamate secreted via xCT suppresses glutamatergic synapse strength by triggering removal of postsynaptic AMPA receptors.

  14. Pannexin 1 Regulates Bidirectional Hippocampal Synaptic Plasticity in Adult Mice

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    Alvaro O. Ardiles

    2014-10-01

    Full Text Available The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca2+ concentration and NMDA receptor (NMDAR composition of GluN2 subunits. Pannexin 1 (Panx1, a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP, it remains unknown whether these channels also modulate long-term depression (LTD or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

  15. Sex hormones and adult hippocampal neurogenesis: Regulation, implications, and potential mechanisms.

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    Mahmoud, Rand; Wainwright, Steven R; Galea, Liisa A M

    2016-04-01

    Neurogenesis within the adult hippocampus is modulated by endogenous and exogenous factors. Here, we review the role of sex hormones in the regulation of adult hippocampal neurogenesis in males and females. The review is framed around the potential functional implications of sex hormone regulation of adult hippocampal neurogenesis, with a focus on cognitive function and mood regulation, which may be related to sex differences in incidence and severity of dementia and depression. We present findings from preclinical studies of endogenous fluctuations in sex hormones relating to reproductive function and ageing, and from studies of exogenous hormone manipulations. In addition, we discuss the modulating roles of sex, age, and reproductive history on the relationship between sex hormones and neurogenesis. Because sex hormones have diverse targets in the central nervous system, we overview potential mechanisms through which sex hormones may influence hippocampal neurogenesis. Lastly, we advocate for a more systematic consideration of sex and sex hormones in studying the functional implications of adult hippocampal neurogenesis.

  16. Vitamin A status regulates glucocorticoid availability in Wistar rats: consequences on cognitive functions and hippocampal neurogenesis ?

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    Damien eBonhomme

    2014-02-01

    Full Text Available A disruption of the vitamin A signaling pathway has been involved in age-related memory decline and hippocampal plasticity alterations. Using vitamin A deficiency (VAD, a nutritional model leading to a hyposignaling of the retinoid pathway, we have recently demonstrated that retinoic acid (RA, the active metabolite of vitamin A, is efficient to reverse VAD-induced spatial memory deficits and adult hippocampal neurogenesis alterations. Besides, excess of glucocorticoids (GCs occurring with aging is known to strongly inhibit hippocampal plasticity and functions and few studies report on the counteracting effects of RA signaling pathway on GCs action. Here, we have addressed whether the modulation of brain GCs availability could be one of the biological mechanisms involved in the effects of vitamin A status on hippocampal plasticity and functions. Thus, we have studied the effects of a vitamin A-free diet for 14 weeks and a 4-week vitamin A supplementation on plasma and hippocampal corticosterone (CORT levels in Wistar rats. We have also investigated corticosteroid binding globulin (CBG binding capacity and 11beta-Hydrosteroid Dehydrogenase type 1 (11β-HSD1 activity, both important modulators of CORT availability at the peripheral and hippocampal levels respectively. Interestingly, we show that the vitamin A status regulates levels of free plasma CORT and hippocampal CORT levels, by acting through a regulation of CBG binding capacity and 11β-HSD1 activity. Moreover, our results suggest that increased CORT levels in VAD rats could have some deleterious consequences on spatial memory, anxiety-like behavior and adult hippocampal neurogenesis whereas these effects could be corrected by a vitamin A supplementation. Thus, the modulation of GCs availability by vitamin A status is an important biological mechanism that should be taken into account in order to prevent age-related cognitive decline and hippocampal plasticity alterations.

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

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    Pearson-Leary, Jiah; McNay, Ewan C

    2016-11-23

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

  18. GABAergic stimulation regulates the phenotype of hippocampal interneurons through the regulation of brain-derived neurotrophic factor.

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    Marty, S; Berninger, B; Carroll, P; Thoenen, H

    1996-03-01

    Gamma-Aminobutyric acid (GABA) switches from enhancing to repressing brain-derived neurotrophic factor (BDNF) mRNA synthesis during the maturation of hippocampal neurons in vitro. Interneurons do not produce BDNF themselves, but BDNF enhances their differentiation. Therefore, the question arose whether hippocampal interneurons regulate their phenotype by regulating BDNF expression and release from adjacent cells. The GABA(A) receptor agonist muscimol and BDNF increased the size and neuropeptide Y (NPY) immunoreactivity of hippocampal interneurons. However, GABAergic stimulation failed to increase NPY immunoreactivity in cultures from BDNF knockout embryos. At later developmental stages, when GABA represses BDNF synthesis, treatment with muscimol induced a decrease in cell size and NPY immunoreactivity of interneurons. Interneurons might thus control their phenotype through the regulation of BDNF synthesis in, and release from, their target neurons.

  19. SIRT1 regulates dendritic development in hippocampal neurons.

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    Juan F Codocedo

    Full Text Available Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway.

  20. SIRT1 Regulates Dendritic Development in Hippocampal Neurons

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    Godoy, Juan A.; Varela-Nallar, Lorena; Inestrosa, Nibaldo C.

    2012-01-01

    Dendritic arborization is required for proper neuronal connectivity. SIRT1, a NAD+ dependent histone deacetylase, has been associated to ageing and longevity, which in neurons is linked to neuronal differentiation and neuroprotection. In the present study, the role of SIRT1 in dendritic development was evaluated in cultured hippocampal neurons which were transfected at 3 days in vitro with a construct coding for SIRT1 or for the dominant negative SIRT1H363Y, which lacks the catalytic activity. Neurons overexpressing SIRT1 showed an increased dendritic arborization, while neurons overexpressing SIRT1H363Y showed a reduction in dendritic arbor complexity. The effect of SIRT1 was mimicked by treatment with resveratrol, a well known activator of SIRT1, which has no effect in neurons overexpressing SIRT1H363Y indicating that the effect of resveratrol was specifically mediated by SIRT1. Moreover, hippocampal neurons overexpressing SIRT1 were resistant to dendritic dystrophy induced by Aβ aggregates, an effect that was dependent on the deacetylase activity of SIRT1. Our findings indicate that SIRT1 plays a role in the development and maintenance of dendritic branching in hippocampal neurons, and suggest that these effects are mediated by the ROCK signaling pathway. PMID:23056585

  1. Neuronal Splicing Regulator RBFOX3 (NeuN) Regulates Adult Hippocampal Neurogenesis and Synaptogenesis

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    Lin, Meng-Ying; Chou, Chih-Hsuan; Wu, I-Ju; Huang, Guo-Jen; Gau, Susan Shur-Fen

    2016-01-01

    Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3. PMID:27701470

  2. Mutations in the BLOC-1 Subunits Dysbindin and Muted Generate Divergent and Dosage-dependent Phenotypes*

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    Larimore, Jennifer; Zlatic, Stephanie A.; Gokhale, Avanti; Tornieri, Karine; Singleton, Kaela S.; Mullin, Ariana P.; Tang, Junxia; Talbot, Konrad; Faundez, Victor

    2014-01-01

    Post-mortem analysis has revealed reduced levels of the protein dysbindin in the brains of those suffering from the neurodevelopmental disorder schizophrenia. Consequently, mechanisms controlling the cellular levels of dysbindin and its interacting partners may participate in neurodevelopmental processes impaired in that disorder. To address this question, we studied loss of function mutations in the genes encoding dysbindin and its interacting BLOC-1 subunits. We focused on BLOC-1 mutants affecting synapse composition and function in addition to their established systemic pigmentation, hematological, and lung phenotypes. We tested phenotypic homogeneity and gene dosage effects in the mouse null alleles muted (Bloc1s5mu/mu) and dysbindin (Bloc1s8sdy/sdy). Transcripts of NMDA receptor subunits and GABAergic interneuron markers, as well as expression of BLOC-1 subunit gene products, were affected differently in the brains of Bloc1s5mu/mu and Bloc1s8sdy/sdy mice. Unlike Bloc1s8sdy/sdy, elimination of one or two copies of Bloc1s5 generated indistinguishable pallidin transcript phenotypes. We conclude that monogenic mutations abrogating the expression of a protein complex subunit differentially affect the expression of other complex transcripts and polypeptides as well as their downstream effectors. We propose that the genetic disruption of different subunits of protein complexes and combinations thereof diversifies phenotypic presentation of pathway deficiencies, contributing to the wide phenotypic spectrum and complexity of neurodevelopmental disorders. PMID:24713699

  3. Factors Regulating the Effects of Hippocampal Inactivation on Renewal of Conditional Fear after Extinction

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    Corcoran, Kevin A.; Maren, Stephen

    2004-01-01

    After extinction of fear to a Pavlovian conditional stimulus (CS), contextual stimuli come to regulate the expression of fear to that CS. There is growing evidence that the context dependence of memory retrieval after extinction involves the hippocampus. In the present experiment, we examine whether hippocampal involvement in memory retrieval…

  4. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; You-zhi ZHANG; Yan-qin LIU; Heng-lin WANG; Li YUAN; Zhi-pu LUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μmol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  5. Moclobemide up-regulates proliferation of hippocampal progenitor cells in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-fengLI; You-zhiZHANG; Yan-qinLIU; Heng-linWANG; LiYUAN; Zhi-puLUO

    2004-01-01

    AIM: To explore the action mechanism of antidepressants. METHODS: The PC 12 cell proliferation was detected by flow cytometry,. The proliferation of hippocampal progenitor cells and level of brain-derived neurotrophic factor (BDNF) were measured by immunohistochemistry. RESULTS: Treatment with N-methylaspartate (NMDA)600 μmol/L for 3 d significantly decreased the percentage of S-phase in PC12 cells, while in the presence of classical antidepressant, moclobemide (MOC) 2 and 10 μnol/L, the percentage in S-phase increased. Furthermore,the proliferation of progenitor cells in hippocampal dentate gyrus (subgranular zone), as well as the level of BDNF in hippocampus significantly decreased in chronically stressed mice, while chronic administration with MOC 40 mg/kg (ip) up-regulated the progenitor cell proliferation and BDNF level in the same time course. CONLUSION:Up-regulation of the proliferation of hippocampal progenitor cells is one of the action mechanisms for MOC, which may be closely related to the elevation of BDNF level at the same time. These results also extend evidence for our hypothesis that up-regulation of the hippocampal neurogenesis is one of the common mechanisms for antidepressants.

  6. In vitro ischemia triggers a transcriptional response to down-regulate synaptic proteins in hippocampal neurons.

    Directory of Open Access Journals (Sweden)

    Joana Fernandes

    Full Text Available Transient global cerebral ischemia induces profound changes in the transcriptome of brain cells, which is partially associated with the induction or repression of genes that influence the ischemic response. However, the mechanisms responsible for the selective vulnerability of hippocampal neurons to global ischemia remain to be clarified. To identify molecular changes elicited by ischemic insults, we subjected hippocampal primary cultures to oxygen-glucose deprivation (OGD, an in vitro model for global ischemia that resulted in delayed neuronal death with an excitotoxic component. To investigate changes in the transcriptome of hippocampal neurons submitted to OGD, total RNA was extracted at early (7 h and delayed (24 h time points after OGD and used in a whole-genome RNA microarray. We observed that at 7 h after OGD there was a general repression of genes, whereas at 24 h there was a general induction of gene expression. Genes related with functions such as transcription and RNA biosynthesis were highly regulated at both periods of incubation after OGD, confirming that the response to ischemia is a dynamic and coordinated process. Our analysis showed that genes for synaptic proteins, such as those encoding for PICK1, GRIP1, TARPγ3, calsyntenin-2/3, SAPAP2 and SNAP-25, were down-regulated after OGD. Additionally, OGD decreased the mRNA and protein expression levels of the GluA1 AMPA receptor subunit as well as the GluN2A and GluN2B subunits of NMDA receptors, but increased the mRNA expression of the GluN3A subunit, thus altering the composition of ionotropic glutamate receptors in hippocampal neurons. Together, our results present the expression profile elicited by in vitro ischemia in hippocampal neurons, and indicate that OGD activates a transcriptional program leading to down-regulation in the expression of genes coding for synaptic proteins, suggesting that the synaptic proteome may change after ischemia.

  7. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

    Science.gov (United States)

    Laßek, Melanie; Weingarten, Jens; Wegner, Martin; Mueller, Benjamin F; Rohmer, Marion; Baeumlisberger, Dominic; Arrey, Tabiwang N; Hick, Meike; Ackermann, Jörg; Acker-Palmer, Amparo; Koch, Ina; Müller, Ulrike; Karas, Michael; Volknandt, Walter

    2016-04-01

    The hallmarks of Alzheimer's disease (AD) are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP) has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ) highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs) was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI) networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.

  8. APP Is a Context-Sensitive Regulator of the Hippocampal Presynaptic Active Zone.

    Directory of Open Access Journals (Sweden)

    Melanie Laßek

    2016-04-01

    Full Text Available The hallmarks of Alzheimer's disease (AD are characterized by cognitive decline and behavioral changes. The most prominent brain region affected by the progression of AD is the hippocampal formation. The pathogenesis involves a successive loss of hippocampal neurons accompanied by a decline in learning and memory consolidation mainly attributed to an accumulation of senile plaques. The amyloid precursor protein (APP has been identified as precursor of Aβ-peptides, the main constituents of senile plaques. Until now, little is known about the physiological function of APP within the central nervous system. The allocation of APP to the proteome of the highly dynamic presynaptic active zone (PAZ highlights APP as a yet unknown player in neuronal communication and signaling. In this study, we analyze the impact of APP deletion on the hippocampal PAZ proteome. The native hippocampal PAZ derived from APP mouse mutants (APP-KOs and NexCreAPP/APLP2-cDKOs was isolated by subcellular fractionation and immunopurification. Subsequently, an isobaric labeling was performed using TMT6 for protein identification and quantification by high-resolution mass spectrometry. We combine bioinformatics tools and biochemical approaches to address the proteomics dataset and to understand the role of individual proteins. The impact of APP deletion on the hippocampal PAZ proteome was visualized by creating protein-protein interaction (PPI networks that incorporated APP into the synaptic vesicle cycle, cytoskeletal organization, and calcium-homeostasis. The combination of subcellular fractionation, immunopurification, proteomic analysis, and bioinformatics allowed us to identify APP as structural and functional regulator in a context-sensitive manner within the hippocampal active zone network.

  9. Regulation of GABA Equilibrium Potential by mGluRs in Rat Hippocampal CA1 Neurons.

    Science.gov (United States)

    Yang, Bo; Rajput, Padmesh S; Kumar, Ujendra; Sastry, Bhagavatula R

    2015-01-01

    The equilibrium potential for GABA-A receptor mediated currents (EGABA) in neonatal central neurons is set at a relatively depolarized level, which is suggested to be caused by a low expression of K+/Cl- co-transporter (KCC2) but a relatively high expression of Na+-K+-Cl- cotransporter (NKCC1). Theta-burst stimulation (TBS) in stratum radiatum induces a negative shift in EGABA in juvenile hippocampal CA1 pyramidal neurons. In the current study, the effects of TBS on EGABA in neonatal and juvenile hippocampal CA1 neurons and the underlying mechanisms were examined. Metabotropic glutamate receptors (mGluRs) are suggested to modulate KCC2 and NKCC1 levels in cortical neurons. Therefore, the involvement of mGluRs in the regulation of KCC2 or NKCC1 activity, and thus EGABA, following TBS was also investigated. Whole-cell patch recordings were made from Wistar rat hippocampal CA1 pyramidal neurons, in a slice preparation. In neonates, TBS induces a positive shift in EGABA, which was prevented by NKCC1 antisense but not NKCC1 sense mRNA. (RS)-a-Methyl-4-carboxyphenylglycine (MCPG), a group I and II mGluR antagonist, blocked TBS-induced shifts in both juvenile and neonatal hippocampal neurons. While blockade of mGluR1 or mGluR5 alone could interfere with TBS-induced shifts in EGABA in neonates, only a combined blockade could do the same in juveniles. These results indicate that TBS induces a negative shift in EGABA in juvenile hippocampal neurons but a positive shift in neonatal hippocampal neurons via corresponding changes in KCC2 and NKCC1 expressions, respectively. mGluR activation seems to be necessary for both shifts to occur while the specific receptor subtype involved seems to vary.

  10. Regulation of GABA Equilibrium Potential by mGluRs in Rat Hippocampal CA1 Neurons.

    Directory of Open Access Journals (Sweden)

    Bo Yang

    Full Text Available The equilibrium potential for GABA-A receptor mediated currents (EGABA in neonatal central neurons is set at a relatively depolarized level, which is suggested to be caused by a low expression of K+/Cl- co-transporter (KCC2 but a relatively high expression of Na+-K+-Cl- cotransporter (NKCC1. Theta-burst stimulation (TBS in stratum radiatum induces a negative shift in EGABA in juvenile hippocampal CA1 pyramidal neurons. In the current study, the effects of TBS on EGABA in neonatal and juvenile hippocampal CA1 neurons and the underlying mechanisms were examined. Metabotropic glutamate receptors (mGluRs are suggested to modulate KCC2 and NKCC1 levels in cortical neurons. Therefore, the involvement of mGluRs in the regulation of KCC2 or NKCC1 activity, and thus EGABA, following TBS was also investigated. Whole-cell patch recordings were made from Wistar rat hippocampal CA1 pyramidal neurons, in a slice preparation. In neonates, TBS induces a positive shift in EGABA, which was prevented by NKCC1 antisense but not NKCC1 sense mRNA. (RS-a-Methyl-4-carboxyphenylglycine (MCPG, a group I and II mGluR antagonist, blocked TBS-induced shifts in both juvenile and neonatal hippocampal neurons. While blockade of mGluR1 or mGluR5 alone could interfere with TBS-induced shifts in EGABA in neonates, only a combined blockade could do the same in juveniles. These results indicate that TBS induces a negative shift in EGABA in juvenile hippocampal neurons but a positive shift in neonatal hippocampal neurons via corresponding changes in KCC2 and NKCC1 expressions, respectively. mGluR activation seems to be necessary for both shifts to occur while the specific receptor subtype involved seems to vary.

  11. Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons

    Science.gov (United States)

    Kirby, Elizabeth D.; Friedman, Aaron R.; Covarrubias, David; Ying, Carl; Sun, Wayne G.; Goosens, Ki A.; Sapolsky, Robert M.; Kaufer, Daniela

    2014-01-01

    Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support of emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information impacts newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits. PMID:21670733

  12. Neuronal Activity Regulates Hippocampal miRNA Expression

    NARCIS (Netherlands)

    Eacker, Stephen M.; Keuss, Matthew J.; Berezikov, Eugene; Dawson, Valina L.; Dawson, Ted M.

    2011-01-01

    Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA) represent a re

  13. Developmental regulation of expression of schizophrenia susceptibility genes in the primate hippocampal formation.

    Science.gov (United States)

    Favre, G; Banta Lavenex, P; Lavenex, P

    2012-10-23

    The hippocampal formation is essential for normal memory function and is implicated in many neurodevelopmental, neurodegenerative and neuropsychiatric disorders. In particular, abnormalities in hippocampal structure and function have been identified in schizophrenic subjects. Schizophrenia has a strong polygenic component, but the role of numerous susceptibility genes in normal brain development and function has yet to be investigated. Here we described the expression of schizophrenia susceptibility genes in distinct regions of the monkey hippocampal formation during early postnatal development. We found that, as compared with other genes, schizophrenia susceptibility genes exhibit a differential regulation of expression in the dentate gyrus, CA3 and CA1, over the course of postnatal development. A number of these genes involved in synaptic transmission and dendritic morphology exhibit a developmental decrease of expression in CA3. Abnormal CA3 synaptic organization observed in schizophrenics might be related to some specific symptoms, such as loosening of association. Interestingly, changes in gene expression in CA3 might occur at a time possibly corresponding to the late appearance of the first clinical symptoms. We also found earlier changes in expression of schizophrenia susceptibility genes in CA1, which might be linked to prodromal psychotic symptoms. A number of schizophrenia susceptibility genes including APOE, BDNF, MTHFR and SLC6A4 are involved in other disorders, and thus likely contribute to nonspecific changes in hippocampal structure and function that must be combined with the dysregulation of other genes in order to lead to schizophrenia pathogenesis.

  14. BDNF Up-Regulates α7 Nicotinic Acetylcholine Receptor Levels on Subpopulations of Hippocampal Interneurons

    OpenAIRE

    Massey, Kerri A; Zago, Wagner M.; Berg, Darwin K.

    2006-01-01

    In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing α7 subunits (α7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of α7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the ef...

  15. Neuronal Activity Regulates Hippocampal miRNA Expression

    Science.gov (United States)

    Eacker, Stephen M.; Keuss, Matthew J.; Berezikov, Eugene; Dawson, Valina L.; Dawson, Ted M.

    2011-01-01

    Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA) represent a relatively recently discovered player in the regulation of translation in the nervous system. We have conducted an in depth analysis of how neuronal activity regulates miRNA expression in the hippocampus. Using deep sequencing we exhaustively identify all miRNAs, including 15 novel miRNAs, expressed in hippocampus of the adult mouse. We identified 119 miRNAs documented in miRBase but less than half of these miRNA were expressed at a level greater than 0.1% of total miRNA. Expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression. These results have important implications into how miRNAs influence activity-dependent translational control. PMID:21984899

  16. Neuronal activity regulates hippocampal miRNA expression.

    Directory of Open Access Journals (Sweden)

    Stephen M Eacker

    Full Text Available Neuronal activity regulates a broad range of processes in the hippocampus, including the precise regulation of translation. Disruptions in proper translational control in the nervous system are associated with a variety of disorders that fall in the autistic spectrum. MicroRNA (miRNA represent a relatively recently discovered player in the regulation of translation in the nervous system. We have conducted an in depth analysis of how neuronal activity regulates miRNA expression in the hippocampus. Using deep sequencing we exhaustively identify all miRNAs, including 15 novel miRNAs, expressed in hippocampus of the adult mouse. We identified 119 miRNAs documented in miRBase but less than half of these miRNA were expressed at a level greater than 0.1% of total miRNA. Expression profiling following induction of neuronal activity by electroconvulsive shock demonstrates that most miRNA show a biphasic pattern of expression: rapid induction of specific mature miRNA expression followed by a decline in expression. These results have important implications into how miRNAs influence activity-dependent translational control.

  17. Association study of dysbindin gene with clinical and outcome measures in a representative cohort of Italian schizophrenic patients.

    Science.gov (United States)

    Tosato, Sarah; Ruggeri, Mirella; Bonetto, Chiara; Bertani, Mariaelena; Marrella, Giovanna; Lasalvia, Antonio; Cristofalo, Doriana; Aprili, Giuseppe; Tansella, Michele; Dazzan, Paola; Diforti, Marta; Murray, Robin M; Collier, David A

    2007-07-05

    There is evidence suggesting that Dysbindin (DTNBP1) is a susceptibility gene for schizophrenia in Caucasian, Chinese, and Japanese populations. We sought to determine if dysbindin was associated with schizophrenia and its symptoms in a representative group of schizophrenic patients from a Community-Based Mental Health Service (CMHS) in Verona, Italy. A prevalence cohort of schizophrenic patients (n = 141) was assessed at baseline and then 3 and 6 years later. Eighty patients and 106 healthy controls were genotyped for polymorphisms in dysbindin. We tested if diagnosis, clinical symptoms as measured by the Brief Psychiatric Rating Scale (BPRS), and functioning as measured by the Global Assessment of Functioning Scale (GAF), were associated with the presence of certain dysbindin polymorphisms. Finally, using the longitudinal clinical data, we tested if patients carrying dysbindin high-risk haplotypes had a more unfavorable longitudinal clinical outcome. A trend towards statistical association (P = 0.058) between schizophrenia and rs2619538 was found. Using GENECOUNTING software, we found that rs2619538-P1583 (P = 0.048), P1320-P1757 (P = 0.034), and rs2619538-P1583-P1578 (P = 0.040) haplotypes occurred more often in cases compared to controls before correction for multiple testing. The rs2619538-P1583 haplotype was more likely to be transmitted to subjects with more severe and persistent psychopathology. These preliminary results are compatible with the view that DTNBP1 is a susceptibility factor for schizophrenia, and is associated with worse psychopathology.

  18. NeuroD2 regulates the development of hippocampal mossy fiber synapses

    Directory of Open Access Journals (Sweden)

    Wilke Scott A

    2012-02-01

    Full Text Available Abstract Background The assembly of neural circuits requires the concerted action of both genetically determined and activity-dependent mechanisms. Calcium-regulated transcription may link these processes, but the influence of specific transcription factors on the differentiation of synapse-specific properties is poorly understood. Here we characterize the influence of NeuroD2, a calcium-dependent transcription factor, in regulating the structural and functional maturation of the hippocampal mossy fiber (MF synapse. Results Using NeuroD2 null mice and in vivo lentivirus-mediated gene knockdown, we demonstrate a critical role for NeuroD2 in the formation of CA3 dendritic spines receiving MF inputs. We also use electrophysiological recordings from CA3 neurons while stimulating MF axons to show that NeuroD2 regulates the differentiation of functional properties at the MF synapse. Finally, we find that NeuroD2 regulates PSD95 expression in hippocampal neurons and that PSD95 loss of function in vivo reproduces CA3 neuron spine defects observed in NeuroD2 null mice. Conclusion These experiments identify NeuroD2 as a key transcription factor that regulates the structural and functional differentiation of MF synapses in vivo.

  19. NEURONAL ACTIVITY AND STRESS DIFFERENTIALLY REGULATE HIPPOCAMPAL AND HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE EXPRESSION IN THE IMMATURE RAT

    OpenAIRE

    Hatalski, C G; Brunson, K. L.; TANTAYANUBUTR, B.; Chen, Y.(California Institute of Technology, Pasadena, USA); Baram, T. Z.

    2000-01-01

    Corticotropin-releasing hormone, a major neuromodulator of the neuroendocrine stress response, is expressed in the immature hippocampus, where it enhances glutamate receptor-mediated excitation of principal cells. Since the peptide influences hippocampal synaptic efficacy, its secretion from peptidergic interneuronal terminals may augment hippocampal-mediated functions such as learning and memory. However, whereas information regarding the regulation of corticotropin-releasing hormone’s abund...

  20. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats

    OpenAIRE

    SCHARFMAN, HELEN E.; MacLusky, Neil J.

    2013-01-01

    Many studies have described potent effects of BDNF, 17β-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17β-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17β-estradiol upregulates mossy fiber BDNF synthesis in the adult fem...

  1. A hippocampal Cdk5 pathway regulates extinction of contextual fear

    Science.gov (United States)

    Sananbenesi, Farahnaz; Fischer, Andre; Wang, Xinyu; Schrick, Christina; Neve, Rachael; Radulovic, Jelena; Tsai, Li-Huei

    2008-01-01

    Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders. PMID:17632506

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

    Directory of Open Access Journals (Sweden)

    Chun-Lei Wang

    2012-10-01

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

  3. Dysbindin and d-amino-acid-oxidase gene polymorphisms associated with positive and negative symptoms in schizophrenia

    DEFF Research Database (Denmark)

    Wirgenes, Katrine V; Djurovic, Srdjan; Agartz, Ingrid;

    2009-01-01

    BACKGROUND: Schizophrenia is a genetically complex disorder with an unknown pathophysiology. Several genes implicated in glutamate metabolism have been associated with the disorder. Recent studies of polymorphisms in the dystrobrevin-binding protein 1 gene (DTNBP1; dysbindin) and D......-amino-acid-oxidase (DAO) gene, both involved in glutamate receptor function, reported associations with negative symptoms and with anxiety and depression, respectively, when measured with the Positive and Negative Syndrome Scale (PANSS). METHODS: In the present study, the suggested association between dysbindin and DAO...... single nucleotide polymorphisms (SNPs) and PANSS scores was analyzed in 155 Norwegian schizophrenia patients. RESULTS: There was a significant association between the dysbindin SNP rs3213207 and severity of both negative symptoms and total symptom load, as well as between the DAO SNP rs2070587 and total...

  4. Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11.

    Science.gov (United States)

    Eriksson, T M; Alvarsson, A; Stan, T L; Zhang, X; Hascup, K N; Hascup, E R; Kehr, J; Gerhardt, G A; Warner-Schmidt, J; Arango-Lievano, M; Kaplitt, M G; Ogren, S O; Greengard, P; Svenningsson, P

    2013-10-01

    Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

  5. S-nitrosylation-dependent proteasomal degradation restrains Cdk5 activity to regulate hippocampal synaptic strength.

    Science.gov (United States)

    Zhang, Peng; Fu, Wing-Yu; Fu, Amy K Y; Ip, Nancy Y

    2015-10-27

    Precise regulation of synaptic strength requires coordinated activity and functions of synaptic proteins, which is controlled by a variety of post-translational modification. Here we report that S-nitrosylation of p35, the activator of cyclin-dependent kinase 5 (Cdk5), by nitric oxide (NO) is important for the regulation of excitatory synaptic strength. While blockade of NO signalling results in structural and functional synaptic deficits as indicated by reduced mature dendritic spine density and surface expression of glutamate receptor subunits, phosphorylation of numerous synaptic substrates of Cdk5 and its activity are aberrantly upregulated following reduced NO production. The results show that the NO-induced reduction in Cdk5 activity is mediated by S-nitrosylation of p35, resulting in its ubiquitination and degradation by the E3 ligase PJA2. Silencing p35 protein in hippocampal neurons partially rescues the NO blockade-induced synaptic deficits. These findings collectively demonstrate that p35 S-nitrosylation by NO signalling is critical for regulating hippocampal synaptic strength.

  6. Microbial regulation of hippocampal miRNA expression: Implications for transcription of kynurenine pathway enzymes.

    Science.gov (United States)

    Moloney, Gerard M; O'Leary, Olivia F; Salvo-Romero, Eloisa; Desbonnet, Lieve; Shanahan, Fergus; Dinan, Timothy G; Clarke, Gerard; Cryan, John F

    2017-09-15

    Increasing evidence points to a functional role of the enteric microbiota in brain development, function and behaviour including the regulation of transcriptional activity in the hippocampus. Changes in CNS miRNA expression may reflect the colonisation status of the gut. Given the pivotal impact of miRNAs on gene expression, our study was based on the hypothesis that gene expression would also be altered in the germ-free state in the hippocampus. We measured miRNAs in the hippocampus of Germ free (GF), conventional (C) and Germ free colonised (exGF) Swiss Webster mice. miRNAs were selected for follow up based on significant differences in expression between groups according to sex and colonisation status. The expression of miR-294-5p was increased in male germ free animals and was normalised following colonisation. Targets of the differentially expressed miRNAs were over-represented in the kynurenine pathway. We show that the microbiota modulates the expression of miRNAs associated with kynurenine pathway metabolism and, demonstrate that the gut microbiota regulates the expression of kynurenine pathway genes in the hippocampus. We also show a sex-specific role for the microbiota in the regulation of miR-294-5p expression in the hippocampus. The gut microbiota plays an important role in modulating small RNAs that influence hippocampal gene expression, a process critical to hippocampal development. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Afadin regulates puncta adherentia junction formation and presynaptic differentiation in hippocampal neurons.

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    Daisaku Toyoshima

    Full Text Available The formation and remodeling of mossy fiber-CA3 pyramidal cell synapses in the stratum lucidum of the hippocampus are implicated in the cellular basis of learning and memory. Afadin and its binding cell adhesion molecules, nectin-1 and nectin-3, together with N-cadherin, are concentrated at puncta adherentia junctions (PAJs in these synapses. Here, we investigated the roles of afadin in PAJ formation and presynaptic differentiation in mossy fiber-CA3 pyramidal cell synapses. At these synapses in the mice in which the afadin gene was conditionally inactivated before synaptogenesis by using nestin-Cre mice, the immunofluorescence signals for the PAJ components, nectin-1, nectin-3 and N-cadherin, disappeared almost completely, while those for the presynaptic components, VGLUT1 and bassoon, were markedly decreased. In addition, these signals were significantly decreased in cultured afadin-deficient hippocampal neurons. Furthermore, the interevent interval of miniature excitatory postsynaptic currents was prolonged in the cultured afadin-deficient hippocampal neurons compared with control neurons, indicating that presynaptic functions were suppressed or a number of synapse was reduced in the afadin-deficient neurons. Analyses of presynaptic vesicle recycling and paired recordings revealed that the cultured afadin-deficient neurons showed impaired presynaptic functions. These results indicate that afadin regulates both PAJ formation and presynaptic differentiation in most mossy fiber-CA3 pyramidal cell synapses, while in a considerable population of these neurons, afadin regulates only PAJ formation but not presynaptic differentiation.

  8. miR-17-92 Cluster Regulates Adult Hippocampal Neurogenesis, Anxiety, and Depression

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    Junghee Jin

    2016-08-01

    Full Text Available Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs, contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1. miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors.

  9. RIT1 GTPase Regulates Sox2 Transcriptional Activity and Hippocampal Neurogenesis.

    Science.gov (United States)

    Mir, Sajad; Cai, Weikang; Andres, Douglas A

    2017-02-10

    Adult neurogenesis, the process of generating mature neurons from neuronal progenitor cells, makes critical contributions to neural circuitry and brain function in both healthy and disease states. Neurogenesis is a highly regulated process in which diverse environmental and physiological stimuli are relayed to resident neural stem cell populations to control the transcription of genes involved in self-renewal and differentiation. Understanding the molecular mechanisms governing neurogenesis is necessary for the development of translational strategies to harness this process for neuronal repair. Here we report that the Ras-related GTPase RIT1 serves to control the sequential proliferation and differentiation of adult hippocampal neural progenitor cells, with in vivo expression of active RIT1 driving robust adult neurogenesis. Gene expression profiling analysis demonstrates increased expression of a specific set of transcription factors known to govern adult neurogenesis in response to active RIT1 expression in the hippocampus, including sex-determining region Y-related HMG box 2 (Sox2), a well established regulator of stem cell self-renewal and neurogenesis. In adult hippocampal neuronal precursor cells, RIT1 controls an Akt-dependent signaling cascade, resulting in the stabilization and transcriptional activation of phosphorylated Sox2. This study supports a role for RIT1 in relaying niche-derived signals to neural/stem progenitor cells to control transcription of genes involved in self-renewal and differentiation.

  10. Homeostatic regulation of gephyrin scaffolds and synaptic strength at mature hippocampal GABAergic postsynapses.

    Science.gov (United States)

    Vlachos, Andreas; Reddy-Alla, Suneel; Papadopoulos, Theofilos; Deller, Thomas; Betz, Heinrich

    2013-11-01

    Gephyrin is a scaffolding protein important for the postsynaptic clustering of inhibitory neurotransmitter receptors. Here, we investigated the properties of gephyrin scaffolds at γ-aminobutyric acid- (GABA-)ergic synapses in organotypic entorhino-hippocampal cultures prepared from a transgenic mouse line, which expresses green fluorescent protein-tagged gephyrin under the control of the Thy1.2 promoter. Fluorescence recovery after photobleaching revealed a developmental stabilization of postsynaptic gephyrin clusters concomitant with an increase in cluster size and synaptic strength between 1 and 4 weeks in vitro. Prolonged treatment of the slice cultures with diazepam or a GABAA receptor antagonist disclosed a homeostatic regulation of both inhibitory synaptic strength and gephyrin cluster size and stability in 4-weeks-old cultures, whereas at 1 week in vitro, the same drug treatments modulated GABAergic postsynapse and gephyrin cluster properties following a Hebbian mode of synaptic plasticity. Our data are consistent with a model in which the postnatal maturation of the hippocampal network endows CA1 pyramidal neurons with the ability to homeostatically adjust the strength of their inhibitory postsynapses to afferent GABAergic drive by regulating gephyrin scaffold properties.

  11. Afadin Regulates Puncta Adherentia Junction Formation and Presynaptic Differentiation in Hippocampal Neurons

    Science.gov (United States)

    Toyoshima, Daisaku; Mandai, Kenji; Maruo, Tomohiko; Supriyanto, Irwan; Togashi, Hideru; Inoue, Takahito; Mori, Masahiro; Takai, Yoshimi

    2014-01-01

    The formation and remodeling of mossy fiber-CA3 pyramidal cell synapses in the stratum lucidum of the hippocampus are implicated in the cellular basis of learning and memory. Afadin and its binding cell adhesion molecules, nectin-1 and nectin-3, together with N-cadherin, are concentrated at puncta adherentia junctions (PAJs) in these synapses. Here, we investigated the roles of afadin in PAJ formation and presynaptic differentiation in mossy fiber-CA3 pyramidal cell synapses. At these synapses in the mice in which the afadin gene was conditionally inactivated before synaptogenesis by using nestin-Cre mice, the immunofluorescence signals for the PAJ components, nectin-1, nectin-3 and N-cadherin, disappeared almost completely, while those for the presynaptic components, VGLUT1 and bassoon, were markedly decreased. In addition, these signals were significantly decreased in cultured afadin-deficient hippocampal neurons. Furthermore, the interevent interval of miniature excitatory postsynaptic currents was prolonged in the cultured afadin-deficient hippocampal neurons compared with control neurons, indicating that presynaptic functions were suppressed or a number of synapse was reduced in the afadin-deficient neurons. Analyses of presynaptic vesicle recycling and paired recordings revealed that the cultured afadin-deficient neurons showed impaired presynaptic functions. These results indicate that afadin regulates both PAJ formation and presynaptic differentiation in most mossy fiber-CA3 pyramidal cell synapses, while in a considerable population of these neurons, afadin regulates only PAJ formation but not presynaptic differentiation. PMID:24587018

  12. Shank1 regulates excitatory synaptic transmission in mouse hippocampal parvalbumin-expressing inhibitory interneurons.

    Science.gov (United States)

    Mao, Wenjie; Watanabe, Takuya; Cho, Sukhee; Frost, Jeffrey L; Truong, Tina; Zhao, Xiaohu; Futai, Kensuke

    2015-04-01

    The Shank genes (SHANK1, 2, 3) encode scaffold proteins highly enriched in postsynaptic densities where they regulate synaptic structure in spiny neurons. Mutations in human Shank genes are linked to autism spectrum disorder and schizophrenia. Shank1 mutant mice exhibit intriguing cognitive phenotypes reminiscent of individuals with autism spectrum disorder. However, the molecular mechanisms leading to the human pathophysiological phenotypes and mouse behaviors have not been elucidated. In this study it is shown that Shank1 protein is highly localized in parvalbumin-expressing (PV+) fast-spiking inhibitory interneurons in the hippocampus. Importantly, a lack of Shank1 in hippocampal CA1 PV+ neurons reduced excitatory synaptic inputs and inhibitory synaptic outputs to pyramidal neurons. Furthermore, it is demonstrated that hippocampal CA1 pyramidal neurons in Shank1 mutant mice exhibit a shift in the excitatory and inhibitory balance (E-I balance), a pathophysiological hallmark of autism spectrum disorder. The mutant mice also exhibit lower expression of gephyrin (a scaffold component of inhibitory synapses), supporting the dysregulation of E-I balance in the hippocampus. These results suggest that Shank1 scaffold in PV+ interneurons regulates excitatory synaptic strength and participates in the maintenance of E-I balance in excitatory neurons.

  13. Oxidative stress-mediated down-regulation of bcl-2 promoter in hippocampal neurons.

    Science.gov (United States)

    Pugazhenthi, Subbiah; Nesterova, Albina; Jambal, Purevsuren; Audesirk, Gerald; Kern, Marcey; Cabell, Leigh; Eves, Eva; Rosner, Marsha R; Boxer, Linda M; Reusch, Jane E-B

    2003-03-01

    Generation of oxidative stress/reactive oxygen species (ROS) is one of the causes of neuronal apoptosis. We have examined the effects of ROS at the transcriptional level in an immortalized hippocampal neuronal cell line (H19-7) and in rat primary hippocampal neurons. Treatment of H19-7 cells with hydrogen peroxide (150 micro m) resulted in a 40% decrease in Bcl-2 protein and a parallel decrease in bcl-2 mRNA levels. H19-7 cells overexpressing bcl-2 were found to be resistant to ROS-induced apoptosis. We had previously shown that bcl-2 promoter activity is positively regulated by the transcription factor cyclic AMP response element binding protein (CREB) in neurons. In the present study, we demonstrate that ROS decreases the activity of luciferase reporter gene driven by a cyclic AMP response element site containing bcl-2 promoter. Exposure of neurons to ROS for 6 h resulted in basal and fibroblast growth factor-2-stimulated phosphorylation/activation of CREB. Chronic 24 h treatment with ROS led to a significant (p < 0.01) decrease in CREB protein and CREB mRNA levels. Adenoviral overexpression of wild type CREB in H19-7 cells resulted in significant (p < 0.01) protection against ROS-induced apoptosis through up-regulation of Bcl-2 expression whereas dominant negative CREB exaggerated the injury. These findings demonstrate that loss of CREB function contributes to oxidative stress-induced neuronal dysfunction.

  14. Regulation of the Hippocampal Network by VGLUT3-Positive CCK- GABAergic Basket Cells

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    Caroline Fasano

    2017-05-01

    Full Text Available Hippocampal interneurons release the inhibitory transmitter GABA to regulate excitation, rhythm generation and synaptic plasticity. A subpopulation of GABAergic basket cells co-expresses the GABA/glycine vesicular transporters (VIAAT and the atypical type III vesicular glutamate transporter (VGLUT3; therefore, these cells have the ability to signal with both GABA and glutamate. GABAergic transmission by basket cells has been extensively characterized but nothing is known about the functional implications of VGLUT3-dependent glutamate released by these cells. Here, using VGLUT3-null mice we observed that the loss of VGLUT3 results in a metaplastic shift in synaptic plasticity at Shaeffer’s collaterals – CA1 synapses and an altered theta oscillation. These changes were paralleled by the loss of a VGLUT3-dependent inhibition of GABAergic current in CA1 pyramidal layer. Therefore presynaptic type III metabotropic could be activated by glutamate released from VGLUT3-positive interneurons. This putative presynaptic heterologous feedback mechanism inhibits local GABAergic tone and regulates the hippocampal neuronal network.

  15. Exploration of the Brn4-regulated genes enhancing adult hippocampal neurogenesis by RNA sequencing.

    Science.gov (United States)

    Guo, Jingjing; Cheng, Xiang; Zhang, Lei; Wang, Linmei; Mao, Yongxin; Tian, Guixiang; Xu, Wenhao; Wu, Yuhao; Ma, Zhi; Qin, Jianbing; Tian, Meiling; Jin, Guohua; Shi, Wei; Zhang, Xinhua

    2017-02-18

    Adult hippocampal neurogenesis is essential for learning and memory, and its dysfunction is involved in neurodegenerative diseases. However, the molecular mechanisms underlying adult hippocampal neurogenesis are still largely unknown. Our previous studies indicated that the transcription factor Brn4 was upregulated and promoted neuronal differentiation of neural stem cells (NSCs) in the surgically denervated hippocampus in rats. In this study, we use high-throughput RNA sequencing to explore the molecular mechanisms underlying the enhancement of adult hippocampal neurogenesis induced by lentivirus-mediated Brn4 overexpression in vivo. After 10 days of the lentivirus injection, we found that the expression levels of genes related to neuronal development and maturation were significantly increased and the expression levels of genes related to NSC maintenance were significantly decreased, indicating enhanced neurogenesis in the hippocampus after Brn4 overexpression. Through RNA sequencing, we found that 658 genes were differentially expressed in the Brn4-overexpressed hippocampi compared with GFP-overexpressed controls. Many of these differentially expressed genes are involved in NSC division and differentiation. By using quantitative real-time PCR, we validated the expression changes of three genes, including Ctbp2, Notch2, and Gli1, all of which are reported to play key roles in neuronal differentiation of NSCs. Importantly, the expression levels of Ctbp2 and Notch2 were also significantly changed in the hippocampus of Brn4 KO mice, which indicates that the expression levels of Ctbp2 and Notch2 may be directly regulated by Brn4. Our current study provides a solid foundation for further investigation and identifies Ctbp2 and Notch2 as possible downstream targets of Brn4. © 2017 Wiley Periodicals, Inc.

  16. NMDA Receptors Regulate the Structural Plasticity of Spines and Axonal Boutons in Hippocampal Interneurons

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    Marta Perez-Rando

    2017-06-01

    Full Text Available N-methyl-D-aspartate receptors (NMDARs are present in both pyramidal neurons and interneurons of the hippocampus. These receptors play an important role in the adult structural plasticity of excitatory neurons, but their impact on the remodeling of interneurons is unknown. Among hippocampal interneurons, somatostatin-expressing cells located in the stratum oriens are of special interest because of their functional importance and structural characteristics: they display dendritic spines, which change density in response to different stimuli. In order to understand the role of NMDARs on the structural plasticity of these interneurons, we have injected acutely MK-801, an NMDAR antagonist, to adult mice which constitutively express enhanced green fluorescent protein (EGFP in these cells. We have behaviorally tested the animals, confirming effects of the drug on locomotion and anxiety-related behaviors. NMDARs were expressed in the somata and dendritic spines of somatostatin-expressing interneurons. Twenty-four hours after the injection, the density of spines did not vary, but we found a significant increase in the density of their en passant boutons (EPB. We have also used entorhino-hippocampal organotypic cultures to study these interneurons in real-time. There was a rapid decrease in the apparition rate of spines after MK-801 administration, which persisted for 24 h and returned to basal levels afterwards. A similar reversible decrease was detected in spine density. Our results show that both spines and axons of interneurons can undergo remodeling and highlight NMDARs as regulators of this plasticity. These results are specially relevant given the importance of all these players on hippocampal physiology and the etiopathology of certain psychiatric disorders.

  17. Brief Report: No Association between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

    Science.gov (United States)

    Schirmbeck, Frederike; Georgi, Alexander; Strohmaier, Jana; Schmael, Christine; Boesshenz, Katja V.; Muhleisen, Thomas W.; Herms, Stefan; Hoffmann, Per; Jamra, Rami Abou; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Nothen, Markus M.; Cichon, Sven; Rietschel, Marcella; Schulze, Thomas G.

    2008-01-01

    Whereas "Dysbindin" is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. ("J Autism Dev…

  18. Brief Report: No Association between Premorbid Adjustment in Adult-Onset Schizophrenia and Genetic Variation in Dysbindin

    Science.gov (United States)

    Schirmbeck, Frederike; Georgi, Alexander; Strohmaier, Jana; Schmael, Christine; Boesshenz, Katja V.; Muhleisen, Thomas W.; Herms, Stefan; Hoffmann, Per; Jamra, Rami Abou; Schumacher, Johannes; Maier, Wolfgang; Propping, Peter; Nothen, Markus M.; Cichon, Sven; Rietschel, Marcella; Schulze, Thomas G.

    2008-01-01

    Whereas "Dysbindin" is considered a schizophrenia vulnerability gene, there is no consistency of findings. Phenotype refinement approaches may help to increase the genetic homogeneity and thus reconcile conflicting results. Premorbid adjustment (PMA) has been suggested to aid the phenotypic dissection. Gornick et al. ("J Autism Dev Disord"…

  19. BDNF up-regulates alpha7 nicotinic acetylcholine receptor levels on subpopulations of hippocampal interneurons.

    Science.gov (United States)

    Massey, Kerri A; Zago, Wagner M; Berg, Darwin K

    2006-12-01

    In the hippocampus, brain-derived neurotrophic factor (BDNF) regulates a number of synaptic components. Among these are nicotinic acetylcholine receptors containing alpha7 subunits (alpha7-nAChRs), which are interesting because of their relative abundance in the hippocampus and their high relative calcium permeability. We show here that BDNF elevates surface and intracellular pools of alpha7-nAChRs on cultured hippocampal neurons and that glutamatergic activity is both necessary and sufficient for the effect. Blocking transmission through NMDA receptors with APV blocked the BDNF effect; increasing spontaneous excitatory activity with the GABA(A) receptor antagonist bicuculline replicated the BDNF effect. BDNF antibodies blocked the BDNF-mediated increase but not the bicuculline one, consistent with enhanced glutamatergic activity acting downstream from BDNF. Increased alpha7-nAChR clusters were most prominent on interneuron subtypes known to directly innervate excitatory neurons. The results suggest that BDNF, acting through glutamatergic transmission, can modulate hippocampal output in part by controlling alpha7-nAChR levels.

  20. Selective regulation of axonal growth from developing hippocampal neurons by tumor necrosis factor superfamily member APRIL☆

    Science.gov (United States)

    Osório, Catarina; Chacón, Pedro J.; White, Matthew; Kisiswa, Lilian; Wyatt, Sean; Rodríguez-Tébar, Alfredo; Davies, Alun M.

    2014-01-01

    APRIL (A Proliferation-Inducing Ligand, TNFSF13) is a member of the tumor necrosis factor superfamily that regulates lymphocyte survival and activation and has been implicated in tumorigenesis and autoimmune diseases. Here we report the expression and first known activity of APRIL in the nervous system. APRIL and one of its receptors, BCMA (B-Cell Maturation Antigen, TNFRSF17), are expressed by hippocampal pyramidal cells of fetal and postnatal mice. In culture, these neurons secreted APRIL, and function-blocking antibodies to either APRIL or BCMA reduced axonal elongation. Recombinant APRIL enhanced axonal elongation, but did not influence dendrite elongation. The effect of APRIL on axon elongation was inhibited by anti-BCMA and the expression of a signaling-defective BCMA mutant in these neurons, suggesting that the axon growth-promoting effect of APRIL is mediated by BCMA. APRIL promoted phosphorylation and activation of ERK1, ERK2 and Akt and serine phosphorylation and inactivation of GSK-3β in cultured hippocampal pyramidal cells. Inhibition of MEK1/MEK2 (activators of ERK1/ERK2), PI3-kinase (activator of Akt) or Akt inhibited the axon growth-promoting action of APRIL, as did pharmacological activation of GSK-3β and the expression of a constitutively active form of GSK-3β. These findings suggest that APRIL promotes axon elongation by a mechanism that depends both on ERK signaling and PI3-kinase/Akt/GSK-3β signaling. PMID:24444792

  1. Glucocorticoid regulation of brain-derived neurotrophic factor: relevance to hippocampal structural and functional plasticity.

    Science.gov (United States)

    Suri, D; Vaidya, V A

    2013-06-01

    Glucocorticoids serve as key stress response hormones that facilitate stress coping. However, sustained glucocorticoid exposure is associated with adverse consequences on the brain, in particular within the hippocampus. Chronic glucocorticoid exposure evokes neuronal cell damage and dendritic atrophy, reduces hippocampal neurogenesis and impairs synaptic plasticity. Glucocorticoids also alter expression and signaling of the neurotrophin, brain-derived neurotrophic factor (BDNF). Since BDNF is known to promote neuroplasticity, enhance cell survival, increase hippocampal neurogenesis and cellular excitability, it has been hypothesized that specific adverse effects of glucocorticoids may be mediated by attenuating BDNF expression and signaling. The purpose of this review is to summarize the current state of literature examining the influence of glucocorticoids on BDNF, and to address whether specific effects of glucocorticoids arise through perturbation of BDNF signaling. We integrate evidence of glucocorticoid regulation of BDNF at multiple levels, spanning from the well-documented glucocorticoid-induced changes in BDNF mRNA to studies examining alterations in BDNF receptor-mediated signaling. Further, we delineate potential lines of future investigation to address hitherto unexplored aspects of the influence of glucocorticoids on BDNF. Finally, we discuss the current understanding of the contribution of BDNF to the modulation of structural and functional plasticity by glucocorticoids, in particular in the context of the hippocampus. Understanding the mechanistic crosstalk between glucocorticoids and BDNF holds promise for the identification of potential therapeutic targets for disorders associated with the dysfunction of stress hormone pathways.

  2. The F-BAR Protein Rapostlin Regulates Dendritic Spine Formation in Hippocampal Neurons*

    Science.gov (United States)

    Wakita, Yohei; Kakimoto, Tetsuhiro; Katoh, Hironori; Negishi, Manabu

    2011-01-01

    Pombe Cdc15 homology proteins, characterized by Fer/CIP4 homology Bin-Amphiphysin-Rvs/extended Fer/CIP4 homology (F-BAR/EFC) domains with membrane invaginating property, play critical roles in a variety of membrane reorganization processes. Among them, Rapostlin/formin-binding protein 17 (FBP17) has attracted increasing attention as a critical coordinator of endocytosis. Here we found that Rapostlin was expressed in the developing rat brain, including the hippocampus, in late developmental stages when accelerated dendritic spine formation and maturation occur. In primary cultured rat hippocampal neurons, knockdown of Rapostlin by shRNA or overexpression of Rapostlin-QQ, an F-BAR domain mutant of Rapostlin that has no ability to induce membrane invagination, led to a significant decrease in spine density. Expression of shRNA-resistant wild-type Rapostlin effectively restored spine density in Rapostlin knockdown neurons, whereas expression of Rapostlin deletion mutants lacking the protein kinase C-related kinase homology region 1 (HR1) or Src homology 3 (SH3) domain did not. In addition, knockdown of Rapostlin or overexpression of Rapostlin-QQ reduced the uptake of transferrin in hippocampal neurons. Knockdown of Rnd2, which binds to the HR1 domain of Rapostlin, also reduced spine density and the transferrin uptake. These results suggest that Rapostlin and Rnd2 cooperatively regulate spine density. Indeed, Rnd2 enhanced the Rapostlin-induced tubular membrane invagination. We conclude that the F-BAR protein Rapostlin, whose activity is regulated by Rnd2, plays a key role in spine formation through the regulation of membrane dynamics. PMID:21768103

  3. Dysbindin基因在精神分裂症中的研究进展%Advances in the studies of the dysbindin gene in schizophrenia

    Institute of Scientific and Technical Information of China (English)

    赵高锋; 邓红; 杨彦春; 陈颖

    2009-01-01

    Recent reports indicate that the dysbindin gene located on chromosome 6p22.3 is a major susceptibility gene for schizophrenia. In the brain, the dysbindin gene may influence glutamatergic neurotransmission by multiple post- and pre-synaptic mechanisms. This paper reviews the research progress on the dysbindin gene in schizophrenia, including the dysbindin gene and its product, the possible pathogenic mechanisms, the association study of the dysbindin gene with schizophrenia, and the cognitive decline caused by the dysbindin variations.%位于染色体6p22.3区域的Dysbindin基因是精神分裂症的易感基因之一.在大脑中,其功能主要是通过复杂的突触后或前机制影响谷氨酸神经递质的释放,现就Dysbindin基因在精神分裂症中的研究情况进行综述,包括Dysbindin基因及其产物,可能的致病机制,与精神分裂症的关联研究以及该基因变异对精神分裂症患者认知功能可能造成的损害.

  4. BDNF regulates the expression and distribution of vesicular glutamate transporters in cultured hippocampal neurons.

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    Carlos V Melo

    Full Text Available BDNF is a pro-survival protein involved in neuronal development and synaptic plasticity. BDNF strengthens excitatory synapses and contributes to LTP, presynaptically, through enhancement of glutamate release, and postsynaptically, via phosphorylation of neurotransmitter receptors, modulation of receptor traffic and activation of the translation machinery. We examined whether BDNF upregulated vesicular glutamate receptor (VGLUT 1 and 2 expression, which would partly account for the increased glutamate release in LTP. Cultured rat hippocampal neurons were incubated with 100 ng/ml BDNF, for different periods of time, and VGLUT gene and protein expression were assessed by real-time PCR and immunoblotting, respectively. At DIV7, exogenous application of BDNF rapidly increased VGLUT2 mRNA and protein levels, in a dose-dependent manner. VGLUT1 expression also increased but only transiently. However, at DIV14, BDNF stably increased VGLUT1 expression, whilst VGLUT2 levels remained low. Transcription inhibition with actinomycin-D or α-amanitine, and translation inhibition with emetine or anisomycin, fully blocked BDNF-induced VGLUT upregulation. Fluorescence microscopy imaging showed that BDNF stimulation upregulates the number, integrated density and intensity of VGLUT1 and VGLUT2 puncta in neurites of cultured hippocampal neurons (DIV7, indicating that the neurotrophin also affects the subcellular distribution of the transporter in developing neurons. Increased VGLUT1 somatic signals were also found 3 h after stimulation with BDNF, further suggesting an increased de novo transcription and translation. BDNF regulation of VGLUT expression was specifically mediated by BDNF, as no effect was found upon application of IGF-1 or bFGF, which activate other receptor tyrosine kinases. Moreover, inhibition of TrkB receptors with K252a and PLCγ signaling with U-73122 precluded BDNF-induced VGLUT upregulation. Hippocampal neurons express both isoforms during

  5. Regulation of extracellular signal-regulated kinase 1/2 inlfuences hippocampal neuronal survival in a rat model of diabetic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Yaning Zhao; Jianmin Li; Qiqun Tang; Pan Zhang; Liwei Jing; Changxiang Chen; Shuxing Li

    2014-01-01

    Activation of extracellular signal-regulated kinase 1/2 has been demonstrated in acute brain ischemia. We hypothesized that activated extracellular signal-regulated kinase 1/2 can protect hippocampal neurons from injury in a diabetic model after cerebral ischemia/reperfusion. In this study, transient whole-brain ischemia was induced by four-vessel occlusion in normal and diabetic rats, and extracellular signal-regulated kinase 1/2 inhibitor (U0126) was administered into diabetic rats 30 minutes before ischemia as a pretreatment. Results showed that the number of surviving neurons in the hippocampal CA1 region was reduced, extracellular signal-regulated kinase 1/2 phosphorylation and Ku70 activity were decreased, and pro-apoptotic Bax expression was upregulated after intervention using U0126. These ifndings demonstrate that inhibition of extracellular signal-regulated kinase 1/2 activity aggravated neuronal loss in the hippocampus in a diabetic rat after cerebral ischemia/reperfusion, further decreased DNA repairing ability and ac-celerated apoptosis in hippocampal neurons. Extracellular signal-regulated kinase 1/2 activation plays a neuroprotective role in hippocampal neurons in a diabetic rat after cerebral ischemia/reperfusion.

  6. PSD-95 regulates synaptic kainate receptors at mouse hippocampal mossy fiber-CA3 synapses.

    Science.gov (United States)

    Suzuki, Etsuko; Kamiya, Haruyuki

    2016-06-01

    Kainate-type glutamate receptors (KARs) are the third class of ionotropic glutamate receptors whose activation leads to the unique roles in regulating synaptic transmission and circuit functions. In contrast to AMPA receptors (AMPARs), little is known about the mechanism of synaptic localization of KARs. PSD-95, a major scaffold protein of the postsynaptic density, is a candidate molecule that regulates the synaptic KARs. Although PSD-95 was shown to bind directly to KARs subunits, it has not been tested whether PSD-95 regulates synaptic KARs in intact synapses. Using PSD-95 knockout mice, we directly investigated the role of PSD-95 in the KARs-mediated components of synaptic transmission at hippocampal mossy fiber-CA3 synapse, one of the synapses with the highest density of KARs. Mossy fiber EPSCs consist of AMPA receptor (AMPAR)-mediated fast component and KAR-mediated slower component, and the ratio was significantly reduced in PSD-95 knockout mice. The size of KARs-mediated field EPSP reduced in comparison with the size of the fiber volley. Analysis of KARs-mediated miniature EPSCs also suggested reduced synaptic KARs. All the evidence supports critical roles of PSD-95 in regulating synaptic KARs. Copyright © 2015 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  7. Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development.

    Science.gov (United States)

    Walton, Noah M; de Koning, Anoek; Xie, Xiuyuan; Shin, Rick; Chen, Qian; Miyake, Shinichi; Tajinda, Katsunori; Gross, Adam K; Kogan, Jeffrey H; Heusner, Carrie L; Tamura, Kouichi; Matsumoto, Mitsuyuki

    2014-09-01

    In the postnatal hippocampus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippocampal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2α-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippocampal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased cAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2α-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippocampus-associated cognitive impairment.

  8. NF-κB Mediated Regulation of Adult Hippocampal Neurogenesis: Relevance to Mood Disorders and Antidepressant Activity

    Directory of Open Access Journals (Sweden)

    Valeria Bortolotto

    2014-01-01

    Full Text Available Adult hippocampal neurogenesis is a peculiar form of process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF-κB family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF-κB signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed.

  9. Carboxypeptidase E protects hippocampal neurons during stress in male mice by up-regulating prosurvival BCL2 protein expression.

    Science.gov (United States)

    Murthy, S R K; Thouennon, E; Li, W-S; Cheng, Y; Bhupatkar, J; Cawley, N X; Lane, M; Merchenthaler, I; Loh, Y P

    2013-09-01

    Prolonged chronic stress causing elevated plasma glucocorticoids leads to neurodegeneration. Adaptation to stress (allostasis) through neuroprotective mechanisms can delay this process. Studies on hippocampal neurons have identified carboxypeptidase E (CPE) as a novel neuroprotective protein that acts extracellularly, independent of its enzymatic activity, although the mechanism of action is unclear. Here, we aim to determine if CPE plays a neuroprotective role in allostasis in mouse hippocampus during chronic restraint stress (CRS), and the molecular mechanisms involved. Quantitative RT-PCR/in situ hybridization and Western blots were used to assay for mRNA and protein. After mild CRS (1 h/d for 7 d), CPE protein and mRNA were significantly elevated in the hippocampal CA3 region, compared to naïve littermates. In addition, luciferase reporter assays identified a functional glucocorticoid regulatory element within the cpe promoter that mediated the up-regulation of CPE expression in primary hippocampal neurons following dexamethasone treatment, suggesting that circulating plasma glucocorticoids could evoke a similar effect on CPE in the hippocampus in vivo. Overexpression of CPE in hippocampal neurons, or CRS in mice, resulted in elevated prosurvival BCL2 protein/mRNA and p-AKT levels in the hippocampus; however, CPE(-/-) mice showed a decrease. Thus, during mild CRS, CPE expression is up-regulated, possibly contributed by glucocorticoids, to mediate neuroprotection of the hippocampus by enhancing BCL2 expression through AKT signaling, and thereby maintaining allostasis.

  10. Notch1 regulates hippocampal plasticity through interaction with the Reelin pathway, glutamatergic transmission and CREB signaling

    Directory of Open Access Journals (Sweden)

    Emanuele eBrai

    2015-11-01

    Full Text Available Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, ApoER2, and the ionotropic receptor, NMDAR. Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced CREB signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia.

  11. Learning-induced plasticity regulates hippocampal sharp wave-ripple drive.

    Science.gov (United States)

    Girardeau, Gabrielle; Cei, Anne; Zugaro, Michaël

    2014-04-01

    Hippocampal sharp wave-ripples (SPW-Rs) and associated place-cell reactivations are crucial for spatial memory consolidation during sleep and rest. However, it remains unclear how learning and consolidation requirements influence and regulate subsequent SPW-R activity. Indeed, SPW-R activity has been observed not only following complex behavioral tasks, but also after random foraging in familiar environments, despite markedly different learning requirements. Because transient increases in SPW-R rates have been reported following training on memory tasks, we hypothesized that SPW-R activity following learning (but not routine behavior) could involve specific regulatory processes related to ongoing consolidation. Interfering with ripples would then result in a dynamic compensatory response only when initial memory traces required consolidation. Here we trained rats on a spatial memory task, and showed that subsequent sleep periods where ripple activity was perturbed by timed electrical stimulation were indeed characterized by increased SPW-R occurrence rates compared with control sleep periods where stimulations were slightly delayed in time and did not interfere with ripples. Importantly, this did not occur following random foraging in a familiar environment. We next showed that this dynamic response was abolished following injection of an NMDA receptor blocker (MK-801) before, but not after training. Our results indicate that NMDA receptor-dependent processes occurring during learning, such as network "tagging" and plastic changes, regulate subsequent ripple-mediated consolidation of spatial memory during sleep.

  12. NT-3 Facilitates Hippocampal Plasticity and Learning and Memory by Regulating Neurogenesis

    Science.gov (United States)

    Sakata, Kazuko; Akbarian, Schahram; Bates, Brian; Jaenisch, Rudolf; Lu, Bai; Shimazu, Kazuhiro; Zhao, Mingrui

    2006-01-01

    In the adult brain, the expression of NT-3 is largely confined to the hippocampal dentate gyrus (DG), an area exhibiting significant neurogenesis. Using a conditional mutant line in which the "NT-3" gene is deleted in the brain, we investigated the role of NT-3 in adult neurogenesis, hippocampal plasticity, and memory. Bromodeoxyuridine…

  13. Synapse-specific mGluR1-dependent long-term potentiation in interneurones regulates mouse hippocampal inhibition

    Science.gov (United States)

    Lapointe, Valérie; Morin, France; Ratté, Stéphanie; Croce, Ariane; Conquet, François; Lacaille, Jean-Claude

    2004-01-01

    Hippocampal CA1 inhibitory interneurones control the excitability and synchronization of pyramidal cells, and participate in hippocampal synaptic plasticity. Pairing theta-burst stimulation (TBS) with postsynaptic depolarization, we induced long-term potentiation (LTP) of putative single-fibre excitatory postsynaptic currents (EPSCs) in stratum oriens/alveus (O/A) interneurones of mouse hippocampal slices. LTP induction was absent in metabotropic glutamate receptor 1 (mGluR1) knockout mice, was correlated with the postsynaptic presence of mGluR1a, and required a postsynaptic Ca2+ rise. Changes in paired-pulse facilitation and coefficient of variation indicated that LTP expression involved presynaptic mechanisms. LTP was synapse specific, occurring selectively at synapses modulated by presynaptic group II, but not group III, mGluRs. Furthermore, the TBS protocol applied in O/A induced a long-term increase of polysynaptic inhibitory responses in CA1 pyramidal cells, that was absent in mGluR1 knockout mice. These results uncover the mechanisms of a novel form of interneurone synaptic plasticity that can adaptively regulate inhibition of hippocampal pyramidal cells. PMID:14673190

  14. Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of FMRP in neurotransmission

    OpenAIRE

    2014-01-01

    Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and the mechanisms of these FMRP actions remain incompletely understood, and the rol...

  15. Oxidative stress and redox regulation on hippocampal-dependent cognitive functions.

    Science.gov (United States)

    Huang, Ting-Ting; Leu, David; Zou, Yani

    2015-06-15

    Hippocampal-dependent cognitive functions rely on production of new neurons and maintenance of dendritic structures to provide the synaptic plasticity needed for learning and formation of new memories. Hippocampal formation is exquisitely sensitive to patho-physiological changes, and reduced antioxidant capacity and exposure to low dose irradiation can significantly impede hippocampal-dependent functions of learning and memory by reducing the production of new neurons and alter dendritic structures in the hippocampus. Although the mechanism leading to impaired cognitive functions is complex, persistent oxidative stress likely plays an important role in the SOD-deficient and radiation-exposed hippocampal environment. Aging is associated with increased production of pro-oxidants and accumulation of oxidative end products. Similar to the hippocampal defects observed in SOD-deficient mice and mice exposed to low dose irradiation, reduced capacity in learning and memory, diminishing hippocampal neurogenesis, and altered dendritic network are universal in the aging brains. Given the similarities in cellular and structural changes in the aged, SOD-deficient, and radiation-exposed hippocampal environment and the corresponding changes in cognitive decline, understanding the shared underlying mechanism will provide more flexible and efficient use of SOD deficiency or irradiation to model age-related changes in cognitive functions and identify potential therapeutic or intervention methods.

  16. DTNBP1 (dysbindin) gene variants modulate prefrontal brain function in schizophrenic patients--support for the glutamate hypothesis of schizophrenias.

    Science.gov (United States)

    Fallgatter, A J; Ehlis, A-C; Herrmann, M J; Hohoff, C; Reif, A; Freitag, C M; Deckert, J

    2010-07-01

    Dysbindin (DTNBP1) is a recently characterized protein that seems to be involved in the modulation of glutamatergic neurotransmission in the human brain, thereby influencing prefrontal cortex function and associated cognitive processes. While association, neuroanatomical and cellular studies indicate that DTNBP1 might be one of several susceptibility genes for schizophrenia, the effect of dysbindin on prefrontal brain function at an underlying neurophysiological level has not yet been explored for these patients. The NoGo-anteriorization (NGA) is a topographical event-related potential measure, which has been established as a valid neurophysiological marker of prefrontal brain function. In the present study, we investigated the influence of seven dysbindin gene variants on the NGA in a group of 44 schizophrenic patients. In line with our a priori hypothesis, one DTNBP1 polymorphism previously linked to schizophrenia (rs2619528) was found to be associated with changes in the NGA; however, the direction of this association directly contrasts with our previous findings in a healthy control sample. This differential impact of DTNBP1 gene variation on prefrontal functioning in schizophrenic patients vs. healthy controls is discussed in terms of abnormal glutamatergic baseline levels in patients suffering from schizophrenic illnesses. This is the first report on a role of DTNBP1 gene variation for prefrontal functioning at a basic neurophysiological level in schizophrenic patients. An impact on fundamental processes of cognitive response control may be one mechanism by which DTNBP1 gene variants via glutamatergic transmission contribute to the pathophysiology underlying schizophrenic illnesses.

  17. Long-term rearrangements of hippocampal mossy fiber terminal connectivity in the adult regulated by experience.

    Science.gov (United States)

    Galimberti, Ivan; Gogolla, Nadine; Alberi, Stefano; Santos, Alexandre Ferrao; Muller, Dominique; Caroni, Pico

    2006-06-01

    We investigated rearrangements of connectivity between hippocampal mossy fibers and CA3 pyramidal neurons. We found that mossy fibers establish 10-15 local terminal arborization complexes (LMT-Cs) in CA3, which exhibit major differences in size and divergence in adult mice. LMT-Cs exhibited two types of long-term rearrangements in connectivity in the adult: progressive expansion of LMT-C subsets along individual dendrites throughout life, and pronounced increases in LMT-C complexities in response to an enriched environment. In organotypic slice cultures, subsets of LMT-Cs also rearranged extensively and grew over weeks and months, altering the strength of preexisting connectivity, and establishing or dismantling connections with pyramidal neurons. Differences in LMT-C plasticity reflected properties of individual LMT-Cs, not mossy fibers. LMT-C maintenance and growth were regulated by spiking activity, mGluR2-sensitive transmitter release from LMTs, and PKC. Thus, subsets of terminal arborization complexes by mossy fibers rearrange their local connectivities in response to experience and age throughout life.

  18. Ezh1 and Ezh2 differentially regulate PSD-95 gene transcription in developing hippocampal neurons.

    Science.gov (United States)

    Henriquez, Berta; Bustos, Fernando J; Aguilar, Rodrigo; Becerra, Alvaro; Simon, Felipe; Montecino, Martin; van Zundert, Brigitte

    2013-11-01

    Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing by catalyzing histone H3 lysine 27 trimethylation (H3K27me3), but its role in the maturation of postmitotic mammalian neurons remains largely unknown. We report that the PRC2 paralogs Ezh1 and Ezh2 are differentially expressed during hippocampal development. We show that depletion of Ezh2 leads to increased expression of PSD-95, a critical plasticity gene, and that reduced PSD-95 gene transcription is correlated with enrichment of Ezh2 at the PSD-95 gene promoter; however, the H3K27me3 epigenetic mark is not present at the PSD-95 gene promoter, likely due to the antagonizing effects of the H3S28P and H3K27Ac marks and the activity of the H3K27 demethylases JMJD3 and UTX. In contrast, increased PSD-95 gene transcription is accompanied by the presence of Ezh1 and elongation-engaged RNA Polymerase II complexes at the PSD-95 gene promoter, while knock-down of Ezh1 reduces PSD-95 transcription. These results indicate that Ezh1 and Ezh2 have antagonistic roles in regulating PSD-95 transcription. © 2013.

  19. Presynaptic GABAB Receptors Regulate Hippocampal Synapses during Associative Learning in Behaving Mice.

    Directory of Open Access Journals (Sweden)

    M Teresa Jurado-Parras

    Full Text Available GABAB receptors are the G-protein-coupled receptors for GABA, the main inhibitory neurotransmitter in the central nervous system. Pharmacological activation of GABAB receptors regulates neurotransmission and neuronal excitability at pre- and postsynaptic sites. Electrophysiological activation of GABAB receptors in brain slices generally requires strong stimulus intensities. This raises the question as to whether behavioral stimuli are strong enough to activate GABAB receptors. Here we show that GABAB1a-/- mice, which constitutively lack presynaptic GABAB receptors at glutamatergic synapses, are impaired in their ability to acquire an operant learning task. In vivo recordings during the operant conditioning reveal a deficit in learning-dependent increases in synaptic strength at CA3-CA1 synapses. Moreover, GABAB1a-/- mice fail to synchronize neuronal activity in the CA1 area during the acquisition process. Our results support that activation of presynaptic hippocampal GABAB receptors is important for acquisition of a learning task and for learning-associated synaptic changes and network dynamics.

  20. Circuits regulating pleasure and happiness: the evolution of the amygdalar-hippocampal-habenular connectivity in vertebrates.

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    Anton J.M. Loonen

    2016-11-01

    Full Text Available Appetitive-searching (reward-seeking and distress-avoiding (misery-fleeing behavior are essential for all free moving animals to stay alive and to have offspring. Therefore, even the oldest ocean-dwelling animal creatures, living about 560 million years ago and human ancestors, must have been capable of generating these behaviors. The current article describes the evolution of the forebrain with special reference to the development of the misery-fleeing system. Although the earliest vertebrate ancestor already possessed a dorsal pallium, which corresponds to the human neocortex, the structure and function of the neocortex was acquired quite recently within the mammalian evolutionary line. Up to, and including, amphibians, the dorsal pallium can be considered to be an extension of the medial pallium, which later develops into the hippocampus. The ventral and lateral pallium largely go up into the corticoid part of the amygdala. The striatopallidum of these early vertebrates becomes extended amygdala, consisting of centromedial amygdala (striatum connected with the bed nucleus of the stria terminalis (pallidum. This amygdaloid system gives output to hypothalamus and brainstem, but also a connection with the cerebral cortex exists, which in part was created after the development of the more recent cerebral neocortex. Apart from bidirectional connectivity with the hippocampal complex, this route can also be considered to be an output channel as the fornix connects the hippocampus with the medial septum, which is the most important input structure of the medial habenula. The medial habenula regulates the activity of midbrain structures adjusting the intensity of the misery-fleeing response. Within the bed nucleus of the stria terminalis the human homologue of the ancient lateral habenula-projecting globus pallidus may exist; this structure is important for the evaluation of efficacy of the reward-seeking response. The described organization offers a

  1. Circuits Regulating Pleasure and Happiness: The Evolution of the Amygdalar-Hippocampal-Habenular Connectivity in Vertebrates

    Science.gov (United States)

    Loonen, Anton J. M.; Ivanova, Svetlana A.

    2016-01-01

    Appetitive-searching (reward-seeking) and distress-avoiding (misery-fleeing) behavior are essential for all free moving animals to stay alive and to have offspring. Therefore, even the oldest ocean-dwelling animal creatures, living about 560 million years ago and human ancestors, must have been capable of generating these behaviors. The current article describes the evolution of the forebrain with special reference to the development of the misery-fleeing system. Although, the earliest vertebrate ancestor already possessed a dorsal pallium, which corresponds to the human neocortex, the structure and function of the neocortex was acquired quite recently within the mammalian evolutionary line. Up to, and including, amphibians, the dorsal pallium can be considered to be an extension of the medial pallium, which later develops into the hippocampus. The ventral and lateral pallium largely go up into the corticoid part of the amygdala. The striatopallidum of these early vertebrates becomes extended amygdala, consisting of centromedial amygdala (striatum) connected with the bed nucleus of the stria terminalis (pallidum). This amygdaloid system gives output to hypothalamus and brainstem, but also a connection with the cerebral cortex exists, which in part was created after the development of the more recent cerebral neocortex. Apart from bidirectional connectivity with the hippocampal complex, this route can also be considered to be an output channel as the fornix connects the hippocampus with the medial septum, which is the most important input structure of the medial habenula. The medial habenula regulates the activity of midbrain structures adjusting the intensity of the misery-fleeing response. Within the bed nucleus of the stria terminalis the human homolog of the ancient lateral habenula-projecting globus pallidus may exist; this structure is important for the evaluation of efficacy of the reward-seeking response. The described organization offers a framework for the

  2. The neuronal ceroid lipofuscinosis Cln8 gene expression is developmentally regulated in mouse brain and up-regulated in the hippocampal kindling model of epilepsy

    Directory of Open Access Journals (Sweden)

    Kuronen Mervi

    2005-04-01

    Full Text Available Abstract Background The neuronal ceroid lipofuscinoses (NCLs are a group of inherited neurodegenerative disorders characterized by accumulation of autofluorescent material in many tissues, especially in neurons. Mutations in the CLN8 gene, encoding an endoplasmic reticulum (ER transmembrane protein of unknown function, underlie NCL phenotypes in humans and mice. The human phenotype is characterized by epilepsy, progressive psychomotor deterioration and visual loss, while motor neuron degeneration (mnd mice with a Cln8 mutation show progressive motor neuron dysfunction and retinal degeneration. Results We investigated spatial and temporal expression of Cln8 messenger ribonucleic acid (mRNA using in situ hybridization, reverse transcriptase polymerase chain reaction (RT-PCR and northern blotting. Cln8 is ubiquitously expressed at low levels in embryonic and adult tissues. In prenatal embryos Cln8 is most prominently expressed in the developing gastrointestinal tract, dorsal root ganglia (DRG and brain. In postnatal brain the highest expression is in the cortex and hippocampus. Expression of Cln8 mRNA in the central nervous system (CNS was also analyzed in the hippocampal electrical kindling model of epilepsy, in which Cln8 expression was rapidly up-regulated in hippocampal pyramidal and granular neurons. Conclusion Expression of Cln8 in the developing and mature brain suggests roles for Cln8 in maturation, differentiation and supporting the survival of different neuronal populations. The relevance of Cln8 up-regulation in hippocampal neurons of kindled mice should be further explored.

  3. Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation

    Directory of Open Access Journals (Sweden)

    Jessberger Sebastian

    2006-11-01

    Full Text Available Abstract Background In the course of adult hippocampal neurogenesis most regulation takes place during the phase of doublecortin (DCX expression, either as pro-proliferative effect on precursor cells or as survival-promoting effect on postmitotic cells. We here obtained quantitative data about the proliferative population and the dynamics of postmitotic dendrite development during the period of DCX expression. The question was, whether any indication could be obtained that the initiation of dendrite development is timely bound to the exit from the cell cycle. Alternatively, the temporal course of morphological maturation might be subject to additional regulatory events. Results We found that (1 20% of the DCX population were precursor cells in cell cycle, whereas more than 70% were postmitotic, (2 the time span until newborn cells had reached the most mature stage associated with DCX expression varied between 3 days and several weeks, (3 positive or negative regulation of precursor cell proliferation did not alter the pattern and dynamics of dendrite development. Dendrite maturation was largely independent of close contacts to astrocytes. Conclusion These data imply that dendrite maturation of immature neurons is initiated at varying times after cell cycle exit, is variable in duration, and is controlled independently of the regulation of precursor cell proliferation. We conclude that in addition to the major regulatory events in cell proliferation and selective survival, additional micro-regulatory events influence the course of adult hippocampal neurogenesis.

  4. The canonical Notch pathway effector RBP-J regulates neuronal plasticity and expression of GABA transporters in hippocampal networks.

    Science.gov (United States)

    Liu, Shuxi; Wang, Yue; Worley, Paul F; Mattson, Mark P; Gaiano, Nicholas

    2015-05-01

    Activation of the Notch pathway in neurons is essential for learning and memory in various species from invertebrates to mammals. However, it remains unclear how Notch signaling regulates neuronal plasticity, and whether the transcriptional regulator and canonical pathway effector RBP-J plays a role. Here, we report that conditional disruption of RBP-J in the postnatal hippocampus leads to defects in long-term potentiation, long-term depression, and in learning and memory. Using gene expression profiling and chromatin immunoprecipitation, we identified two GABA transporters, GAT2 and BGT1, as putative Notch/RBP-J pathway targets, which may function downstream of RBP-J to limit the accumulation of GABA in the Schaffer collateral pathway. Our results reveal an essential role for canonical Notch/RBP-J signaling in hippocampal synaptic plasticity and suggest that role, at least in part, is mediated by the regulation of GABAergic signaling.

  5. Serotonin (5-HT) regulates neurite outgrowth through 5-HT1A and 5-HT7 receptors in cultured hippocampal neurons.

    Science.gov (United States)

    Rojas, Paulina S; Neira, David; Muñoz, Mauricio; Lavandero, Sergio; Fiedler, Jenny L

    2014-08-01

    Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth.

  6. Differential regulation of BDNF, synaptic plasticity and sprouting in the hippocampal mossy fiber pathway of male and female rats.

    Science.gov (United States)

    Scharfman, Helen E; MacLusky, Neil J

    2014-01-01

    Many studies have described potent effects of BDNF, 17β-estradiol or androgen on hippocampal synapses and their plasticity. Far less information is available about the interactions between 17β-estradiol and BDNF in hippocampus, or interactions between androgen and BDNF in hippocampus. Here we review the regulation of BDNF in the mossy fiber pathway, a critical part of hippocampal circuitry. We discuss the emerging view that 17β-estradiol upregulates mossy fiber BDNF synthesis in the adult female rat, while testosterone exerts a tonic suppression of mossy fiber BDNF levels in the adult male rat. The consequences are interesting to consider: in females, increased excitability associated with high levels of BDNF in mossy fibers could improve normal functions of area CA3, such as the ability to perform pattern completion. However, memory retrieval may lead to anxiety if stressful events are recalled. Therefore, the actions of 17β-estradiol on the mossy fiber pathway in females may provide a potential explanation for the greater incidence of anxiety-related disorders and post-traumatic stress syndrome (PTSD) in women relative to men. In males, suppression of BDNF-dependent plasticity in the mossy fibers may be protective, but at the 'price' of reduced synaptic plasticity in CA3. This article is part of the Special Issue entitled 'BDNF Regulation of Synaptic Structure, Function, and Plasticity'.

  7. Dysbindin (DTNBP1, 6p22.3) is Associated with Childhood-Onset Psychosis and Endophenotypes Measured by the Premorbid Adjustment Scale (PAS)

    Science.gov (United States)

    Gornick, M. C.; Addington, A. M.; Sporn, A.; Gogtay, N.; Greenstein, D.; Lenane, M.; Gochman, P.; Ordonez, A.; Balkissoon, R.; Vakkalanka, R.; Weinberger, D. R.; Rapoport, J. L.; Straub, R. E.

    2005-01-01

    Straub "et al." ("2002") recently identified the 6p22.3 gene dysbindin (DTNBP1) through positional cloning as a schizophrenia susceptibility gene. We studied a rare cohort of 102 children with onset of psychosis before age 13. Standardized ratings of early development, medication response, neuropsychological and cognitive performance, premorbid…

  8. Fractalkine and CX3CR1 regulate hippocampal neurogenesis in adult and aged rats

    Science.gov (United States)

    Bachstetter, Adam D.; Morganti, Josh M.; Jernberg, Jennifer; Schlunk, Andrea; Mitchell, Staten H.; Brewster, Kaelin W.; Hudson, Charles E.; Cole, Michael J; Harrison, Jeffrey K.; Bickford, Paula C.; Gemma, Carmelina

    2010-01-01

    Microglia have neuroprotective capacities, yet chronic activation can promote neurotoxic inflammation. Neuronal fractalkine (FKN), acting on CX3CR1, has been shown to suppress excessive microglia activation. We found that disruption in FKN/ CX3CR1 signaling in young adult rodents decreased survival and proliferation of neural progenitor cells through IL-1β. Aged rats were found to have decreased levels of hippocampal FKN protein; moreover, interruption of CX3CR1 function in these animals did not affect neurogenesis. The age-related loss of FKN could be restored by exogenous FKN reversing the age-related decrease in hippocampal neurogenesis. There were no measureable changes in young animals by the addition of exogenous FKN. The results suggest that FKN/ CX3CR1 signaling has a regulatory role in modulating hippocampal neurogenesis via mechanisms that involve indirect modification of the niche environment. As elevated neuroinflammation is associated with many age-related neurodegenerative diseases, enhancing FKN/ CX3CR1 interactions could provide an alternative therapeutic approach to slow age-related neurodegeneration. PMID:20018408

  9. The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner

    Directory of Open Access Journals (Sweden)

    Ayden Gouveia

    2016-10-01

    Full Text Available While epigenetic modifications have emerged as attractive substrates to integrate environmental changes into the determination of cell identity and function, specific signals that directly activate these epigenetic modifications remain unknown. Here, we examine the role of atypical protein kinase C (aPKC-mediated Ser436 phosphorylation of CBP, a histone acetyltransferase, in adult hippocampal neurogenesis and memory. Using a knockin mouse strain (CbpS436A in which the aPKC-CBP pathway is deficient, we observe impaired hippocampal neuronal differentiation, maturation, and memory and diminished binding of CBP to CREB in 6-month-old CbpS436A mice, but not at 3 months of age. Importantly, elevation of CREB activity rescues these deficits, and CREB activity is reduced whereas aPKC activity is increased in the murine hippocampus as they age from 3 to 6 months regardless of genotype. Thus, the aPKC-CBP pathway is a homeostatic compensatory mechanism that modulates hippocampal neurogenesis and memory in an age-dependent manner in response to reduced CREB activity.

  10. The impact of a Dysbindin schizophrenia susceptibility variant on fiber tract integrity in healthy individuals: a TBSS-based diffusion tensor imaging study.

    Science.gov (United States)

    Nickl-Jockschat, Thomas; Stöcker, Tony; Markov, Valentin; Krug, Axel; Huang, Ruihuang; Schneider, Frank; Habel, Ute; Zerres, Klaus; Nöthen, Markus M; Treutlein, Jens; Rietschel, Marcella; Shah, N Jon; Kircher, Tilo

    2012-04-02

    Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts. Copyright © 2011. Published by Elsevier Inc.

  11. Loss of dysbindin-1 in mice impairs reward-based operant learning by increasing impulsive and compulsive behavior.

    Science.gov (United States)

    Carr, Gregory V; Jenkins, Kimberly A; Weinberger, Daniel R; Papaleo, Francesco

    2013-03-15

    The dystrobrevin-binding protein 1 (DTNBP1) gene, which encodes the dysbindin-1 protein, is a potential schizophrenia susceptibility gene. Polymorphisms in the DTNBP1 gene have been associated with altered cognitive abilities. In the present study, dysbindin-1 null mutant (dys-/-), heterozygous (dys+/-), and wild-type (dys+/+) mice, on a C57BL/6J genetic background, were tested in either a match to sample or nonmatch to sample visual discrimination task. This visual discrimination task was designed to measure rule learning and detect any changes in response timing over the course of testing. Dys-/- mice displayed significant learning deficits and required more trials to acquire this task. However, once criterion was reached, there were no differences between the genotypes on any behavioral measures. Dys-/- mice exhibited increased compulsive and impulsive behaviors compared to control littermates suggesting the inability to suppress incorrectly-timed responses underlies their increased time to acquisition. Indeed, group comparisons of behavior differences between the first and last day of testing showed that only dys-/- mice consistently decreased measures of perseverative, premature, timeout, and total responses. These findings illustrate how some aspects of altered cognitive performance in dys-/- mice might be related to increased impulsive and compulsive behaviors, analogous to cognitive deficits in some individuals with psychiatric disorders.

  12. Functional identification of activity-regulated, high-affinity glutamine transport in hippocampal neurons inhibited by riluzole.

    Science.gov (United States)

    Erickson, Jeffrey D

    2017-07-01

    Glutamine (Gln) is considered the preferred precursor for the neurotransmitter pool of glutamate (Glu), the major excitatory transmitter in the mammalian CNS. Here, an activity-regulated, high-affinity Gln transport system is described in developing and mature neuron-enriched hippocampal cultures that is potently inhibited by riluzole (IC50 1.3 ± 0.5 μM), an anti-glutamatergic drug, and is blocked by low concentrations of 2-(methylamino)isobutyrate (MeAIB), a system A transport inhibitor. K(+) -stimulated MeAIB transport displays an affinity (Km ) for MeAIB of 37 ± 1.2 μM, saturates at ~ 200 μM, is dependent on extracellular Ca(2+) , and is blocked by inhibition of voltage-gated Ca(2+) channels. Spontaneous MeAIB transport is also dependent on extracellullar Ca(2+) and voltage-gated calcium channels, but is also blocked by the Na(+) channel blocker tetrodotoxin, by Glu receptor antagonists, and by GABA indicating its dependence on intact neural circuits driven by endogenous glutamatergic activity. The transport of MeAIB itself does not rely on Ca(2+) , but on Na(+) ions, and is pH sensitive. Activity-regulated, riluzole-sensitive spontaneous and K(+) -stimulated transport is minimal at 7-8 days in vitro, coordinately induced during the next 2 weeks and is maximally expressed by days in vitro > 20; the known period for maturation of the Glu/Gln cycle and regulated pre-synaptic Glu release. Competition analyses with various amino acids indicate that Gln is the most likely physiological substrate. Activity-regulated Gln/MeAIB transport is not observed in astrocytes. The functional identification of activity-regulated, high-affinity, riluzole-sensitive Gln/MeAIB transport in hippocampal neurons may have important ramifications in the neurobiology of activity-stimulated pre-synaptic Glu release, the Glu/Gln cycle between astrocytes and neurons, and neuronal Glu-induced excitotoxicity. Cover Image for this issue: doi: 10.1111/jnc.13805. © 2017

  13. ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.

    Science.gov (United States)

    Tindi, Jaafar O; Chávez, Andrés E; Cvejic, Svetlana; Calvo-Ochoa, Erika; Castillo, Pablo E; Jordan, Bryen A

    2015-06-17

    NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia. Copyright

  14. Hippocampal Deletion of BDNF Gene Attenuates Gamma Oscillations in Area CA1 by Up-Regulating 5-HT3 Receptor

    OpenAIRE

    Ying Huang; Alexei Morozov

    2011-01-01

    BACKGROUND: Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this recept...

  15. Cell surface area regulation in neurons in hippocampal slice cultures is resistant to oxygen-glucose deprivation

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    Natalya Shulyakova

    2010-09-01

    Full Text Available Natalya Shulyakova1,2, Jamie Fong2, Diana Diec2, Adrian Nahirny1,2, Linda R Mills1,21Department of Physiology, University of Toronto, Toronto, ON, Canada, M5T 2S8; 2Toronto Western Hospital Research Institute, University Health Network, 11-430, 399 Bathurst St, Toronto, ON, Canada, M5T 2S8Background: Neurons swell in response to a variety of insults. The capacity to recover, ie, to shrink, is critical for neuronal function and survival. Studies on dissociated neurons have shown that during swelling and shrinking, neurons reorganize their plasma membrane; as neurons swell, in response to hypo-osmotic media, the bilayer area increases. Upon restoration of normo-osmotic media, neurons shrink, forming transient invaginations of the plasma membrane known as vacuole-like dilations (VLDs, to accommodate the decrease in the bilayer.Methods: Here we used confocal microscopy to monitor neuronal swelling and shrinking in the three-dimensional (3D environment of post-natal rat hippocampal slice cultures. To label neurons, we used biolistic transfection, to introduce enhanced green fluorescent protein (eGFP targeted to the cytoplasm; and a membrane targeted GFP (lckGFP, targeted to the plasma membrane.Results: Neurons in slice cultures swelled and shrank in response to hypo-osmotic to normo-osmotic media changes. Oxygen-glucose deprivation (OGD caused sustained neuronal swelling; after reperfusion, some neurons recovered but in others, VLD recovery was stalled. OGD did not impair neuronal capacity to recover from a subsequent osmotic challenge.Conclusion: These results suggest cell surface area regulation (SAR is an intrinsic property of neurons, and that neuronal capacity for SAR may play an important role in the brain’s response to ischemic insults.Keywords: neurons, swelling, ischemia, cell surface area, hippocampal slice culture

  16. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

    Science.gov (United States)

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

    2017-03-15

    Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

  17. REM Sleep-Dependent Bidirectional Regulation of Hippocampal-Based Emotional Memory and LTP.

    Science.gov (United States)

    Ravassard, Pascal; Hamieh, Al Mahdy; Joseph, Mickaël Antoine; Fraize, Nicolas; Libourel, Paul-Antoine; Lebarillier, Léa; Arthaud, Sébastien; Meissirel, Claire; Touret, Monique; Malleret, Gaël; Salin, Paul-Antoine

    2016-04-01

    Prolonged rapid-eye-movement (REM) sleep deprivation has long been used to study the role of REM sleep in learning and memory processes. However, this method potentially induces stress and fatigue that may directly affect cognitive functions. Here, by using a short-term and nonstressful REM sleep deprivation (RSD) method we assessed in rats the bidirectional influence of reduced and increased REM sleep amount on hippocampal-dependent emotional memory and plasticity. Our results indicate that 4 h RSD impaired consolidation of contextual fear conditioning (CFC) and induction of long-term potentiation (LTP), while decreasing density of Egr1/Zif268-expressing neurons in the CA1 region of the dorsal hippocampus. LTP and Egr1 expression were not affected in ventral CA1. Conversely, an increase in REM sleep restores and further facilitates CFC consolidation and LTP induction, and also increases Egr1 expression in dorsal CA1. Moreover, CFC consolidation, Egr1 neuron density, and LTP amplitude in dorsal CA1 show a positive correlation with REM sleep amount. Altogether, these results indicate that mild changes in REM sleep amount bidirectionally affect memory and synaptic plasticity mechanisms occurring in the CA1 area of the dorsal hippocampus.

  18. The Susd2 protein regulates neurite growth and excitatory synaptic density in hippocampal cultures.

    Science.gov (United States)

    Nadjar, Yann; Triller, Antoine; Bessereau, Jean-Louis; Dumoulin, Andrea

    2015-03-01

    Complement control protein (CCP) domains have adhesion properties and are commonly found in proteins that control the complement immune system. However, an increasing number of proteins containing CCP domains have been reported to display neuronal functions. Susd2 is a transmembrane protein containing one CCP domain. It was previously identified as a tumor-reversing protein, but has no characterized function in the CNS. The present study investigates the expression and function of Susd2 in the rat hippocampus. Characterization of Susd2 during development showed a peak in mRNA expression two weeks after birth. In hippocampal neuronal cultures, the same expression profile was observed at 15days in vitro for both mRNA and protein, a time consistent with synaptogenesis in our model. At the subcellular level, Susd2 was located on the soma, axons and dendrites, and appeared to associate preferentially with excitatory synapses. Inhibition of Susd2 by shRNAs led to decreased numbers of excitatory synaptic profiles, exclusively. Also, morphological parameters were studied on young (5DIV) developing neurons. After Susd2 inhibition, an increase in dendritic tree length but a decrease in axon elongation were observed, suggesting changes in adhesion properties. Our results demonstrate a dual role for Susd2 at different developmental stages, and raise the question whether Susd2 and other CCP-containing proteins expressed in the CNS could be function-related.

  19. Regulation of dopamine D1 receptor dynamics within the postsynaptic density of hippocampal glutamate synapses.

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    Laurent Ladepeche

    Full Text Available Dopamine receptor potently modulates glutamate signalling, synaptic plasticity and neuronal network adaptations in various pathophysiological processes. Although key intracellular signalling cascades have been identified, the cellular mechanism by which dopamine and glutamate receptor-mediated signalling interplay at glutamate synapse remain poorly understood. Among the cellular mechanisms proposed to aggregate D1R in glutamate synapses, the direct interaction between D1R and the scaffold protein PSD95 or the direct interaction with the glutamate NMDA receptor (NMDAR have been proposed. To tackle this question we here used high-resolution single nanoparticle imaging since it provides a powerful way to investigate at the sub-micron resolution the dynamic interaction between these partners in live synapses. We demonstrate in hippocampal neuronal networks that dopamine D1 receptors (D1R laterally diffuse within glutamate synapses, in which their diffusion is reduced. Disrupting the interaction between D1R and PSD95, through genetical manipulation and competing peptide, did not affect D1R dynamics in glutamatergic synapses. However, preventing the physical interaction between D1R and the GluN1 subunit of NMDAR abolished the synaptic stabilization of diffusing D1R. Together, these data provide direct evidence that the interaction between D1R and NMDAR in synapses participate in the building of the dopamine-receptor-mediated signalling, and most likely to the glutamate-dopamine cross-talk.

  20. The up-regulation of voltage-gated sodium channels subtypes coincides with an increased sodium current in hippocampal neuronal culture model.

    Science.gov (United States)

    Guo, Feng; Xu, Xiaoxue; Cai, Jiqun; Hu, Huiyuan; Sun, Wei; He, Guilin; Shao, Dongxue; Wang, Lei; Chen, Tianbao; Shaw, Chris; Zhu, Tong; Hao, Liying

    2013-02-01

    Voltage-gated sodium channels (VGSC) have been linked to inherited forms of epilepsy. The expression and biophysical properties of VGSC in the hippocampal neuronal culture model have not been clarified. In order to evaluate mechanisms of epileptogenesis that are related to VGSC, we examined the expression and function of VGSC in the hippocampal neuronal culture model in vitro and spontaneously epileptic rats (SER) in vivo. Our data showed that the peak amplitude of transient, rapidly-inactivating Na(+) current (I(Na,T)) in model neurons was significantly increased compared with control neurons, and the activation curve was shifted to the negative potentials in model neurons in whole cell recording by patch-clamp. In addition, channel activity of persistent, non-inactivating Na(+) current (I(Na,P)) was obviously increased in the hippocampal neuronal culture model as judged by single-channel patch-clamp recording. Furthermore, VGSC subtypes Na(V)1.1, Na(V)1.2 and Na(V)1.3 were up-regulated at the protein expression level in model neurons and SER as assessed by Western blotting. Four subtypes of VGSC proteins in SER were clearly present throughout the hippocampus, including CA1, CA3 and dentate gyrus regions, and neurons expressing VGSC immunoreactivity were also detected in hippocampal neuronal culture model by immunofluorescence. These findings suggested that the up-regulation of voltage-gated sodium channels subtypes in neurons coincided with an increased sodium current in the hippocampal neuronal culture model, providing a possible explanation for the observed seizure discharge and enhanced excitability in epilepsy.

  1. Hippocampal histone acetylation regulates object recognition and the estradiol-induced enhancement of object recognition.

    Science.gov (United States)

    Zhao, Zaorui; Fan, Lu; Fortress, Ashley M; Boulware, Marissa I; Frick, Karyn M

    2012-02-15

    Histone acetylation has recently been implicated in learning and memory processes, yet necessity of histone acetylation for such processes has not been demonstrated using pharmacological inhibitors of histone acetyltransferases (HATs). As such, the present study tested whether garcinol, a potent HAT inhibitor in vitro, could impair hippocampal memory consolidation and block the memory-enhancing effects of the modulatory hormone 17β-estradiol E2. We first showed that bilateral infusion of garcinol (0.1, 1, or 10 μg/side) into the dorsal hippocampus (DH) immediately after training impaired object recognition memory consolidation in ovariectomized female mice. A behaviorally effective dose of garcinol (10 μg/side) also significantly decreased DH HAT activity. We next examined whether DH infusion of a behaviorally subeffective dose of garcinol (1 ng/side) could block the effects of DH E2 infusion on object recognition and epigenetic processes. Immediately after training, ovariectomized female mice received bilateral DH infusions of vehicle, E2 (5 μg/side), garcinol (1 ng/side), or E2 plus garcinol. Forty-eight hours later, garcinol blocked the memory-enhancing effects of E2. Garcinol also reversed the E2-induced increase in DH histone H3 acetylation, HAT activity, and levels of the de novo methyltransferase DNMT3B, as well as the E2-induced decrease in levels of the memory repressor protein histone deacetylase 2. Collectively, these findings suggest that histone acetylation is critical for object recognition memory consolidation and the beneficial effects of E2 on object recognition. Importantly, this work demonstrates that the role of histone acetylation in memory processes can be studied using a HAT inhibitor.

  2. A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Leiter, Odette; Kempermann, Gerd; Walker, Tara L

    2016-01-01

    Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus-a region crucial for learning and memory.

  3. Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons.

    Science.gov (United States)

    Chamma, Ingrid; Heubl, Martin; Chevy, Quentin; Renner, Marianne; Moutkine, Imane; Eugène, Emmanuel; Poncer, Jean Christophe; Lévi, Sabine

    2013-09-25

    The neuronal K/Cl transporter KCC2 exports chloride ions and thereby influences the efficacy and polarity of GABA signaling in the brain. KCC2 is also critical for dendritic spine morphogenesis and the maintenance of glutamatergic transmission in cortical neurons. Because KCC2 plays a pivotal role in the function of central synapses, it is of particular importance to understand the cellular and molecular mechanisms underlying its regulation. Here, we studied the impact of membrane diffusion and clustering on KCC2 function. KCC2 forms clusters in the vicinity of both excitatory and inhibitory synapses. Using quantum-dot-based single-particle tracking on rat primary hippocampal neurons, we show that KCC2 is slowed down and confined at excitatory and inhibitory synapses compared with extrasynaptic regions. However, KCC2 escapes inhibitory synapses faster than excitatory synapses, reflecting stronger molecular constraints at the latter. Interfering with KCC2-actin interactions or inhibiting F-actin polymerization releases diffusion constraints on KCC2 at excitatory but not inhibitory synapses. Thus, F-actin constrains KCC2 diffusion at excitatory synapses, whereas KCC2 is confined at inhibitory synapses by a distinct mechanism. Finally, increased neuronal activity rapidly increases the diffusion coefficient and decreases the dwell time of KCC2 at excitatory synapses. This effect involves NMDAR activation, Ca(2+) influx, KCC2 S940 dephosphorylation and calpain protease cleavage of KCC2 and is accompanied by reduced KCC2 clustering and ion transport function. Thus, activity-dependent regulation of KCC2 lateral diffusion and clustering allows for a rapid regulation of chloride homeostasis in neurons.

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

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    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.

  5. Store-operated Ca2+ entry in hippocampal neurons: Regulation by protein tyrosine phosphatase PTP1B.

    Science.gov (United States)

    Koss, David J; Riedel, Gernot; Bence, Kendra; Platt, Bettina

    2013-02-01

    Store operated Ca(2+) entry (SOCE) replenishes intracellular Ca(2+) stores and activates a number of intracellular signalling pathways. Whilst several molecular components forming store operated Ca(2+) channels (SOCC) have been identified, their modulation in neurons remains poorly understood. Here, we extend on our previous findings and show that neuronal SOCE is modulated by tyrosine phosphorylation. Cyclopiazonic acid induced SOCE was characterised in hippocampal cultures derived from forebrain specific protein tyrosine phosphatase 1B knockout (PTP1B KO) mice and wild type (WT) litter mates using Fura-2 Ca(2+) imaging. PTP1B KO cultures expressed elevated SOCE relative to WT cultures without changes in cytoplasmic Ca(2+) homeostasis or depolarisation-induced Ca(2+) influx. WT and PTP1B KO cultures displayed similar pharmacological sensitivities towards the SOCE inhibitors gadolinium and 2-aminoethoxydiphenyl borate, as well as the tyrosine kinase inhibitor Ag126 indicating an augmentation of native SOCCs by PTP1B. Following store depletion WT culture homogenates showed heightened phospho-tyrosine levels, an increase in Src tyrosine kinase activation and two minor PTP1B species. These data suggest tyrosine phosphorylation gating SOCE, and implicate PTP1B as a key regulatory enzyme. The involvement of PTP1B in SOCE and its relation to SOCC components and mechanism of regulation are discussed.

  6. 5-HT3a Receptors Modulate Hippocampal Gamma Oscillations by Regulating Synchrony of Parvalbumin-Positive Interneurons.

    Science.gov (United States)

    Huang, Ying; Yoon, Kristopher; Ko, Ho; Jiao, Song; Ito, Wataru; Wu, Jian-Young; Yung, Wing-Ho; Lu, Bai; Morozov, Alexei

    2016-02-01

    Gamma-frequency oscillatory activity plays an important role in information integration across brain areas. Disruption in gamma oscillations is implicated in cognitive impairments in psychiatric disorders, and 5-HT3 receptors (5-HT3Rs) are suggested as therapeutic targets for cognitive dysfunction in psychiatric disorders. Using a 5-HT3aR-EGFP transgenic mouse line and inducing gamma oscillations by carbachol in hippocampal slices, we show that activation of 5-HT3aRs, which are exclusively expressed in cholecystokinin (CCK)-containing interneurons, selectively suppressed and desynchronized firings in these interneurons by enhancing spike-frequency accommodation in a small conductance potassium (SK)-channel-dependent manner. Parvalbumin-positive interneurons therefore received diminished inhibitory input leading to increased but desynchronized firings of PV cells. As a consequence, the firing of pyramidal neurons was desynchronized and gamma oscillations were impaired. These effects were independent of 5-HT3aR-mediated CCK release. Our results therefore revealed an important role of 5-HT3aRs in gamma oscillations and identified a novel crosstalk among different types of interneurons for regulation of network oscillations. The functional link between 5-HT3aR and gamma oscillations may have implications for understanding the cognitive impairments in psychiatric disorders.

  7. β-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a β-subunit-like fashion.

    Science.gov (United States)

    Hessler, Sabine; Zheng, Fang; Hartmann, Stephanie; Rittger, Andrea; Lehnert, Sandra; Völkel, Meike; Nissen, Matthias; Edelmann, Elke; Saftig, Paul; Schwake, Michael; Huth, Tobias; Alzheimer, Christian

    2015-02-25

    The β-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a β-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain. Copyright © 2015 the authors 0270-6474/15/353298-14$15.00/0.

  8. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner.

    Science.gov (United States)

    Clarke, G; Grenham, S; Scully, P; Fitzgerald, P; Moloney, R D; Shanahan, F; Dinan, T G; Cryan, J F

    2013-06-01

    Bacterial colonisation of the intestine has a major role in the post-natal development and maturation of the immune and endocrine systems. These processes are key factors underpinning central nervous system (CNS) signalling. Regulation of the microbiome-gut-brain axis is essential for maintaining homeostasis, including that of the CNS. However, there is a paucity of data pertaining to the influence of microbiome on the serotonergic system. Germ-free (GF) animals represent an effective preclinical tool to investigate such phenomena. Here we show that male GF animals have a significant elevation in the hippocampal concentration of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid, its main metabolite, compared with conventionally colonised control animals. Moreover, this alteration is sex specific in contrast with the immunological and neuroendocrine effects which are evident in both sexes. Concentrations of tryptophan, the precursor of serotonin, are increased in the plasma of male GF animals, suggesting a humoral route through which the microbiota can influence CNS serotonergic neurotransmission. Interestingly, colonisation of the GF animals post weaning is insufficient to reverse the CNS neurochemical consequences in adulthood of an absent microbiota in early life despite the peripheral availability of tryptophan being restored to baseline values. In addition, reduced anxiety in GF animals is also normalised following restoration of the intestinal microbiota. These results demonstrate that CNS neurotransmission can be profoundly disturbed by the absence of a normal gut microbiota and that this aberrant neurochemical, but not behavioural, profile is resistant to restoration of a normal gut flora in later life.

  9. The α7 nicotinic acetylcholine receptor function in hippocampal neurons is regulated by the lipid composition of the plasma membrane.

    Science.gov (United States)

    Colón-Sáez, José O; Yakel, Jerrel L

    2011-07-01

    The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in cellular events such as neurotransmitter release, second messenger cascades, cell survival and apoptosis. In addition, they are a therapeutic target for the treatment of neurological disorders such as Alzheimer's disease and schizophrenia, and drugs that potentiate α7 nAChRs through the regulation of desensitization are currently being developed. Recently, these channels were found to be localized into lipid rafts. Here we show that the disruption of lipid rafts in rat primary hippocampal neurons, through cholesterol-scavenging drugs (methyl-β-cyclodextrin) and the enzymatic breakdown of sphingomyelin (sphingomyelinase), results in significant changes in the desensitization kinetics of native and expressed α7 nAChRs. These effects can be prevented by cotreatment with cholesterol and sphingomyelin, and can be mimicked by treatment with cholesterol and sphingomyelin synthesis inhibitors (mevastatin and myriocin, respectively), suggesting that the effects on desensitization kinetics are indeed due to changes in the levels of cholesterol and sphingomyelin in the plasma membrane. These data provide new insights into themechanism of desensitization of α7 nAChRs by providing evidence that the lipid composition of the plasma membrane can modulate the activity of the α7 nAChRs.

  10. A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Odette Leiter

    2016-01-01

    Full Text Available Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus—a region crucial for learning and memory.

  11. Ephrin-A3 reverse signaling regulates hippocampal neuronal damage and astrocytic glutamate transport after transient global ischemia.

    Science.gov (United States)

    Yang, Jinshan; Luo, Xiang; Huang, Xiaojiang; Ning, Qin; Xie, Minjie; Wang, Wei

    2014-11-01

    Increasing evidence indicates that the Eph receptors and their ephrin ligands are involved in the regulation of interactions between neurons and astrocytes. Moreover, astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptors is necessary for controlling the abundance of glial glutamate transporters. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. In the present study, we found that the EphA4 receptor and its ephrin-A3 ligand, which were distributed in neurons and astrocytes, respectively, in the hippocampus showed a coincident up-regulation of protein expression in the early stage of ischemia. Application of clustered EphA4 decreased the expressions of astrocytic glutamate transporters together with astrocytic glutamate uptake capacity through activating ephrin-A3 reverse signaling. In consequence, neuronal loss was aggravated in the CA1 region of the hippocampus accompanied by impaired hippocampus-dependent spatial memory when clustered EphA4 treatment was administered prior to transient global ischemia. These findings indicate that EphA4-mediated ephrin-A3 reverse signaling is a crucial mechanism for astrocytes to control glial glutamate transporters and prevent glutamate excitotoxicity under pathological conditions. Astrocytic ephrin-A3 reverse signaling mediated by EphA4 receptor is necessary for controlling the abundance of glial glutamate transporters under physiological conditions. However, the role of ephrin-A3 reverse signaling in astrocytic function and neuronal death under ischemic conditions remains unclear. We found EphA4-mediated ephrin-A3 reverse signaling to be a crucial mechanism for astrocytes to control glial glutamate transporters and protect hippocampal neurons from glutamate excitotoxicity under ischemic conditions, this cascade representing a potential therapeutic target for stroke.

  12. Hippocampal deletion of BDNF gene attenuates gamma oscillations in area CA1 by up-regulating 5-HT3 receptor.

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    Ying Huang

    Full Text Available BACKGROUND: Pyramidal neurons in the hippocampal area CA3 express high levels of BDNF, but how this BDNF contributes to oscillatory properties of hippocampus is unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we examined carbachol-induced gamma oscillations in hippocampal slices lacking BDNF gene in the area CA3. The power of oscillations was reduced in the hippocampal area CA1, which coincided with increases in the expression and activity of 5-HT3 receptor. Pharmacological block of this receptor partially restored power of gamma oscillations in slices from KO mice, but had no effect in slices from WT mice. CONCLUSION/SIGNIFICANCE: These data suggest that BDNF facilitates gamma oscillations in the hippocampus by attenuating signaling through 5-HT3 receptor. Thus, BDNF modulates hippocampal oscillations through serotonergic system.

  13. Hippocampal Regulation of Context-Dependent Neuronal Activity in the Lateral Amygdala

    Science.gov (United States)

    Maren, Stephen; Hobin, Jennifer A.

    2007-01-01

    Pavlovian fear conditioning is a robust and enduring form of emotional learning that provides an ideal model system for studying contextual regulation of memory retrieval. After extinction the expression of fear conditional responses (CRs) is context-specific: A conditional stimulus (CS) elicits greater conditional responding outside compared with…

  14. Continuous versus cyclic progesterone exposure differentially regulates hippocampal gene expression and functional profiles.

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    Liqin Zhao

    Full Text Available This study investigated the impact of chronic exposure to continuous (CoP4 versus cyclic progesterone (CyP4 alone or in combination with 17β-estradiol (E2 on gene expression profiles targeting bioenergetics, metabolism and inflammation in the adult female rat hippocampus. High-throughput qRT-PCR analyses revealed that ovarian hormonal depletion induced by ovariectomy (OVX led to multiple significant gene expression alterations, which were to a great extent reversed by co-administration of E2 and CyP4. In contrast, co-administration of E2 and CoP4 induced a pattern highly resembling OVX. Bioinformatics analyses further revealed clear disparities in functional profiles associated with E2+CoP4 and E2+CyP4. Genes involved in mitochondrial energy (ATP synthase α subunit; Atp5a1, redox homeostasis (peroxiredoxin 5; Prdx5, insulin signaling (insulin-like growth factor I; Igf1, and cholesterol trafficking (liver X receptor α subtype; Nr1h3, differed in direction of regulation by E2+CoP4 (down-regulation relative to OVX and E2+CyP4 (up-regulation relative to OVX. In contrast, genes involved in amyloid metabolism (β-secretase; Bace1 differed only in degree of regulation, as both E2+CoP4 and E2+CyP4 induced down-regulation at different efficacy. E2+CyP4-induced changes could be associated with regulation of progesterone receptor membrane component 1(Pgrmc1. In summary, results from this study provide evidence at the molecular level that differing regimens of hormone therapy (HT can induce disparate gene expression profiles in brain. From a translational perspective, confirmation of these results in a model of natural menopause, would imply that the common regimen of continuous combined HT may have adverse consequences whereas a cyclic combined regimen, which is more physiological, could be an effective strategy to maintain neurological health and function throughout menopausal aging.

  15. Gap Junctions in the Ventral Hippocampal-Medial Prefrontal Pathway Are Involved in Anxiety Regulation

    Science.gov (United States)

    Schoenfeld, Timothy J.; Kloth, Alexander D.; Hsueh, Brian; Runkle, Matthew B.; Kane, Gary A.; Wang, Samuel S.-H.

    2014-01-01

    Anxiety disorders are highly prevalent but little is known about their underlying mechanisms. Gap junctions exist in brain regions important for anxiety regulation, such as the ventral hippocampus (vHIP) and mPFC, but their functions in these areas have not been investigated. Using pharmacological blockade of neuronal gap junctions combined with electrophysiological recordings, we found that gap junctions play a role in theta rhythm in the vHIP and mPFC of adult mice. Bilateral infusion of neuronal gap junction blockers into the vHIP decreased anxiety-like behavior on the elevated plus maze and open field. Similar anxiolytic effects were observed with unilateral infusion of these drugs into the vHIP combined with contralateral infusion into the mPFC. No change in anxious behavior was observed with gap junction blockade in the unilateral vHIP alone or in the bilateral dorsal HIP. Since physical exercise is known to reduce anxiety, we examined the effects of long-term running on the expression of the neuronal gap junction protein connexin-36 among inhibitory interneurons and found a reduction in the vHIP. Despite this change, we observed no alteration in theta frequency or power in long-term runners. Collectively, these findings suggest that neuronal gap junctions in the vHIP–mPFC pathway are important for theta rhythm and anxiety regulation under sedentary conditions but that additional mechanisms are likely involved in running-induced reduction in anxiety. PMID:25411496

  16. Electroacupuncture pretreatment exhibits anti-depressive effects by regulating hippocampal proteomics in rats with chronic restraint stress

    Directory of Open Access Journals (Sweden)

    Zhuo Guo

    2015-01-01

    Full Text Available The clinical effect of electroacupuncture on depression is widely recognized. However, the signal transduction pathways and target proteins involved remain unclear. In the present study, rat models of chronic restraint stress were used to explore the mechanism by which electroacupuncture alleviates depression. Rats were randomly divided into control, model, and electroacupuncture groups. Chronic restraint stress was induced in the model and electroacupuncture groups by restraining rats for 28 days. In the electroacupuncture group, electroacupuncture pretreatment at Baihui (GV20 and Yintang (GV29 acupoints was performed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes prior to restraint for 28 days. Open field tests and body weight measurements were carried out to evaluate the depressive symptoms at specific time points. On day 28, the crossing number, rearing number, and body weights of the model group were significantly lower than those in the control group. Behavior test results indicated that rat models of depressive-like symptoms were successfully established by chronic restraint stress combined with solitary raising. On day 28, an isobaric tag for a relative and absolute quantitation-based quantitative proteomic approach was performed to identify differentially expressed proteins in hippocampal samples obtained from the model and electroacupuncture groups. The potential function of these differential proteins was predicted through the use of the Cluster of Orthologous Groups of proteins (COG database. Twenty-seven differential proteins (uncharacteristic proteins expected were selected from the model and electroacupuncture groups. In addition to unknown protein functions, COG are mainly concentrated in general prediction function, mechanism of signal transduction, amino acid transport and metabolism groups. This suggests that electroacupuncture improved depressive-like symptoms by regulating differential proteins, and most of these related

  17. Electroacupuncture pretreatment exhibits anti-depressive effects by regulating hippocampal proteomics in rats with chronic restraint stress

    Institute of Scientific and Technical Information of China (English)

    Zhuo Guo; Xu-hui Zhang; Ya Tu; Tian-wei Guo; Yun-chu Wu; Xue-qin Yang; Lan Sun; Xin-jing Yang; Wen-yue Zhang; Yu Wang

    2015-01-01

    The clinical effect of electroacupuncture on depression is widely recognized. However, the signal transduction pathways and target proteins involved remain unclear. In the present study, rat models of chronic restraint stress were used to explore the mechanism by which electroacupuncture alleviates depression. Rats were randomly divided into control, model, and electroacupuncture groups. Chronic restraint stress was induced in the model and elec-troacupuncture groups by restraining rats for 28 days. In the electroacupuncture group, electroacupuncture pretreatment atBaihui (GV20) andYintang (GV29) acupoints was per-formed daily (1 mA, 2 Hz, discontinuous wave, 20 minutes) prior to restraint for 28 days. Open ifeld tests and body weight measurements were carried out to evaluate the depressive symptoms at speciifc time points. On day 28, the crossing number, rearing number, and body weights of the model group were signiifcantly lower than those in the control group. Behavior test results indicated that rat models of depressive-like symptoms were successfully established by chronic restraint stress combined with solitary raising. On day 28, an isobaric tag for a relative and abso-lute quantitation-based quantitative proteomic approach was performed to identify differentially expressed proteins in hippocampal samples obtained from the model and electroacupuncture groups. The potential function of these differential proteins was predicted through the use of the Cluster of Orthologous Groups of proteins (COG) database. Twenty-seven differential pro-teins (uncharacteristic proteins expected) were selected from the model and electroacupuncture groups. In addition to unknown protein functions, COG are mainly concentrated in general prediction function, mechanism of signal transduction, amino acid transport and metabolism groups. This suggests that electroacupuncture improved depressive-like symptoms by regulating differential proteins, and most of these related proteins

  18. Activation of AMP-activated protein kinase regulates hippocampal neuronal pH by recruiting Na(+)/H(+) exchanger NHE5 to the cell surface.

    Science.gov (United States)

    Jinadasa, Tushare; Szabó, Elöd Z; Numat, Masayuki; Orlowski, John

    2014-07-25

    Strict regulation of intra- and extracellular pH is an important determinant of nervous system function as many voltage-, ligand-, and H(+)-gated cationic channels are exquisitely sensitive to transient fluctuations in pH elicited by neural activity and pathophysiologic events such as hypoxia-ischemia and seizures. Multiple Na(+)/H(+) exchangers (NHEs) are implicated in maintenance of neural pH homeostasis. However, aside from the ubiquitous NHE1 isoform, their relative contributions are poorly understood. NHE5 is of particular interest as it is preferentially expressed in brain relative to other tissues. In hippocampal neurons, NHE5 regulates steady-state cytoplasmic pH, but intriguingly the bulk of the transporter is stored in intracellular vesicles. Here, we show that NHE5 is a direct target for phosphorylation by the AMP-activated protein kinase (AMPK), a key sensor and regulator of cellular energy homeostasis in response to metabolic stresses. In NHE5-transfected non-neuronal cells, activation of AMPK by the AMP mimetic AICAR or by antimycin A, which blocks aerobic respiration and causes acidification, increased cell surface accumulation and activity of NHE5, and elevated intracellular pH. These effects were effectively blocked by the AMPK antagonist compound C, the NHE inhibitor HOE694, and mutation of a predicted AMPK recognition motif in the NHE5 C terminus. This regulatory pathway was also functional in primary hippocampal neurons, where AMPK activation of NHE5 protected the cells from sustained antimycin A-induced acidification. These data reveal a unique role for AMPK and NHE5 in regulating the pH homeostasis of hippocampal neurons during metabolic stress.

  19. NO regulates the strength of synaptic inputs onto hippocampal CA1 neurons via NO-GC1/cGMP signalling.

    Science.gov (United States)

    Neitz, A; Mergia, E; Neubacher, U; Koesling, D; Mittmann, T

    2015-06-01

    GABAergic interneurons are the predominant source of inhibition in the brain that coordinate the level of excitation and synchronization in neuronal circuitries. However, the underlying cellular mechanisms are still not fully understood. Here we report nitric oxide (NO)/NO-GC1 signalling as an important regulatory mechanism of GABAergic and glutamatergic synaptic transmission in the hippocampal CA1 region. Deletion of the NO receptor NO-GC1 induced functional alterations, indicated by a strong reduction of spontaneous and evoked inhibitory postsynaptic currents (IPSCs), which could be compensated by application of the missing second messenger cGMP. Moreover, we found a general impairment in the strength of inhibitory and excitatory synaptic inputs onto CA1 pyramidal neurons deriving from NO-GC1KO mice. Finally, we disclosed one subpopulation of GABAergic interneurons, fast-spiking interneurons, that receive less excitatory synaptic input and consequently respond with less spike output after blockage of the NO/cGMP signalling pathway. On the basis of these and previous findings, we propose NO-GC1 as the major NO receptor which transduces the NO signal into cGMP at presynaptic terminals of different neuronal subtypes in the hippocampal CA1 region. Furthermore, we suggest NO-GC1-mediated cGMP signalling as a mechanism which regulates the strength of synaptic transmission, hence being important in gating information processing between hippocampal CA3 and CA1 region.

  20. Tumor necrosis factor expressed by primary hippocampal neurons and SH-SY5Y cells is regulated by alpha(2)-adrenergic receptor activation.

    Science.gov (United States)

    Renauld, A E; Spengler, R N

    2002-01-15

    Neuron expression of the cytokine tumor necrosis factor-alpha (TNF), and the regulation of the levels of TNF by alpha(2)-adrenergic receptor activation were investigated. Adult rat hippocampal neurons and phorbol ester (PMA)-differentiated SH-SY5Y cells were examined. Intracellular levels of TNF mRNA accumulation, as well as TNF protein and that released into the supernatant were quantified by in situ hybridization, immunocytochemistry and bioanalysis, respectively. Both neuron cultures demonstrated constitutive production of TNF. Activation of the alpha(2)-adrenergic receptor increased intracellular levels of TNF mRNA and protein in SH-SY5Y cells after addition of graded concentrations of the selective agonist, Brimonidine (UK-14304) to parallel cultures. Intracellular levels of mRNA were increased in a concentration-dependent fashion within 15 min of UK-14304 addition and were sustained during 24 hr of receptor activation. In addition, the levels of TNF in the supernatant were increased in both types of neuron cultures within 15 min of alpha(2)-adrenergic receptor activation. Furthermore, levels of TNF significantly increased in the supernatants of both neuron cultures after potassium-induced depolarization. A reduction in this depolarization-induced release occurred in hippocampal neuron cultures after exposure to the sympathomimetic tyramine with media replacement to deplete endogenous catecholamines. This finding reveals a role for endogenous catecholamines in the regulation of TNF production. Potassium-induced depolarization resulted in the release of TNF in hippocampal neuron cultures within 15 min but not until 24 hr in SH-SY5Y cultures demonstrating a temporally mediated event dependent upon cell type. Neuron expression of TNF, regulated by alpha(2)-adrenergic receptor activation demonstrates not only how a neuron controls its own production of this pleiotropic cytokine, but also displays a normal role for neurons in directing the many functions of TNF.

  1. Sex Steroid Hormones Matter for Learning and Memory: Estrogenic Regulation of Hippocampal Function Inmale and Female Rodents

    Science.gov (United States)

    Frick, Karyn M.; Kim, Jaekyoon; Tuscher, Jennifer J.; Fortress, Ashley M.

    2015-01-01

    Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17ß-estradiol (E[subscript 2]), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes…

  2. The signaling mechanisms of hippocampal endoplasmic reticulum stress affecting neuronal plasticity-related protein levels in high fat diet-induced obese rats and the regulation of aerobic exercise.

    Science.gov (United States)

    Cai, Ming; Wang, Hong; Li, Jing-Jing; Zhang, Yun-Li; Xin, Lei; Li, Feng; Lou, Shu-Jie

    2016-10-01

    High fat diet (HFD)-induced obesity has been shown to reduce the levels of neuronal plasticity-related proteins, specifically brain-derived neurotrophic factor (BDNF) and synaptophysin (SYN), in the hippocampus. However, the underlying mechanisms are not fully clear. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating gene expression and protein production by affecting stress signaling pathways and ER functions of protein folding and post-translational modification in peripheral tissues of obese rodent models. Additionally, HFD that is associated with hyperglycemia could induce hippocampal ERS, thus impairing insulin signaling and cognitive health in HFD mice. One goal of this study was to determine whether hyperglycemia and hyperlipidemia could cause hippocampal ERS in HFD-induced obese SD rats, and explore the potential mechanisms of ERS regulating hippocampal BDNF and SYN proteins production. Additionally, although regular aerobic exercise could reduce central inflammation and elevate hippocampal BDNF and SYN levels in obese rats, the regulated mechanisms are poorly understood. Nrf2-HO-1 pathways play roles in anti-ERS, anti-inflammation and anti-apoptosis in peripheral tissues. Therefore, the other goal of this study was to determine whether aerobic exercise could activate Nrf2-HO-1 in hippocampus to alleviate obesity-induced hippocampal ERS, which would lead to increased BDNF and SYN levels. Male SD rats were fed on HFD for 8weeks to establish the obese model. Then, 8weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that HFD-induced obesity caused hyperglycemia and hyperlipidemia, and significantly promoted hippocampal glucose transporter 3 (GLUT3) and fatty acid transport protein 1 (FATP1) protein expression. These results were associated with the activation of hippocampal ERS and ERS-mediated apoptosis. At the same time, we found that excessive hippocampal ERS not only

  3. Distribution of cocaine- and amphetamine-regulated transcript in the hippocampal formation of the guinea pig and domestic pig.

    Science.gov (United States)

    Kolenkiewicz, M; Robak, A; Równiak, M; Bogus-Nowakowska, K; Całka, J; Majewski, M

    2009-02-01

    This study provides a detailed description concerning the distribution of cocaineand amphetamine-regulated transcript (CART) subunits - CART(61-102) and rhCART(28-116) - in the hippocampal formation (HF) of the guinea pig and domestic pig, focussing on the dentate gyrus (DG) and hippocampus proper (HP). Although in both studied species CART-immunoreactive (CART-IR) neuronal somata and processes were present generally in the same layers, some species-specific differences were still found. In the granular layer (GL) of both species, the ovalshaped neurons and some thick varicose fibres were encountered. In the guinea pig there was an immunoreactive "band of dots", probably representing crosssectioned terminals within the DG molecular layer (MOL), whereas in the domestic pig, some varicose fibres were detected, thus suggesting a different orientation of, at least, some nerve terminals. Furthermore, some CART-positive cells and fibres were observed in the hilus (HL) of the guinea pig, whereas in the analogical part of the domestic pig only nerve terminals were labelled. In both species, in the pyramidal layer (PL) of the hippocampus proper, CART-IR triangular somata were observed in the CA3 sector, as well as some positive processes in MOL; however, a few immunoreactive perikarya were found only in the CA1 sector of the guinea pig. As regards the localization patterns of two isoforms of CART in the guinea pig, both peptide fragments were present simultaneously in each of the labelled neurons or fibres, whereas in the domestic pig three types of fibres may be distinguished within the area of the DG. In the hilus and MOL of the dentate gyrus, there were fibres expressing both isoforms of CART in their whole length (fibres of the first type). Fibres of the second type (in GL) coexpressed both peptides only on their short segments, and the last ones (in MOL) expressed solely rhCART(28-116). These results indicate that the distribution of the two CART isoforms are

  4. Leptin Induces Hippocampal Synaptogenesis via CREB-Regulated MicroRNA-132 Suppression of p250GAP

    Science.gov (United States)

    Dhar, Matasha; Zhu, Mingyan; Impey, Soren; Lambert, Talley J.; Bland, Tyler; Karatsoreos, Ilia N.; Nakazawa, Takanobu

    2014-01-01

    Leptin acts in the hippocampus to enhance cognition and reduce depression and anxiety. Cognitive and emotional disorders are associated with abnormal hippocampal dendritic spine formation and synaptogenesis. Although leptin has been shown to induce synaptogenesis in the hypothalamus, its effects on hippocampal synaptogenesis and the mechanism(s) involved are not well understood. Here we show that leptin receptors (LepRs) are critical for hippocampal dendritic spine formation in vivo because db/db mice lacking the long form of the leptin receptor (LepRb) have reduced spine density on CA1 and CA3 neurons. Leptin promotes the formation of mature spines and functional glutamate synapses on hippocampal pyramidal neurons in both dissociated and slice cultures. These effects are blocked by short hairpin RNAs specifically targeting the LepRb and are absent in cultures from db/db mice. Activation of the LepR leads to cAMP response element–binding protein (CREB) phosphorylation and initiation of CREB-dependent transcription via the MAPK kinase/Erk pathway. Furthermore, both Mek/Erk and CREB activation are required for leptin-induced synaptogenesis. Leptin also increases expression of microRNA-132 (miR132), a well-known CREB target, which is also required for leptin-induced synaptogenesis. Last, leptin suppresses the expression of p250GAP, a miR132 target, and this suppression is obligatory for leptin's effects as is the downstream target of p250GAP, Rac1. LepRs appear to be critical in vivo as db/db mice have lowered hippocampal miR132 levels and elevated p250GAP expression. In conclusion, we identify a novel signaling pathway by which leptin increases synaptogenesis through inducing CREB transcription and increasing microRNA-mediated suppression of p250GAP activity, thus removing a known inhibitor of Rac1-stimulated synaptogenesis. PMID:24877561

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

    Science.gov (United States)

    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.

  6. Tat-HSP22 inhibits oxidative stress-induced hippocampal neuronal cell death by regulation of the mitochondrial pathway.

    Science.gov (United States)

    Jo, Hyo Sang; Kim, Dae Won; Shin, Min Jea; Cho, Su Bin; Park, Jung Hwan; Lee, Chi Hern; Yeo, Eun Ji; Choi, Yeon Joo; Yeo, Hyeon Ji; Sohn, Eun Jeong; Son, Ora; Cho, Sung-Woo; Kim, Duk-Soo; Yu, Yeon Hee; Lee, Keun Wook; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2017-01-04

    Oxidative stress plays an important role in the progression of various neuronal diseases including ischemia. Heat shock protein 22 (HSP22) is known to protect cells against oxidative stress. However, the protective effects and mechanisms of HSP22 in hippocampal neuronal cells under oxidative stress remain unknown. In this study, we determined whether HSP22 protects against hydrogen peroxide (H2O2)-induced oxidative stress in HT-22 using Tat-HSP22 fusion protein. We found that Tat-HSP22 transduced into HT-22 cells and that H2O2-induced cell death, oxidative stress, and DNA damage were significantly reduced by Tat-HSP22. In addition, Tat-HSP22 markedly inhibited H2O2-induced mitochondrial membrane potential, cytochrome c release, cleaved caspase-3, and Bax expression levels, while Bcl-2 expression levels were increased in HT-22 cells. Further, we showed that Tat-HSP22 transduced into animal brain and inhibited cleaved-caspase-3 expression levels as well as significantly inhibited hippocampal neuronal cell death in the CA1 region of animals in the ischemic animal model. In the present study, we demonstrated that transduced Tat-HSP22 attenuates oxidative stress-induced hippocampal neuronal cell death through the mitochondrial signaling pathway and plays a crucial role in inhibiting neuronal cell death, suggesting that Tat-HSP22 protein may be used to prevent oxidative stress-related brain diseases including ischemia.

  7. Hippocampal formation

    NARCIS (Netherlands)

    Cappaert, N.L.M.; van Strien, N.M.; Witter, M.P.; Paxinos, G.

    2015-01-01

    The hippocampal formation and parahippocampal region are prominent components of the rat nervous system and play a crucial role in learning, memory, and spatial navigation. Many new details regarding the entorhinal cortex have been discovered since the previous edition, and the growing interest in t

  8. The mammalian adult neurogenesis gene ontology (MANGO) provides a structural framework for published information on genes regulating adult hippocampal neurogenesis.

    Science.gov (United States)

    Overall, Rupert W; Paszkowski-Rogacz, Maciej; Kempermann, Gerd

    2012-01-01

    Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies, is essential in any field for comprehensive interpretation of existing knowledge but, until now, such a structure has been lacking for adult neurogenesis. We have created a resource with three components 1. A structured ontology describing the key stages in the development of adult hippocampal neural stem cells into functional granule cell neurons. 2. A comprehensive survey of the literature to annotate the results of all published reports on gene function in adult hippocampal neurogenesis (257 manuscripts covering 228 genes) to the appropriate terms in our ontology. 3. An easy-to-use searchable interface to the resulting database made freely available online. The manuscript presents an overview of the database highlighting global trends such as the current bias towards research on early proliferative stages, and an example gene set enrichment analysis. A limitation of the resource is the current scope of the literature which, however, is growing by around 100 publications per year. With the ontology and database in place, new findings can be rapidly annotated and regular updates of the database will be made publicly available. The resource we present allows relevant interpretation of gene expression screens in terms of defined stages of postnatal neuronal development. Annotation of genes by hand from the adult neurogenesis literature ensures the data are directly applicable to the system under study. We believe this approach could also serve as an example to other fields in a 'bottom-up' community effort complementing the already successful 'top-down' approach of the Gene Ontology.

  9. The mammalian adult neurogenesis gene ontology (MANGO provides a structural framework for published information on genes regulating adult hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Rupert W Overall

    Full Text Available BACKGROUND: Adult hippocampal neurogenesis is not a single phenotype, but consists of a number of sub-processes, each of which is under complex genetic control. Interpretation of gene expression studies using existing resources often does not lead to results that address the interrelatedness of these processes. Formal structure, such as provided by ontologies, is essential in any field for comprehensive interpretation of existing knowledge but, until now, such a structure has been lacking for adult neurogenesis. METHODOLOGY/PRINCIPAL FINDINGS: We have created a resource with three components 1. A structured ontology describing the key stages in the development of adult hippocampal neural stem cells into functional granule cell neurons. 2. A comprehensive survey of the literature to annotate the results of all published reports on gene function in adult hippocampal neurogenesis (257 manuscripts covering 228 genes to the appropriate terms in our ontology. 3. An easy-to-use searchable interface to the resulting database made freely available online. The manuscript presents an overview of the database highlighting global trends such as the current bias towards research on early proliferative stages, and an example gene set enrichment analysis. A limitation of the resource is the current scope of the literature which, however, is growing by around 100 publications per year. With the ontology and database in place, new findings can be rapidly annotated and regular updates of the database will be made publicly available. CONCLUSIONS/SIGNIFICANCE: The resource we present allows relevant interpretation of gene expression screens in terms of defined stages of postnatal neuronal development. Annotation of genes by hand from the adult neurogenesis literature ensures the data are directly applicable to the system under study. We believe this approach could also serve as an example to other fields in a 'bottom-up' community effort complementing the already

  10. Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model

    Science.gov (United States)

    Subburaju, S; Coleman, A J; Ruzicka, W B; Benes, F M

    2016-01-01

    Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ. PMID:26812044

  11. Toward dissecting the etiology of schizophrenia: HDAC1 and DAXX regulate GAD67 expression in an in vitro hippocampal GABA neuron model.

    Science.gov (United States)

    Subburaju, S; Coleman, A J; Ruzicka, W B; Benes, F M

    2016-01-26

    Schizophrenia (SZ) is associated with GABA neuron dysfunction in the hippocampus, particularly the stratum oriens of sector CA3/2. A gene expression profile analysis of human postmortem hippocampal tissue followed by a network association analysis had shown a number of genes differentially regulated in SZ, including the epigenetic factors HDAC1 and DAXX. To characterize the contribution of these factors to the developmental perturbation hypothesized to underlie SZ, lentiviral vectors carrying short hairpin RNA interference (shRNAi) for HDAC1 and DAXX were used. In the hippocampal GABA neuron culture model, HiB5, transduction with HDAC1 shRNAi showed a 40% inhibition of HDAC1 mRNA and a 60% inhibition of HDAC1 protein. GAD67, a enzyme associated with GABA synthesis, was increased twofold (mRNA); the protein showed a 35% increase. The expression of DAXX, a co-repressor of HDAC1, was not influenced by HDAC1 inhibition. Transduction of HiB5 cells with DAXX shRNAi resulted in a 30% inhibition of DAXX mRNA that translated into a 90% inhibition of DAXX protein. GAD1 mRNA was upregulated fourfold, while its protein increased by ~30%. HDAC1 expression was not altered by inhibition of DAXX. However, a physical interaction between HDAC1 and DAXX was demonstrated by co-immunoprecipitation. Inhibition of HDAC1 or DAXX increased expression of egr-1, transcription factor that had previously been shown to regulate the GAD67 promoter. Our in vitro results point to a key role of both HDAC1 and DAXX in the regulation of GAD67 in GABAergic HiB5 cells, strongly suggesting that these epigenetic/transcription factors contribute to mechanisms underlying GABA cell dysfunction in SZ.

  12. The interplay between the hippocampus and the amygdala in regulating aberrant hippocampal neurogenesis during protracted abstinence from alcohol dependence

    Directory of Open Access Journals (Sweden)

    Chitra D Mandyam

    2013-06-01

    Full Text Available The development of alcohol dependence involves elevated anxiety, low mood, and increased sensitivity to stress, collectively labeled negative affect. Particularly interesting is the recent accumulating evidence that sensitized extrahypothalamic stress systems (e.g., hyperglutamatergic activity, blunted hypothalamic-pituitary-adrenal [HPA] hormonal levels, altered corticotropin-releasing factor signaling, and altered glucocorticoid receptor signaling in the extended amygdala are evident in withdrawn dependent rats, supporting the hypothesis that pathological neuroadaptations in the extended amygdala contribute to the negative affective state. Notably, hippocampal neurotoxicity observed as aberrant dentate gyrus (DG neurogenesis (neurogenesis is a process where neural stem cells in the adult hippocampal subgranular zone generate DG granule cell neurons and DG neurodegeneration are observed in withdrawn dependent rats. These correlations between withdrawal and aberrant neurogenesis in dependent rats suggest that alterations in the DG could be hypothesized to be due to compromised HPA axis activity and associated hyperglutamatergic activity originating from the basolateral amygdala in withdrawn dependent rats. This review discusses a possible link between the neuroadaptations in the extended amygdala stress systems and the resulting pathological plasticity that could facilitate recruitment of new emotional memory circuits in the hippocampus as a function of aberrant DG neurogenesis.

  13. A lentiviral sponge for miR-101 regulates RanBP9 expression and amyloid precursor protein metabolism in hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Christian eBarbato

    2014-02-01

    Full Text Available Neurodegeneration associated with amyloid β (Aβ peptide accumulation, synaptic loss, and memory impairment are pathophysiological features of Alzheimer's disease (AD. Numerous microRNAs regulate amyloid precursor protein (APP expression and metabolism. We previously reported that miR-101 is a negative regulator of APP expression in cultured hippocampal neurons. In this study, a search for predicted APP metabolism-associated miR-101 targets led to the identification of a conserved miR-101 binding site within the 3’ untranslated region (UTR of the mRNA encoding Ran-binding protein 9 (RanBP9. RanBP9 increases APP processing by β-amyloid converting enzyme 1 (BACE1, secretion of soluble APPβ (sAPPβ, and generation of Aβ. MiR-101 significantly reduced reporter gene expression when co-transfected with a RanBP9 3'-UTR reporter construct, while site-directed mutagenesis of the predicted miR-101 target site eliminated the reporter response. To investigate the effect of stable inhibition of miR-101 both in vitro and in vivo, a microRNA sponge was developed to bind miR-101 and derepress its targets. Four tandem bulged miR-101 responsive elements (REs, located downstream of the enhanced green fluorescence protein (EGFP open reading frame and driven by the synapsin promoter, were placed in a lentiviral vector to create the pLSyn-miR-101 sponge. Delivery of the sponge to primary hippocampal neurons significantly increased both APP and RanBP9 expression, as well as sAPPβ levels in the conditioned medium. Importantly, silencing of endogenous RanBP9 reduced sAPPβ levels in miR-101 sponge-containing hippocampal cultures, indicating that miR-101 inhibition may increase amyloidogenic processing of APP by RanBP9. Lastly, the impact of miR-101 on its targets was demonstrated in vivo by intrahippocampal injection of the pLSyn-miR-101 sponge into C57BL6 mice. This study thus provides the basis for studying the consequences of long-term miR-101 inhibition on

  14. Cyanidin-3-O-galactoside and Blueberry Extracts Supplementation Improves Spatial Memory and Regulates Hippocampal ERK Expression in Senescence-accelerated Mice

    Institute of Scientific and Technical Information of China (English)

    TAN Long; YANG Hong Peng; PANG Wei; LU Hao; HU Yan Dan; LI Jing; LU Shi Jun; ZHANG Wan Qi; JIANG Yu Gang

    2014-01-01

    Objective To investigate whether the antioxidation and the regulation on the Extracellular Regulated Protein Kinases (ERK) signaling pathway are involved in the protective effects of blueberry on central nervous system. Methods 30 Senescence-accelerated mice prone 8 (SAMP8) mice were divided into three groups and treated with normal diet, blueberry extracts (200 mg/kg·bw/day) and cyaniding-3-O-galactoside (Cy-3-GAL) (50 mg/kg·bw/day) from blueberry for 8 weeks. 10 SAMR1 mice were set as control group. The capacity of spatial memory was assessed by Passive avoidance task and Morris water maze. Histological analyses on hippocampus were completed. Malondialdehyde (MDA) levels, Superoxide Dismutase (SOD) activity and the expression of ERK were detected. Results Both Cy-3-GAL and blueberry extracts were shown effective functions to relieve cellular injury, improve hippocampal neurons survival and inhibit the pyramidal cell layer damage. Cy-3-GAL and blueberry extracts also increased SOD activity and reduced MDA content in brain tissues and plasma, and increased hippocampal phosphorylated ERK (p-ERK) expression in SAMP8 mice. Further more, the passive avoidance task test showed that both the latency time and the number of errors were improved by Cy-3-GAL treatment, and the Morris Water Maze test showed significant decreases of latency were detected by Cy-3-GAL and blueberry extracts treatment on day 4. Conclusion Blueberry extracts may reverse the declines of cognitive and behavioral function in the ageing process through several pathways, including enhancing the capacity of antioxidation, altering stress signaling. Cy-3-GAL may be an important active ingredient for these biological effects.

  15. Volume regulated anion channel currents of rat hippocampal neurons and their contribution to oxygen-and-glucose deprivation induced neuronal death.

    Directory of Open Access Journals (Sweden)

    Huaqiu Zhang

    Full Text Available Volume-regulated anion channels (VRAC are widely expressed chloride channels that are critical for the cell volume regulation. In the mammalian central nervous system, the physiological expression of neuronal VRAC and its role in cerebral ischemia are issues largely unknown. We show that hypoosmotic medium induce an outwardly rectifying chloride conductance in CA1 pyramidal neurons in rat hippocampal slices. The induced chloride conductance was sensitive to some of the VRAC inhibitors, namely, IAA-94 (300 µM and NPPB (100 µM, but not to tamoxifen (10 µM. Using oxygen-and-glucose deprivation (OGD to simulate ischemic conditions in slices, VRAC activation appeared after OGD induced anoxic depolarization (AD that showed a progressive increase in current amplitude over the period of post-OGD reperfusion. The OGD induced VRAC currents were significantly inhibited by inhibitors for glutamate AMPA (30 µM NBQX and NMDA (40 µM AP-5 receptors in the OGD solution, supporting the view that induction of AD requires an excessive Na(+-loading via these receptors that in turn to activate neuronal VRAC. In the presence of NPPB and DCPIB in the post-OGD reperfusion solution, the OGD induced CA1 pyramidal neuron death, as measured by TO-PRO-3-I staining, was significantly reduced, although DCPIB did not appear to be an effective neuronal VRAC blocker. Altogether, we show that rat hippocampal pyramidal neurons express functional VRAC, and ischemic conditions can initial neuronal VRAC activation that may contribute to ischemic neuronal damage.

  16. Adult hippocampal neurogenesis and plasticity in the infrapyramidal bundle of the mossy fiber projection: I. Co-regulation by activity

    Directory of Open Access Journals (Sweden)

    Benedikt eRömer

    2011-09-01

    Full Text Available Besides the massive plasticity at the level of synapses, we find in the hippocampus of adult mice and rats two systems with very strong macroscopic structural plasticity: adult neurogenesis, that is the lifelong generation of new granule cells, and dynamic changes in the mossy fibers linking the dentate gyrus to area CA3. In particular the anatomy of the infrapyramidal mossy fiber tract (IMF changes in response to a variety of extrinsic and intrinsic stimuli. Because mossy fibers are the axons of granule cells, the question arises whether these two types of plasticity are linked. Using immunohistochemistry for markers associated with axonal growth and POMC-GFP mice to visualize the postmitotic maturation phase of adult hippocampal neurogenesis, we found that newly generated mossy fibers preferentially but not exclusively contribute to the IMF. The neurogenic stimulus of an enriched environment increased the volume of the IMF. In addition, the IMF grew with a time course consistent with axonal outgrowth from the newborn neurons after the induction of neurogenic seizures using kainate,.These results indicate that two aspects of plasticity in the adult hippocampus, mossy fiber size and neurogenesis, are related and may share underlying mechanisms. In a second, related study (Krebs et al., Frontiers in Neurogenesis ##reference## we have addressed the question of whether there is a shared genetics underlying both traits.

  17. [Hippocampal stroke].

    Science.gov (United States)

    Rollnik, J D; Traitel, B; Dietrich, B; Lenz, O

    2015-02-01

    Unilateral cerebral ischemia of the hippocampus is very rare. This paper reviews the literature and presents the case of a 59-year-old woman with an amnestic syndrome due to a left hippocampal stroke. The patient suffered from retrograde amnesia which was most severe over the 2 days prior to presenting and a slight anterograde amnesia. In addition, a verbal memory disorder was confirmed 1 week after admission by neurological tests. As risk factors, arterial hypertension and a relative hyper-beta lipoproteinemia were found. This case shows that unilateral amnestic stroke, e.g. in the hippocampus region, may be the cause of an amnestic syndrome and should be included in the differential diagnostics.

  18. GDNF pre-treatment aggravates neuronal cell loss in oxygen-glucose deprived hippocampal slice cultures: a possible effect of glutamate transporter up-regulation.

    Science.gov (United States)

    Bonde, C; Sarup, A; Schousboe, A; Gegelashvili, G; Noraberg, J; Zimmer, J

    2003-01-01

    Besides its neurotrophic and neuroprotective effects on dopaminergic neurons and spinal motoneurons, glial cell line-derived neurotrophic factor (GDNF) has potent neuroprotective effects in cerebral ischemia. The protective effect has so far been related to reduced activation of N-methyl-D-aspartate receptors (NMDAr). This study tested the effects of GDNF on glutamate transporter expression, with the hypothesis that modulation of glutamate transporter activity would affect the outcome of cerebral ischemia. Organotypic hippocampal slice cultures, derived from 1-week-old rats, were treated with 100 ng/ml GDNF for either 2 or 5 days, followed by Western blot analysis of NMDAr subunit 1 (NR1) and two glutamate transporter subtypes, GLAST and GLT-1. After 5-day exposure to GDNF, expression of GLAST and GLT-1 was up-regulated to 169 and 181% of control values, respectively, whereas NR1 was down-regulated to 64% of control. However, despite these changes that potentially would support neuronal resistance to excitotoxicity, the long-term treatment with GDNF was found to aggravate the neuronal damage induced by oxygen-glucose deprivation (OGD). The increased cell death, assessed by propidium iodide (PI) uptake, occurred not only among the most susceptible CA1 pyramidal cells, but also in CA3 and fascia dentata. Given that glutamate transporters are able to release glutamate by reversed action during energy failure, it is suggested that the observed increase in OGD-induced cell death in the GDNF-pretreated cultures was caused by the build-up of excitotoxic concentrations of extracellular glutamate released through the glutamate transporters, which were up-regulated by GDNF. Although the extent and consequences of glutamate release via reversal of GLAST and GLT-1 transporters seem to vary in different energy failure models, the present findings should be taken into account in clinical trials of GDNF.

  19. Fluoxetine ameliorates cognitive impairments induced by chronic cerebral hypoperfusion via down-regulation of HCN2 surface expression in the hippocampal CA1 area in rats.

    Science.gov (United States)

    Luo, Pan; Zhang, Xiaoxue; Lu, Yun; Chen, Cheng; Li, Changjun; Zhou, Mei; Lu, Qing; Xu, Xulin; Shen, Guanxin; Guo, Lianjun

    2016-01-01

    Chronic cerebral hypoperfusion (CCH) causes cognitive impairments and increases the risk of Alzheimer's disease (AD) and vascular dementia (VD) through several biologically plausible pathways, yet the underlying neurobiological mechanisms are still poorly understood. In this study, we investigated whether fluoxetine, a selective serotonin reuptake inhibitor (SSRI), could play a neuroprotective role against chronic cerebral hypoperfusion injury and to clarify underlying mechanisms of its efficacy. Rats were subjected to permanent bilateral occlusion of the common carotid arteries (two-vessel occlusion, 2VO). Two weeks later, rats were treated with 30 mg/kg fluoxetine (intragastric injection, i.g.) for 6 weeks. Cognitive function was evaluated by Morris water maze (MWM) and novel objects recognition (NOR) test. Long-term potentiation (LTP) was used to address the underlying synaptic mechanisms. Western blotting was used to quantify the protein levels. Our results showed that fluoxetine treatment significantly improved the cognitive impairments caused by 2VO, accompanied with a reversion of 2VO-induced inhibitory of LTP. Furthermore, 2VO caused an up-regulation of hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) surface expressions in the hippocampal CA1 area and fluoxetine also effectively recovered the disorder of HCN2 surface expressions, which may be a possible mechanism that fluoxetine treatment ameliorates cognitive impairments in rats with CCH.

  20. Antidepressant like effects of hydrolysable tannins of Terminalia catappa leaf extract via modulation of hippocampal plasticity and regulation of monoamine neurotransmitters subjected to chronic mild stress (CMS).

    Science.gov (United States)

    Chandrasekhar, Y; Ramya, E M; Navya, K; Phani Kumar, G; Anilakumar, K R

    2017-02-01

    Terminalia catappa L. belonging to Combretaceae family is a folk medicine, known for its multiple pharmacological properties, but the neuro-modulatory effect of TC against chronic mild stress was seldom explored. The present study was designed to elucidate potential antidepressant-like effect of Terminalia cattapa (leaf) hydro-alcoholic extract (TC) by using CMS model for a period of 7 weeks. Identification of hydrolysable tannins was done by using LC-MS. After the CMS exposure, mice groups were administered with imipramine (IMP, 10mg/kg, i.p.) and TC (25, 50 and 100mg/kg of TC, p.o.). Behavioural paradigms used for the study included forced swimming test (FST), tail suspension test (TST) and sucrose preference test (SPT). After behavioural tests, monoamine neurotransmitter, cortisol, AchE, oxidative stress levels and mRNA expression studies relevant to depression were assessed. TC supplementation significantly reversed CMS induced immobility time in FST and other behavioural paradigms. Moreover, TC administration significantly restored CMS induced changes in concentrations of hippocampal neurotransmitters (5-HT, DA and NE) as well as levels of acetyl cholinesterase, cortisol, monoamine oxidases (MAO-A, MAO-B), BDNF, CREB, and p-CREB. It suggests that TC supplementation could supress stress induced depression by regulating monoamine neurotransmitters, CREB, BDNF, cortisol, AchE level as well as by amelioration of oxidative stress. Hence TC can be used as a complementary medicine against depression-like disorder.

  1. Postnatal development of temporal integration, spike timing and spike threshold regulation by a dendrotoxin-sensitive K⁺ current in rat CA1 hippocampal cells.

    Science.gov (United States)

    Giglio, Anna M; Storm, Johan F

    2014-01-01

    Spike timing and network synchronization are important for plasticity, development and maturation of brain circuits. Spike delays and timing can be strongly modulated by a low-threshold, slowly inactivating, voltage-gated potassium current called D-current (ID ). ID can delay the onset of spiking, cause temporal integration of multiple inputs, and regulate spike threshold and network synchrony. Recent data indicate that ID can also undergo activity-dependent, homeostatic regulation. Therefore, we have studied the postnatal development of ID -dependent mechanisms in CA1 pyramidal cells in hippocampal slices from young rats (P7-27), using somatic whole-cell recordings. At P21-27, these neurons showed long spike delays and pronounced temporal integration in response to a series of brief depolarizing current pulses or a single long pulse, whereas younger cells (P7-20) showed shorter discharge delays and weak temporal integration, although the spike threshold became increasingly negative with maturation. Application of α-dendrotoxin (α-DTX), which blocks ID , reduced the spiking latency and temporal integration most strongly in mature cells, while shifting the spike threshold most strongly in a depolarizing direction in these cells. Voltage-clamp analysis revealed an α-DTX-sensitive outward current (ID ) that increased in amplitude during development. In contrast to P21-23, ID in the youngest group (P7-9) showed smaller peri-threshold amplitude. This may explain why long discharge delays and robust temporal integration only appear later, 3 weeks postnatally. We conclude that ID properties and ID -dependent functions develop postnatally in rat CA1 pyramidal cells, and ID may modulate network activity and plasticity through its effects on synaptic integration, spike threshold, timing and synchrony.

  2. Excitatory Synaptic Drive and Feedforward Inhibition in the Hippocampal CA3 Circuit Are Regulated by SynCAM 1

    OpenAIRE

    Park, Kellie A.; Ribic, Adema; Laage Gaupp, Fabian M.; Coman, Daniel; Huang, Yuegao; Dulla, Chris G.; Hyder, Fahmeed; Biederer, Thomas

    2016-01-01

    Select adhesion proteins control the development of synapses and modulate their structural and functional properties. Despite these important roles, the extent to which different synapse-organizing mechanisms act across brain regions to establish connectivity and regulate network properties is incompletely understood. Further, their functional roles in different neuronal populations remain to be defined. Here, we applied diffusion tensor imaging (DTI), a modality of magnetic resonance imaging...

  3. Pilocarpine-induced seizures trigger differential regulation of microRNA-stability related genes in rat hippocampal neurons

    Science.gov (United States)

    Kinjo, Erika R.; Higa, Guilherme S. V.; Santos, Bianca A.; de Sousa, Erica; Damico, Marcio V.; Walter, Lais T.; Morya, Edgard; Valle, Angela C.; Britto, Luiz R. G.; Kihara, Alexandre H.

    2016-01-01

    Epileptogenesis in the temporal lobe elicits regulation of gene expression and protein translation, leading to reorganization of neuronal networks. In this process, miRNAs were described as being regulated in a cell-specific manner, although mechanistics of miRNAs activity are poorly understood. The specificity of miRNAs on their target genes depends on their intracellular concentration, reflecting the balance of biosynthesis and degradation. Herein, we confirmed that pilocarpine application promptly (<30 min) induces status epilepticus (SE) as revealed by changes in rat electrocorticogram particularly in fast-beta range (21–30 Hz). SE simultaneously upregulated XRN2 and downregulated PAPD4 gene expression in the hippocampus, two genes related to miRNA degradation and stability, respectively. Moreover, SE decreased the number of XRN2-positive cells in the hilus, while reduced the number of PAPD4-positive cells in CA1. XRN2 and PAPD4 levels did not change in calretinin- and CamKII-positive cells, although it was possible to determine that PAPD4, but not XRN2, was upregulated in parvalbumin-positive cells, revealing that SE induction unbalances the accumulation of these functional-opposed proteins in inhibitory interneurons that directly innervate distinct domains of pyramidal cells. Therefore, we were able to disclose a possible mechanism underlying the differential regulation of miRNAs in specific neurons during epileptogenesis. PMID:26869208

  4. Mitogen and stress-activated kinases 1/2 regulate ischemia-induced hippocampal progenitor cell proliferation and neurogenesis.

    Science.gov (United States)

    Karelina, K; Liu, Y; Alzate-Correa, D; Wheaton, K L; Hoyt, K R; Arthur, J S C; Obrietan, K

    2015-01-29

    Pathophysiological conditions such as cerebral ischemia trigger the production of new neurons from the neurogenic niche within the subgranular zone (SGZ) of the dentate gyrus. The functional significance of ischemia-induced neurogenesis is believed to be the regeneration of lost cells, thus contributing to post-ischemia recovery. However, the cell signaling mechanisms by which this process is regulated are still under investigation. Here, we investigated the role of mitogen and stress-activated protein kinases (MSK1/2) in the regulation of progenitor cell proliferation and neurogenesis after cerebral ischemia. Using the endothelin-1 model of ischemia, wild-type (WT) and MSK1(-/-)/MSK2(-/-) (MSK dKO) mice were injected with BrdU and sacrificed 2 days, 4 weeks, or 6 weeks later for the analysis of progenitor cell proliferation, neurogenesis, and neuronal morphology, respectively. We report a decrease in SGZ progenitor cell proliferation in MSK dKO mice compared to WT mice. Moreover, MSK dKO mice exhibited reduced neurogenesis and a delayed maturation of ischemia-induced newborn neurons. Further, structural analysis of neuronal arborization revealed reduced branching complexity in MSK dKO compared to WT mice. Taken together, this dataset suggests that MSK1/2 plays a significant role in the regulation of ischemia-induced progenitor cell proliferation and neurogenesis. Ultimately, revealing the cell signaling mechanisms that promote neuronal recovery will lead to novel pharmacological approaches for the treatment of neurodegenerative diseases such as cerebral ischemia. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  5. Regulation of Dendritic Branching and Filopodia Formation in Hippocampal Neurons by Specific Acylated Protein MotifsD⃞V⃞

    Science.gov (United States)

    Gauthier-Campbell, Catherine; Bredt, David S.; Murphy, Timothy H.; El-Husseini, Alaa El-Din

    2004-01-01

    Although neuronal axons and dendrites with their associated filopodia and spines exhibit a profound cell polarity, the mechanism by which they develop is largely unknown. Here, we demonstrate that specific palmitoylated protein motifs, characterized by two adjacent cysteines and nearby basic residues, are sufficient to induce filopodial extensions in heterologous cells and to increase the number of filopodia and the branching of dendrites and axons in neurons. Such motifs are present at the N-terminus of GAP-43 and the C-terminus of paralemmin, two neuronal proteins implicated in cytoskeletal organization and filopodial outgrowth. Filopodia induction is blocked by mutations of the palmitoylated sites or by treatment with 2-bromopalmitate, an agent that inhibits protein palmitoylation. Moreover, overexpression of a constitutively active form of ARF6, a GTPase that regulates membrane cycling and dendritic branching reversed the effects of the acylated protein motifs. Filopodia induction by the specific palmitoylated motifs was also reduced upon overexpression of a dominant negative form of the GTPase cdc42. These results demonstrate that select dually lipidated protein motifs trigger changes in the development and growth of neuronal processes. PMID:14978216

  6. Hippocampal Neurogenesis and Ageing

    OpenAIRE

    Couillard-Després, Sébastien

    2012-01-01

    Although significant inconsistencies remain to be clarified, a role for neurogenesis in hippocampal functions, such as cognition, has been suggested by several reports. Yet, investigation in various species of mammals, including humans, revealed that rates of hippocampal neurogenesis are steadily declining with age. The very low levels of hippocampal neurogenesis persisting in the aged brain have been suspected to underlie the cognitive deficits observed in elderly. However, current evidence ...

  7. Early Growth Response 1 (Egr-1) Regulates N-Methyl-d-aspartate Receptor (NMDAR)-dependent Transcription of PSD-95 and α-Amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor (AMPAR) Trafficking in Hippocampal Primary Neurons*

    Science.gov (United States)

    Qin, Xike; Jiang, Yongjun; Tse, Yiu Chung; Wang, Yunling; Wong, Tak Pan; Paudel, Hemant K.

    2015-01-01

    The N-methyl-d-aspartate receptor (NMDAR) controls synaptic plasticity and memory function and is one of the major inducers of transcription factor Egr-1 in the hippocampus. However, how Egr-1 mediates the NMDAR signal in neurons has remained unclear. Here, we show that the hippocampus of mice lacking Egr-1 displays electrophysiology properties and ultrastructure that are similar to mice overexpressing PSD-95, a major scaffolding protein of postsynaptic density involved in synapse formation, synaptic plasticity, and synaptic targeting of AMPA receptors (AMPARs), which mediate the vast majority of excitatory transmission in the CNS. We demonstrate that Egr-1 is a transcription repressor of the PSD-95 gene and is recruited to the PSD-95 promoter in response to NMDAR activation. Knockdown of Egr-1 in rat hippocampal primary neurons blocks NMDAR-induced PSD-95 down-regulation and AMPAR endocytosis. Likewise, overexpression of Egr-1 in rat hippocampal primary neurons causes reduction in PSD-95 protein level and promotes AMPAR endocytosis. Our data indicate that Egr-1 is involved in NMDAR-mediated PSD-95 down-regulation and AMPAR endocytosis, a process important in the expression of long term depression. PMID:26475861

  8. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    Science.gov (United States)

    Barmashenko, Gleb; Buttgereit, Jens; Herring, Neil; Bader, Michael; Özcelik, Cemil; Manahan-Vaughan, Denise; Braunewell, Karl H.

    2014-01-01

    The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B) and its ligand C-type natriuretic peptide (CNP), one of several cGMP producing signaling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD) in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP). We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BΔKC) lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BΔKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1–100 Hz was assessed in transgenic rats, the threshold for both, LTP and LTD induction, was shifted to lower frequencies. In parallel, NPR-BΔKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signaling has a modulatory role for synaptic information storage and learning. PMID:25520616

  9. Matrix Metalloprotease 3 Activity Supports Hippocampal EPSP-to-Spike Plasticity Following Patterned Neuronal Activity via the Regulation of NMDAR Function and Calcium Flux.

    Science.gov (United States)

    Brzdąk, Patrycja; Włodarczyk, Jakub; Mozrzymas, Jerzy W; Wójtowicz, Tomasz

    2017-01-01

    Matrix metalloproteases (MMPs) comprise a family of endopeptidases that are involved in remodeling the extracellular matrix and play a critical role in learning and memory. At least 24 different MMP subtypes have been identified in the human brain, but less is known about the subtype-specific actions of MMP on neuronal plasticity. The long-term potentiation (LTP) of excitatory synaptic transmission and scaling of dendritic and somatic neuronal excitability are considered substrates of memory storage. We previously found that MMP-3 and MMP-2/9 may be differentially involved in shaping the induction and expression of excitatory postsynaptic potential (EPSP)-to-spike (E-S) potentiation in hippocampal brain slices. MMP-3 and MMP-2/9 proteolysis was previously shown to affect the integrity or mobility of synaptic N-methyl-D-aspartate receptors (NMDARs) in vitro. However, the functional outcome of such MMP-NMDAR interactions remains largely unknown. The present study investigated the role of these MMP subtypes in E-S plasticity and NMDAR function in mouse hippocampal acute brain slices. The temporal requirement for MMP-3/NMDAR activity in E-S potentiation within the CA1 field largely overlapped, and MMP-3 but not MMP-2/9 activity was crucial for the gain-of-function of NMDARs following LTP induction. Functional changes in E-S plasticity following MMP-3 inhibition largely correlated with the expression of cFos protein, a marker of activity-related gene transcription. Recombinant MMP-3 promoted a gain in NMDAR-mediated field potentials and somatodendritic Ca(2+) waves. These results suggest that long-term hippocampal E-S potentiation requires transient MMP-3 activity that promotes NMDAR-mediated postsynaptic Ca(2+) entry that is vital for the activation of downstream signaling cascades and gene transcription.

  10. Regulation of hippocampal synaptic plasticity thresholds and changes in exploratory and learning behavior in dominant negative NPR-B mutant rats

    Directory of Open Access Journals (Sweden)

    Gleb eBarmashenko

    2014-12-01

    Full Text Available The second messenger cyclic GMP affects synaptic transmission and modulates synaptic plasticity and certain types of learning and memory processes. The impact of the natriuretic peptide receptor B (NPR-B and its ligand C-type natriuretic peptide (CNP, one of several cGMP producing signalling systems, on hippocampal synaptic plasticity and learning is, however, less well understood. We have previously shown that the NPR-B ligand CNP increases the magnitude of long-term depression (LTD in hippocampal area CA1, while reducing the induction of long-term potentiation (LTP. We have extended this line of research to show that bidirectional plasticity is affected in the opposite way in rats expressing a dominant-negative mutant of NPR-B (NSE-NPR-BdeltaKC lacking the intracellular guanylyl cyclase domain under control of a promoter for neuron-specific enolase. The brain cells of these transgenic rats express functional dimers of the NPR-B receptor containing the dominant-negative NPR-BdeltaKC mutant, and therefore show decreased CNP-stimulated cGMP-production in brain membranes. The NPR-B transgenic rats display enhanced LTP but reduced LTD in hippocampal slices. When the frequency-dependence of synaptic modification to afferent stimulation in the range of 1-100 Hz was assessed in transgenic rats the threshold for LTP induction was raised, but LTD induction was facilitated. In parallel, NPR-BdeltaKC rats exhibited an enhancement in exploratory and learning behavior. These results indicate that bidirectional plasticity and learning and memory mechanism are affected in transgenic rats expressing a dominant-negative mutant of NPR-B. Our data substantiate the hypothesis that NPR-B-dependent cGMP signalling has a modulatory role for synaptic information storage and learning.

  11. Calcium-sensitive regulation of monoamine oxidase-A contributes to the production of peroxyradicals in hippocampal cultures: implications for Alzheimer disease-related pathology

    Directory of Open Access Journals (Sweden)

    Li XinMin

    2007-09-01

    Full Text Available Abstract Background Calcium (Ca2+ has recently been shown to selectively increase the activity of monoamine oxidase-A (MAO-A, a mitochondria-bound enzyme that generates peroxyradicals as a natural by-product of the deamination of neurotransmitters such as serotonin. It has also been suggested that increased intracellular free Ca2+ levels as well as MAO-A may be contributing to the oxidative stress associated with Alzheimer disease (AD. Results Incubation with Ca2+ selectively increases MAO-A enzymatic activity in protein extracts from mouse hippocampal HT-22 cell cultures. Treatment of HT-22 cultures with the Ca2+ ionophore A23187 also increases MAO-A activity, whereas overexpression of calbindin-D28K (CB-28K, a Ca2+-binding protein in brain that is greatly reduced in AD, decreases MAO-A activity. The effects of A23187 and CB-28K are both independent of any change in MAO-A protein or gene expression. The toxicity (via production of peroxyradicals and/or chromatin condensation associated with either A23187 or the AD-related β-amyloid peptide, which also increases free intracellular Ca2+, is attenuated by MAO-A inhibition in HT-22 cells as well as in primary hippocampal cultures. Conclusion These data suggest that increases in intracellular Ca2+ availability could contribute to a MAO-A-mediated mechanism with a role in AD-related oxidative stress.

  12. VEGF regulates hippocampal neurogenesis and reverses cognitive deficits in immature rats after status epilepticus through the VEGF R2 signaling pathway.

    Science.gov (United States)

    Han, Wei; Song, Xiaojie; He, Rong; Li, Tianyi; Cheng, Li; Xie, Lingling; Chen, Hengsheng; Jiang, Li

    2017-02-10

    Epilepsy is the most common chronic disease in children, who exhibit a higher risk for status epilepticus (SE) than adults. Hippocampal neurogenesis is altered by epilepsy, particularly in the immature brain, which may influence cognitive development. Vascular endothelial growth factor (VEGF) represents an attractive target to modulate brain function at the neurovascular interface and is a double-edged sword in seizures. We used the lithium-pilocarpine-induced epilepsy model in immature Sprague-Dawley rats to study the effects of VEGF on hippocampal neurogenesis in the acute phase and on long-term cognitive behaviors in immature rats following status epilepticus (SE). VEGF correlates with cell proliferation in the immature brain after SE. By preprocessing VEGF in the lateral ventricles prior to the induction of the SE model, we found that VEGF increased the proliferation of neural stem cells (NSCs) and promoted the migration of newly generated cells via the VEGF receptor 2 (VEGFR2) signaling pathway. VEGF also inhibited cell loss and reversed the cognitive deficits that accompany SE. Based on our results, VEGF positively contributes to the initial stages of neurogenesis and alleviates cognitive deficits following seizures; moreover, the VEGF/VEGFR2 signaling pathway may provide a novel treatment strategy for epilepsy.

  13. Empathy in hippocampal amnesia.

    Science.gov (United States)

    Beadle, J N; Tranel, D; Cohen, N J; Duff, M C

    2013-01-01

    Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. The scientific investigation of empathy has focused on characterizing its cognitive and neural substrates, and has pointed to the importance of a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate). While the hippocampus has rarely been the focus of empathy research, the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity) make it well-suited to meet some of the crucial demands of empathy, and a careful investigation of this possibility could make a significant contribution to the neuroscientific understanding of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female) with focal, bilateral hippocampal (HC) damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. Unlike healthy comparison participants, in response to the empathy inductions hippocampal patients reported no increase in empathy ratings or prosocial behavior. The results provide preliminary evidence for a role for hippocampal declarative memory in empathy.

  14. gamma-Aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life.

    Science.gov (United States)

    Ben-Ari, Y; Tseeb, V; Raggozzino, D; Khazipov, R; Gaiarsa, J L

    1994-01-01

    The properties of neonatal GABAergic synapses were investigated in neurones of the hippocampal CA3 region. GABA, acting on GABAA receptors, provides most of the excitatory drive on immature CA3 pyramidal neurones at an early stage of development, whereas glutamatergic synapses (in particular, those mediated by AMPA receptors) are mostly quiescent. Thus, during the first postnatal week of life, bicuculline fully blocked spontaneous and evoked depolarising potentials, and GABAA receptor agonists depolarised CA3 pyramidal neurones. GABAA mediated currents also had a reduced sensitivity to benzodiazepines. In the presence of bicuculline, between P0 and P4, increasing the stimulus strength reveals an excitatory postsynaptic potential which is mostly mediated by NMDA receptors. During the same developmental period, pre- (but not post) synaptic GABAB inhibition is present. Intracellular injections of biocytin showed that the axonal network of the GABAergic interneurones is well developed at birth, whereas the pyramidal recurrent collaterals are only beginning to develop. Finally, chronic bicuculline treatment of hippocampal neurones in culture reduced the extent of neuritic arborisation, suggesting that GABA acts as a trophic factor in that period. In conclusion, it is suggested that during the first postnatal week of life, when excitatory inputs are still poorly developed, GABAA receptors provide the excitatory drive necessary for pyramidal cell outgrowth. Starting from the end of the first postnatal week of life, when excitatory inputs are well developed, GABA (acting on both GABAA and GABAB receptors) will hyperpolarise the CA3 pyramidal neurones and, as in the adult, will prevent excessive neuronal discharges. Our electrophysiological and morphological studies have shown that hippocampal GABAergic interneurones are in a unique position to modulate the development of CA3 pyramidal neurones. Developing neurones require a certain degree of membrane depolarisation, and a

  15. Neuropeptides and hippocampal neurogenesis.

    Science.gov (United States)

    Zaben, M J; Gray, W P

    2013-12-01

    Hippocampal neurogenesis is important for modulating the behavioural responses to stress and for certain forms of learning and memory. The mechanisms underlying the necessary coupling of neuronal activity to neural stem/progenitor cell (NSPC) function remain poorly understood. Within the dentate subgranular stem cell niche, local interneurons appear to play an important part in this excitation-neurogenesis coupling via GABAergic transmission, which promotes neuronal differentiation and integration. Neuropeptides such as neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and galanin have emerged as important mediators for signalling local and extrinsic interneuronal activity to subgranular zone precursors. Here we review the distribution of these neuropeptides and their receptors in the neurogenic area of the hippocampus and their precise effects on hippocampal neurogenesis. We also discuss neuropeptides' potential involvement in functional aspects of hippocampal neurogenesis particularly their involvement in the modulation of learning and memory and behavior responses.

  16. Empathy in hippocampal amnesia

    Directory of Open Access Journals (Sweden)

    Janelle N Beadle

    2013-03-01

    Full Text Available The scientific investigation of empathy has become a cornerstone in the field of social cognition. Empathy is critical to the quality of our relationships with others and plays an important role in life satisfaction and well-being. Scientific investigations of empathy have focused on characterizing its cognitive and neural substrates, pointing to a network of brain regions involved in emotional experience and perspective taking (e.g., ventromedial prefrontal cortex, amygdala, anterior insula, cingulate. While the hippocampus has rarely been the focus of empathy research, we propose that there are compelling reasons to inquire about the contribution of the hippocampus to social cognition. We propose that the hallmark properties of the hippocampal declarative memory system (e.g., representational flexibility, relational binding, on-line processing capacity make it well-suited to meet the demands of empathy. The present study is a preliminary investigation of the role of the hippocampal declarative memory system in empathy. Participants were three patients (1 female with focal, bilateral hippocampal (HC damage and severe declarative memory impairments and three healthy demographically matched comparison participants. Empathy was measured as a trait through a battery of gold standard questionnaires and through on-line ratings and prosocial behavior in response to a series of empathy inductions. Patients with hippocampal amnesia reported lower cognitive and emotional trait empathy than healthy comparison participants. In response to the empathy inductions, unlike healthy comparison participants, hippocampal patients reported no increase in empathy ratings or prosocial behavior from the control condition. Taken together, these results provide preliminary evidence for a role of hippocampal declarative memory in empathy.

  17. The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin

    Science.gov (United States)

    Arnold, Miranda; Cross, Rebecca; Singleton, Kaela S.; Zlatic, Stephanie; Chapleau, Christopher; Mullin, Ariana P.; Rolle, Isaiah; Moore, Carlene C.; Theibert, Anne; Pozzo-Miller, Lucas; Faundez, Victor; Larimore, Jennifer

    2016-01-01

    AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3) and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1). Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD) and schizophrenia (SZ); yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse ortholog of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function. PMID:27713690

  18. The Endosome Localized Arf-GAP AGAP1 Modulates Dendritic Spine Morphology Downstream of the Neurodevelopmental Disorder Factor Dysbindin

    Directory of Open Access Journals (Sweden)

    Miranda Arnold

    2016-09-01

    Full Text Available AGAP1 is an Arf1 GTPase activating protein that interacts with the vesicle-associated protein complexes adaptor protein 3 (AP-3 and Biogenesis of Lysosome Related Organelles Complex-1 (BLOC-1. Overexpression of AGAP1 in non-neuronal cells results in an accumulation of endosomal cargoes, which suggests a role in endosome-dependent traffic. In addition, AGAP1 is a candidate susceptibility gene for two neurodevelopmental disorders, autism spectrum disorder (ASD and schizophrenia (SZ; yet its localization and function in neurons have not been described. Here, we describe that AGAP1 localizes to axons, dendrites, dendritic spines, and synapses, colocalizing preferentially with markers of early and recycling endosomes. Functional studies reveal overexpression and down-regulation of AGAP1 affects both neuronal endosomal trafficking and dendritic spine morphology, supporting a role for AGAP1 in the recycling endosomal trafficking involved in their morphogenesis. Finally, we determined the sensitivity of AGAP1 expression to mutations in the DTNBP1 gene, which is associated with neurodevelopmental disorder, and found that AGAP1 mRNA and protein levels are selectively reduced in the null allele of the mouse orthologue of DTNBP1. We postulate that endosomal trafficking contributes to the pathogenesis of neurodevelopmental disorders affecting dendritic spine morphology, and thus excitatory synapse structure and function.

  19. The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.

    Directory of Open Access Journals (Sweden)

    Sergiy V Korol

    Full Text Available Glucagon-like peptide-1 (GLP-1 is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM, an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM plus diazepam (1 μM, only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.

  20. Effect of Opioid on Adult Hippocampal Neurogenesis

    OpenAIRE

    Yue Zhang; Loh, Horace H.; Ping-Yee Law

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opia...

  1. Culturing rat hippocampal neurons.

    Science.gov (United States)

    Audesirk, G; Audesirk, T; Ferguson, C

    2001-01-01

    Cultured neurons are widely used to investigate the mechanisms of neurotoxicity. Embryonic rat hippocampal neurons may be grown as described under a wide variety of conditions to suit differing experimental procedures, including electrophysiology, morphological analysis of neurite development, and various biochemical and molecular analyses.

  2. Kv2 channel regulation of action potential repolarization and firing patterns in superior cervical ganglion neurons and hippocampal CA1 pyramidal neurons.

    Science.gov (United States)

    Liu, Pin W; Bean, Bruce P

    2014-04-02

    Kv2 family "delayed-rectifier" potassium channels are widely expressed in mammalian neurons. Kv2 channels activate relatively slowly and their contribution to action potential repolarization under physiological conditions has been unclear. We explored the function of Kv2 channels using a Kv2-selective blocker, Guangxitoxin-1E (GxTX-1E). Using acutely isolated neurons, mixed voltage-clamp and current-clamp experiments were done at 37°C to study the physiological kinetics of channel gating and action potentials. In both rat superior cervical ganglion (SCG) neurons and mouse hippocampal CA1 pyramidal neurons, 100 nm GxTX-1E produced near-saturating block of a component of current typically constituting ∼60-80% of the total delayed-rectifier current. GxTX-1E also reduced A-type potassium current (IA), but much more weakly. In SCG neurons, 100 nm GxTX-1E broadened spikes and voltage clamp experiments using action potential waveforms showed that Kv2 channels carry ∼55% of the total outward current during action potential repolarization despite activating relatively late in the spike. In CA1 neurons, 100 nm GxTX-1E broadened spikes evoked from -70 mV, but not -80 mV, likely reflecting a greater role of Kv2 when other potassium channels were partially inactivated at -70 mV. In both CA1 and SCG neurons, inhibition of Kv2 channels produced dramatic depolarization of interspike voltages during repetitive firing. In CA1 neurons and some SCG neurons, this was associated with increased initial firing frequency. In all neurons, inhibition of Kv2 channels depressed maintained firing because neurons entered depolarization block more readily. Therefore, Kv2 channels can either decrease or increase neuronal excitability depending on the time scale of excitation.

  3. Age dependent differences in the regulation of hippocampal steroid hormones and receptor genes: relations to motivation and cognition in male rats.

    Science.gov (United States)

    Meyer, K; Korz, V

    2013-02-01

    Estrogen and estrogenic functions are age-dependently involved in the modulation of learning, memory and mood in female humans and animals. However, the investigation of estrogenic effects in males has been largely neglected. Therefore, we investigated the hippocampal gene expression of estrogen receptors α and β (ERα, β) in 8-week-old, 12-week-old and 24-week-old male rats. To control for possible interactions between the expression of the estrogen receptor genes and other learning-related steroid receptors, androgen receptors (AR), corticosterone-binding glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) were also measured. Furthermore, the concentrations of the ligands 17β-estradiol, testosterone and corticosterone were measured. The spatial training was conducted in a hole-board. The 8-week-old rats exhibited higher levels of general activity and exploration during the training and performed best with respect to spatial learning and memory, whereas no difference was found between the 12-week-old and 24-week-old rats. The trained 8-week-old rats exhibited increased gene expression of ERα compared with the untrained rats in this age group as well as the trained 12-week-old and 24-week-old rats. The concentrations of estradiol and testosterone, however, were generally higher in the 24-week-old rats than in the 8-week-old and 12-week-old rats. The ERα mRNA concentrations correlated positively with behavior that indicate general learning motivation. These results suggest a specific role of ERα in the age-related differences in motivation and subsequent success in the task. Thus, estrogen and estrogenic functions may play a more prominent role in young male behavior and development than has been previously assumed.

  4. Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors.

    Science.gov (United States)

    Wetmore, C; Olson, L; Bean, A J

    1994-03-01

    We have examined the influence of glutamate on cortical brain-derived neurotrophic factor (BDNF) expression using in situ hybridization and immunohistochemistry. Kainic acid (KA) produced an upregulation of hippocampal and neocortical BDNF mRNA as well as BDNF protein that was blocked by a non-NMDA antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but was not affected by the NMDA antagonist 2-amino-7-phosphonoheptanoic acid (AP7). Basal levels of BDNF mRNA were not affected by NMDA, DNQX, or AP7 treatment. BDNF protein was also increased after kainate exposure with a spatial and temporal course distinct from that seen for the expression of BDNF mRNA. A dramatic shift in BDNF immunoreactivity (-IR) was observed from intracellular compartments to the neuropil surrounding CA3 pyramidal cells 2-3 hr after KA exposure. This shift in localization of BDNF-IR suggests a constitutive release of BDNF at the level of the cell body and dendrites. Moreover, we have localized mRNAs for full-length and truncated trkB, to a co-incident population of neurons and glia. These data suggest the neurons that produce BDNF also express components necessary for a biological response to the same neurotrophic factor. The present study also demonstrates increased BDNF-IR in the mossy fiber terminal zone of hippocampus after exposure to KA, as well as an increase in trkB mRNA, and provides evidence of local release of this neurotrophin into the surrounding neuropil where it would be available for local utilization. The synthesis and putative release of BDNF from somatic and/or dendritic sites within the hippocampus provide evidence of a potential autocrine or paracrine role for BDNF, and establish a local source of trophic support for the maintenance of synaptic plasticity and anatomic reorganization in the mature nervous system.

  5. Variability in State-Dependent Plasticity of Intrinsic Properties during Cell-Autonomous Self-Regulation of Calcium Homeostasis in Hippocampal Model Neurons1,2,3

    Science.gov (United States)

    Srikanth, Sunandha

    2015-01-01

    Abstract How do neurons reconcile the maintenance of calcium homeostasis with perpetual switches in patterns of afferent activity? Here, we assessed state-dependent evolution of calcium homeostasis in a population of hippocampal pyramidal neuron models, through an adaptation of a recent study on stomatogastric ganglion neurons. Calcium homeostasis was set to emerge through cell-autonomous updates to 12 ionic conductances, responding to different types of synaptically driven afferent activity. We first assessed the impact of theta-frequency inputs on the evolution of ionic conductances toward maintenance of calcium homeostasis. Although calcium homeostasis emerged efficaciously across all models in the population, disparate changes in ionic conductances that mediated this emergence resulted in variable plasticity to several intrinsic properties, also manifesting as significant differences in firing responses across models. Assessing the sensitivity of this form of plasticity, we noted that intrinsic neuronal properties and the firing response were sensitive to the target calcium concentration and to the strength and frequency of afferent activity. Next, we studied the evolution of calcium homeostasis when afferent activity was switched, in different temporal sequences, between two behaviorally distinct types of activity: theta-frequency inputs and sharp-wave ripples riding on largely silent periods. We found that the conductance values, intrinsic properties, and firing response of neurons exhibited differential robustness to an intervening switch in the type of afferent activity. These results unveil critical dissociations between different forms of homeostasis, and call for a systematic evaluation of the impact of state-dependent switches in afferent activity on neuronal intrinsic properties during neural coding and homeostasis. PMID:26464994

  6. Expression of brain derived neurotrophic factor, activity-regulated cytoskeleton protein mRNA, and enhancement of adult hippocampal neurogenesis in rats after sub-chronic and chronic treatment with the triple monoamine re-uptake inhibitor tesofensine.

    Science.gov (United States)

    Larsen, Marianne H; Rosenbrock, Holger; Sams-Dodd, Frank; Mikkelsen, Jens D

    2007-01-26

    The changes of gene expression resulting from long-term exposure to monoamine antidepressant drugs in experimental animals are key to understanding the mechanisms of action of this class of drugs in man. Many of these genes and their products are either relevant biomarkers or directly involved in structural changes that are perhaps necessary for the antidepressant effect. Tesofensine is a novel triple monoamine reuptake inhibitor that acts to increase noradrenaline, serotonin, and dopamine neurotransmission. This study was undertaken to examine the effect of sub-chronic (5 days) and chronic (14 days) administration of Tesofensine on the expression of brain derived neurotrophic factor (BDNF) and activity-regulated cytoskeleton protein (Arc) in the rat hippocampus. Furthermore, hippocampi from the same animals were used to investigate the effect on cell proliferation by means of Ki-67- and NeuroD-immunoreactivity. We find that chronic, but not sub-chronic treatment with Tesofensine increases BDNF mRNA in the CA3 region of the hippocampus (35%), and Arc mRNA in the CA1 of the hippocampus (65%). Furthermore, the number of Ki-67- and neuroD-positive cells increased after chronic, but not sub-chronic treatment. This study shows that Tesofensine enhances hippocampal gene expression and new cell formation indicative for an antidepressant potential of this novel drug substance.

  7. Hippocampal sclerosis dementia

    Science.gov (United States)

    Onyike, Chiadi U.; Pletnikova, Olga; Sloane, Kelly L.; Sullivan, Campbell; Troncoso, Juan C.; Rabins, Peter V.

    2013-01-01

    Objective To describe characteristics of hippocampal sclerosis dementia. Methods Convenience sample of Hippocampal sclerosis dementia (HSD) recruited from the Johns Hopkins University Brain Resource Center. Twenty-four cases with post-mortem pathological diagnosis of hippocampal sclerosis dementia were reviewed for clinical characterization. Results The cases showed atrophy and neuronal loss localized to the hippocampus, amygdala and entorrhinal cortex. The majority (79.2%) had amnesia at illness onset, and many (54.2%) showed abnormal conduct and psychiatric disorder. Nearly 42% presented with an amnesic state, and 37.5% presented with amnesia plus abnormal conduct and psychiatric disorder. All eventually developed a behavioral or psychiatric disorder. Disorientation, executive dysfunction, aphasia, agnosia and apraxia were uncommon at onset. Alzheimer disease (AD) was the initial clinical diagnosis in 89% and the final clinical diagnosis in 75%. Diagnosis of frontotemporal dementia (FTD) was uncommon (seen in 8%). Conclusion HSD shows pathological characteristics of FTD and clinical features that mimic AD and overlap with FTD. The findings, placed in the context of earlier work, support the proposition that HSD belongs to the FTD family, where it may be identified as an amnesic variant. PMID:24363834

  8. Prolonged exposure to WIN55,212-2 causes down-regulation of the CB1 receptor and the development of tolerance to its anticonvulsant effects in the hippocampal neuronal culture model of acquired epilepsy

    Science.gov (United States)

    Blair, Robert E.; Deshpande, Laxmikant S.; Sombati, Sompong; Elphick, Maurice R.; Martin, Billy R.; DeLorenzo, Robert J.

    2009-01-01

    Summary Cannabinoids have been shown to cause CB1-receptor dependent anticonvulsant activity in both in vivo and in vitro models of status epilepticus (SE) and acquired epilepsy (AE). It has been further demonstrated in these models that the endocannabinoid system functions in a tonic manner to suppress seizure discharges through a CB1-receptor dependent pathway. Although acute cannabinoid treatment has anticonvulsant activity, little is known concerning the effects of prolonged exposure to CB1 agonists and development of tolerance on the epileptic phenotype. This study was carried out to evaluate the effects of prolonged exposure to the CB1 agonist WIN55,212-2 on seizure activity in a hippocampal neuronal culture model of low-Mg2+ induced spontaneous recurrent epileptiform discharges (SREDs). Following low-Mg2+ induced SREDs, cultures were returned to maintenance media containing 10, 100 or 1000 nM WIN55,212-2 from 4 to 24 hours. Whole-cell current-clamp analysis of WIN55,212-2 treated cultures revealed a concentration-dependent increase in SRED frequency. Immunocytochemical staining revealed that WIN55,212-2 treatment induced a concentration-dependent down-regulation of the CB1 receptor in neuronal processes and at both glutamatergic and GABAergic presynaptic terminals. Prolonged exposure to the inactive enantiomer WIN55,212-3 in low-Mg2+ treated cultures had no effect on the frequency of SREDs or CB1 receptor staining. The results from this study further substantiate a role for a tonic CB1 receptor-dependent endocannabinoid regulation of seizure discharge and suggest that prolonged exposure to cannabinoids results in the development of tolerance to the anticonvulsant effects of cannabinoids and an exacerbation of seizure activity in the epileptic phenotype. PMID:19540252

  9. Reducing central serotonin in adulthood promotes hippocampal neurogenesis.

    Science.gov (United States)

    Song, Ning-Ning; Jia, Yun-Fang; Zhang, Lei; Zhang, Qiong; Huang, Ying; Liu, Xiao-Zhen; Hu, Ling; Lan, Wei; Chen, Ling; Lesch, Klaus-Peter; Chen, Xiaoyan; Xu, Lin; Ding, Yu-Qiang

    2016-02-03

    Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER(T2) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.

  10. Nicotine shifts the temporal activation of hippocampal protein kinase A and extracellular signal-regulated kinase 1/2 to enhance long-term, but not short-term, hippocampus-dependent memory.

    Science.gov (United States)

    Gould, Thomas J; Wilkinson, Derek S; Yildirim, Emre; Poole, Rachel L F; Leach, Prescott T; Simmons, Steven J

    2014-03-01

    Acute nicotine enhances hippocampus-dependent learning through nicotine binding to β2-containing nicotinic acetylcholine receptors (nAChRs), but it is unclear if nicotine is targeting processes involved in short-term memory (STM) leading to a strong long-term memory (LTM) or directly targeting LTM. In addition, the molecular mechanisms involved in the effects of nicotine on learning are unknown. Previous research indicates that protein kinase A (PKA), extracellular signal-regulated kinase 1/2 (ERK1/2), and protein synthesis are crucial for LTM. Therefore, the present study examined the effects of nicotine on STM and LTM and the involvement of PKA, ERK1/2, and protein synthesis in the nicotine-induced enhancement of hippocampus-dependent contextual learning in C57BL/6J mice. The protein synthesis inhibitor anisomycin impaired contextual conditioning assessed at 4 h but not 2 h post-training, delineating time points for STM (2 h) and LTM (4 h and beyond). Nicotine enhanced contextual conditioning at 4, 8, and 24 h but not 2 h post-training, indicating nicotine specifically enhances LTM but not STM. Furthermore, nicotine did not rescue deficits in contextual conditioning produced by anisomycin, suggesting that the nicotine enhancement of contextual conditioning occurs through a protein synthesis-dependent mechanism. In addition, inhibition of dorsal hippocampal PKA activity blocked the effect of acute nicotine on learning, and nicotine shifted the timing of learning-related PKA and ERK1/2 activity in the dorsal and ventral hippocampus. Thus, the present results suggest that nicotine specifically enhances LTM through altering the timing of PKA and ERK1/2 signaling in the hippocampus, and suggests that the timing of PKA and ERK1/2 activity could contribute to the strength of memories.

  11. Presynaptic Ca2+-activated K+ channels in glutamatergic hippocampal terminals and their role in spike repolarization and regulation of transmitter release.

    Science.gov (United States)

    Hu, H; Shao, L R; Chavoshy, S; Gu, N; Trieb, M; Behrens, R; Laake, P; Pongs, O; Knaus, H G; Ottersen, O P; Storm, J F

    2001-12-15

    Large-conductance Ca(2+)-activated K(+) channels (BK, also called Maxi-K or Slo channels) are widespread in the vertebrate nervous system, but their functional roles in synaptic transmission in the mammalian brain are largely unknown. By combining electrophysiology and immunogold cytochemistry, we demonstrate the existence of functional BK channels in presynaptic terminals in the hippocampus and compare their functional roles in somata and terminals of CA3 pyramidal cells. Double-labeling immunogold analysis with BK channel and glutamate receptor antibodies indicated that BK channels are targeted to the presynaptic membrane facing the synaptic cleft in terminals of Schaffer collaterals in stratum radiatum. Whole-cell, intracellular, and field-potential recordings from CA1 pyramidal cells showed that the presynaptic BK channels are activated by calcium influx and can contribute to repolarization of the presynaptic action potential (AP) and negative feedback control of Ca(2+) influx and transmitter release. This was observed in the presence of 4-aminopyridine (4-AP, 40-100 microm), which broadened the presynaptic compound action potential. In contrast, the presynaptic BK channels did not contribute significantly to regulation of action potentials or transmitter release under basal experimental conditions, i.e., without 4-AP, even at high stimulation frequencies. This is unlike the situation in the parent cell bodies (CA3 pyramidal cells), where BK channels contribute strongly to action potential repolarization. These results indicate that the functional role of BK channels depends on their subcellular localization.

  12. An exploratory model for G x E interaction on hippocampal volume in schizophrenia; obstetric complications and hypoxia-related genes

    DEFF Research Database (Denmark)

    Haukvik, Unn Kristin; Saetre, Peter; McNeil, Thomas;

    2010-01-01

    Smaller hippocampal volume has repeatedly been reported in schizophrenia patients. Obstetric complications (OCs) and single nucleotide polymorphism (SNP) variation in schizophrenia susceptibility genes have independently been related to hippocampal volume. We investigated putative independent...... and interaction effects of severe hypoxia-related OCs and variation in four hypoxia-regulated schizophrenia susceptibility genes (BDNF, DTNBP1, GRM3 and NRG1) on hippocampal volume in schizophrenia patients and healthy controls....

  13. The Yin and Yang of Memory Consolidation: Hippocampal and Neocortical

    Science.gov (United States)

    Rossato, Janine I.; Jacobse, Justin; Grieves, Roddy M.; Spooner, Patrick A.; Battaglia, Francesco P.; Fernández, Guillen; Morris, Richard G. M.

    2017-01-01

    While hippocampal and cortical mechanisms of memory consolidation have long been studied, their interaction is poorly understood. We sought to investigate potential interactions with respect to trace dominance, strengthening, and interference associated with postencoding novelty or sleep. A learning procedure was scheduled in a watermaze that placed the impact of novelty and sleep in opposition. Distinct behavioural manipulations—context preexposure or interference during memory retrieval—differentially affected trace dominance and trace survival, respectively. Analysis of immediate early gene expression revealed parallel up-regulation in the hippocampus and cortex, sustained in the hippocampus in association with novelty but in the cortex in association with sleep. These findings shed light on dynamically interacting mechanisms mediating the stabilization of hippocampal and neocortical memory traces. Hippocampal memory traces followed by novelty were more dominant by default but liable to interference, whereas sleep engaged a lasting stabilization of cortical traces and consequent trace dominance after preexposure. PMID:28085883

  14. Effects of sex and DTNBP1 (dysbindin) null gene mutation on the developmental GluN2B-GluN2A switch in the mouse cortex and hippocampus.

    Science.gov (United States)

    Sinclair, Duncan; Cesare, Joseph; McMullen, Mary; Carlson, Greg C; Hahn, Chang-Gyu; Borgmann-Winter, Karin E

    2016-01-01

    Neurodevelopmental disorders such as autism spectrum disorders and schizophrenia differentially impact males and females and are highly heritable. The ways in which sex and genetic vulnerability influence the pathogenesis of these disorders are not clearly understood. The n-methyl-d-aspartate (NMDA) receptor pathway has been implicated in schizophrenia and autism spectrum disorders and changes dramatically across postnatal development at the level of the GluN2B-GluN2A subunit "switch" (a shift from reliance on GluN2B-containing receptors to reliance on GluN2A-containing receptors). We investigated whether sex and genetic vulnerability (specifically, null mutation of DTNBP1 [dysbindin; a possible susceptibility gene for schizophrenia]) influence the developmental GluN2B-GluN2A switch. Subcellular fractionation to enrich for postsynaptic density (PSD), together with Western blotting and kinase assay, were used to investigate the GluN2B-GluN2A switch in the cortex and hippocampus of male and female DTNBP1 null mutant mice and their wild-type littermates. Main effects of sex and DTNBP1 genotype, and interactions with age, were assessed using factorial ANOVA. Sex differences in the GluN2B-GluN2A switch emerged across development at the frontal cortical synapse, in parameters related to GluN2B. Males across genotypes displayed higher GluN2B:GluN2A and GluN2B:GluN1 ratios (p influence the GluN2B-GluN2A switch at the synapse in a brain-region-specific fashion involving pY1472-GluN2B, Fyn, and PLCγ. This highlights the possible mechanisms through which risk factors may mediate their effects on vulnerability to disorders of NMDA receptor dysfunction.

  15. Maternal anxiety and infants' hippocampal development: timing matters.

    Science.gov (United States)

    Qiu, A; Rifkin-Graboi, A; Chen, H; Chong, Y-S; Kwek, K; Gluckman, P D; Fortier, M V; Meaney, M J

    2013-09-24

    Exposure to maternal anxiety predicts offspring brain development. However, because children's brains are commonly assessed years after birth, the timing of such maternal influences in humans is unclear. This study aimed to examine the consequences of antenatal and postnatal exposure to maternal anxiety upon early infant development of the hippocampus, a key structure for stress regulation. A total of 175 neonates underwent magnetic resonance imaging (MRI) at birth and among them 35 had repeated scans at 6 months of age. Maternal anxiety was assessed using the State-Trait Anxiety Inventory (STAI) at week 26 of pregnancy and 3 months after delivery. Regression analyses showed that antenatal maternal anxiety did not influence bilateral hippocampal volume at birth. However, children of mothers reporting increased anxiety during pregnancy showed slower growth of both the left and right hippocampus over the first 6 months of life. This effect of antenatal maternal anxiety upon right hippocampal growth became statistically stronger when controlling for postnatal maternal anxiety. Furthermore, a strong positive association between postnatal maternal anxiety and right hippocampal growth was detected, whereas a strong negative association between postnatal maternal anxiety and the left hippocampal volume at 6 months of life was found. Hence, the postnatal growth of bilateral hippocampi shows distinct responses to postnatal maternal anxiety. The size of the left hippocampus during early development is likely to reflect the influence of the exposure to perinatal maternal anxiety, whereas right hippocampal growth is constrained by antenatal maternal anxiety, but enhanced in response to increased postnatal maternal anxiety.

  16. Necroptosis Mediates TNF-Induced Toxicity of Hippocampal Neurons

    Directory of Open Access Journals (Sweden)

    Shan Liu

    2014-01-01

    Full Text Available Tumor necrosis factor-α (TNF-α is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  17. Necroptosis mediates TNF-induced toxicity of hippocampal neurons.

    Science.gov (United States)

    Liu, Shan; Wang, Xing; Li, Yun; Xu, Lei; Yu, Xiaoliang; Ge, Lin; Li, Jun; Zhu, Yongjin; He, Sudan

    2014-01-01

    Tumor necrosis factor-α (TNF-α) is a critical proinflammatory cytokine regulating neuroinflammation. Elevated levels of TNF-α have been associated with various neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. However, the signaling events that lead to TNF-α-initiated neurotoxicity are still unclear. Here, we report that RIP3-mediated necroptosis, a form of regulated necrosis, is activated in the mouse hippocampus after intracerebroventricular injection of TNF-α. RIP3 deficiency attenuates TNF-α-initiated loss of hippocampal neurons. Furthermore, we characterized the molecular mechanism of TNF-α-induced neurotoxicity in HT-22 hippocampal neuronal cells. HT-22 cells are sensitive to TNF-α only upon caspase blockage and subsequently undergo necrosis. The cell death is suppressed by knockdown of CYLD or RIP1 or RIP3 or MLKL, suggesting that this necrosis is necroptosis and mediated by CYLD-RIP1-RIP3-MLKL signaling pathway. TNF-α-induced necroptosis of HT-22 cells is largely independent of both ROS accumulation and calcium influx although these events have been shown to be critical for necroptosis in certain cell lines. Taken together, these data not only provide the first in vivo evidence for a role of RIP3 in TNF-α-induced toxicity of hippocampal neurons, but also demonstrate that TNF-α promotes CYLD-RIP1-RIP3-MLKL-mediated necroptosis of hippocampal neurons largely bypassing ROS accumulation and calcium influx.

  18. Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure.

    Science.gov (United States)

    Cacao, Eliedonna; Cucinotta, Francis A

    2016-03-01

    Radiation impairment of neurogenesis in the hippocampal dentate gyrus is one of several factors associated with cognitive detriments after treatment of brain cancers in children and adults with radiation therapy. Mouse models have been used to study radiation-induced changes in neurogenesis, however the models are limited in the number of doses, dose fractions, age and time after exposure conditions that have been studied. The purpose of this study is to develop a novel predictive mathematical model of radiation-induced changes to neurogenesis using a system of nonlinear ordinary differential equations (ODEs) to represent the time, age and dose-dependent changes to several cell populations participating in neurogenesis as reported in mouse experiments exposed to low-LET radiation. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation treatment in altering neurogenesis: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN) and (4) glioblasts (GB). Because neurogenesis is decreasing with increasing mouse age, a description of the age-related dynamics of hippocampal neurogenesis is considered in the model, which is shown to be an important factor in comparisons to experimental data. A key feature of the model is the description of negative feedback regulation on early and late neuronal proliferation after radiation exposure. The model is augmented with parametric descriptions of the dose and time after irradiation dependences of activation of microglial cells and a possible shift of NSC proliferation from neurogenesis to gliogenesis reported at higher doses (∼10 Gy). Predictions for dose-fractionation regimes and for different mouse ages, and prospects for future work are then discussed.

  19. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

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

    2017-01-01

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

  20. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

    Hibar, Derrek P; Adams, Hieab H H; Jahanshad, Neda; Chauhan, Ganesh; Stein, Jason L; Hofer, Edith; Renteria, Miguel E; Bis, Joshua C; Arias-Vasquez, Alejandro; Ikram, M Kamran; Desrivières, Sylvane; Vernooij, Meike W; Abramovic, Lucija|info:eu-repo/dai/nl/34549072X; Alhusaini, Saud; Amin, Najaf; Andersson, Micael; Arfanakis, Konstantinos; Aribisala, Benjamin S; Armstrong, Nicola J; Athanasiu, Lavinia; Axelsson, Tomas; Beecham, Ashley H; Beiser, Alexa; Bernard, Manon; Blanton, Susan H; Bohlken, Marc M; Boks, Marco P|info:eu-repo/dai/nl/286852071; Bralten, Janita; Brickman, Adam M; Carmichael, Owen; Chakravarty, M Mallar; Chen, Qiang; Ching, Christopher R K; Chouraki, Vincent; Cuellar-Partida, Gabriel; Crivello, Fabrice; Den Braber, Anouk; Doan, Nhat Trung; Ehrlich, Stefan; Giddaluru, Sudheer; Goldman, Aaron L; Gottesman, Rebecca F; Grimm, Oliver; Griswold, Michael E; Guadalupe, Tulio; Gutman, Boris A; Hass, Johanna; Haukvik, Unn K; Hoehn, David; Holmes, Avram J; Hoogman, Martine; Janowitz, Deborah; Jia, Tianye; Jørgensen, Kjetil N; Karbalai, Nazanin; Kasperaviciute, Dalia; Kim, Sungeun; Klein, Marieke; Kraemer, Bernd; Lee, Phil H; Liewald, David C M; Lopez, Lorna M; Luciano, Michelle; Macare, Christine; Marquand, Andre F; Matarin, Mar; Mather, Karen A; Mattheisen, Manuel; McKay, David R; Milaneschi, Yuri; Muñoz Maniega, Susana; Nho, Kwangsik; Nugent, Allison C; Nyquist, Paul; Loohuis, Loes M Olde; Oosterlaan, Jaap; Papmeyer, Martina; Pirpamer, Lukas; Pütz, Benno; Ramasamy, Adaikalavan; Richards, Jennifer S; Risacher, Shannon L; Roiz-Santiañez, Roberto; Rommelse, Nanda; Ropele, Stefan; Rose, Emma J; Royle, Natalie A; Rundek, Tatjana; Sämann, Philipp G; Saremi, Arvin; Satizabal, Claudia L; Schmaal, Lianne; Schork, Andrew J; Shen, Li; Shin, Jean; Shumskaya, Elena; Smith, Albert V; Sprooten, Emma; Strike, Lachlan T; Teumer, Alexander; Tordesillas-Gutierrez, Diana; Toro, Roberto; Trabzuni, Daniah; Trompet, Stella; Vaidya, Dhananjay; Van der Grond, Jeroen; Van der Lee, Sven J; Van der Meer, Dennis; Van Donkelaar, Marjolein M J; Van Eijk, Kristel R|info:eu-repo/dai/nl/344497569; Van Erp, Theo G M; Van Rooij, Daan; Walton, Esther; Westlye, Lars T; Whelan, Christopher D; Windham, Beverly G; Winkler, Anderson M; Wittfeld, Katharina; Woldehawariat, Girma; Wolf, Christiane; Wolfers, Thomas; Yanek, Lisa R; Yang, Jingyun; Zijdenbos, Alex; Zwiers, Marcel P; Agartz, Ingrid; Almasy, Laura; Ames, David; Amouyel, Philippe; Andreassen, Ole A; Arepalli, Sampath; Assareh, Amelia A; Barral, Sandra; Bastin, Mark E; Becker, Diane M; Becker, James T; Bennett, David A; Blangero, John; van Bokhoven, Hans; Boomsma, Dorret I; Brodaty, Henry; Brouwer, Rachel M|info:eu-repo/dai/nl/304811432; Brunner, Han G; Buckner, Randy L; Buitelaar, Jan K; Bulayeva, Kazima B; Cahn, Wiepke|info:eu-repo/dai/nl/250566370; Calhoun, Vince D; Cannon, Dara M; Cavalleri, Gianpiero L; Cheng, Ching-Yu; Cichon, Sven; Cookson, Mark R; Corvin, Aiden; Crespo-Facorro, Benedicto; Curran, Joanne E; Czisch, Michael; Dale, Anders M; Davies, Gareth E; De Craen, Anton J M; De Geus, Eco J C; De Jager, Philip L; De Zubicaray, Greig I; Deary, Ian J; Debette, Stéphanie; DeCarli, Charles; Delanty, Norman; Depondt, Chantal; DeStefano, Anita; Dillman, Allissa; Djurovic, Srdjan; Donohoe, Gary; Drevets, Wayne C; Duggirala, Ravi; Dyer, Thomas D; Enzinger, Christian; Erk, Susanne; Espeseth, Thomas; Fedko, Iryna O; Fernández, Guillén; Ferrucci, Luigi; Fisher, Simon E; Fleischman, Debra A; Ford, Ian; Fornage, Myriam; Foroud, Tatiana M; Fox, Peter T; Francks, Clyde; Fukunaga, Masaki; Gibbs, J Raphael; Glahn, David C; Gollub, Randy L; Göring, Harald H H; Green, Robert C; Gruber, Oliver; Gudnason, Vilmundur; Guelfi, Sebastian; Håberg, Asta K; Hansell, Narelle K; Hardy, John; Hartman, Catharina A; Hashimoto, Ryota; Hegenscheid, Katrin; Heinz, Andreas; Le Hellard, Stephanie; Hernandez, Dena G; Heslenfeld, Dirk J; Ho, Beng-Choon; Hoekstra, Pieter J; Hoffmann, Wolfgang; Hofman, Albert; Holsboer, Florian; Homuth, Georg; Hosten, Norbert; Hottenga, Jouke-Jan; Huentelman, Matthew; Pol, Hilleke E Hulshoff|info:eu-repo/dai/nl/142348228; Ikeda, Masashi; Jack, Clifford R; Jenkinson, Mark; Johnson, Robert; Jönsson, Erik G; Jukema, J Wouter; Kahn, René S|info:eu-repo/dai/nl/073778532; Kanai, Ryota; Kloszewska, Iwona; Knopman, David S; Kochunov, Peter; Kwok, John B; Lawrie, Stephen M; Lemaître, Hervé; Liu, Xinmin; Longo, Dan L; Lopez, Oscar L; Lovestone, Simon; Martinez, Oliver; Martinot, Jean-Luc; Mattay, Venkata S; McDonald, Colm; McIntosh, Andrew M; McMahon, Francis J; McMahon, Katie L; Mecocci, Patrizia; Melle, Ingrid; Meyer-Lindenberg, Andreas; Mohnke, Sebastian; Montgomery, Grant W; Morris, Derek W; Mosley, Thomas H; Mühleisen, Thomas W; Müller-Myhsok, Bertram; Nalls, Michael A; Nauck, Matthias; Nichols, Thomas E; Niessen, Wiro J; Nöthen, Markus M; Nyberg, Lars; Ohi, Kazutaka; Olvera, Rene L; Ophoff, Roel A; Pandolfo, Massimo; Paus, Tomas; Pausova, Zdenka; Penninx, Brenda W J H; Pike, G Bruce; Potkin, Steven G; Psaty, Bruce M; Reppermund, Simone; Rietschel, Marcella; Roffman, Joshua L; Romanczuk-Seiferth, Nina; Rotter, Jerome I; Ryten, Mina; Sacco, Ralph L; Sachdev, Perminder S; Saykin, Andrew J; Schmidt, Reinhold; Schmidt, Helena; Schofield, Peter R; Sigursson, Sigurdur; Simmons, Andrew; Singleton, Andrew; Sisodiya, Sanjay M; Smith, Colin; Smoller, Jordan W; Soininen, Hilkka; Steen, Vidar M; Stott, David J; Sussmann, Jessika E; Thalamuthu, Anbupalam; Toga, Arthur W; Traynor, Bryan J; Troncoso, Juan; Tsolaki, Magda; Tzourio, Christophe; Uitterlinden, Andre G; Hernández, Maria C Valdés; Van der Brug, Marcel; van der Lugt, Aad; van der Wee, Nic J A; Van Haren, Neeltje E M|info:eu-repo/dai/nl/271562161; van 't Ent, Dennis; Van Tol, Marie-Jose; Vardarajan, Badri N; Vellas, Bruno; Veltman, Dick J; Völzke, Henry; Walter, Henrik; Wardlaw, Joanna M; Wassink, Thomas H; Weale, Michael E; Weinberger, Daniel R; Weiner, Michael W; Wen, Wei; Westman, Eric; White, Tonya; Wong, Tien Y; Wright, Clinton B; Zielke, Ronald H; Zonderman, Alan B; Martin, Nicholas G; Van Duijn, Cornelia M; Wright, Margaret J; Longstreth, W T; Schumann, Gunter; Grabe, Hans J; Franke, Barbara; Launer, Lenore J; Medland, Sarah E; Seshadri, Sudha; Thompson, Paul M; Ikram, M Arfan

    2017-01-01

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

  1. Novel genetic loci associated with hippocampal volume

    NARCIS (Netherlands)

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

    2017-01-01

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

  2. Neuregulin Directly Decreases Voltage-Gated Sodium Current in Hippocampal ErbB4-Expressing Interneurons

    OpenAIRE

    Janssen, Megan J.; Leiva-Salcedo, Elias; Buonanno, Andres

    2012-01-01

    The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term poten...

  3. A comparative proteome analysis of hippocampal tissue from schizophrenic and Alzheimer's disease individuals.

    Science.gov (United States)

    Edgar, P F; Schonberger, S J; Dean, B; Faull, R L; Kydd, R; Cooper, G J

    1999-03-01

    The proteins expressed by a genome have been termed the proteome. Comparative proteome analysis of brain tissue offers a novel means to identify biologically significant gene products that underlie psychopathology. In this study we collected post mortem hippocampal tissue from the brains of seven schizophrenic, seven Alzheimer's disease (AD) and seven control individuals. Hippocampal proteomes were visualised by two-dimensional gel electrophoresis of homogenised tissue. A mean of 549 (s.d. 35) proteins were successfully matched between each disease group and the control group. In comparison with the control hippocampal proteome, eight proteins in the schizophrenic hippocampal proteome were found to be decreased and eight increased in concentration, whereas, in the AD hippocampal proteome, 35 proteins were decreased and 73 were increased in concentration (Pdiazepam binding inhibitor (DBI) by N-terminal sequence analysis. DBI can regulate the action of the GABA(A) receptor. Protein changes involved 6% of the assessed AD hippocampal proteome, whereas, in schizophrenia protein changes involved less than 1% of the assessed hippocampal proteome. We conclude that schizophrenia has a subtle neuropathological presentation and comparative proteome analysis is a viable means by which to investigate diseases of the brain at the molecular level.

  4. Hippocampal ER stress and learning deficits following repeated pyrethroid exposure.

    Science.gov (United States)

    Hossain, Muhammad M; DiCicco-Bloom, Emanuel; Richardson, Jason R

    2015-01-01

    Endoplasmic reticulum (ER) stress is implicated as a significant contributor to neurodegeneration and cognitive dysfunction. Previously, we reported that the widely used pyrethroid pesticide deltamethrin causes ER stress-mediated apoptosis in SK-N-AS neuroblastoma cells. Whether or not this occurs in vivo remains unknown. Here, we demonstrate that repeated deltamethrin exposure (3 mg/kg every 3 days for 60 days) causes hippocampal ER stress and learning deficits in adult mice. Repeated exposure to deltamethrin caused ER stress in the hippocampus as indicated by increased levels of C/EBP-homologous protein (131%) and glucose-regulated protein 78 (96%). This was accompanied by increased levels of caspase-12 (110%) and activated caspase-3 (50%). To determine whether these effects resulted in learning deficits, hippocampal-dependent learning was evaluated using the Morris water maze. Deltamethrin-treated animals exhibited profound deficits in the acquisition of learning. We also found that deltamethrin exposure resulted in decreased BrdU-positive cells (37%) in the dentate gyrus of the hippocampus, suggesting potential impairment of hippocampal neurogenesis. Collectively, these results demonstrate that repeated deltamethrin exposure leads to ER stress, apoptotic cell death in the hippocampus, and deficits in hippocampal precursor proliferation, which is associated with learning deficits.

  5. Ecologically relevant spatial memory use modulates hippocampal neurogenesis

    OpenAIRE

    LaDage, Lara D.; Roth, Timothy C.; Fox, Rebecca A.; Pravosudov, Vladimir V.

    2009-01-01

    The adult hippocampus in birds and mammals undergoes neurogenesis and the resulting new neurons appear to integrate structurally and functionally into the existing neural architecture. However, the factors underlying the regulation of new neuron production is still under scrutiny. In recent years, the concept that spatial memory affects adult hippocampal neurogenesis has gained acceptance, although results attempting to causally link memory use to neurogenesis remain inconclusive, possibly ow...

  6. Hippocampal Abnormalities and Seizure Recurrence

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-08-01

    Full Text Available Hippocampal volumetry and T2 relaxometry were performed on 84 consecutive patients (adolescents and adults with partial epilepsy submitted to antiepileptic drug (AED withdrawal after at least 2 years of seizure control, in a study at State University of Campinas-UNICAMP, Brazil.

  7. Chronic exercise dampens hippocampal glutamate overflow induced by kainic acid in rats.

    Science.gov (United States)

    Holmes, Philip V; Reiss, Jenny I; Murray, Patrick S; Dishman, Rod K; Spradley, Jessica M

    2015-05-01

    Our laboratory has previously reported that chronic, voluntary exercise diminishes seizure-related behaviors induced by convulsant doses of kainic acid. The present experiments tested the hypothesis that exercise exerts this protective effect through a mechanism involving suppression of glutamate release in the hippocampal formation. Following three weeks of voluntary wheel running or sedentary conditions, rats were injected with 10 mg/kg of kainic acid, and hippocampal glutamate was measured in real time using a telemetric, in vivo voltammetry system. A separate experiment measured electroencephalographic (EEG) activity following kainic acid treatment. Results of the voltammetry experiment revealed that the rise in hippocampal glutamate induced by kainic acid is attenuated in exercising rats compared to sedentary controls, indicating that the exercise-induced protection against seizures involves regulation of hippocampal glutamate release. The findings reveal the potential benefit of regular exercise in the treatment and prevention of seizure disorders and suggest a possible neurobiological mechanism underlying this effect.

  8. BDNF downregulates 5-HT(2A) receptor protein levels in hippocampal cultures

    DEFF Research Database (Denmark)

    Trajkovska, V; Santini, M A; Marcussen, Anders Bue;

    2009-01-01

    Both brain-derived neurotrophic factor (BDNF) and the serotonin receptor 2A (5-HT(2A)) have been related to depression pathology. Specific 5-HT(2A) receptor changes seen in BDNF conditional mutant mice suggest that BDNF regulates the 5-HT(2A) receptor level. Here we show a direct effect of BDNF...... on 5-HT(2A) receptor protein levels in primary hippocampal neuronal and mature hippocampal organotypic cultures exposed to different BDNF concentrations for either 1, 3, 5 or 7 days. In vivo effects of BDNF on hippocampal 5-HT(2A) receptor levels were further corroborated in (BDNF +/-) mice...... with reduced BDNF levels. In primary neuronal cultures, 7 days exposure to 25 and 50ng/mL BDNF resulted in downregulation of 5-HT(2A), but not of 5-HT(1A), receptor protein levels. The BDNF-associated downregulation of 5-HT(2A) receptor levels was also observed in mature hippocampal organotypic cultures...

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

    Directory of Open Access Journals (Sweden)

    Caitlin M. Vander Weele

    2013-06-01

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

  10. Hippocampal adult neurogenesis: Does the immune system matter?

    Science.gov (United States)

    de Miranda, Aline Silva; Zhang, Cun-Jin; Katsumoto, Atsuko; Teixeira, Antônio Lúcio

    2017-01-15

    Adult hippocampal neurogenesis involves proliferation, survival, differentiation and integration of newborn neurons into pre-existing neuronal networks. Although its functional significance in the central nervous system (CNS) has not comprehensively elucidated, adult neurogenesis has been attributed a role in cognition, learning and memory. There is a growing body of evidence that CNS resident as well as peripheral immune cells participate in regulating hippocampal adult neurogenesis. Microglial cells are closely associated with neural stem/progenitor cell (NSPC) in the neurogenic niche engaged in a bidirectional communication with neurons, which may be important for adult neurogenesis. Microglial and neuronal crosstalk is mediated in part by CX3CL1/CX3CR1 signaling and a disruption in this pathway has been associated with impaired neurogenesis. It has been also reported that microglial neuroprotective or neurotoxic effects in adult neurogenesis occur in a context-dependent manner. Apart from microglia other brain resident and peripheral immune cells including pericytes, perivascular macrophages, mast cells and T-cells also modulate this phenomenon. It is worth mentioning that under some physiological circumstances such as normal aging there is a significant decrease in hippocampal neurogenesis. A role for innate and adaptive immune system in adult neurogenesis has been also reported during aging. Here, we review the current evidence regarding neuro-immune interactions in the regulation of neurogenesis under distinct conditions, including aging.

  11. Porcupine Controls Hippocampal AMPAR Levels, Composition, and Synaptic Transmission

    Directory of Open Access Journals (Sweden)

    Nadine Erlenhardt

    2016-02-01

    Full Text Available AMPA receptor (AMPAR complexes contain auxiliary subunits that modulate receptor trafficking and gating. In addition to the transmembrane AMPAR regulatory proteins (TARPs and cornichons (CNIH-2/3, recent proteomic studies identified a diverse array of additional AMPAR-associated transmembrane and secreted partners. We systematically surveyed these and found that PORCN and ABHD6 increase GluA1 levels in transfected cells. Knockdown of PORCN in rat hippocampal neurons, which express it in high amounts, selectively reduces levels of all tested AMPAR complex components. Regulation of AMPARs is independent of PORCN’s membrane-associated O-acyl transferase activity. PORCN knockdown in hippocampal neurons decreases AMPAR currents and accelerates desensitization and leads to depletion of TARP γ-8 from AMPAR complexes. Conditional PORCN knockout mice also exhibit specific changes in AMPAR expression and gating that reduce basal synaptic transmission but leave long-term potentiation intact. These studies define additional roles for PORCN in controlling synaptic transmission by regulating the level and composition of hippocampal AMPAR complexes.

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

    NARCIS (Netherlands)

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

    2001-01-01

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

  13. Hippocampal GABA transporter distribution in patients with temporal lobe epilepsy and hippocampal sclerosis

    NARCIS (Netherlands)

    Schijns, O.; Karaca, U.; Andrade, P.; Nijs, L. de; Kusters, B.; Peeters, A.; Dings, J.; Pannek, H.; Ebner, A.; Rijkers, K.; Hoogland, G.

    2015-01-01

    PURPOSE: To determine hippocampal expression of neuronal GABA-transporter (GAT-1) and glial GABA-transporter (GAT-3) in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). METHODS: Hippocampal sections were immunohistochemically stained for GABA-transporter 1 and GABA-transpor

  14. Hippocampal amnesia disrupts creative thinking.

    Science.gov (United States)

    Duff, Melissa C; Kurczek, Jake; Rubin, Rachael; Cohen, Neal J; Tranel, Daniel

    2013-12-01

    Creativity requires the rapid combination and recombination of existing mental representations to create novel ideas and ways of thinking. The hippocampal system, through its interaction with neocortical storage sites, provides a relational database necessary for the creation, updating, maintenance, and juxtaposition of mental representations used in service of declarative memory. Given this functionality, we hypothesized that hippocampus would play a critical role in creative thinking. We examined creative thinking, as measured by verbal and figural forms of the torrance tests of creative thinking (TTCT), in a group of participants with hippocampal damage and severe declarative memory impairment as well as in a group of demographically matched healthy comparison participants. The patients with bilateral hippocampal damage performed significantly worse than comparison participants on both the verbal and figural portions of the TTCT. These findings suggest that hippocampus plays a role critical in creative thinking, adding to a growing body of work pointing to the diverse ways the hallmark processing features of hippocampus serve a variety of behaviors that require flexible cognition.

  15. Glucocorticoid effects on hippocampal protein synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Schlatter, L.K.

    1988-01-01

    Following subcutaneous injection of rats with 5 mg corticosterone, hippocampal slices in vitro show increased ({sup 35}S)-methionine labeling of a cytosolic protein with an apparent molecular weight (M{sub r}) of 35,000 and an isoelectric point (IEP) of 6.6. This labeling is temporally consistent with a transcriptional event, and is steroid- and tissue-specific. The pear serum concentration of steroid occurs one hour or less following the injection. Maximal labeling of this protein is reached whenever serum corticosterone values are approximately 100 ng/ml. When endogenous corticosterone levels are elevated to 100 ng/ml through stressors or exogenous ACTH injections the same maximal increase in synthesis of the 35,000 M{sub r} protein is observed. Adrenalectomy prevents the observed response from occurring following stressor application or ACTH injections. Comparison of the increases observed after administration of the type 2 receptor agonist RU 28362 and aldosterone, which has a higher affinity for the type 1 receptor, shows a 50-fold greater sensitivity of the response to the type 2 receptor agonist. Synthesis of this protein following serum increases of steroid possibly correlates to the theorized function of the type 2 receptor feedback regulation. The similar protein in the liver has an IEP of 6.8 and a slightly higher M{sub r}. A second hippocampal protein with an M{sub r} of 46,000 and an IEP of 6.2 is also increased in labeling. Two additional liver proteins, one of Mr 53,000 (IEP of 6.2) and the other with an M{sub r} of 45,000 (IEP of 8.7-7.8) are increased in the liver following glucocorticoid administration.

  16. Inhibition of GABA release by presynaptic ionotropic GABA receptors in hippocampal CA3.

    Science.gov (United States)

    Axmacher, Nikolai; Draguhn, Andreas

    2004-02-09

    Vesicular transmitter release can be regulated by transmitter-gated ion channels at presynaptic axon terminals. The central inhibitory transmitter GABA acts on such presynaptic ionotropic receptors in various cells, including inhibitory interneurons. Here we report that GABA-mediated postsynaptic inhibitory currents in CA3 pyramidal cells of rat hippocampal slices are suppressed by agonists of GABAA receptors. The effect is present for both stimulus-induced and miniature IPSCs, indicating a reduction in the probability of vesicular release by presynaptic, action-potential-independent mechanisms. We conclude that the release of GABA from hippocampal CA3 interneurons is regulated by a negative feedback via presynaptic ionotropic GABA autoreceptors.

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

    Science.gov (United States)

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

    2014-02-01

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

  18. Sericin can reduce hippocampal neuronal apoptosis by activating the Akt signal transduction pathway in a rat model of diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Zhihong Chen; Yaqiang He; Chengjun Song; Zhijun Dong; Zhejun Su; Jingfeng Xue

    2012-01-01

    In the present study, a rat model of type 2 diabetes mellitus was established by continuous peritoneal injection of streptozotocin. Following intragastric perfusion of sericin for 35 days, blood glucose levels significantly reduced, neuronal apoptosis in the hippocampal CA1 region decreased, hippocampal phosphorylated Akt and nuclear factor kappa B expression were enhanced, but Bcl-xL/Bcl-2 associated death promoter expression decreased. Results demonstrated that sericin can reduce hippocampal neuronal apoptosis in a rat model of diabetes mellitus by regulating abnormal changes in the Akt signal transduction pathway.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-01-15

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

  20. Effect of Opioid on Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Yue Zhang

    2016-01-01

    Full Text Available During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

  1. Effect of Opioid on Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Zhang, Yue; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

  2. The Contradictory Effects of Neuronal Hyperexcitationon Adult Hippocampal Neurogenesis.

    Directory of Open Access Journals (Sweden)

    Juan Manuel Encinas

    2016-03-01

    Full Text Available Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An excitation-neurogenesis rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis.

  3. Anti-Inflammatory and Cytoprotective Effects of TMC-256C1 from Marine-Derived Fungus Aspergillus sp. SF-6354 via up-Regulation of Heme Oxygenase-1 in Murine Hippocampal and Microglial Cell Lines

    Directory of Open Access Journals (Sweden)

    Dong-Cheol Kim

    2016-04-01

    Full Text Available In the course of searching for bioactive secondary metabolites from marine fungi, TMC-256C1 was isolated from an ethyl acetate extract of the marine-derived fungus Aspergillus sp. SF6354. TMC-256C1 displayed anti-neuroinflammatory effect in BV2 microglial cells induced by lipopolysaccharides (LPS as well as neuroprotective effect against glutamate-stimulated neurotoxicity in mouse hippocampal HT22 cells. TMC-256C1 was shown to develop a cellular resistance to oxidative damage caused by glutamate-induced cytotoxicity and reactive oxygen species (ROS generation in HT22 cells, and suppress the inflammation process in LPS-stimulated BV2 cells. Furthermore, the neuroprotective and anti-neuroinflammatory activities of TMC-256C1 were associated with upregulated expression of heme oxygenase (HO-1 and nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2 in HT22 and BV2 cells. We also found that TMC-256C1 activated p38 mitogen-activated protein kinases (MAPK and phosphatidylinositol 3-kinase (PI3K/Akt signaling pathways in HT22 and BV2 cells. These results demonstrated that TMC-256C1 activates HO-1 protein expression, probably by increasing nuclear Nrf2 levels via the activation of the p38 MAPK and PI3K/Akt pathways.

  4. Hippocampal volume reduction in congenital central hypoventilation syndrome.

    Directory of Open Access Journals (Sweden)

    Paul M Macey

    Full Text Available Children with congenital central hypoventilation syndrome (CCHS, a genetic disorder characterized by diminished drive to breathe during sleep and impaired CO(2 sensitivity, show brain structural and functional changes on magnetic resonance imaging (MRI scans, with impaired responses in specific hippocampal regions, suggesting localized injury.We assessed total volume and regional variation in hippocampal surface morphology to identify areas affected in the syndrome. We studied 18 CCHS (mean age+/-std: 15.1+/-2.2 years; 8 female and 32 healthy control (age 15.2+/-2.4 years; 14 female children, and traced hippocampi on 1 mm(3 resolution T1-weighted scans, collected with a 3.0 Tesla MRI scanner. Regional hippocampal volume variations, adjusted for cranial volume, were compared between groups based on t-tests of surface distances to the structure midline, with correction for multiple comparisons. Significant tissue losses emerged in CCHS patients on the left side, with a trend for loss on the right; however, most areas affected on the left also showed equivalent right-sided volume reductions. Reduced regional volumes appeared in the left rostral hippocampus, bilateral areas in mid and mid-to-caudal regions, and a dorsal-caudal region, adjacent to the fimbria.The volume losses may result from hypoxic exposure following hypoventilation during sleep-disordered breathing, or from developmental or vascular consequences of genetic mutations in the syndrome. The sites of change overlap regions of abnormal functional responses to respiratory and autonomic challenges. Affected hippocampal areas have roles associated with memory, mood, and indirectly, autonomic regulation; impairments in these behavioral and physiological functions appear in CCHS.

  5. A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis.

    Science.gov (United States)

    O'Leary, Olivia F; Cryan, John F

    2014-12-01

    Adult hippocampal neurogenesis is implicated in antidepressant action, stress responses, and cognitive functioning. The hippocampus is functionally segregated along its longitudinal axis into dorsal (dHi) and ventral (vHi) regions in rodents, and analogous posterior and anterior regions in primates, whereby the vHi preferentially regulates stress and anxiety, while the dHi preferentially regulates spatial learning and memory. Given the role of neurogenesis in functions preferentially regulated by the dHi or vHi, it is plausible that neurogenesis is preferentially regulated in either the dHi or vHi depending upon the stimulus. We appraise here the literature on the effects of stress and antidepressants on neurogenesis along the hippocampal longitudinal axis and explore whether preferential regulation of neurogenesis in the vHi/anterior hippocampus contributes to stress resilience and antidepressant action.

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

    Science.gov (United States)

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

    2015-01-15

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

  7. Developmental and Activity-Dependent miRNA Expression Profiling in Primary Hippocampal Neuron Cultures

    NARCIS (Netherlands)

    M. van Spronsen (Myrrhe); E.Y. van Battum (Eljo); M. Kuijpers (Marijn); V.R. Vangoor (Vamshidhar); M.L. Rietman (M. Liset); J. Pothof (Joris); L.F. Gumy (Laura); W.F.J. van IJcken (Wilfred); A.S. Akhmanova (Anna); R.J. Pasterkamp (Jeroen); C.C. Hoogenraad (Casper)

    2013-01-01

    textabstractMicroRNAs (miRNAs) are evolutionarily conserved non-coding RNAs of ∼22 nucleotides that regulate gene expression at the level of translation and play vital roles in hippocampal neuron development, function and plasticity. Here, we performed a systematic and in-depth analysis of miRNA exp

  8. Novel genetic loci associated with hippocampal volume

    Science.gov (United States)

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

    2017-01-01

    The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=−0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness. PMID:28098162

  9. Activation of c-Jun N-terminal kinase 1/2 regulated by nitric oxide is associated with neuronal survival in hippocampal neurons in a rat model of ischemia

    Institute of Scientific and Technical Information of China (English)

    ZENG Xian-wei; LI Ming-wei; PAN Jing; JI Tai-ling; YANG Bin; ZHANG Bo; WANG Xiao-qiang

    2011-01-01

    Background C-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in cerebral ischemia.Although the mechanistic basis for this activation of JNK1/2 is uncertain,oxidative stress may play a role.The purpose of this study was to investigate whether the activation of JNK1/2 is associated with the production of endogenous nitric oxide (NO).Methods Ischemia and reperfusion (I/R) was induced by cerebral four-vessel occlusion.Sprague-Dawley (SD) rats were divided into 6 groups:sham group,I/R group,neuronal nitric oxide synthase (nNOS) inhibitor (7-nitroindazole,7-NI)given group,inducible nitric oxide synthase (iNOS) inhibitor (2-amino-5,6-dihydro-methylthiazine,AMT) given group,sodium chloride control group,and 1% dimethyl sulfoxide (DMSO) control group.The levels of protein expression and phospho-JNK1/2 were detected by Western blotting and the survival hippocampus neurons in CA1 zone were observed by cresyl violet staining.Results The study illustrated two peaks of JNK1/2 activation occurred at 30 minutes and 3 days during reperfusion.7-NI inhibited JNK1/2 activation during the early reperfusion,whereas AMT preferably attenuated JNK1/2 activation during the later reperfusion.Administration of 7-NI and AMT can decrease I/R-induced neuronal loss in hippocampal CA1 region.Conclusion JNK1/2 activation is associated with endogenous NO in response to ischemic insult.

  10. Hippocampal subfield volumes in mood disorders.

    Science.gov (United States)

    Cao, B; Passos, I C; Mwangi, B; Amaral-Silva, H; Tannous, J; Wu, M-J; Zunta-Soares, G B; Soares, J C

    2017-01-24

    Volume reduction and shape abnormality of the hippocampus have been associated with mood disorders. However, the hippocampus is not a uniform structure and consists of several subfields, such as the cornu ammonis (CA) subfields CA1-4, the dentate gyrus (DG) including a granule cell layer (GCL) and a molecular layer (ML) that continuously crosses adjacent subiculum (Sub) and CA fields. It is known that cellular and molecular mechanisms associated with mood disorders may be localized to specific hippocampal subfields. Thus, it is necessary to investigate the link between the in vivo hippocampal subfield volumes and specific mood disorders, such as bipolar disorder (BD) and major depressive disorder (MDD). In the present study, we used a state-of-the-art hippocampal segmentation approach, and we found that patients with BD had reduced volumes of hippocampal subfields, specifically in the left CA4, GCL, ML and both sides of the hippocampal tail, compared with healthy subjects and patients with MDD. The volume reduction was especially severe in patients with bipolar I disorder (BD-I). We also demonstrated that hippocampal subfield volume reduction was associated with the progression of the illness. For patients with BD-I, the volumes of the right CA1, ML and Sub decreased as the illness duration increased, and the volumes of both sides of the CA2/3, CA4 and hippocampal tail had negative correlations with the number of manic episodes. These results indicated that among the mood disorders the hippocampal subfields were more affected in BD-I compared with BD-II and MDD, and manic episodes had focused progressive effect on the CA2/3 and CA4 and hippocampal tail.Molecular Psychiatry advance online publication, 24 January 2017; doi:10.1038/mp.2016.262.

  11. Hippocampal CA1 Ripples as Inhibitory Transients.

    Directory of Open Access Journals (Sweden)

    Paola Malerba

    2016-04-01

    Full Text Available Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  12. Hippocampal CA1 Ripples as Inhibitory Transients.

    Science.gov (United States)

    Malerba, Paola; Krishnan, Giri P; Fellous, Jean-Marc; Bazhenov, Maxim

    2016-04-01

    Memories are stored and consolidated as a result of a dialogue between the hippocampus and cortex during sleep. Neurons active during behavior reactivate in both structures during sleep, in conjunction with characteristic brain oscillations that may form the neural substrate of memory consolidation. In the hippocampus, replay occurs within sharp wave-ripples: short bouts of high-frequency activity in area CA1 caused by excitatory activation from area CA3. In this work, we develop a computational model of ripple generation, motivated by in vivo rat data showing that ripples have a broad frequency distribution, exponential inter-arrival times and yet highly non-variable durations. Our study predicts that ripples are not persistent oscillations but result from a transient network behavior, induced by input from CA3, in which the high frequency synchronous firing of perisomatic interneurons does not depend on the time scale of synaptic inhibition. We found that noise-induced loss of synchrony among CA1 interneurons dynamically constrains individual ripple duration. Our study proposes a novel mechanism of hippocampal ripple generation consistent with a broad range of experimental data, and highlights the role of noise in regulating the duration of input-driven oscillatory spiking in an inhibitory network.

  13. Inverse correspondence between hippocampal perfusion and verbal memory performance in older adults.

    Science.gov (United States)

    Rane, Swati; Ally, Brandon A; Hussey, Erin; Wilson, Tracy; Thornton-Wells, Tricia; Gore, John C; Donahue, Manus J

    2013-03-01

    Understanding physiological changes that precede irreversible tissue damage in age-related pathology is central to optimizing treatments that may prevent, or delay, cognitive decline. Cerebral perfusion is a tightly regulated physiological property, coupled to tissue metabolism and function, and abnormal (both elevated and reduced) hippocampal perfusion has been reported in a range of cognitive disorders. However, the size and location of the hippocampus complicates perfusion quantification, as many perfusion techniques acquire data with spatial resolution on the order of or beyond the size of the hippocampus, and are thus suboptimal in this region (especially in the presence of hippocampal atrophy and reduced flow scenarios). Here, the relationship between hippocampal perfusion and atrophy as a function of memory performance was examined in cognitively normal healthy older adults (n = 20; age=67 ± 7 yr) with varying genetic risk for dementia using a custom arterial spin labeling acquisition and analysis procedure. When controlling for hippocampal volume, it was found that hippocampal perfusion correlated inversely (P = 0.04) with memory performance despite absent hippocampal tissue atrophy or white matter disease. The hippocampal flow asymmetry (left hippocampus perfusion-right hippocampus perfusion) was significantly (P = 0.04) increased in APOE-ϵ4 carriers relative to noncarriers. These findings demonstrate that perfusion correlates more strongly than tissue volume with memory performance in cognitively normal older adults, and furthermore that an inverse trend between these two parameters suggests that elevation of neuronal activity, possibly mediated by neuroinflammation and/or excitation/inhibition imbalance, may be closely associated with minor changes in memory performance. Copyright © 2012 Wiley Periodicals, Inc.

  14. α-Calcium calmodulin kinase II modulates the temporal structure of hippocampal bursting patterns.

    Directory of Open Access Journals (Sweden)

    Jeiwon Cho

    Full Text Available The alpha calcium calmodulin kinase II (α-CaMKII is known to play a key role in CA1/CA3 synaptic plasticity, hippocampal place cell stability and spatial learning. Additionally, there is evidence from hippocampal electrophysiological slice studies that this kinase has a role in regulating ion channels that control neuronal excitability. Here, we report in vivo single unit studies, with α-CaMKII mutant mice, in which threonine 305 was replaced with an aspartate (α-CaMKII(T305D mutants, that indicate that this kinase modulates spike patterns in hippocampal pyramidal neurons. Previous studies showed that α-CaMKII(T305D mutants have abnormalities in both hippocampal LTP and hippocampal-dependent learning. We found that besides decreased place cell stability, which could be caused by their LTP impairments, the hippocampal CA1 spike patterns of α-CaMKII(T305D mutants were profoundly abnormal. Although overall firing rate, and overall burst frequency were not significantly altered in these mutants, inter-burst intervals, mean number of intra-burst spikes, ratio of intra-burst spikes to total spikes, and mean intra-burst intervals were significantly altered. In particular, the intra burst intervals of place cells in α-CaMKII(T305D mutants showed higher variability than controls. These results provide in vivo evidence that besides its well-known function in synaptic plasticity, α-CaMKII, and in particular its inhibitory phosphorylation at threonine 305, also have a role in shaping the temporal structure of hippocampal burst patterns. These results suggest that some of the molecular processes involved in acquiring information may also shape the patterns used to encode this information.

  15. Exercise Influence on Hippocampal Function: Possible Involvement of Orexin-A

    Science.gov (United States)

    Chieffi, Sergio; Messina, Giovanni; Villano, Ines; Messina, Antonietta; Esposito, Maria; Monda, Vincenzo; Valenzano, Anna; Moscatelli, Fiorenzo; Esposito, Teresa; Carotenuto, Marco; Viggiano, Andrea; Cibelli, Giuseppe; Monda, Marcellino

    2017-01-01

    In the present article, we provide a brief review of current knowledge regarding the effects induced by physical exercise on hippocampus. Research involving animals and humans supports the view that physical exercise, enhancing hippocampal neurogenesis and function, improves cognition, and regulates mood. These beneficial effects depend on the contribute of more factors including the enhancement of vascularization and upregulation of growth factors. Among these, the BDNF seems to play a significant role. Another putative factor that might contribute to beneficial effects of exercise is the orexin-A. In support of this hypothesis there are the following observations: (1) orexin-A enhances hippocampal neurogenesis and function and (2) the levels of orexin-A increase with physical exercise. The beneficial effects of exercise may represent an important resource to hinder the cognitive decline associated with the aging-related hippocampal deterioration and ameliorate depressive symptoms. PMID:28261108

  16. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

    Science.gov (United States)

    Duarte-Guterman, Paula; Yagi, Shunya; Chow, Carmen; Galea, Liisa A M

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus.

  17. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons.

    Science.gov (United States)

    Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop

    2017-02-23

    Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances.

  18. Hippocampal Erk Mechanisms Linking Prediction Error to Fear Extinction: Roles of Shock Expectancy and Contextual Aversive Valence

    Science.gov (United States)

    Huh, Kyu Hwan; Guzman, Yomayra F.; Tronson, Natalie C.; Guedea, Anita L.; Gao, Can; Radulovic, Jelena

    2009-01-01

    Extinction of fear requires learning that anticipated aversive events no longer occur. Animal models reveal that sustained phosphorylation of the extracellular signal-regulated kinase (Erk) in hippocampal CA1 neurons plays an important role in this process. However, the key signals triggering and regulating the activity of Erk are not known. By…

  19. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory

    Science.gov (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise

    2016-01-01

    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are “earmarked” for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength. The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories. PMID:26804338

  20. Synaptic plasticity in the hippocampal area CA1-subiculum projection: implications for theories of memory.

    Science.gov (United States)

    O'Mara, S M; Commins, S; Anderson, M

    2000-01-01

    This paper reviews investigations of synaptic plasticity in the major, and underexplored, pathway from hippocampal area CA1 to the subiculum. This brain area is the major synaptic relay for the majority of hippocampal area CA1 neurons, making the subiculum the last relay of the hippocampal formation prior to the cortex. The subiculum thus has a very major role in mediating hippocampal-cortical interactions. We demonstrate that the projection from hippocampal area CA1 to the subiculum sustains plasticity on a number of levels. We show that this pathway is capable of undergoing both long-term potentiation (LTP) and paired-pulse facilitation (PPF, a short-term plastic effect). Although we failed to induce long-term depression (LTD) of this pathway with low-frequency stimulation (LFS) and two-pulse stimulation (TPS), both protocols can induce a "late-developing" potentiation of synaptic transmission. We further demonstrate that baseline synaptic transmission can be dissociated from paired-pulse stimulation of the same pathway; we also show that it is possible, using appropriate protocols, to change PPF to paired-pulse depression, thus revealing subtle and previously undescribed mechanisms which regulate short-term synaptic plasticity. Finally, we successfully recorded from individual subicular units in the freely-moving animal, and provide a description of the characteristics of such neurons in a pellet-chasing task. We discuss the implications of these findings in relation to theories of the biological consolidation of memory.

  1. Resilience to chronic stress is mediated by hippocampal brain-derived neurotrophic factor.

    Science.gov (United States)

    Taliaz, Dekel; Loya, Assaf; Gersner, Roman; Haramati, Sharon; Chen, Alon; Zangen, Abraham

    2011-03-23

    Chronic stress is a trigger for several psychiatric disorders, including depression; however, critical individual differences in resilience to both the behavioral and the neurochemical effects of stress have been reported. A prominent mechanism by which the brain reacts to acute and chronic stress is activation of the hypothalamic-pituitary-adrenal (HPA) axis, which is inhibited by the hippocampus via a polysynaptic circuit. Alterations in secretion of stress hormones and levels of brain-derived neurotrophic factor (BDNF) in the hippocampus were implicated in depression and the effects of antidepressant medications. However, the potential role of hippocampal BDNF in behavioral resilience to chronic stress and in the regulation of the HPA axis has not been evaluated. In the present study, Sprague Dawley rats were subjected to 4 weeks of chronic mild stress (CMS) to induce depressive-like behaviors after lentiviral vectors were used to induce localized BDNF overexpression or knockdown in the hippocampus. The behavioral outcome was measured during 3 weeks after the CMS procedure, then plasma samples were taken for measurements of corticosterone levels, and finally hippocampal tissue was taken for BDNF measurements. We found that hippocampal BDNF expression plays a critical role in resilience to chronic stress and that reduction of hippocampal BDNF expression in young, but not adult, rats induces prolonged elevations in corticosterone secretion. The present study describes a mechanism for individual differences in responses to chronic stress and implicates hippocampal BDNF in the development of neural circuits that control adequate stress adaptations.

  2. β-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory.

    Science.gov (United States)

    Hagena, Hardy; Hansen, Niels; Manahan-Vaughan, Denise

    2016-04-01

    Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on β-adrenergic receptors (β-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to β-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on β-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal β-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories.

  3. Synaptic network activity induces neuronal differentiation of adult hippocampal precursor cells through BDNF signaling

    Directory of Open Access Journals (Sweden)

    Harish Babu

    2009-09-01

    Full Text Available Adult hippocampal neurogenesis is regulated by activity. But how do neural precursor cells in the hippocampus respond to surrounding network activity and translate increased neural activity into a developmental program? Here we show that long-term potential (LTP-like synaptic activity within a cellular network of mature hippocampal neurons promotes neuronal differentiation of newly generated cells. In co-cultures of precursor cells with primary hippocampal neurons, LTP-like synaptic plasticity induced by addition of glycine in Mg2+-free media for 5 min, produced synchronous network activity and subsequently increased synaptic strength between neurons. Furthermore, this synchronous network activity led to a significant increase in neuronal differentiation from the co-cultured neural precursor cells. When applied directly to precursor cells, glycine and Mg2+-free solution did not induce neuronal differentiation. Synaptic plasticity-induced neuronal differentiation of precursor cells was observed in the presence of GABAergic neurotransmission blockers but was dependent on NMDA-mediated Ca2+ influx. Most importantly, neuronal differentiation required the release of brain-derived neurotrophic factor (BDNF from the underlying substrate hippocampal neurons as well as TrkB receptor phosphorylation in precursor cells. This suggests that activity-dependent stem cell differentiation within the hippocampal network is mediated via synaptically evoked BDNF signaling.

  4. Role of cyclic nucleotide-gated channels in the modulation of mouse hippocampal neurogenesis.

    Directory of Open Access Journals (Sweden)

    Maria Vittoria Podda

    Full Text Available Neural stem cells generate neurons in the hippocampal dentate gyrus in mammals, including humans, throughout adulthood. Adult hippocampal neurogenesis has been the focus of many studies due to its relevance in processes such as learning and memory and its documented impairment in some neurodegenerative diseases. However, we are still far from having a complete picture of the mechanism regulating this process. Our study focused on the possible role of cyclic nucleotide-gated (CNG channels. These voltage-independent channels activated by cyclic nucleotides, first described in retinal and olfactory receptors, have been receiving increasing attention for their involvement in several brain functions. Here we show that the rod-type, CNGA1, and olfactory-type, CNGA2, subunits are expressed in hippocampal neural stem cells in culture and in situ in the hippocampal neurogenic niche of adult mice. Pharmacological blockade of CNG channels did not affect cultured neural stem cell proliferation but reduced their differentiation towards the neuronal phenotype. The membrane permeant cGMP analogue, 8-Br-cGMP, enhanced neural stem cell differentiation to neurons and this effect was prevented by CNG channel blockade. In addition, patch-clamp recording from neuron-like differentiating neural stem cells revealed cGMP-activated currents attributable to ion flow through CNG channels. The current work provides novel insights into the role of CNG channels in promoting hippocampal neurogenesis, which may prove to be relevant for stem cell-based treatment of cognitive impairment and brain damage.

  5. Apoptosis and autophagy control cell proliferation in the dentate gyrus following hippocampal lesion

    Institute of Scientific and Technical Information of China (English)

    Ju Zhou; Wei Peng; Qi Zhu; Shan Gong; Lidong Shan; Tadashi Hisamitsu; Shiyu Guo; Xinghong Jiang

    2010-01-01

    Brain injuries often result in the promotion of cell proliferation in the hippocampal dentate gyrus(DG),but the number of newborn cells declines with time.However,the cause of this decline remains poorly understood.Elucidation of the fate of these newborn cells will further the understanding of the pathological process and treatment of brain injury.In the present study,the number of newborn cells was quantitatively analyzed using an unbiased stereological method following hippocampal lesion by kainic acid,in combination with detection of apoptosis and autophagy.Results revealed that hippocampal lesion resulted in a significantly increased number of 5-bromo-2-deoxyuridine(BrdU)-positive cells in the DG,which subsequently decreased with time.BrdU/cleaved caspase-3 double-labeled cells were detected in the granular cell layer and hilus of DG.However,expressions of LC3-11,Beclin 1,and p53 were upregulated,and pro-caspase-3 and Bcl-2 were downregulated.Results indicated that hippocampal lesion in adult rats resulted in significant cell proliferation in the DG,which subsequently reduced with time.In addition,results suggested that apoptosis and autophagic processes could regulate cell proliferation in the DG following hippocampal lesion.

  6. Immunohistochemical visualization of hippocampal neuron activity after spatial learning in a mouse model of neurodevelopmental disorders.

    Science.gov (United States)

    Provenzano, Giovanni; Pangrazzi, Luca; Poli, Andrea; Berardi, Nicoletta; Bozzi, Yuri

    2015-05-12

    Induction of phosphorylated extracellular-regulated kinase (pERK) is a reliable molecular readout of learning-dependent neuronal activation. Here, we describe a pERK immunohistochemistry protocol to study the profile of hippocampal neuron activation following exposure to a spatial learning task in a mouse model characterized by cognitive deficits of neurodevelopmental origin. Specifically, we used pERK immunostaining to study neuronal activation following Morris water maze (MWM, a classical hippocampal-dependent learning task) in Engrailed-2 knockout (En2(-/-)) mice, a model of autism spectrum disorders (ASD). As compared to wild-type (WT) controls, En2(-/-) mice showed significant spatial learning deficits in the MWM. After MWM, significant differences in the number of pERK-positive neurons were detected in specific hippocampal subfields of En2(-/-) mice, as compared to WT animals. Thus, our protocol can robustly detect differences in pERK-positive neurons associated to hippocampal-dependent learning impairment in a mouse model of ASD. More generally, our protocol can be applied to investigate the profile of hippocampal neuron activation in both genetic or pharmacological mouse models characterized by cognitive deficits.

  7. Noradrenergic mechanism involved in the nociceptive modulation of hippocampal CA3 region of normal rats.

    Science.gov (United States)

    Jin, Hua; Teng, Yueqiu; Zhang, Xuexin; Yang, Chunxiao; Xu, Manying; Yang, Lizhuang

    2014-06-27

    Norepinephrine (NE) is an important neurotransmitter in the brain, and regulates antinociception. However, the mechanism of action of NE on pain-related neurons in the hippocampal CA3 region is not clear. This study examines the effects of NE, phentolamine on the electrical activities of pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal CA3 region of rats. Trains of electric impulses applied to the right sciatic nerve were used as noxious stimulation. The electrical activities of PENs or PINs in the hippocampal CA3 region were recorded by using a glass microelectrode. Our results revealed that, in the hippocampal CA3 region, the intra-CA3 region microinjection of NE decreased the pain-evoked discharged frequency and prolonged the discharged latency of PEN, and increased the pain-evoked discharged frequency and shortened discharged inhibitory duration (ID) of PIN, exhibiting the specific analgesic effect of NE. While intra-CA3 region microinjection of phentolamine produced the opposite response. It implies that phentolamine can block the effect of endogenous NE to cause the enhanced response of PEN and PIN to noxious stimulation. On the basis of above findings we can deduce that NE, phentolamine and alpha-adrenoceptor are involved in the modulation of nociceptive information transmission in the hippocampal CA3 region.

  8. Inflammasome-IL-1β signaling mediates ethanol inhibition of hippocampal neurogenesis

    Directory of Open Access Journals (Sweden)

    Fulton eCrews

    2012-05-01

    Full Text Available AbstractRegulation of hippocampal neurogenesis is poorly understood, but appears to contribute to mood and cognition. Ethanol and neuroinflammation are known to reduce neurogenesis. We have found that ethanol induces neuroinflammation supporting the hypothesis that ethanol induction of neuroinflammation contributes to ethanol inhibition of neurogenesis. To identify the key proinflammatory molecule that may be responsible for ethanol-impaired neurogenesis we used an ex vivo model of organotypic hippocampal-entorhinal cortex (HEC brain slice cultures. Here, we demonstrated a key role of proinflammatory cytokine IL-1β signaling in mediating ethanol inhibition of neurogenesis. Ethanol inhibition of neurogenesis was reversed by neutralizing antibody to IL-1β or blockade of the IL-1β receptor with antagonist IL-1RIa. Ethanol-impaired neurogenesis is associated with strong induction of IL-1β and inflammasome proteins NALP1 and NALP3 in both neurons and astrocytes. Blockade of IL-1β synthesis with inflammasome inhibitors Parthenolide and Bay11708 significantly reversed ethanol inhibited neurogenesis. Furthermore, we also found that IL-1β and inflammasome proteins NALP1 and NALP3 are increased in hippocampal neurons and astrocytes in postmortem alcoholic human brain. Together, these novel findings demonstrate that targeting inflammasome-IL-1β signaling can normalize ethanol-impaired hippocampal neurogenesis, which may have therapeutic implications for treatment of cognitive impairment associated with hippocampal dysfunction in alcoholics.

  9. AP2γ controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior.

    Science.gov (United States)

    Mateus-Pinheiro, A; Alves, N D; Patrício, P; Machado-Santos, A R; Loureiro-Campos, E; Silva, J M; Sardinha, V M; Reis, J; Schorle, H; Oliveira, J F; Ninkovic, J; Sousa, N; Pinto, L

    2016-10-25

    Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2γ (AP2γ, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2γ is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2γ in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2γ-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2γ deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho)physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain.Molecular Psychiatry advance online publication, 25 October 2016; doi:10.1038/mp.2016.169.

  10. Supramammillary serotonin reduction alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in a Morris water maze

    Science.gov (United States)

    Hernández-Pérez, J. Jesús; Gutiérrez-Guzmán, Blanca E.; López-Vázquez, Miguel Á.; Olvera-Cortés, María E.

    2015-01-01

    Hippocampal theta activity is related to spatial information processing, and high-frequency theta activity, in particular, has been linked to efficient spatial memory performance. Theta activity is regulated by the synchronizing ascending system (SAS), which includes mesencephalic and diencephalic relays. The supramamillary nucleus (SUMn) is located between the reticularis pontis oralis and the medial septum (MS), in close relation with the posterior hypothalamic nucleus (PHn), all of which are part of this ascending system. It has been proposed that the SUMn plays a role in the modulation of hippocampal theta-frequency; this could occur through direct connections between the SUMn and the hippocampus or through the influence of the SUMn on the MS. Serotonergic raphe neurons prominently innervate the hippocampus and several components of the SAS, including the SUMn. Serotonin desynchronizes hippocampal theta activity, and it has been proposed that serotonin may regulate learning through the modulation of hippocampal synchrony. In agreement with this hypothesis, serotonin depletion in the SUMn/PHn results in deficient spatial learning and alterations in CA1 theta activity-related learning in a Morris water maze. Because it has been reported that SUMn inactivation with lidocaine impairs the consolidation of reference memory, we asked whether changes in hippocampal theta activity related to learning would occur through serotonin depletion in the SUMn, together with deficiencies in memory. We infused 5,7-DHT bilaterally into the SUMn in rats and evaluated place learning in the standard Morris water maze task. Hippocampal (CA1 and dentate gyrus), septal and SUMn EEG were recorded during training of the test. The EEG power in each region and the coherence between the different regions were evaluated. Serotonin depletion in the SUMn induced deficient spatial learning and altered the expression of hippocampal high-frequency theta activity. These results provide evidence in

  11. Hippocampal Abnormalities in Prolonged Febrile Seizures

    Directory of Open Access Journals (Sweden)

    J Gordon Millichap

    2006-10-01

    Full Text Available Apparent diffusion coefficient (ADC measurements were used to characterize hippocampal edema within 5 days of a prolonged febrile seizure (PFS in a study at Great Ormond Street Hospital, London, UK.

  12. Hippocampal signaling pathways are involved in stress-induced impairment of memory formation in rats.

    Science.gov (United States)

    Sardari, Maryam; Rezayof, Ameneh; Khodagholi, Fariba

    2015-11-02

    Stress is a potent modulator of hippocampal-dependent memory formation. The aim of the present study was to assess the role of hippocampal signaling pathways in stress-induced memory impairment in male Wistar rats. The animals were exposed to acute elevated platform (EP) stress and memory formation was measured by a step-through type passive avoidance task. The results indicated that post-training or pre-test exposure to EP stress impaired memory consolidation or retrieval respectively. Using western blot analysis, it was found that memory retrieval was associated with the increase in the levels of phosphorylated cAMP-responsive element binding protein (P-CREB), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and its downstream targets in the hippocampus. In contrast, the stress exposure decreased the hippocampal levels of these proteins. In addition, stress-induced impairment of memory consolidation or retrieval was associated with the decrease in the P-CREB/CREB ratio and the PGC-1α level in the hippocampus. On the other hand, the hippocampal level of nuclear factor E2-related factor 2 (Nrf2) and gamma-glutamylcysteine synthetase (γ-GCS) which are the master regulators of defense system were decreased by the stress exposure. The increased hippocampal levels of Nrf2 and it׳s downstream was observed during memory retrieval, while stress-induced impairment of memory consolidation or retrieval inhibited this hippocampal signaling pathway. Overall, these findings suggest that down-regulation of CREB/PGC-1α signaling cascade and Nrf2 antioxidant pathways in the hippocampus may be associated with memory impairment induced by stress. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. Updating the Lamellar Hypothesis of Hippocampal Organization

    OpenAIRE

    Robert S Sloviter; Terje eLømo

    2012-01-01

    In 1971, Andersen and colleagues proposed that excitatory activity in the entorhinal cortex propagates topographically to the dentate gyrus, and on through a trisynaptic circuit lying within transverse hippocampal slices or lamellae [Andersen, Bliss, and Skrede. 1971. Lamellar organization of hippocampal pathways. Exp Brain Res 13, 222-238]. In this way, a relatively simple structure might mediate complex functions in a manner analogous to the way independent piano keys can produce a nearly i...

  14. Hippocampal neuroplasticity in major depressive disorder.

    Science.gov (United States)

    Malykhin, N V; Coupland, N J

    2015-11-19

    One of the most replicated findings has been that hippocampus volume is decreased in patients with major depressive disorder (MDD). Recent volumetric magnetic resonance imaging (MRI) studies suggest that localized differences in hippocampal volume may be more prominent than global differences. Preclinical and post-mortem studies in MDD indicated that different subfields of the hippocampus may respond differently to stress and may also have differential levels of plasticity in response to antidepressant treatment. Advances in high-field MRI allowed researchers to visualize and measure hippocampal subfield volumes in MDD patients in vivo. The results of these studies provide the first in vivo evidence that hippocampal volume reductions in MDD are specific to the cornu ammonis and dentate gyrus hippocampal subfields, findings that appear, on the surface, consistent with preclinical evidence for localized mechanisms of hippocampal neuroplasticity. In this review we discuss how recent advances in neuroimaging allow researchers to further understand hippocampal neuroplasticity in MDD and how it is related to antidepressant treatment, memory function, and disease progression.

  15. A mid-life vitamin A supplementation prevents age-related spatial memory deficits and hippocampal neurogenesis alterations through CRABP-I.

    Directory of Open Access Journals (Sweden)

    Katia Touyarot

    Full Text Available Age-related memory decline including spatial reference memory is considered to begin at middle-age and coincides with reduced adult hippocampal neurogenesis. Moreover, a dysfunction of vitamin A hippocampal signalling pathway has been involved in the appearance of age-related memory deficits but also in adult hippocampal neurogenesis alterations. The present study aims at testing the hypothesis that a mid-life vitamin A supplementation would be a successful strategy to prevent age-related memory deficits. Thus, middle-aged Wistar rats were submitted to a vitamin A enriched diet and were tested 4 months later in a spatial memory task. In order to better understand the potential mechanisms mediating the effects of vitamin A supplementation on hippocampal functions, we studied different aspects of hippocampal adult neurogenesis and evaluated hippocampal CRABP-I expression, known to modulate differentiation processes. Here, we show that vitamin A supplementation from middle-age enhances spatial memory and improves the dendritic arborisation of newborn immature neurons probably resulting in a better survival and neuronal differentiation in aged rats. Moreover, our results suggest that hippocampal CRABP-I expression which controls the intracellular availability of retinoic acid (RA, may be an important regulator of neuronal differentiation processes in the aged hippocampus. Thus, vitamin A supplementation from middle-age could be a good strategy to maintain hippocampal plasticity and functions.

  16. Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis.

    Science.gov (United States)

    Yousef, Hanadie; Morgenthaler, Adam; Schlesinger, Christina; Bugaj, Lukasz; Conboy, Irina M; Schaffer, David V

    2015-05-01

    Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.

  17. Hippocampal Dendritic Spines Are Segregated Depending on Their Actin Polymerization

    Directory of Open Access Journals (Sweden)

    Nuria Domínguez-Iturza

    2016-01-01

    Full Text Available Dendritic spines are mushroom-shaped protrusions of the postsynaptic membrane. Spines receive the majority of glutamatergic synaptic inputs. Their morphology, dynamics, and density have been related to synaptic plasticity and learning. The main determinant of spine shape is filamentous actin. Using FRAP, we have reexamined the actin dynamics of individual spines from pyramidal hippocampal neurons, both in cultures and in hippocampal organotypic slices. Our results indicate that, in cultures, the actin mobile fraction is independently regulated at the individual spine level, and mobile fraction values do not correlate with either age or distance from the soma. The most significant factor regulating actin mobile fraction was the presence of astrocytes in the culture substrate. Spines from neurons growing in the virtual absence of astrocytes have a more stable actin cytoskeleton, while spines from neurons growing in close contact with astrocytes show a more dynamic cytoskeleton. According to their recovery time, spines were distributed into two populations with slower and faster recovery times, while spines from slice cultures were grouped into one population. Finally, employing fast lineal acquisition protocols, we confirmed the existence of loci with high polymerization rates within the spine.

  18. Rat hippocampal GABAergic molecular markers are differentially affected by ageing.

    Science.gov (United States)

    Vela, José; Gutierrez, Antonia; Vitorica, Javier; Ruano, Diego

    2003-04-01

    We previously reported that the pharmacological properties of the hippocampal GABAA receptor and the expression of several subunits are modified during normal ageing. However, correlation between these post-synaptic modifications and pre-synaptic deficits were not determined. To address this issue, we have analysed the mRNA levels of several GABAergic molecular markers in young and old rat hippocampus, including glutamic acid decarboxylase enzymes, parvalbumin, calretinin, somatostatin, neuropeptide Y and vasoactive intestinal peptide (VIP). There was a differential age-related decrease in these interneuronal mRNAs that was inversely correlated with up-regulation of the alpha1 GABA receptor subunit. Somatostatin and neuropeptide Y mRNAs were most frequently affected (75% of the animals), then calretinin and VIP mRNAs (50% of the animals), and parvalbumin mRNA (25% of the animals) in the aged hippocampus. This selective vulnerability was well correlated at the protein/cellular level as analysed by immunocytochemistry. Somatostatin interneurones, which mostly innervate principal cell distal dendrites, were more vulnerable than calretinin interneurones, which target other interneurones. Parvalbumin interneurones, which mostly innervate perisomatic domains of principal cells, were preserved. This age-dependent differential reduction of specific hippocampal inteneuronal subpopulations might produce functional alterations in the GABAergic tone which might be compensated, at the post-synaptic level, by up-regulation of the expression of the alpha1 GABAA receptor subunit.

  19. Hippocampal EEG and behaviour in dog. II. Hippocampal EEG correlates with elementary motor acts

    NARCIS (Netherlands)

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

    1979-01-01

    A positive correlation has been shown between the speed of forced stepping on a conveyor belt and the amplitude and frequency of the concomitant hippocampal EEG. Significant modulation in the spectral properties of the dog's hippocampal EEG has been found in relation to 3 elementary motor acts: ste

  20. Hippocampal atrophy rates in Alzheimer disease

    Science.gov (United States)

    Henneman, W J.P.; Sluimer, J D.; Barnes, J; van der Flier, W M.; Sluimer, I C.; Fox, N C.; Scheltens, P; Vrenken, H; Barkhof, F

    2009-01-01

    Objective: To investigate the added value of hippocampal atrophy rates over whole brain volume measurements on MRI in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls. Methods: We included 64 patients with AD (67 ± 9 years; F/M 38/26), 44 patients with MCI (71 ± 6 years; 21/23), and 34 controls (67 ± 9 years; 16/18). Two MR scans were performed (scan interval: 1.8 ± 0.7 years; 1.0 T), using a coronal three-dimensional T1-weighted gradient echo sequence. At follow-up, 3 controls and 23 patients with MCI had progressed to AD. Hippocampi were manually delineated at baseline. Hippocampal atrophy rates were calculated using regional, nonlinear fluid registration. Whole brain baseline volumes and atrophy rates were determined using automated segmentation and registration tools. Results: All MRI measures differed between groups (p < 0.005). For the distinction of MCI from controls, larger effect sizes of hippocampal measures were found compared to whole brain measures. Between MCI and AD, only whole brain atrophy rate differed significantly. Cox proportional hazards models (variables dichotomized by median) showed that within all patients without dementia, hippocampal baseline volume (hazard ratio [HR]: 5.7 [95% confidence interval: 1.5–22.2]), hippocampal atrophy rate (5.2 [1.9–14.3]), and whole brain atrophy rate (2.8 [1.1–7.2]) independently predicted progression to AD; the combination of low hippocampal volume and high atrophy rate yielded a HR of 61.1 (6.1–606.8). Within patients with MCI, only hippocampal baseline volume and atrophy rate predicted progression. Conclusion: Hippocampal measures, especially hippocampal atrophy rate, best discriminate mild cognitive impairment (MCI) from controls. Whole brain atrophy rate discriminates Alzheimer disease (AD) from MCI. Regional measures of hippocampal atrophy are the strongest predictors of progression to AD. GLOSSARY AD = Alzheimer disease; BET = brain

  1. Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease.

    Science.gov (United States)

    Quiroz, Yakeel T; Budson, Andrew E; Celone, Kim; Ruiz, Adriana; Newmark, Randall; Castrillón, Gabriel; Lopera, Francisco; Stern, Chantal E

    2010-12-01

    The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimer's disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively-intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin-1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms. Twenty carriers of the Alzheimer's-associated E280A PS1 mutation and 19 PS1-negative control subjects participated. Both groups were matched for age, sex, education level, and neuropsychological test performance. All participants performed a face-name associative encoding task while in a Phillips 1.5T fMRI scanner. Analysis focused on the hippocampal system. Despite identical behavioral performance, presymptomatic PS1 mutation carriers exhibited increased activation of the right anterior hippocampus during encoding of novel face-name associations compared to matched controls. Our results demonstrate that functional changes within the hippocampal memory system occur years before cognitive decline in FAD. These presymptomatic changes in hippocampal physiology in FAD suggest that hippocampal fMRI patterns during associative encoding may also provide a preclinical biomarker in sporadic AD.

  2. Hippocampal place cells, context, and episodic memory.

    Science.gov (United States)

    Smith, David M; Mizumori, Sheri J Y

    2006-01-01

    Although most observers agree that the hippocampus has a critical role in learning and memory, there remains considerable debate about the precise functional contribution of the hippocampus to these processes. Two of the most influential accounts hold that the primary function of the hippocampus is to generate cognitive maps and to mediate episodic memory processes. The well-documented spatial firing patterns (place fields) of hippocampal neurons in rodents, along with the spatial learning impairments observed with hippocampal damage support the cognitive mapping hypothesis. The amnesia for personally experienced events seen in humans with hippocampal damage and the data of animal models, which show severe memory deficits associated with hippocampal lesions, support the episodic memory account. Although an extensive literature supports each of these hypotheses, a specific contribution of place cells to episodic memory has not been clearly demonstrated. Recent data from our laboratory, together with previous findings, indicate that hippocampal place fields and neuronal responses to task-relevant stimuli are highly sensitive to the context, even when the contexts are defined by abstract task demands rather than the spatial geometry of the environment. On the basis of these findings, it is proposed that place fields reflect a more general context processing function of the hippocampus. Hippocampal context representations could serve to differentiate contexts and prime the relevant memories and behaviors. Since episodic memories, by definition, include information about the time and place where the episode occurred, contextual information is a necessary prerequisite for any episodic memory. Thus, place fields contribute importantly to episodic memory as part of the needed context representations. Additionally, recent findings indicate that hippocampal neurons differentiate contexts at progressively finer levels of detail, suggesting a hierarchical coding scheme which

  3. Magnolol Enhances Hippocampal Neurogenesis and Exerts Antidepressant-Like Effects in Olfactory Bulbectomized Mice.

    Science.gov (United States)

    Matsui, Nobuaki; Akae, Haruka; Hirashima, Nana; Kido, Yuki; Tanabe, Satoshi; Koseki, Mayumi; Fukuyama, Yoshiyasu; Akagi, Masaaki

    2016-11-01

    Magnolol is the main constituent of Magnolia bark and has been reported to exhibit antidepressant effects in rodent models. Hippocampal neurogenesis and neurotrophins such as brain-derived neurotrophic factor are integrally involved in the action of conventional antidepressants. Here, we investigated the effects of magnolol on depressive behaviours, impaired hippocampal neurogenesis and neurotrophin-related signal transduction in an olfactory bulbectomy (OBX) mouse model of depression. Mice were submitted to OBX to induce depressive behaviour, which was evaluated in the tail suspension test. Magnolol was administered orally by gavage needle. Neurogenesis was assessed by analysis of cells expressing NeuN, a neuronal marker, and 5-bromo-2'-deoxyuridine (BrdU) uptake. Phosphorylation levels of protein kinase B (Akt), extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein were evaluated by Western blot. Fourteen day treatment with magnolol (50 or 100 mg/kg/day) significantly improved OBX-induced depressive behaviour in tail suspension test. In agreement, magnolol significantly rescued impairments of hippocampal neurogenesis. Moreover, single treatments with magnolol (50 mg/kg) significantly increased phosphorylation of Akt, extracellular signal-regulated kinase and cyclic AMP-responsive element-binding protein after 3 h. The present data indicate that magnolol exerts antidepressant-like effects on behaviours by enhancing hippocampal neurogenesis and neurotrophin-related intracellular signalling in OBX mice. Copyright © 2016 John Wiley & Sons, Ltd.

  4. 5-Hydroxymethylfurfural from wine-processed Fructus corni inhibits hippocampal neuron apoptosis***

    Institute of Scientific and Technical Information of China (English)

    Hai Gu; Zequn Jiang; Mingyan Wang; Haiying Jiang; Fengming Zhao; Xia Ding; Baochang Cai; Zhen Zhan

    2013-01-01

    Previous studies have shown that 5-hydroxymethylfurfural, a compound extracted from wine- pro-cessed Fructus corni, has a protective effect on hippocampal neurons. The present study was de-signed to explore the related mechanisms. Our study revealed that high and medium doses (10, 1μmol/L) of 5-hydroxymethylfurfural could improve the morphology of H2O2-treated rat hippocampal neurons as revealed by inverted phase-contrast microscopy and transmission electron microscopy. MTT results showed that incubation with high and medium doses of 5-hydroxymethylfurfural caused a significant increase in the viability of neuronal cells injured by H2O2. Flow cytometry assays con-firmed that H2O2 could induce cellapoptosis, while high and medium doses of 5-hydroxymethylfurfural had a visible protective effect on apoptotic rat hippocampal neurons. Re-al-time PCR and western blot analysis showed that high and medium doses of 5-hydroxymethylfurfural prevented H2O2-induced up-regulation of p53, Bax and caspase-3 and antagonized the down-regulation of Bcl-2 induced by H2O2 treatment. These results suggested that 5-hydroxymethylfurfural could inhibit apoptosis of cultured rat hippocampal neurons injured by H2O2 via increase in Bcl-2 levels and decrease in p53, Bax and caspase-3 protein expression lev-els.

  5. Neuregulin directly decreases voltage-gated sodium current in hippocampal ErbB4-expressing interneurons.

    Science.gov (United States)

    Janssen, Megan J; Leiva-Salcedo, Elias; Buonanno, Andres

    2012-10-03

    The Neuregulin 1 (NRG1)/ErbB4 signaling pathway has been genetically and functionally implicated in the etiology underlying schizophrenia, and in the regulation of glutamatergic pyramidal neuron function and plasticity. However, ErbB4 receptors are expressed in subpopulations of GABAergic interneurons, but not in hippocampal or cortical pyramidal neurons, indicating that NRG1 effects on principal neurons are indirect. Consistent with these findings, NRG1 effects on hippocampal long-term potentiation at CA1 pyramidal neuron synapses in slices are mediated indirectly by dopamine. Here we studied whether NRG/ErbB signaling directly regulates interneuron intrinsic excitability by pharmacologically isolating ErbB4-expressing neurons in rat dissociated hippocampal cultures, which lack dopaminergic innervation. We found that NRG1 acutely attenuates ErbB4-expressing interneuron excitability by depolarizing the firing threshold; neurons treated with the pan-ErbB inhibitor PD158780 or negative for ErbB4 were unaffected. These effects of NRG1 are primarily attributable to decreased voltage-gated sodium channel activity, as current density was attenuated by ∼60%. In stark contrast, NRG1 had minor effects on whole-cell potassium currents. Our data reveal the direct actions of NRG1 signaling in ErbB4-expressing interneurons, and offer novel insight into how NRG1/ErbB4 signaling can impact hippocampal activity.

  6. Identification of conserved modes of expression profiles during hippocampal development and neuronal differentiation in vitro.

    Science.gov (United States)

    Dabrowski, Michal; Adach, Alicja; Aerts, Stein; Moreau, Yves; Kaminska, Bozena

    2006-04-01

    Gene expression profiles can be regarded as sums of simpler modes, analogous to the modes of a vibrating violin string. Decomposition of temporal gene expression profiles into modes by singular value decomposition (SVD) was reported before, but the question as to what degree the SVD modes can be interpreted in terms of biology remains open. We report and compare the results of SVD of published datasets from hippocampal development, neuronal differentiation in vitro, and a control time-series hippocampal dataset. We demonstrate that the first SVD mode reflects the magnitude of expression, interpretable on the Affymetrix platform. In the datasets from gene profiling of hippocampal development and neuronal differentiation, the second mode reflects a monotonous change in expression, either up- or down-regulation, in the time course of experiment. We demonstrate that the top two SVD modes are conserved between datasets and therefore, likely reflect properties of the underlying system (gene expression in hippocampus) rather than of a particular experiment or dataset. Our results also indicate that the magnitude of expression, and the direction of change in expression during hippocampal development, are uncorrelated, suggesting that they are regulated by largely independent mechanisms.

  7. Negative rebound in hippocampal neurogenesis following exercise cessation.

    Science.gov (United States)

    Nishijima, Takeshi; Kamidozono, Yoshika; Ishiizumi, Atsushi; Amemiya, Seiichiro; Kita, Ichiro

    2017-03-01

    Physical exercise can improve brain function, but the effects of exercise cessation are largely unknown. This study examined the time-course profile of hippocampal neurogenesis following exercise cessation. Male C57BL/6 mice were randomly assigned to either a control (Con) or an exercise cessation (ExC) group. Mice in the ExC group were reared in a cage with a running wheel for 8 wk and subsequently placed in a standard cage to cease the exercise. Exercise resulted in a significant increase in the density of doublecortin (DCX)-positive immature neurons in the dentate gyrus (at week 0). Following exercise cessation, the density of DCX-positive neurons gradually decreased and was significantly lower than that in the Con group at 5 and 8 wk after cessation, indicating that exercise cessation leads to a negative rebound in hippocampal neurogenesis. Immunohistochemistry analysis suggests that the negative rebound in neurogenesis is caused by diminished cell survival, not by suppression of cell proliferation and neural maturation. Neither elevated expression of ΔFosB, a transcription factor involved in neurogenesis regulation, nor increased plasma corticosterone, were involved in the negative neurogenesis rebound. Importantly, exercise cessation suppressed ambulatory activity, and a significant correlation between change in activity and DCX-positive neuron density suggested that the decrease in activity is involved in neurogenesis impairment. Forced treadmill running following exercise cessation failed to prevent the negative neurogenesis rebound. This study indicates that cessation of exercise or a decrease in physical activity is associated with an increased risk for impaired hippocampal function, which might increase vulnerability to stress-induced mood disorders.

  8. Moxibustion upregulates hippocampal progranulin expression

    Directory of Open Access Journals (Sweden)

    Tao Yi

    2016-01-01

    Full Text Available In China, moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome, but its mechanisms are largely unknown. More recently, the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome, and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis. In the present study, we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms. Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome. The acupoints Guanyuan (CV4 and Zusanli (ST36, bilateral were simultaneously administered moxibustion. Untreated chronic fatigue syndrome rats and normal rats were used as controls. Results from the forced swimming test, open field test, tail suspension test, real-time PCR, enzyme-linked immunosorbent assay, and western blot assay showed that moxibustion treatment decreased mRNA expression of corticotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone and corticosterone levels in plasma, and markedly increased progranulin mRNA and protein expression in the hippocampus. These findings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome, at least in part, by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

  9. Moxibustion upregulates hippocampal progranulin expression

    Institute of Scientific and Technical Information of China (English)

    Tao Yi; Li Qi; Ji Li; Jing-jing Le; Lei Shao; Xin Du; Jing-cheng Dong

    2016-01-01

    In China, moxibustion is reported to be useful and has few side effects for chronic fatigue syndrome, but its mechanisms are largely un-known. More recently, the focus has been on the wealth of information supporting stress as a factor in chronic fatigue syndrome, and largely concerns dysregulation in the stress-related hypothalamic-pituitary-adrenal axis. In the present study, we aimed to determine the effect of moxibustion on behavioral symptoms in chronic fatigue syndrome rats and examine possible mechanisms. Rats were subjected to a combination of chronic restraint stress and forced swimming to induce chronic fatigue syndrome. The acupointsGuanyuan (CV4) and Zusanli (ST36, bilateral) were simultaneously administered moxibustion. Untreated chronic fatigue syndrome rats and normal rats were used as controls. Results from the forced swimming test, open ifeld test, tail suspension test, real-time PCR, enzyme-linked immunosor-bent assay, and western blot assay showed that moxibustion treatment decreased mRNA expression of corticotropin-releasing hormone in the hypothalamus, and adrenocorticotropic hormone and corticosterone levels in plasma, and markedly increased progranulin mRNA and protein expression in the hippocampus. These ifndings suggest that moxibustion may relieve the behavioral symptoms of chronic fatigue syndrome, at least in part, by modulating the hypothalamic-pituitary-adrenal axis and upregulating hippocampal progranulin.

  10. Environmental enrichment and working memory tasks decrease hippocampal cell proliferation after wheel running--A role for the prefrontal cortex in hippocampal plasticity?

    Science.gov (United States)

    Schaefers, Andrea T U

    2015-10-22

    Despite an increasing amount of evidence about the regulation of adult hippocampal neurogenesis on the local level, less attention has been paid to its systemic embedding in wider brain circuits. The aim of the present study was to obtain evidence for a potential role of the prefrontal cortex in the regulation of adult hippocampal neurogenesis. We hypothesised that activation of the prefrontal cortex by environmental enrichment or a working-memory task would decrease previously enhanced cell proliferation rates. Wheel running was applied as a common stimulator of cell proliferation in CD1 mice reared under deprivation of natural environmental stimulation. Next, the animals were assigned to four groups for different treatments in the following three days: housing under continued deprivation, environmental enrichment, a spatial-delayed alternation task in an automated T-maze that activates the prefrontal cortex by working-memory requirements or a control task in the automated T-maze differing only in the single parameter working-memory-associated delay. Both the environmental enrichment and spatial-delayed alternation tasks decreased cell proliferation rates in the dentate gyrus compared to deprived housing and the control task in the T-maze. As the control animals underwent the same procedures and stressors and differed only in the single parameter working-memory-associated delay, the working-memory requirement seems to be the crucial factor for decreasing cell proliferation rates. Taken together, these results suggest that the prefrontal cortex may play a role in the regulation of hippocampal cell proliferation.

  11. The Antidepressant Effect of the Total Flavonoids Extracted from Cottonseed and its Regulation on Hippocampal Monoamines%棉籽总黄酮抗抑郁活性及其对海马单胺水平的调节

    Institute of Scientific and Technical Information of China (English)

    赵楠; 张有志; 杨明; 王伊文; 赵毅民; 宫泽辉; 李云峰

    2011-01-01

      Objective:To explore the antidepressant effect of the total flavonoids extracted from cottonseed (CTN-T) and its possible mechanism. Methods:The learned helplessness model in rats was used to evaluate the antidepressant effect of CTN-T. Using the 5-hydroxytryptophan (5-HTP)induced head twitch response test and yohimbine toxicity potentiation test in mice,the possible monoamine targets of the antidepressant action of CTN-T were detected. Moreover, high performance liquid chromatography and electrochemical detection (HPLC-ECD) was used to determine the content of monoamine and metabolites in the hippocampus of rats following CTN-T administration. Results:Repeated administration of CTN-T (50,100 mg·kg-1,ig,twice per day for 4 d) significantly decreased the helplessness behavior induced by inescapable foot-shock in learned helplessness test in rats. Repeated administration of CTN-T (50,75 mg·kg-1, ig,twice per day for 4 d) significantly increased the 5-HTP induced head twitch response in mice,while CTN-T (60 mg·kg-1,ig,twice per day for 4 d) had a tendency to potentiate yohimbine toxicity in mice. Repeated administration of CTN-T (25~75 mg·kg-1,ig,twice per day for 4 d),the neurochemical assays showed that the content of 5-hydroxytryptamine (5-HT) was increased in rat hippocampus at 25 and 100 mg·kg-1 dose of CTN-T,and that the content of norepinephrine (NE) was increased at 50 and 100 mg·kg-1 dose of CTN-T. By contrast,CTN-T had no effects on the content of dopamine (DA),epinephrine (E),5-hydroxyindolacetic acid (5-HIAA) and the rate of 5-HT/5-HIAA. Conclusion:CTN-T exerts antidepressant effects which may be closely related to the strengthening of the hippocampal serotonergic and noradrenergic function.%  目的:探讨棉籽总黄酮(total flavonoids extracted from cottonseed,CTN-T)的抗抑郁作用及可能的作用机制。方法:在大鼠获得性无助模型上评价CTN-T的抗抑郁作用;采用5-羟色氨酸(5-hydroxytryptophan,5-HTP)诱

  12. Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons

    Directory of Open Access Journals (Sweden)

    Pham Serena

    2011-08-01

    Full Text Available Abstract Background Oxidative stress plays an important role in neuronal dysfunction and neuron loss in Alzheimer's brain. Previous studies have reported downregulation of CREB-mediated transcription by oxidative stress and Aβ. The promoter for CREB itself contains cyclic AMP response elements. Therefore, we examined the expression of CREB in the hippocampal neurons of Tg2576 mice, AD post-mortem brain and in cultured rat hippocampal neurons exposed to Aβ aggregates. Results Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis. Conclusions Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.

  13. Developmental changes in hippocampal associative coding.

    Science.gov (United States)

    Goldsberry, Mary E; Kim, Jangjin; Freeman, John H

    2015-03-11

    Behavioral analyses of the ontogeny of memory have shown that hippocampus-dependent learning emerges relatively late in postnatal development compared with simple associative learning. Maturation of hippocampal mnemonic mechanisms has been hypothesized to underlie the development of the later emerging learning processes. However, the role of hippocampal maturation in learning has not been examined directly. The goal of the present study was to examine developmental changes in hippocampal neuronal coding during acquisition of a hippocampus-dependent learning task. We recorded activity from CA1 pyramidal cells in rat pups while they were trained on trace eyeblink conditioning. Trace eyeblink conditioning is a Pavlovian conditioning task that involves the association of a conditioned stimulus (CS) with an unconditioned stimulus over a stimulus-free trace interval. The inclusion of the trace interval is what makes the task hippocampus dependent. In the present study, rats were trained at 21-23, 24-26, and 31-33 d of age. Previous research from our laboratory and others shows that trace conditioning begins to emerge during the third postnatal week. The results indicate that hippocampal neurons show a substantial increase in responsiveness to task-relevant events during development. Moreover, there is an age-related increase in the proportion of neurons that respond to a combination of trial events (e.g., CS and trace). Our findings indicate that the developmental emergence of hippocampally mediated learning is related to increases in the strength and complexity of CA1 associative coding.

  14. Growth hormone rescues hippocampal synaptic function after sleep deprivation

    OpenAIRE

    Kim, EunYoung; Grover, Lawrence M; Bertolotti, Don; Green, Todd L.

    2010-01-01

    Sleep is required for, and sleep loss impairs, normal hippocampal synaptic N-methyl-d-aspartate (NMDA) glutamate receptor function and expression, hippocampal NMDA receptor-dependent synaptic plasticity, and hippocampal-dependent memory function. Although sleep is essential, the signals linking sleep to hippocampal function are not known. One potential signal is growth hormone. Growth hormone is released during sleep, and its release is suppressed during sleep deprivation. If growth hormone l...

  15. Childhood maltreatment modifies the relationship of depression with hippocampal volume

    NARCIS (Netherlands)

    Gerritsen, L.; van Velzen, L.; Schmaal, L.; van der Graaf, Y.; van der Wee, N.; van Tol, M. -J.; Penninx, B.; Geerlings, M.

    2015-01-01

    Background. Childhood maltreatment (CM) may modify the relationship between major depressive disorder (MDD) and hippocampal volume reduction. To disentangle the impact of MDD and CM on hippocampal volume we investigated the association between MDD and hippocampal volume in persons with and without a

  16. An Experimental Study of the Regulation of BDNF/TrkB Signal Pathway by Different Isoforms of TrkB in Epileptic Hippocampal Neurons%TrkB不同亚型对癫海马神经元BDNF/TrkB信号通路调控的研究

    Institute of Scientific and Technical Information of China (English)

    吴秋静; 常伟; 潘立平; 宋毅军; 赵文

    2014-01-01

    Objective To investigate the mechanism of brain derived neurotrophic factor (BDNF) regulated by differ-ent isoforms of tyrosine kinase receptor B (TrkB) in epileptic hippocampal neurons. Methods Primary hippocampal neu-rons were cultured in vitro for 7 days, and divided into two groups, ALLN (calcineurin inhibitor) group and Anisomycin (trans-lation inhibitor) group. ALLN group included control group, control+BDNF group, epilepsy group, epilepsy+BDNF group, control+ALLN group, epilepsy+ALLN group and epilepsy+ALLN+BDNF group. Anisomycin group was sub-divided into con-trol group, control+BDNF group, epilepsy group, epilepsy+BDNF group, control+Anisomycin group, epilepsy+Anisomycin group and epilepsy+Anisomycin+BDNF group. The immunofluorescent technique was used to identificate the hippocampal neurons. Epileptiform discharges were detected by electrophysiological techniques. Western blot assay was used to deter-mine the protein expression of TrkB and phosphorylated TrkB (p-TrkB) in all cell groups. Results (1) In ALLN group, the gray value of p-TrkB/TrkB was higher in control+BDNF group compared with that of control group, the value was higher in epilepsy+BDNF group than that of epilepsy group but was lower than that of control+BDNF group. The gray value of p-TrkB/TrkB was lower in epilepsy+ALLN+BDNF group than that of epilepsy+BDNF group, but no significant difference compared with that of epilepsy+ALLN group. (2) In Anisomycin group:the gray value of p-TrkB/TrkB was higher in control+BDNF group than that of control group. The gray value of p-TrkB/TrkB was higher in epilepsy+BDNF group than that of epilepsy group, but which was lower than that of control+BDNF group. The gray value of p-TrkB/TrkB was higher in epilepsy+Aniso-mycin+BDNF group than that of epilepsy+BDNF group and epilepsy+Anisomycin group. Conclusion The decreased ex-pression of TrkB.T can improve the inhibition of BDNF/TrkB signaling, and BDNF can activate BDNF/TrkB signal pathway in epileptic

  17. Neuromorphic VLSI realization of the hippocampal formation.

    Science.gov (United States)

    Aggarwal, Anu

    2016-05-01

    The medial entorhinal cortex grid cells, aided by the subicular head direction cells, are thought to provide a matrix which is utilized by the hippocampal place cells for calculation of position of an animal during spatial navigation. The place cells are thought to function as an internal GPS for the brain and provide a spatiotemporal stamp on episodic memories. Several computational neuroscience models have been proposed to explain the place specific firing patterns of the cells of the hippocampal formation - including the GRIDSmap model for grid cells and Bayesian integration for place cells. In this work, we present design and measurement results from a first ever system of silicon circuits which successfully realize the function of the hippocampal formation of brain based on these models.

  18. Taurine increases hippocampal neurogenesis in aging mice

    Directory of Open Access Journals (Sweden)

    Elias Gebara

    2015-05-01

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

  19. Localized gene transfer into organotypic hippocampal slice cultures and acute hippocampal slices

    DEFF Research Database (Denmark)

    Casaccia-Bonnefil, P; Benedikz, Eirikur; Shen, H;

    1993-01-01

    Viral vectors derived from herpes simplex virus, type-1 (HSV), can transfer and express genes into fully differentiated, post-mitotic neurons. These vectors also transduce cells effectively in organotypic hippocampal slice cultures. Nanoliter quantities of a virus stock of HSVlac, an HSV vector...... or hippocampal slices. The rapid expression of beta-gal by HSVlac allowed efficient transduction of acute hippocampal slices. Many genes have been transduced and expressed using HSV vectors; therefore, this microapplication method can be applied to many neurobiological questions....

  20. Electrical coupling between hippocampal astrocytes in rat brain slices.

    Science.gov (United States)

    Meme, William; Vandecasteele, Marie; Giaume, Christian; Venance, Laurent

    2009-04-01

    Gap junctions in astrocytes play a crucial role in intercellular communication by supporting both biochemical and electrical coupling between adjacent cells. Despite the critical role of electrical coupling in the network organization of these glial cells, the electrophysiological properties of gap junctions have been characterized in cultures while no direct evidence has been sought in situ. In the present study, gap-junctional currents were investigated using simultaneous dual whole-cell patch-clamp recordings between astrocytes from rat hippocampal slices. Bidirectional electrotonic coupling was observed in 82% of the cell pairs with an average coupling coefficient of 5.1%. Double patch-clamp analysis indicated that junctional currents were independent of the transjunctional voltage over a range from -100 to +110 mV. Interestingly, astrocytic electrical coupling displayed weak low-pass filtering properties compared to neuronal electrical synapses. Finally, during uncoupling processes triggered by either the gap-junction inhibitor carbenoxolone or endothelin-1, an increase in the input resistance in the injected cell paralleled the decrease in the coupling coefficient. Altogether, these results demonstrate that hippocampal astrocytes are electrically coupled through gap-junction channels characterized by properties that are distinct from those of electrical synapses between neurons. In addition, gap-junctional communication is efficiently regulated by endogenous compounds. This is taken to represent a mode of communication that may have important implications for the functional role of astrocyte networks in situ.

  1. Adult hippocampal neurogenesis buffers stress responses and depressive behaviour.

    Science.gov (United States)

    Snyder, Jason S; Soumier, Amélie; Brewer, Michelle; Pickel, James; Cameron, Heather A

    2011-08-03

    Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.

  2. Vasopressin inhibits LTP in the CA2 mouse hippocampal area.

    Directory of Open Access Journals (Sweden)

    Magda Chafai

    Full Text Available Growing evidence points to vasopressin (AVP as a social behavior regulator modulating various memory processes and involved in pathologies such as mood disorders, anxiety and depression. Accordingly, AVP antagonists are actually envisaged as putative treatments. However, the underlying mechanisms are poorly characterized, in particular the influence of AVP on cellular or synaptic activities in limbic brain areas involved in social behavior. In the present study, we investigated AVP action on the synapse between the entorhinal cortex and CA2 hippocampal pyramidal neurons, by using both field potential and whole-cell recordings in mice brain acute slices. Short application (1 min of AVP transiently reduced the synaptic response, only following induction of long-term potentiation (LTP by high frequency stimulation (HFS of afferent fibers. The basal synaptic response, measured in the absence of HFS, was not affected. The Schaffer collateral-CA1 synapse was not affected by AVP, even after LTP, while the Schaffer collateral-CA2 synapse was inhibited. Although investigated only recently, this CA2 hippocampal area appears to have a distinctive circuitry and a peculiar role in controlling episodic memory. Accordingly, AVP action on LTP-increased synaptic responses in this limbic structure may contribute to the role of this neuropeptide in controlling memory and social behavior.

  3. Enhanced Glutamatergic Synaptic Plasticity in the Hippocampal CA1 Field of Food-Restricted Rats: Involvement of CB1 Receptors.

    Science.gov (United States)

    Talani, Giuseppe; Licheri, Valentina; Biggio, Francesca; Locci, Valentina; Mostallino, Maria Cristina; Secci, Pietro Paolo; Melis, Valentina; Dazzi, Laura; Carta, Gianfranca; Banni, Sebastiano; Biggio, Giovanni; Sanna, Enrico

    2016-04-01

    The endogenous endocannabinoid system has a crucial role in regulating appetite and feeding behavior in mammals, as well as working memory and reward mechanisms. In order to elucidate the possible role of cannabinoid type-1 receptors (CB1Rs) in the regulation of hippocampal plasticity in animals exposed to food restriction (FR), we limited the availability of food to a 2-h daily period for 3 weeks in Sprague-Dawley rats. FR rats showed a higher long-term potentiation at hippocampal CA1 excitatory synapses with a parallel increase in glutamate release when compared with animals fed ad libitum. FR rats showed a significant increase in the long-term spatial memory determined by Barnes maze. FR was also associated with a decreased inhibitory effect of the CB1R agonist win55,212-2 on glutamatergic field excitatory postsynaptic potentials, together with a decrease in hippocampal CB1R protein expression. In addition, hippocampal brain-derived neurotrophic factor protein levels and mushroom dendritic spine density were significantly enhanced in FR rats. Altogether, our data suggest that alterations of hippocampal CB1R expression and function in FR rats are associated with dendritic spine remodeling and functional potentiation of CA1 excitatory synapses, and these findings are consistent with increasing evidence supporting the idea that FR may improve cognitive functions.

  4. Hippocampal neuronal nitric oxide synthase mediates the stress-related depressive behaviors of glucocorticoids by downregulating glucocorticoid receptor.

    Science.gov (United States)

    Zhou, Qi-Gang; Zhu, Li-Juan; Chen, Chen; Wu, Hai-Yin; Luo, Chun-Xia; Chang, Lei; Zhu, Dong-Ya

    2011-05-25

    The molecular mechanisms underlying the behavioral effects of glucocorticoids are poorly understood. We report here that hippocampal neuronal nitric oxide synthase (nNOS) is a crucial mediator. Chronic mild stress and glucocorticoids exposures caused hippocampal nNOS overexpression via activating mineralocorticoid receptor. In turn, hippocampal nNOS-derived nitric oxide (NO) significantly downregulated local glucocorticoid receptor expression through both soluble guanylate cyclase (sGC)/cGMP and peroxynitrite (ONOO(-))/extracellular signal-regulated kinase signal pathways, and therefore elevated hypothalamic corticotrophin-releasing factor, a peptide that governs the hypothalamic-pituitary-adrenal axis. More importantly, nNOS deletion or intrahippocampal nNOS inhibition and NO-cGMP signaling blockade (using NO scavenger or sGC inhibitor) prevented the corticosterone-induced behavioral modifications, suggesting that hippocampal nNOS is necessary for the role of glucocorticoids in mediating depressive behaviors. In addition, directly delivering ONOO(-) donor into hippocampus caused depressive-like behaviors. Our findings reveal a role of hippocampal nNOS in regulating the behavioral effects of glucocorticoids.

  5. Adult hippocampal neurogenesis and cognitive aging

    Directory of Open Access Journals (Sweden)

    Román Darío Moreno Fernández

    2013-12-01

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

  6. Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

    Science.gov (United States)

    Zhang, Kuo; Pan, Xing; Wang, Fang; Ma, Jie; Su, Guangyue; Dong, Yingxu; Yang, Jingyu; Wu, Chunfu

    2016-01-01

    Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation. PMID:27502757

  7. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl phthalate in male Long Evans rats.

    Directory of Open Access Journals (Sweden)

    Catherine A Smith

    Full Text Available Early developmental exposure to di(2-ethylhexyl phthalate (DEHP has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  8. Reduced hippocampal dendritic spine density and BDNF expression following acute postnatal exposure to di(2-ethylhexyl) phthalate in male Long Evans rats.

    Science.gov (United States)

    Smith, Catherine A; Holahan, Matthew R

    2014-01-01

    Early developmental exposure to di(2-ethylhexyl) phthalate (DEHP) has been linked to a variety of neurodevelopmental changes, particularly in rodents. The primary goal of this work was to establish whether acute postnatal exposure to a low dose of DEHP would alter hippocampal dendritic morphology and BDNF and caspase-3 mRNA expression in male and female Long Evans rats. Treatment with DEHP in male rats led to a reduction in spine density on basal and apical dendrites of neurons in the CA3 dorsal hippocampal region compared to vehicle-treated male controls. Dorsal hippocampal BDNF mRNA expression was also down-regulated in male rats exposed to DEHP. No differences in hippocampal spine density or BDNF mRNA expression were observed in female rats treated with DEHP compared to controls. DEHP treatment did not affect hippocampal caspase-3 mRNA expression in male or female rats. These results suggest a gender-specific vulnerability to early developmental DEHP exposure in male rats whereby postnatal DEHP exposure may interfere with normal synaptogenesis and connectivity in the hippocampus. Decreased expression of BDNF mRNA may represent a molecular mechanism underlying the reduction in dendritic spine density observed in hippocampal CA3 neurons. These findings provide initial evidence for a link between developmental exposure to DEHP, reduced levels of BDNF and hippocampal atrophy in male rats.

  9. Lysophosphatidic Acid Receptor Is a Functional Marker of Adult Hippocampal Precursor Cells

    Directory of Open Access Journals (Sweden)

    Tara L. Walker

    2016-04-01

    Full Text Available Here, we show that the lysophosphatidic acid receptor 1 (LPA1 is expressed by a defined population of type 1 stem cells and type 2a precursor cells in the adult mouse dentate gyrus. LPA1, in contrast to Nestin, also marks the quiescent stem cell population. Combining LPA1-GFP with EGFR and prominin-1 expression, we have enabled the prospective separation of both proliferative and non-proliferative precursor cell populations. Transcriptional profiling of the isolated proliferative precursor cells suggested immune mechanisms and cytokine signaling as molecular regulators of adult hippocampal precursor cell proliferation. In addition to LPA1 being a marker of this important stem cell population, we also show that the corresponding ligand LPA is directly involved in the regulation of adult hippocampal precursor cell proliferation and neurogenesis, an effect that can be attributed to LPA signaling via the AKT and MAPK pathways.

  10. Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory

    Directory of Open Access Journals (Sweden)

    Silvia Pasini

    2015-04-01

    Full Text Available Prior studies suggested that the transcription factor ATF4 negatively regulates synaptic plastic and memory. By contrast, we provide evidence from direct in vitro and in vivo knockdown of ATF4 in rodent hippocampal neurons and from ATF4-null mice that implicate ATF4 as essential for normal synaptic plasticity and memory. In particular, hippocampal ATF4 downregulation produces deficits in long-term spatial memory and behavioral flexibility without affecting associative memory or anxiety-like behavior. ATF4 knockdown or loss also causes profound impairment of both long-term potentiation (LTP and long-term depression (LTD as well as decreased glutamatergic function. We conclude that ATF4 is a key regulator of the physiological state necessary for neuronal plasticity and memory.

  11. Developmental hypothyroidism abolishes bilateral differences in sonic hedgehog gene control in the rat hippocampal dentate gyrus.

    Science.gov (United States)

    Tanaka, Takeshi; Wang, Liyun; Kimura, Masayuki; Abe, Hajime; Mizukami, Sayaka; Yoshida, Toshinori; Shibutani, Makoto

    2015-03-01

    Both developmental and adult-stage hypothyroidism disrupt rat hippocampal neurogenesis. We previously showed that exposing mouse offspring to manganese permanently disrupts hippocampal neurogenesis and abolishes the asymmetric distribution of cells expressing Mid1, a molecule regulated by sonic hedgehog (Shh) signaling. The present study examined the involvement of Shh signaling on the disruption of hippocampal neurogenesis in rats with hypothyroidism. Pregnant rats were treated with methimazole (MMI) at 0 or 200 ppm in the drinking water from gestation day 10-21 days after delivery (developmental hypothyroidism). Adult male rats were treated with MMI in the same manner from postnatal day (PND) 46 to PND 77 (adult-stage hypothyroidism). Developmental hypothyroidism reduced the number of Mid1(+) cells within the subgranular zone of the dentate gyrus of offspring on PND 21, and consequently abolished the normal asymmetric predominance of Mid1(+) cells on the right side through the adult stage. In control animals, Shh was expressed in a subpopulation of hilar neurons, showing asymmetric distribution with left side predominance on PND 21; however, this asymmetry did not continue through the adult stage. Developmental hypothyroidism increased Shh(+) neurons bilaterally and abolished the asymmetric distribution pattern on PND 21. Adult hypothyroidism also disrupted the asymmetric distribution of Mid1(+) cells but did not affect the distribution of Shh(+) hilar neurons. The results suggest that the hippocampal neurogenesis disruption seen in hypothyroidism involves changes in asymmetric Shh(+) neuron distribution in developmental hypothyroidism and altered Mid1 expression in both developmental and adult-stage hypothyroidism.

  12. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration

    Directory of Open Access Journals (Sweden)

    Julie Anne Seguin

    2008-12-01

    Full Text Available Julie Anne Seguin, Jordan Brennan, Emily Mangano, Shawn HayleyInstitute of Neuroscience, Carleton University, Ottawa, Ontario, CanadaAbstract: Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1β (IL-1β, IL-6, and tumor necrosis factor-α (TNF-α (associated with depression influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-α reduced 5-bromo-2-deoxyuridine (BrdU labeling within the hippocampus, whereas IL-1β and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1β actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.Keywords: cytokine, depression, neuroplasticity, hippocampus, stressor

  13. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.

    Science.gov (United States)

    Seguin, Julie Anne; Brennan, Jordan; Mangano, Emily; Hayley, Shawn

    2009-01-01

    Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) (associated with depression) influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-alpha reduced 5-bromo-2-deoxyuridine (BrdU) labeling within the hippocampus, whereas IL-1beta and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1beta actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.

  14. Retinoic acid restores adult hippocampal neurogenesis and reverses spatial memory deficit in vitamin A deprived rats.

    Directory of Open Access Journals (Sweden)

    Emilie Bonnet

    Full Text Available A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD on neurogenesis and memory and the ability of retinoic acid (RA treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function.

  15. Nicotinic modulation of hippocampal cell signaling and associated effects on learning and memory.

    Science.gov (United States)

    Kutlu, Munir Gunes; Gould, Thomas J

    2016-03-01

    The hippocampus is a key brain structure involved in synaptic plasticity associated with long-term declarative memory formation. Importantly, nicotine and activation of nicotinic acetylcholine receptors (nAChRs) can alter hippocampal plasticity and these changes may occur through modulation of hippocampal kinases and transcription factors. Hippocampal kinases such as cAMP-dependent protein kinase (PKA), calcium/calmodulin-dependent protein kinases (CAMKs), extracellular signal-regulated kinases 1 and 2 (ERK1/2), and c-jun N-terminal kinase 1 (JNK1), and the transcription factor cAMP-response element-binding protein (CREB) that are activated either directly or indirectly by nicotine may modulate hippocampal plasticity and in parallel hippocampus-dependent learning and memory. Evidence suggests that nicotine may alter hippocampus-dependent learning by changing the time and magnitude of activation of kinases and transcription factors normally involved in learning and by recruiting additional cell signaling molecules. Understanding how nicotine alters learning and memory will advance basic understanding of the neural substrates of learning and aid in understanding mental disorders that involve cognitive and learning deficits.

  16. The cumulative analgesic effect of repeated electroacupuncture involves synaptic remodeling in the hippocampal CA3 region

    Institute of Scientific and Technical Information of China (English)

    Qiuling Xu; Tao Liu; Shuping Chen; Yonghui Gao; Junying Wang; Lina Qiao; Junling Liu

    2012-01-01

    In the present study, we examined the analgesic effect of repeated electroacupuncture at bilateral Zusanli (ST36) and Yanglingquan (GB34) once a day for 14 consecutive days in a rat model of chronic sciatic nerve constriction injury-induced neuropathic pain. In addition, concomitant changes in calcium/calmodulin-dependent protein kinase II expression and synaptic ultrastructure of neurons in the hippocampal CA3 region were examined. The thermal pain threshold (paw withdrawal latency) was increased significantly in both groups at 2 weeks after electroacupuncture intervention compared with 2 days of electroacupuncture. In ovariectomized rats with chronic constriction injury, the analgesic effect was significantly reduced. Electroacupuncture for 2 weeks significantly diminished the injury-induced increase in synaptic cleft width and thinning of the postsynaptic density, and it significantly suppressed the down-regulation of intracellular calcium/ calmodulin-dependent protein kinase II expression in the hippocampal CA3 region. Repeated electroacupuncture intervention had a cumulative analgesic effect on injury-induced neuropathic pain reactions, and it led to synaptic remodeling of hippocampal neurons and upregulated calcium/calmodulin-dependent protein kinase II expression in the hippocampal CA3 region.

  17. Neurabin contributes to hippocampal long-term potentiation and contextual fear memory.

    Directory of Open Access Journals (Sweden)

    Long-Jun Wu

    Full Text Available Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP was significantly reduced, whereas long-term depression (LTD was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845 but no change at the CaMKII/PKC site (Ser831. Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

  18. Neurabin contributes to hippocampal long-term potentiation and contextual fear memory.

    Science.gov (United States)

    Wu, Long-Jun; Ren, Ming; Wang, Hansen; Kim, Susan S; Cao, Xiaoyan; Zhuo, Min

    2008-01-09

    Neurabin is a scaffolding protein that interacts with actin and protein phosphatase-1. Highly enriched in the dendritic spine, neurabin is important for spine morphogenesis and synaptic formation. However, less is known about the role of neurabin in hippocampal plasticity and its possible effect on behavioral functions. Using neurabin knockout (KO) mice, here we studied the function of neurabin in hippocampal synaptic transmission, plasticity and behavioral memory. We demonstrated that neurabin KO mice showed a deficit in contextual fear memory but not auditory fear memory. Whole-cell patch clamp recordings in the hippocampal CA1 neurons showed that long-term potentiation (LTP) was significantly reduced, whereas long-term depression (LTD) was unaltered in neurabin KO mice. Moreover, increased AMPA receptor but not NMDA receptor-mediated synaptic transmission was found in neurabin KO mice, and is accompanied by decreased phosphorylation of GluR1 at the PKA site (Ser845) but no change at the CaMKII/PKC site (Ser831). Pre-conditioning with LTD induction rescued the following LTP in neurabin KO mice, suggesting the loss of LTP may be due to the saturated synaptic transmission. Our results indicate that neurabin regulates contextual fear memory and LTP in hippocampal CA1 pyramidal neurons.

  19. Agmatine Prevents Adaptation of the Hippocampal Glutamate System in Chronic Morphine-Treated Rats.

    Science.gov (United States)

    Wang, Xiao-Fei; Zhao, Tai-Yun; Su, Rui-Bin; Wu, Ning; Li, Jin

    2016-12-01

    Chronic exposure to opioids induces adaptation of glutamate neurotransmission, which plays a crucial role in addiction. Our previous studies revealed that agmatine attenuates opioid addiction and prevents the adaptation of glutamate neurotransmission in the nucleus accumbens of chronic morphine-treated rats. The hippocampus is important for drug addiction; however, whether adaptation of glutamate neurotransmission is modulated by agmatine in the hippocampus remains unknown. Here, we found that continuous pretreatment of rats with ascending doses of morphine for 5 days resulted in an increase in the hippocampal extracellular glutamate level induced by naloxone (2 mg/kg, i.p.) precipitation. Agmatine (20 mg/kg, s.c.) administered concurrently with morphine for 5 days attenuated the elevation of extracellular glutamate levels induced by naloxone precipitation. Furthermore, in the hippocampal synaptosome model, agmatine decreased the release and increased the uptake of glutamate in synaptosomes from chronic morphine-treated rats, which might contribute to the reduced elevation of glutamate levels induced by agmatine. We also found that expression of the hippocampal NR2B subunit, rather than the NR1 subunit, of N-methyl-D-aspartate receptors (NMDARs) was down-regulated after chronic morphine treatment, and agmatine inhibited this reduction. Taken together, agmatine prevented the adaptation of the hippocampal glutamate system caused by chronic exposure to morphine, including modulating extracellular glutamate concentration and NMDAR expression, which might be one of the mechanisms underlying the attenuation of opioid addiction by agmatine.

  20. Effect of extracellular signal regulated kinase on cultured hippocampal neurons of rats with oxygen-g1ucose deprivation%细胞外信号调节激酶对氧糖剥夺后大鼠海马神经元的作用研究

    Institute of Scientific and Technical Information of China (English)

    华烨; 丁新生; 孔岳南

    2011-01-01

    Objective: To investigate the effect of excelluar signal-regulated kinase (ERK) on rat hippocampal neurons with oxygen-glucose deprivation (OGD). Methods:Cultured hippocampal neurons were designed into four groups:normal group,OGD group,PD98059 10 μmol/L and 30 μmoL/L groups. The apoptosis of neurons was determined by flow cytometry, and Western blot was used to evaluate protein expression of ERKI/2 and pERKI/2. Results:Compared with normal control group, neuron apoptosis increased while pERK1/2 protein expression decreased obviously in OGD group (both P < 0.01). Neuron apoptosis increased and pERK1/2 protein expression decreased more significantly in PD98059 groups compared with OGD group (both P < 0.01 ). Changes in 30 μmol/L PD98059 group were more significant than 10 μmol/L PD98059 group (P < 0.01 ). Each group showed no significant change in ERK expression (P > 0.05). Conclusion:ERK may be involved in neuronal apoptosis after OGD, and inhibition of ERK pathway can promote neuronal apoptosis.%目的:研究细胞外信号调节激酶对氧糖剥夺(oxygen-glucose deprivation,OGD)后大鼠海马神经元的作用.方法:建立培养乳鼠海马神经元OGD模型,并分为正常对照组、OGD组、PD 98059 10 μmol/L、30 μmol/L组.流式细胞仪Annexin V/PI双染色法检测神经元细胞凋亡率,Western blot法检测ERKl/2、pERKl/2的表达.结果:与正常对照组相比,OGD组神经元的凋亡率升高(P<0.01),pERKl/2的表达降低(P<0.01),与OGD组相比,PD98059组神经元凋亡率明显升高(P<0.01),pERKl/2的表达明显降低(P<0.01),30;μmol/L组较10 μmol/L组凋亡率升高及pERKl/2表达降低更为显著(P<0.01),各组ERK含量无明显变化(P>0.05).结论:ERK可能参与氧糖剥夺后的神经元凋亡,抑制ERK通路可促进神经元凋亡.

  1. Cell-Type Specific Inactivation of Hippocampal CA1 Disrupts Location-Dependent Object Recognition in the Mouse

    Science.gov (United States)

    Haettig, Jakob; Sun, Yanjun; Wood, Marcelo A.; Xu, Xiangmin

    2013-01-01

    The allatostatin receptor (AlstR)/ligand inactivation system enables potent regulation of neuronal circuit activity. To examine how different cell types participate in memory formation, we have used this system through Cre-directed, cell-type specific expression in mouse hippocampal CA1 in vivo and examined functional effects of inactivation of…

  2. The transcriptional repressor Zbtb20 is essential for specification of hippocampal projection neurons and territory in mice

    DEFF Research Database (Denmark)

    Rosenthal, Eva Helga

    for specification of both hippocampal pyramidal neurons and territory in a mouse knockout model. Homozygous Zbtb20-/- mice are viable at birth, but display dwarfism and die during the first month of postnatal life. Characterization of the Zbtb20-/- brain phenotype reveals a small vestigial hippocampus...... as an essential regulator of various aspects of neuronal development and corticogenesis in the hippocampus....

  3. Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice

    OpenAIRE

    Devesa, Pablo; Agasse, Fabienne; Xapelli, Sara; Almengló, Cristina; Devesa, Jesús; Malva, Joao O.; Arce, Víctor M

    2014-01-01

    Background Accumulating evidence suggests that growth hormone (GH) may play a major role in the regulation of postnatal neurogenesis, thus supporting the possibility that it may be also involved in promoting brain repair after brain injury. In order to gain further insight on this possibility, in this study we have investigated the pathways signaling the effect of GH treatment on the proliferation and survival of hippocampal subgranular zone (SGZ)-derived neurospheres. Results Our results dem...

  4. Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis

    OpenAIRE

    2016-01-01

    Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences betw...

  5. Gender Differences in the Neurobiology of Anxiety:Focus on Adult Hippocampal Neurogenesis

    OpenAIRE

    2016-01-01

    Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences betw...

  6. Food restriction modifies ultrastructure of hippocampal synapses.

    Science.gov (United States)

    Babits, Réka; Szőke, Balázs; Sótonyi, Péter; Rácz, Bence

    2016-04-01

    Consumption of high-energy diets may compromise health and may also impair cognition; these impairments have been linked to tasks that require hippocampal function. Conversely, food restriction has been shown to improve certain aspects of hippocampal function, including spatial memory and memory persistence. These diet-dependent functional changes raise the possibility that the synaptic structure underlying hippocampal function is also affected. To examine how short-term food restriction (FR) alters the synaptic structure of the hippocampus, we used quantitative electron microscopy to analyze the organization of neuropil in the CA1 stratum radiatum of the hippocampus in young rats, consequent to reduced food. While four weeks of FR did not modify the density, size, or shape of postsynaptic spines, the synapses established by these spines were altered, displaying increased mean length, and more frequent perforations of postsynaptic densities. That the number of perforated synapses (believed to be an indicator of synaptic enhancement) increased, and that the CA1 spine population had on average significantly longer PSDs suggests that synaptic efficacy of axospinous synapses also increased in the CA1. Taken together, our ultrastructural data reveal previously unrecognized structural changes at hippocampal synapses as a function of food restriction, supporting a link between metabolic balance and synaptic plasticity.

  7. Relationships between hippocampal activity and breathing patterns

    DEFF Research Database (Denmark)

    Harper, R M; Poe, G R; Rector, D M;

    1998-01-01

    Single cell discharge, EEG activity, and optical changes accompanying alterations in breathing patterns, as well as the knowledge that respiratory musculature is heavily involved in movement and other behavioral acts, implicate hippocampal regions in some aspects of breathing control. The control...

  8. Nocturnal Mnemonics: Sleep and Hippocampal Memory Processing

    Directory of Open Access Journals (Sweden)

    Jared M. Saletin

    2012-05-01

    Full Text Available As critical as waking brain function is to learning and memory, an established literature now describes an equally important yet complementary role for sleep in information processing. This overview examines the specific contribution of sleep to human hippocampal memory processing; both the detriments caused by a lack of sleep, and conversely, the proactive benefits that develop following the presence of sleep. First, a role for sleep before learning is discussed, preparing the hippocampus for initial memory encoding. Second, a role for sleep after learning is considered, modulating the post-encoding consolidation of hippocampal-dependent memory. Third, a model is outlined in which these encoding and consolidation operations are symbiotically accomplished, associated with specific NREM sleep physiological oscillations. As a result, the optimal network outcome is achieved, increasing hippocampal independence and hence overnight consolidation, while restoring next-day sparse hippocampal encoding capacity for renewed learning ability upon awakening. Finally, emerging evidence is considered suggesting that, unlike previous conceptions, sleep does not universally consolidate all information equally. Instead, and based on explicit as well as motivational cues during initial encoding, sleep executes the discriminatory offline consolidation only of select information. Consequently, sleep promotes the targeted strengthening of some memories while actively forgetting others; a proposal with significant theoretical and clinical ramifications.

  9. Hippocampal kindling: corticosterone modulation of induced seizures

    NARCIS (Netherlands)

    Kloet, E.R. de; Cottrell, G.A.; Nyakas, C.; Bohus, B.

    1984-01-01

    The effect of adrenalectomy (ADX) and corticosterone replacement was studied on seizures induced by hippocampal kindling. A complex series of changes occurred in after-discharge (AD) and behavioural depression (BD) during the immediate hours after ADX, culminating at day 1 in markedly decreased AD a

  10. Stimulus Configuration, Classical Conditioning, and Hippocampal Function.

    Science.gov (United States)

    Schmajuk, Nestor A.; DiCarlo, James J.

    1991-01-01

    The participation of the hippocampus in classical conditioning is described in terms of a multilayer network portraying stimulus configuration. A model of hippocampal function is presented, and computer simulations are used to study neural activity in the various brain areas mapped according to the model. (SLD)

  11. Hippocampal gamma oscillations increase with memory load

    NARCIS (Netherlands)

    Van Vugt, Marieke K.; Schulze-Bonhage, Andreas; Litt, Brian; Brandt, Armin; Kahana, Michael J.

    2010-01-01

    Although the hippocampus plays a crucial role in encoding and retrieval of contextually mediated episodic memories, considerable controversy surrounds the role of the hippocampus in short-term or working memory. To examine both hippocampal and neocortical contributions to working memory function, we

  12. Glucocorticoid receptor knockdown and adult hippocampal neurogenesis

    NARCIS (Netherlands)

    Hooijdonk, Leonarda Wilhelmina Antonia van

    2010-01-01

    The research in this thesis is aimed at the elucidation of the role of the glucocorticoid receptor (GR) in hippocampal neuroplasticity and functioning. To achieve this, we have developed a novel method to specifically knockdown GR in a discrete cell population of the mouse brain. In this thesis I r

  13. Hippocampal theta frequency shifts and operant behaviour

    NARCIS (Netherlands)

    Lopes da Silva, F.H.; Kamp, A.

    1. 1. A shift of hippocampal dominant theta frequency to 6 c/sec has been demonstrated in the post-reward period in two dogs, which occurs consistently related in time to a well defined behavioural pattern in the course of an operant conditioning paradigm. 2. 2. The frequency shift was detected and

  14. Prefrontal-hippocampal interactions in memory and emotion

    Directory of Open Access Journals (Sweden)

    Jingji eJin

    2015-12-01

    Full Text Available The hippocampal formation (HPC and medial prefrontal cortex (mPFC have well-established roles in memory encoding and retrieval. However, the mechanisms underlying interactions between the HPC and mPFC in achieving these functions is not fully understood. Considerable research supports the idea that a direct pathway from the HPC and subiculum to the mPFC is critically involved in cognitive and emotional regulation of mnemonic processes. More recently, evidence has emerged that an indirect pathway from the HPC to the mPFC via midline thalamic nucleus reuniens (RE may plays a role in spatial and emotional memory processing. Here we will consider how bidirectional interactions between the HPC and mPFC are involved in working memory, episodic memory and emotional memory in animals and humans. We will also consider how dysfunctions in bidirectional HPC-mPFC pathways contribute to psychiatric disorders.

  15. Protective effects of resveratrol on the inhibition of hippocampal neurogenesis induced by ethanol during early postnatal life.

    Science.gov (United States)

    Xu, Le; Yang, Yang; Gao, Lixiong; Zhao, Jinghui; Cai, Yulong; Huang, Jing; Jing, Sheng; Bao, Xiaohang; Wang, Ying; Gao, Junwei; Xu, Haiwei; Fan, Xiaotang

    2015-07-01

    Ethanol (EtOH) exposure during early postnatal life triggers obvious neurotoxic effects on the developing hippocampus and results in long-term effects on hippocampal neurogenesis. Resveratrol (RSV) has been demonstrated to exert potential neuroprotective effects by promoting hippocampal neurogenesis. However, the effects of RSV on the EtOH-mediated impairment of hippocampal neurogenesis remain undetermined. Thus, mice were pretreated with RSV and were later exposed to EtOH to evaluate its protective effects on EtOH-mediated toxicity during hippocampal development. The results indicated that a brief exposure of EtOH on postnatal day 7 resulted in a significant impairment in hippocampal neurogenesis and a depletion of hippocampal neural precursor cells (NPCs). This effect was attenuated by pretreatment with RSV. Furthermore, EtOH exposure resulted in a reduction in spine density on the granular neurons of the dentate gyrus (DG), and the spines exhibited a less mature morphological phenotype characterized by a higher proportion of stubby spines and a lower proportion of mushroom spines. However, RSV treatment effectively reversed these responses. We further confirmed that RSV treatment reversed the EtOH-induced down-regulation of hippocampal pERK and Hes1 protein levels, which may be related to the proliferation and maintenance of NPCs. Furthermore, EtOH exposure in the C17.2 NPCs also diminished cell proliferation and activated apoptosis, which could be reversed by pretreatment of RSV. Overall, our results suggest that RSV pretreatment protects against EtOH-induced defects in neurogenesis in postnatal mice and may thus play a critical role in preventing EtOH-mediated toxicity in the developing hippocampus.

  16. Impact of treadmill running and sex on hippocampal neurogenesis in the mouse model of amyotrophic lateral sclerosis.

    Directory of Open Access Journals (Sweden)

    Xiaoxing Ma

    Full Text Available Hippocampal neurogenesis in the subgranular zone (SGZ of dentate gyrus (DG occurs throughout life and is regulated by pathological and physiological processes. The role of oxidative stress in hippocampal neurogenesis and its response to exercise or neurodegenerative diseases remains controversial. The present study was designed to investigate the impact of oxidative stress, treadmill exercise and sex on hippocampal neurogenesis in a murine model of heightened oxidative stress (G93A mice. G93A and wild type (WT mice were randomized to a treadmill running (EX or a sedentary (SED group for 1 or 4 wk. Immunohistochemistry was used to detect bromodeoxyuridine (BrdU labeled proliferating cells, surviving cells, and their phenotype, as well as for determination of oxidative stress (3-NT; 8-OHdG. BDNF and IGF1 mRNA expression was assessed by in situ hybridization. Results showed that: (1 G93A-SED mice had greater hippocampal neurogenesis, BDNF mRNA, and 3-NT, as compared to WT-SED mice. (2 Treadmill running promoted hippocampal neurogenesis and BDNF mRNA content and lowered DNA oxidative damage (8-OHdG in WT mice. (3 Male G93A mice showed significantly higher cell proliferation but a lower level of survival vs. female G93A mice. We conclude that G93A mice show higher hippocampal neurogenesis, in association with higher BDNF expression, yet running did not further enhance these phenomena in G93A mice, probably due to a 'ceiling effect' of an already heightened basal levels of hippocampal neurogenesis and BDNF expression.

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

    Science.gov (United States)

    Murphy, D D; Cole, N B; Segal, M

    1998-09-15

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

  18. Neuroprotective effects of ginsenoside Rb1 on hippocampal neuronal injury and neurite outgrowth

    Institute of Scientific and Technical Information of China (English)

    Juan Liu; Jing He; Liang Huang; Ling Dou; Shuang Wu; Qionglan Yuan

    2014-01-01

    Ginsenoside Rb1 has been reported to exert anti-aging and anti-neurodegenerative effects. In the present study, we investigate whether ginsenoside Rb1 is involved in neurite outgrowth and neuroprotection against damage induced by amyloid beta (25-35) in cultured hippocampal neu-rons, and explore the underlying mechanisms. Ginsenoside Rb1 significantly increased neurite outgrowth in hippocampal neurons, and increased the expression of phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2. These effects were abrogated by API-2 and PD98059, inhibitors of the signaling proteins Akt and MEK. Additionally, cultured hippo-campal neurons were exposed to amyloid beta (25-35) for 30 minutes; ginsenoside Rb1 prevented apoptosis induced by amyloid beta (25-35), and this effect was blocked by API-2 and PD98059. Furthermore, ginsenoside Rb1 significantly reversed the reduction in phosphorylated-Akt and phosphorylated extracellular signal-regulated kinase 1/2 levels induced by amyloid beta (25-35), and API-2 neutralized the effect of ginsenoside Rb1. The present results indicate that ginsenoside Rb1 enhances neurite outgrowth and protects against neurotoxicity induced by amyloid beta (25-35) via a mechanism involving Akt and extracellular signal-regulated kinase 1/2 signaling.

  19. Updating the lamellar hypothesis of hippocampal organization

    Directory of Open Access Journals (Sweden)

    Robert S Sloviter

    2012-12-01

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

  20. Role of Mitochondrial Metabolism in the Control of Early Lineage Progression and Aging Phenotypes in Adult Hippocampal Neurogenesis.

    Science.gov (United States)

    Beckervordersandforth, Ruth; Ebert, Birgit; Schäffner, Iris; Moss, Jonathan; Fiebig, Christian; Shin, Jaehoon; Moore, Darcie L; Ghosh, Laboni; Trinchero, Mariela F; Stockburger, Carola; Friedland, Kristina; Steib, Kathrin; von Wittgenstein, Julia; Keiner, Silke; Redecker, Christoph; Hölter, Sabine M; Xiang, Wei; Wurst, Wolfgang; Jagasia, Ravi; Schinder, Alejandro F; Ming, Guo-Li; Toni, Nicolas; Jessberger, Sebastian; Song, Hongjun; Lie, D Chichung

    2017-02-08

    Precise regulation of cellular metabolism is hypothesized to constitute a vital component of the developmental sequence underlying the life-long generation of hippocampal neurons from quiescent neural stem cells (NSCs). The identity of stage-specific metabolic programs and their impact on adult neurogenesis are largely unknown. We show that the adult hippocampal neurogenic lineage is critically dependent on the mitochondrial electron transport chain and oxidative phosphorylation machinery at the stage of the fast proliferating intermediate progenitor cell. Perturbation of mitochondrial complex function by ablation of the mitochondrial transcription factor A (Tfam) reproduces multiple hallmarks of aging in hippocampal neurogenesis, whereas pharmacological enhancement of mitochondrial function ameliorates age-associated neurogenesis defects. Together with the finding of age-associated alterations in mitochondrial function and morphology in NSCs, these data link mitochondrial complex function to efficient lineage progression of adult NSCs and identify mitochondrial function as a potential target to ameliorate neurogenesis-defects in the aging hippocampus.

  1. Effects of Arc/Arg3.1 gene deletion on rhythmic synchronization of hippocampal CA1 neurons during locomotor activity and sleep.

    NARCIS (Netherlands)

    Malkki, H.A.I.; Mertens, P.E.C.; Lankelma, J.V.; Vinck, M.; van Schalkwijk, F.J.; van Mourik-Donga, L.B.; Battaglia, F.P.; Mahlke, C.; Kuhl, D.; Pennartz, C.M.A.

    2016-01-01

    The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1

  2. Effects of Arc/Arg3.1 gene deletion on rhythmic synchronization of hippocampal CA1 neurons during locomotor activity and sleep.

    NARCIS (Netherlands)

    Malkki, H.A.I.; Mertens, P.E.C.; Lankelma, J.V.; Vinck, M.; van Schalkwijk, F.J.; van Mourik-Donga, L.B.; Battaglia, F.P.; Mahlke, C.; Kuhl, D.; Pennartz, C.M.A.

    2016-01-01

    The activity-regulated cytoskeletal-associated protein/activity regulated gene (Arc/Arg3.1) is crucial for long-term synaptic plasticity and memory formation. However, the neurophysiological substrates of memory deficits occurring in the absence of Arc/Arg3.1 are unknown. We compared hippocampal CA1

  3. CX3CR1 deficiency alters hippocampal-dependent plasticity phenomena blunting the effects of enriched environment

    Directory of Open Access Journals (Sweden)

    Laura eMaggi

    2011-10-01

    Full Text Available In recent years several evidence demonstrated that some features of hippocampal biology, like neurogenesis, synaptic transmission, learning and memory performances are deeply modulated by social, motor and sensorial experiences. Fractalkine/CX3CL1 is a transmembrane chemokine abundantly expressed in the brain by neurons, where it modulates glutamatergic transmission and long-term plasticity processes regulating the intercellular communication between glia and neurons, being its specific receptor CX3CR1 expressed by microglia. In this paper we investigated the role of CX3CL1/CX3CR1 signaling on experience-dependent hippocampal plasticity processes. At this aim wt and CX3CR1GFP/GFP mice were exposed to long-lasting-enriched environment (EE and the effects on hippocampal functions were studied by electrophysiological recordings of long-term potentiation (LTP of synaptic activity, behavioral tests of learning and memory in the Morris water maze paradigm and analysis of neurogenesis in the subgranular zone of the dentate gyrus (DG.We found that CX3CR1 deficiency increases hippocampal plasticity and spatial memory blunting the potentiating effects of EE. In contrast, exposure to EE increased the number and migration of neural progenitors in the DG of both wt and CX3CR1GFP/GFP mice. These data indicate that CX3CL1/CX3CR1-mediated signaling is crucial for a normal experience-dependent modulation of hippocampal functions.

  4. NMDA receptors in the midbrain play a critical role in dopamine-mediated hippocampal synaptic potentiation caused by morphine.

    Science.gov (United States)

    Hu, Ling; Jing, Xiang-Hong; Cui, Cai-Lian; Xing, Guo-Gang; Zhu, Bing

    2014-05-01

    A single exposure to drugs of abuse produces an NMDAR (N-methyl-D-aspartate receptor)-dependent synaptic potentiation at excitatory synapses of dopamine (DA) neurons in the ventral tegmental area (VTA) of the midbrain. All addictive drugs can increase DA concentrations in projection areas of the midbrain, including the hippocampus. Hippocampal DA release subsequently modulates hippocampal plasticity and drug-associated memories. Using in vivo electrophysiological recording techniques in anesthetized rats, we show that systemic injection of morphine induced hippocampal synaptic potentiation in a dose-dependent manner. Intra-VTA but not intra-hippocampus injection of morphine evoked this potentiation. Local hippocampal dopamine D1 receptors (D1R) are required in the morphine-induced synaptic potentiation and conditioned place preference (CPP). Moreover, both NMDAR activation in the VTA and VTA/hippocampus dopaminergic connections are essential for the morphine-evoked potentiation and CPP. These findings suggest that NMDAR signalings in the midbrain play a key role in regulating dopamine-mediated hippocampal synaptic plasticity underlying drug-induced associative memory.

  5. Photoperiod affects the diurnal rhythm of hippocampal neuronal morphology of Siberian hamsters.

    Science.gov (United States)

    Ikeno, Tomoko; Weil, Zachary M; Nelson, Randy J

    2013-11-01

    Individuals of many species can regulate their physiology, morphology, and behavior in response to annual changes of day length (photoperiod). In mammals, the photoperiodic signal is mediated by a change in the duration of melatonin, leading to alterations in gene expressions, neuronal circuits, and hormonal secretion. The hippocampus is one of the most plastic structures in the adult brain and hippocampal neuronal morphology displays photoperiod-induced differences. Because the hippocampus is important for emotional and cognitive behaviors, photoperiod-driven remodeling of hippocampal neurons is implicated in seasonal differences of affect, including seasonal affective disorder (SAD) in humans. Because neuronal architecture is also affected by the day-night cycle in several brain areas, we hypothesized that hippocampal neuronal morphology would display a diurnal rhythm and that day length would influence that rhythm. In the present study, we examined diurnal and seasonal differences in hippocampal neuronal morphology, as well as mRNA expression of the neurotrophic factors (i.e., brain-derived neurotrophic factor [Bdnf], tropomyosin receptor kinase B [trkB; a receptor for BDNF], and vascular endothelial growth factor [Vegf]) and a circadian clock gene, Bmal1, in the hippocampus of Siberian hamsters. Diurnal rhythms in total length of dendrites, the number of primary dendrites, dendritic complexity, and distance of the furthest intersection from the cell body were observed only in long-day animals; however, diurnal rhythms in the number of branch points and mean length of segments were observed only in short-day animals. Spine density of dendrites displayed diurnal rhythmicity with different peak times between the CA1 and DG subregions and between long and short days. These results indicate that photoperiod affects daily morphological changes of hippocampal neurons and the daily rhythm of spine density, suggesting the possibility that photoperiod-induced adjustments

  6. Protective mechanisms of microRNA-27a against oxygen-glucose deprivation-induced injuries in hippocampal neurons

    Institute of Scientific and Technical Information of China (English)

    Qun Cai; Ting Wang; Wen-jie Yang; Xing Fen

    2016-01-01

    Hypoxic injuries during fetal distress have been shown to cause reduced expression of microRNA-27a (miR-27a), which regulates sensi-tivity of cortical neurons to apoptosis. We hypothesized that miR-27a overexpression attenuates hypoxia-and ischemia-induced neuronal apoptosis by regulating FOXO1, an important transcription factor for regulating the oxidative stress response. miR-27a mimic was transfected into hippocampal neurons to overexpress miR-27a. Results showed increased hippocampal neuronal viability and decreased caspase-3 ex-pression. The luciferase reporter gene system demonstrated that miR-27a directly binded to FOXO1 3′UTR in hippocampal neurons and inhibited FOXO1 expression, suggesting that FOXO1 was the target gene for miR-27a. These ifndings conifrm that miR-27a protects hippo-campal neurons against oxygen-glucose deprivation-induced injuries. The mechanism might be mediated by modulation of FOXO1 and apoptosis-related gene caspase-3 expression.

  7. Exploring the potential relationship between Notch pathway genes expression and their promoter methylation in mice hippocampal neurogenesis.

    Science.gov (United States)

    Zhang, Zhen; Gao, Feng; Kang, Xiaokui; Li, Jia; Zhang, Litong; Dong, Wentao; Jin, Zhangning; Li, Fan; Gao, Nannan; Cai, Xinwang; Yang, Shuyuan; Zhang, Jianning; Ren, Xinliang; Yang, Xinyu

    2015-04-01

    The Notch pathway is a highly conserved pathway that regulates hippocampal neurogenesis during embryonic development and adulthood. It has become apparent that intracellular epigenetic modification including DNA methylation is deeply involved in fate specification of neural stem cells (NSCs). However, it is still unclear whether the Notch pathway regulates hippocampal neurogenesis by changing the Notch genes' DNA methylation status. Here, we present the evidence from DNA methylation profiling of Notch1, Hes1 and Ngn2 promoters during neurogenesis in the dentate gyrus (DG) of postnatal, adult and traumatic brains. We observed the expression of Notch1, Hes1 and Ngn2 in hippocampal DG with qPCR, Western blot and immunofluorescence staining. In addition, we investigated the methylation status of Notch pathway genes using the bisulfite sequencing PCR (BSP) method. The number of Notch1 or Hes1 (+) and BrdU (+) cells decreased in the subgranular zone (SGZ) of the DG in the hippocampus following TBI. Nevertheless, the number of Ngn2-positive cells in the DG of injured mice was markedly higher than in the DG of non-TBI mice. Accordingly, the DNA methylation level of the three gene promoters changed with their expression in the DG. These findings suggest that the strict spatio-temporal expression of Notch effector genes plays an important role during hippocampal neurogenesis and suggests the possibility that Notch1, Hes1 and Ngn2 were regulated by changing some specific CpG sites of their promoters to further orchestrate neurogenesis in vivo.

  8. Microglial VPAC1R mediates a novel mechanism of neuroimmune-modulation of hippocampal precursor cells via IL-4 release.

    Science.gov (United States)

    Nunan, Robert; Sivasathiaseelan, Harri; Khan, Damla; Zaben, Malik; Gray, William

    2014-08-01

    Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro-neurogenic effect of microglia via the VPAC1 receptor. This VIP-induced enhancement is mediated by IL-4 release, which directly targets NSPCs. This demonstrates a potential neuro-immuno-neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease.

  9. Hippocampal internal architecture and postoperative seizure outcome in temporal lobe epilepsy due to hippocampal sclerosis.

    Science.gov (United States)

    Elkommos, Samia; Weber, Bernd; Niehusmann, Pitt; Volmering, Elisa; Richardson, Mark P; Goh, Yen Y; Marson, Anthony G; Elger, Christian; Keller, Simon S

    2016-02-01

    Semi-quantitative analysis of hippocampal internal architecture (HIA) on MRI has been shown to be a reliable predictor of the side of seizure onset in patients with temporal lobe epilepsy (TLE). In the present study, we investigated the relationship between postoperative seizure outcome and preoperative semi-quantitative measures of HIA. We determined HIA on high in-plane resolution preoperative T2 short tau inversion recovery MR images in 79 patients with presumed unilateral mesial TLE (mTLE) due to hippocampal sclerosis (HS) who underwent amygdalohippocampectomy and postoperative follow up. HIA was investigated with respect to postoperative seizure freedom, neuronal density determined from resected hippocampal specimens, and conventionally acquired hippocampal volume. HIA ratings were significantly related to some neuropathological features of the resected hippocampus (e.g. neuronal density of selective CA regions, Wyler grades), and bilaterally with preoperative hippocampal volume. However, there were no significant differences in HIA ratings of the to-be-resected or contralateral hippocampus between patients rendered seizure free (ILAE 1) compared to those continuing to experience seizures (ILAE 2-5). This work indicates that semi-quantitative assessment of HIA on high-resolution MRI provides a surrogate marker of underlying histopathology, but cannot prospectively distinguish between patients who will continue to experience postoperative seizures and those who will be rendered seizure free. The predictive power of HIA for postoperative seizure outcome in non-lesional patients with TLE should be explored. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

    Science.gov (United States)

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

    2015-11-01

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

  11. Nascent Proteome Remodeling following Homeostatic Scaling at Hippocampal Synapses.

    Science.gov (United States)

    Schanzenbächer, Christoph T; Sambandan, Sivakumar; Langer, Julian D; Schuman, Erin M

    2016-10-19

    Homeostatic scaling adjusts the strength of synaptic connections up or down in response to large changes in input. To identify the landscape of proteomic changes that contribute to opposing forms of homeostatic plasticity, we examined the plasticity-induced changes in the newly synthesized proteome. Cultured rat hippocampal neurons underwent homeostatic up-scaling or down-scaling. We used BONCAT (bio-orthogonal non-canonical amino acid tagging) to metabolically label, capture, and identify newly synthesized proteins, detecting and analyzing 5,940 newly synthesized proteins using mass spectrometry and label-free quantitation. Neither up- nor down-scaling produced changes in the number of different proteins translated. Rather, up- and down-scaling elicited opposing translational regulation of several molecular pathways, producing targeted adjustments in the proteome. We discovered ∼300 differentially regulated proteins involved in neurite outgrowth, axon guidance, filopodia assembly, excitatory synapses, and glutamate receptor complexes. We also identified differentially regulated proteins that are associated with multiple diseases, including schizophrenia, epilepsy, and Parkinson's disease.

  12. Electroacupuncture at Du channel and meridian of foot- Taiyang for hippocampal neurons in rats with depression

    Institute of Scientific and Technical Information of China (English)

    Min Pi; Wenshu Luo; Lihong Diao; Xiaodan Rao; Haibo Yu; Zhuoxin Yang

    2007-01-01

    BACKGROUND: Long-term anti-depression treatment can promote the regeneration of hippocampal regeneration. Up-regulation of hippocampal regeneration can reverse or prevent against the injury of stress to cerebrum, especially to hippocampal structure and function. Therefore, promoting hippocampal neuronal regeneration may be a new strategy for treating depression and anxiety.OBJECTIVE: To observe the effect of electro-acupuncture at Du channel and meridian of foot-Taiyang on hippocampal neurons from model rats of depression.DESIGN: A randomized controlled animal experiment.SETTING: Department of Acupuncture and Moxibustion, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine.MATERIALS: Twenty-four Wistar rats, of either gender, aged 2 months old, weighing 200 - 220 g, were provided by the Animal Experimental Center, Guangzhou University of Traditional Chinese Medicine.METHODS: This experiment was carried out in the Clinical Molecular Biochemical Laboratory, Shenzhen Affiliated Hospital, Guangzhou University of Traditional Chinese Medicine between October 2006 and April 2007.①The involved rats were randomized into 4 groups according to body mass: blank control group,model group, electroacupuncture A group and electroacupuncture B group, with 6 in each. Rats in the blank control group were free to access to water, and were not given any intervention. Rats in the latter 3 groups were developed into rat depression models by chronic stress combined with feeding alone, and received 21-day unpredictable various stresses. Rats in the model group were euthanized at 14 days after modeling,and their brain tissues were harvested. Rats in the electroacupuncture A group were modeled, then points "Baihui" and "Shenting" were chosen, and given electroacupuncture, once a day, 20 minutes once. Rats in the electroacupuncture B group were modeled, then points "Baihui", "Shenting", "Xinshu"and "Ganshu" were chosen, and frequency and therapeutic time were

  13. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    Directory of Open Access Journals (Sweden)

    Eleni Paizanis

    2007-01-01

    Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

  14. Hippocampal Processing of Ambiguity Enhances Fear Memory.

    Science.gov (United States)

    Amadi, Ugwechi; Lim, Seh Hong; Liu, Elizabeth; Baratta, Michael V; Goosens, Ki A

    2017-02-01

    Despite the ubiquitous use of Pavlovian fear conditioning as a model for fear learning, the highly predictable conditions used in the laboratory do not resemble real-world conditions, in which dangerous situations can lead to unpleasant outcomes in unpredictable ways. In the current experiments, we varied the timing of aversive events after predictive cues in rodents and discovered that temporal ambiguity of aversive events greatly enhances fear. During fear conditioning with unpredictably timed aversive events, pharmacological inactivation of the dorsal hippocampus or optogenetic silencing of cornu ammonis 1 cells during aversive negative prediction errors prevented this enhancement of fear without affecting fear learning for predictable events. Dorsal hippocampal inactivation also prevented ambiguity-related enhancement of fear during auditory fear conditioning under a partial-reinforcement schedule. These results reveal that information about the timing and occurrence of aversive events is rapidly acquired and that unexpectedly timed or omitted aversive events generate hippocampal signals to enhance fear learning.

  15. Inhibitory microcircuit modules in hippocampal learning.

    Science.gov (United States)

    Caroni, Pico

    2015-12-01

    It has recently become possible to investigate connectivities and roles of identified hippocampal GABAergic interneurons (INs) in behaving rodents. INs targeting distinct pyramidal neuron subcompartments are recruited dynamically at defined phases of behavior and learning. They include Parvalbumin Axo-axonic and perisomatic Basket cells, and Somatostatin radiatum-oriens and oriens-lacunosum moleculare cells. Each IN is in turn either activated or inhibited upon specific behavioral and network state requirements through specific inputs and neuromodulators. Subpopulations of these principal neurons and INs interconnect selectively, suggesting selective processing and routing of alternate information streams. First canonical functional modules have emerged, which will have to be further defined and linked to identified afferents and efferents towards a circuit understanding of how hippocampal networks support behavior.

  16. A Compressed Sensing Perspective of Hippocampal Function

    Directory of Open Access Journals (Sweden)

    Panagiotis ePetrantonakis

    2014-08-01

    Full Text Available Hippocampus is one of the most important information processing units in the brain. Input from the cortex passes through convergent axon pathways to the downstream hippocampal subregions and, after being appropriately processed, is fanned out back to the cortex. Here, we review evidence of the hypothesis that information flow and processing in the hippocampus complies with the principles of Compressed Sensing (CS. The CS theory comprises a mathematical framework that describes how and under which conditions, restricted sampling of information (data set can lead to condensed, yet concise, forms of the initial, subsampled information entity (i.e. of the original data set. In this work, hippocampus related regions and their respective circuitry are presented as a CS-based system whose different components collaborate to realize efficient memory encoding and decoding processes. This proposition introduces a unifying mathematical framework for hippocampal function and opens new avenues for exploring coding and decoding strategies in the brain.

  17. Prediction of dementia by hippocampal shape analysis

    DEFF Research Database (Denmark)

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

    2010-01-01

    This work investigates the possibility of predicting future onset of dementia in subjects who are cognitively normal, using hippocampal shape and volume information extracted from MRI scans. A group of 47 subjects who were non-demented normal at the time of the MRI acquisition, but were diagnosed...... and, if necessary, manually corrected by a trained observer. From this data a statistical model of hippocampal shape was constructed, using an entropy-based particle system. This shape model provided the input for a Support Vector Machine classifier to predict dementia. Cross validation experiments...... showed that shape information can predict future onset of dementia in this dataset with an accuracy of 70%. By incorporating both shape and volume information into the classifier, the accuracy increased to 74%....

  18. Functional Role of Adult Hippocampal Neurogenesis as a Therapeutic Strategy for Mental Disorders

    Directory of Open Access Journals (Sweden)

    Heechul Jun

    2012-01-01

    Full Text Available Adult neurogenesis, the process of generating new neurons from neural stem cells, plays significant roles in synaptic plasticity, memory, and mood regulation. In the mammalian brain, it continues to occur well into adulthood in discrete regions, namely, the hippocampus and olfactory bulb. During the past decade, significant progress has been made in understanding the mechanisms regulating adult hippocampal neurogenesis and its role in the etiology of mental disorders. In addition, adult hippocampal neurogenesis is highly correlated with the remission of the antidepressant effect. In this paper, we discuss three major psychiatric disorders, depression, schizophrenia, and drug addiction, in light of preclinical evidence used in establishing the neurobiological significance of adult neurogenesis. We interpret the significance of these results and pose questions that remain unanswered. Potential treatments which include electroconvulsive therapy, deep brain stimulation, chemical antidepressants, and exercise therapy are discussed. While consensus lacks on specific mechanisms, we highlight evidence which indicates that these treatments may function via an increase in neural progenitor proliferation and changes to the hippocampal circuitry. Establishing a significant role of adult neurogenesis in the pathogenicity of psychiatric disorders may hold the key to potential strategies toward effective treatment.

  19. Maturation and integration of adult born hippocampal neurons: signal convergence onto small Rho GTPases

    Directory of Open Access Journals (Sweden)

    Krishna eVadodaria

    2013-08-01

    Full Text Available Adult neurogenesis, restricted to specific regions in the mammalian brain, represents one of the most interesting forms of plasticity in the mature nervous system. Adult-born hippocampal neurons play important roles in certain forms of learning and memory, and altered hippocampal neurogenesis has been associated with a number of neuropsychiatric diseases such as major depression and epilepsy. Newborn neurons go through distinct developmental steps from a dividing neurogenic precursor to a synaptically integrated mature neuron. Previous studies have uncovered several molecular signaling pathways involved in distinct steps of this maturational process. In this context, the small Rho GTPases, Cdc42, Rac1 and RhoA have recently been shown to regulate the morphological and synaptic maturation of adult-born dentate granule cells in vivo. Distinct upstream regulators, including several growth factors that modulate maturation and integration of newborn neurons have been shown to also recruit the small Rho GTPases. Here we review recent findings and highlight the possibility that small Rho GTPases may act as central assimilators, downstream of critical input onto adult-born hippocampal neurons contributing to their maturation and integration into the existing dentate gyrus circuitry.

  20. Hippocampal Fast Glutamatergic Transmission Is Transiently Regulated by Corticosterone Pulsatility

    NARCIS (Netherlands)

    Sarabdjitsingh, R Angela; Pasricha, Natasha; Smeets, Johanna A S; Kerkhofs, Amber; Mikasova, Lenka; Karst, Henk; Groc, Laurent; Joëls, Marian

    2016-01-01

    In recent years it has become clear that corticosteroid hormones (such as corticosterone) are released in ultradian pulses as a natural consequence of pituitary-adrenal interactions. All organs, including the brain, are thus exposed to pulsatile changes in corticosteroid hormone level, important to

  1. GENE EXPRESSION CHANGES AFTER SEIZURE PRECONDITIONING IN THE THREE MAJOR HIPPOCAMPAL CELL LAYERS

    Science.gov (United States)

    Borges, Karin; Shaw, Renee; Dingledine, Raymond

    2008-01-01

    Rodents experience hippocampal damage after status epilepticus (SE) mainly in pyramidal cells while sparing the dentate granule cell layer (DGCL). Hippocampal damage was prevented in rats that had been preconditioned by brief seizures on two consecutive days before SE. To identify neuroprotective genes and biochemical pathways changed after preconditioning we compared the effect of preconditioning on gene expression in the CA1 and CA3 pyramidal and DGCLs, harvested by laser capture microscopy. In the DGCL the expression of 632 genes was altered, compared to only 151 and 58 genes in CA1 and CA3 pyramidal cell layers. Most of the differentially expressed genes regulate tissue structure and intra- and extracellular signaling, including neurotransmission. A selective upregulation of energy metabolism transcripts occurred in CA1 pyramidal cells relative to the DGCL. These results reveal a broad transcriptional response of the DGCL to preconditioning, and suggest several mechanisms underlying the neuroprotective effect of preconditioning seizures. PMID:17239605

  2. Network dynamics mediated by heterogeneous topology as related to hippocampal memory management

    Science.gov (United States)

    Wang, Jane; Poe, Gina; Zochowski, Michal

    2009-03-01

    Hippocampal-cortical network interactions, including reactivation of recently acquired memories in the hippocampus during sleep, are key to the consolidation of memory traces to long-term storage sites in the neocortex. Network heterogeneities, in the form of regional changes in the connectivity densities of excitatory synapses, support this process in simulated hippocampal-cortical networks by regulating intrinsic network dynamics and thus mediating stimulus familiarity detection as well as selective memory consolidation. We characterize this network model by investigating dynamics due to distributed and overlapping memory structures and examine the ability of regional heterogeneities to both selectively activate in the presence of controlled stimuli and reactivate in the absence of stimuli, the former being indicative of active exploration and the latter of memory replay during sleep.

  3. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons.

    Science.gov (United States)

    Wang, Baiping; Wang, Zilai; Sun, Lu; Yang, Li; Li, Hongmei; Cole, Allysa L; Rodriguez-Rivera, Jennifer; Lu, Hui-Chen; Zheng, Hui

    2014-10-01

    Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.

  4. Active sulforhodamine 101 uptake into hippocampal astrocytes.

    Directory of Open Access Journals (Sweden)

    Christian Schnell

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

  5. Updating the lamellar hypothesis of hippocampal organization.

    Science.gov (United States)

    Sloviter, Robert S; Lømo, Terje

    2012-01-01

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

  6. Tuberous sclerosis complex coexistent with hippocampal sclerosis.

    Science.gov (United States)

    Lang, Min; Prayson, Richard A

    2016-02-01

    Tuberous sclerosis and hippocampal sclerosis are both well-defined entities associated with medically intractable epilepsy. To our knowledge, there has been only one prior case of these two pathologies being co-existent. We report a 7-month-old boy who presented with intractable seizures at 2 months of age. MRI studies showed diffuse volume loss in the brain with bilateral, multiple cortical tubers and subcortical migration abnormalities. Subependymal nodules were noted without subependymal giant cell astrocytoma. Genetic testing revealed TSC2 and PRD gene deletions. Histopathology of the hippocampus showed CA1 sclerosis marked by loss of neurons in the CA1 region. Sections from the temporal, parietal and occipital lobes showed multiple cortical tubers characterized by cortical architectural disorganization, gliosis, calcifications and increased number of large balloon cells. Focal white matter balloon cells and spongiform changes were also present. The patient underwent resection of the right fronto-parietal lobe and a subsequent resection of the right temporal, parietal and occipital lobes. The patient is free of seizures on anti-epileptic medication 69 months after surgery. Although hippocampal sclerosis is well documented to be associated with coexistent focal cortical dysplasia, the specific co-existence of cortical tubers and hippocampal sclerosis appears to be rare.

  7. Fluctuations in endogenous kynurenic acid control hippocampal glutamate and memory.

    Science.gov (United States)

    Pocivavsek, Ana; Wu, Hui-Qiu; Potter, Michelle C; Elmer, Greg I; Pellicciari, Roberto; Schwarcz, Robert

    2011-10-01

    Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the α7 nicotinic acetylcholine receptor (α7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30-300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor (S)-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3-3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 μl) or ESBA (10 mM, 10 μl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 μM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

  8. Specific regulatory motifs predict glucocorticoid responsiveness of hippocampal gene expression.

    Science.gov (United States)

    Datson, N A; Polman, J A E; de Jonge, R T; van Boheemen, P T M; van Maanen, E M T; Welten, J; McEwen, B S; Meiland, H C; Meijer, O C

    2011-10-01

    The glucocorticoid receptor (GR) is an ubiquitously expressed ligand-activated transcription factor that mediates effects of cortisol in relation to adaptation to stress. In the brain, GR affects the hippocampus to modulate memory processes through direct binding to glucocorticoid response elements (GREs) in the DNA. However, its effects are to a high degree cell specific, and its target genes in different cell types as well as the mechanisms conferring this specificity are largely unknown. To gain insight in hippocampal GR signaling, we characterized to which GRE GR binds in the rat hippocampus. Using a position-specific scoring matrix, we identified evolutionary-conserved putative GREs from a microarray based set of hippocampal target genes. Using chromatin immunoprecipitation, we were able to confirm GR binding to 15 out of a selection of 32 predicted sites (47%). The majority of these 15 GREs are previously undescribed and thus represent novel GREs that bind GR and therefore may be functional in the rat hippocampus. GRE nucleotide composition was not predictive for binding of GR to a GRE. A search for conserved flanking sequences that may predict GR-GRE interaction resulted in the identification of GC-box associated motifs, such as Myc-associated zinc finger protein 1, within 2 kb of GREs with GR binding in the hippocampus. This enrichment was not present around nonbinding GRE sequences nor around proven GR-binding sites from a mesenchymal stem-like cell dataset that we analyzed. GC-binding transcription factors therefore may be unique partners for DNA-bound GR and may in part explain cell-specific transcriptional regulation by glucocorticoids in the context of the hippocampus.

  9. Intracellular messengers in the generation and degeneration of hippocampal neuroarchitecture.

    Science.gov (United States)

    Mattson, M P; Guthrie, P B; Kater, S B

    1988-01-01

    The actions and interactions of the neurotransmitter glutamate and the intracellular messengers calcium, cyclic AMP, and protein kinase C (PKC) in the regulation of neurite outgrowth and cell survival were examined in hippocampal pyramidal-like neurons in isolated cell culture. Low, subtoxic levels of glutamate (10-100 microM) caused the regression of dendrites but not axons; millimolar levels caused cell death. Calcium ionophore A23187 (50-100 nM) and the PKC activator phorbol-12-myristate-13-acetate (PMA; 10-50 nM) caused the regression of both axons and dendrites, whereas the adenylate cyclase activator forskolin enhanced outgrowth rates in both axons and dendrites. The effects of glutamate, A23187, PMA, and forskolin on outgrowth were mediated locally at the growth cones; dendrites were more sensitive than axons to each of these agents. High levels of A23187 (1 microM) or PMA (100 nM) significantly reduced cell survival. Co2+ and trifluoperazine each significantly reduced glutamate-induced dendritic regression and neurotoxicity suggesting that calcium influx and/or PKC activation mediated glutamate's actions. Fura-2 measurements showed that glutamate caused a rapid rise in intracellular calcium levels; this rise was prevented by Co2+. PMA and forskolin did not alter intracellular calcium levels, nor did these agents affect glutamate-induced calcium rises. Taken together, the results indicate that parallel intracellular messenger pathways that influence neurite outgrowth and cell survival are operative in hippocampal neurons; these messengers may play roles in the formation and modification of neuronal circuitry.

  10. Early detection of Alzheimer's disease using MRI hippocampal texture

    DEFF Research Database (Denmark)

    Sørensen, Lauge; Igel, Christian; Hansen, Naja Liv

    2016-01-01

    Cognitive impairment in patients with Alzheimer's disease (AD) is associated with reduction in hippocampal volume in magnetic resonance imaging (MRI). However, it is unknown whether hippocampal texture changes in persons with mild cognitive impairment (MCI) that does not have a change...... in hippocampal volume. We tested the hypothesis that hippocampal texture has association to early cognitive loss beyond that of volumetric changes. The texture marker was trained and evaluated using T1-weighted MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, and subsequently...

  11. Experience-Dependent Induction of Hippocampal ΔFosB Controls Learning.

    Science.gov (United States)

    Eagle, Andrew L; Gajewski, Paula A; Yang, Miyoung; Kechner, Megan E; Al Masraf, Basma S; Kennedy, Pamela J; Wang, Hongbing; Mazei-Robison, Michelle S; Robison, Alfred J

    2015-10-07

    The hippocampus (HPC) is known to play an important role in learning, a process dependent on synaptic plasticity; however, the molecular mechanisms underlying this are poorly understood. ΔFosB is a transcription factor that is induced throughout the brain by chronic exposure to drugs, stress, and variety of other stimuli and regulates synaptic plasticity and behavior in other brain regions, including the nucleus accumbens. We show here that ΔFosB is also induced in HPC CA1 and DG subfields by spatial learning and novel environmental exposure. The goal of the current study was to examine the role of ΔFosB in hippocampal-dependent learning and memory and the structural plasticity of HPC synapses. Using viral-mediated gene transfer to silence ΔFosB transcriptional activity by expressing ΔJunD (a negative modulator of ΔFosB transcriptional function) or to overexpress ΔFosB, we demonstrate that HPC ΔFosB regulates learning and memory. Specifically, ΔJunD expression in HPC impaired learning and memory on a battery of hippocampal-dependent tasks in mice. Similarly, general ΔFosB overexpression also impaired learning. ΔJunD expression in HPC did not affect anxiety or natural reward, but ΔFosB overexpression induced anxiogenic behaviors, suggesting that ΔFosB may mediate attentional gating in addition to learning. Finally, we found that overexpression of ΔFosB increases immature dendritic spines on CA1 pyramidal cells, whereas ΔJunD reduced the number of immature and mature spine types, indicating that ΔFosB may exert its behavioral effects through modulation of HPC synaptic function. Together, these results suggest collectively that ΔFosB plays a significant role in HPC cellular morphology and HPC-dependent learning and memory. Consolidation of our explicit memories occurs within the hippocampus, and it is in this brain region that the molecular and cellular processes of learning have been most closely studied. We know that connections between hippocampal

  12. Agmatine increases proliferation of cultured hippocampal progenitor cells and hippocampal neurogenesis in chronically stressed mice

    Institute of Scientific and Technical Information of China (English)

    Yun-feng LI; Hong-xia CHEN; Ying LIU; You-zhi ZHANG; Yan-qin LIU; Jin LI

    2006-01-01

    Aim:To explore the mechanism of agmatine's antidepressant action.Methods: Male mice were subjected to a variety of unpredictable stressors on a daily basis over a 24-d period.The open-field behaviors of the mice were displayed and recorded using a Videomex-V image analytic system automatically.For bromodeoxyuridine (BrdU;thymidine analog as a marker for dividing cells) labeling,the mice were injected with BrdU (100 mg/kg,ip,twice per d for 2 d),and the hippocampal neurogenesis in stressed mice was measured by immunohistochemistry.The proliferation of cultured hippocampal progenitor cells from neonatal rats was determined by colorimetric assay (cell counting kit-8) and 3H-thymidine incorporation assay.Results:After the onset of chronic stress,the locomotor activity of the mice in the open field significantly decreased,while coadministration of agmatine 10 mg/kg (po) blocked it.Furthermore,the number of BrdU-labeled cells in the hippocampal dentate gyrus significantly decreased in chronically stressed mice, which was also blocked by chronic coadministration with agmatine 10 mg/kg (po). Four weeks after the BrdU injection, some of the new born cells matured and became neurons, as determined by double labeling for BrdU and neuron specific enolase (NSE), a marker for mature neurons.In vitro treatment with agmatine 0.1-10 μmo1/L for 3 d significantly increased the proliferation of the cultured hippocampal progenitor cells in a dose-dependent manner.Conclusion:We have found that agmatine increases proliferation of hippocampal progenitor cells in vitro and the hippocampal neurogenesis in vivo in chronically stressed mice.This may be one of the important mechanisms involved in agmatine's antidepressant action.

  13. Leptin-induced downregulation of the rat hippocampal somatostatinergic system may potentiate its anorexigenic effects.

    Science.gov (United States)

    Perianes-Cachero, Arancha; Burgos-Ramos, Emma; Puebla-Jiménez, Lilian; Canelles, Sandra; Viveros, María Paz; Mela, Virginia; Chowen, Julie A; Argente, Jesús; Arilla-Ferreiro, Eduardo; Barrios, Vicente

    2012-12-01

    The learning and memory mechanisms in the hippocampus translate hormonal signals of energy balance into behavioral outcomes involved in the regulation of food intake. As leptin and its receptors are expressed in the hippocampus and somatostatin (SRIF), an orexigenic neuropeptide, may inhibit leptin-mediated suppression of food intake in other brain areas, we asked whether chronic leptin infusion induces changes in the hippocampal somatostatinergic system and whether these modifications are involved in leptin-mediated effects. We studied 18 male Wistar rats divided into three groups: controls (C), treated intracerebroventricularly (icv) with leptin (12 μg/day) for 14 days (L) and a pair-fed group (PF) that received the same amount of food consumed by the L group. Food restriction increased whereas leptin decreased the hippocampal SRIF receptor density, due to changes in SRIF receptor 2 protein levels. These changes in the PF group were concurrent with an increase of hippocampal G protein-coupled receptor kinase 2 protein levels and activation of Akt and cyclic AMP response element binding protein. The inhibitory effect of SRIF on adenylyl cyclase (AC) activity, however, was decreased in L rats, coincident with lower G inhibitory α3 and higher AC-I levels as well as signal transducer and activator of transcription factor 3 activation. In addition, 20 male Wistar rats were included to analyze whether the leptin antagonist L39A/D40A/F41A and the SRIF receptor agonist SMS 201-995 modify SRIF signaling and food intake, respectively. Administration of L39A/D40A/F41A reversed changes in SRIF signaling, whereas SMS 201-995 ameliorated food consumption in L. Altogether, these results suggest that increased somatostatinergic tone in PF rats may be a mechanism to improve the hippocampal orexigenic effects in a situation of metabolic demand, whereas down-regulation of this system in L rats may represent a mechanism to enhance the anorexigenic effects of leptin.

  14. Depression, hypothalamic pituitary adrenal axis, and hippocampal and entorhinal cortex volumes--the SMART Medea study.

    Science.gov (United States)

    Gerritsen, Lotte; Comijs, Hannie C; van der Graaf, Yolanda; Knoops, Arnoud J G; Penninx, Brenda W J H; Geerlings, Mirjam I

    2011-08-15

    Structural brain changes have often been found in major depressive disorder (MDD), and it is thought that hypothalamic-pituitary-adrenal (HPA) axis hyperactivity may explain this relation. We investigated the association of MDD and history of depression with hippocampal and entorhinal cortex volumes and whether HPA axis activity explained this association. In 636 participants with a history of atherosclerotic disease (mean age 62 ± 9 years, 81% male) from the second Manifestation of ARTerial disease-Memory depression and aging (SMART-Medea) study, a 12-month diagnosis of MDD and history of depression were assessed. Age of first depressive episode was classified into early-onset depression (< 50 years) and late-onset depression (≥ 50 years). HPA axis regulation was assessed by four morning saliva samples, two evening samples, and one awakening sample after .5 mg dexamethasone. Hippocampus and entorhinal cortex volume were manually outlined on three-dimensional T1-weighted magnetic resonance images. General linear models adjusted for demographics, vascular risk, antidepressant use, and white matter lesions showed that ever having had MDD was associated with smaller hippocampal volumes but not with entorhinal cortex volumes. Remitted MDD was related to smaller entorhinal cortex volumes (p < .05). Participants with early-onset depression had smaller hippocampal volumes than those who were never depressed (p < .05), whereas participants with late-onset depression had smaller entorhinal cortex volumes (p < .05). HPA axis activity did not explain these differences. We found differential associations of age of onset of depression on hippocampal and entorhinal cortex volumes, which could not be explained by alterations in HPA axis regulation. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Amyloid Beta-peptide (25-35) changes (Ca2+) in hippocampal neurons

    DEFF Research Database (Denmark)

    Mogensen, Helle Smidt; Beatty, Diane; Morris, Stephen

    1998-01-01

    neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat......neuroscience, Alzheimer, calcium ion, hippocampal neurons, amyloid-beta-peptide, hydrogen ion, rat...

  16. Myelin-specific T helper 17 cells promote adult hippocampal neurogenesis through indirect mechanisms [v1; ref status: indexed, http://f1000r.es/3ny

    Directory of Open Access Journals (Sweden)

    Johannes Niebling

    2014-07-01

    Full Text Available CD4+ T cells provide a neuro-immunological link in the regulation of adult hippocampal neurogenesis, but the exact mechanisms underlying enhanced neural precursor cell proliferation and the relative contribution of different T helper (Th cell subsets have remained unclear. Here, we explored the proneurogenic potential of interleukin 17-producing T helper (Th17 cells, a developmentally and functionally distinct Th cell subset that is a key mediator of autoimmune neurodegeneration. We found that base-line proliferation of hippocampal precursor cells in a T cell-deficient mouse model of impaired hippocampal neurogenesis can be restored upon adoptive transfer with homogeneous Th17 populations enriched for myelin-reactive T cell receptors. In these experiments, enhanced proliferation was independent of direct interactions of infiltrating Th17 cells with precursor cells or neighboring cells in the hippocampal neurogenic niche. Complementary studies in immunocompetent mice identified several receptors for Th17 cell-derived cytokines with mRNA expression in hippocampal precursor cells and dentate gyrus tissue, suggesting that Th17 cell activity in peripheral lymphoid tissues might promote hippocampal neurogenesis through secreted cytokines.

  17. Chronic treatment with ginsenoside Rg1 promotes memory and hippocampal long-term potentiation in middle-aged mice.

    Science.gov (United States)

    Zhu, G; Wang, Y; Li, J; Wang, J

    2015-04-30

    Ginseng serves as a potential candidate for the treatment of aging-related memory decline or memory loss. However, the related mechanism is not fully understood. In this study, we applied an intraperitoneal injection of ginsenoside Rg1, an active compound from ginseng in middle-aged mice and detected memory improvement and the underlying mechanisms. Our results showed that a period of 30-day administration of ginsenoside Rg1 enhanced long-term memory in the middle-aged animals. Consistent with the memory improvement, ginsenoside Rg1 administration facilitated weak theta-burst stimulation (TBS)-induced long-term potentiation (LTP) in acute hippocampal slices from middle-aged animals. Ginsenoside Rg1 administration increased the dendritic apical spine numbers and area in the CA1 region. In addition, ginsenoside Rg1 administration up-regulated the expression of hippocampal p-AKT, brain-derived neurotrophic factor (BDNF), proBDNF and glutamate receptor 1 (GluR1), but not p-ERK. Interestingly, the phosphatase and tensin homolog deleted on chromosome ten (PTEN) inhibitor (bpV) mimicked the ginsenoside Rg1 effects, including increasing p-AKT expression, promoting hippocampal basal synaptic transmission, LTP and memory. Taken together, our data suggest that ginsenoside Rg1 treatment improves memory in middle-aged mice possibly through regulating the PI3K/AKT pathway, altering apical spines and facilitating hippocampal LTP. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  18. Epigenetic regulation of estrogen-dependent memory

    Science.gov (United States)

    Fortress, Ashley M.; Frick, Karyn M.

    2014-01-01

    Hippocampal memory formation is highly regulated by post-translational histone modifications and DNA methylation. Accordingly, these epigenetic processes play a major role in the effects of modulatory factors, such as sex steroid hormones, on hippocampal memory. Our laboratory recently demonstrated that the ability of the potent estrogen 17β-estradiol (E2) to enhance hippocampal-dependent novel object recognition memory in ovariectomized female mice requires ERK-dependent histone H3 acetylation and DNA methylation in the dorsal hippocampus. Although these data provide valuable insight into the chromatin modifications that mediate the memory-enhancing effects of E2, epigenetic regulation of gene expression is enormously complex. Therefore, more research is needed to fully understand how E2 and other hormones employ epigenetic alterations to shape behavior. This review discusses the epigenetic alterations shown thus far to regulate hippocampal memory, briefly reviews the effects of E2 on hippocampal function, and describes in detail our work on epigenetic regulation of estrogenic memory enhancement. PMID:24878494

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

    Directory of Open Access Journals (Sweden)

    Eun Joo Bae

    2015-01-01

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

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

    Institute of Scientific and Technical Information of China (English)

    Eun Joo Bae; Seongkweon Hong; Dong Won Kim; Jun Hwi Cho; Yun Lyul Lee; Moo-Ho Won; Joon Ha Park; Bai Hui Chen; Bing Chun Yan; Bich Na Shin; Jeong Hwi Cho; In Hye Kim; Ji Hyeon Ahn; Jae Chul Lee; Hyun-Jin Tae

    2015-01-01

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

  1. Immune-based regulation of adult neurogenesis: implications for learning and memory.

    Science.gov (United States)

    Ziv, Yaniv; Schwartz, Michal

    2008-02-01

    Neurogenesis, the formation of new neurons from stem/progenitor cells, occurs in the hippocampal dentate gyrus throughout life. Although the exact function of adult hippocampal neurogenesis is currently unknown, recent studies suggest that the newly formed neuronal population plays an important role in hippocampal-dependent cognitive abilities, including declarative memory. The process of adult neurogenesis is greatly influenced by the interaction between cells of the adaptive immune system and CNS-resident immune cells. Our laboratory has recently demonstrated that immune cells contribute to maintaining life-long hippocampal neurogenesis. The regulation of such immune-cell activity is crucial: too little immune activity (as in immune deficiency syndromes) or too much immune activity (as in severe inflammatory diseases) can lead to impaired hippocampal neurogenesis, which could then result in impaired hippocampal-dependent cognitive abilities. From these converging discoveries arise a mechanism that can explain one route by which our body affects our mind.

  2. Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior

    Science.gov (United States)

    Hussaini, Syed Mohammed Qasim; Choi, Chan-Il; Cho, Chang Hoon; Kim, Hyo Jin; Jun, Heechul; Jang, Mi-Hyeon

    2014-01-01

    In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification, and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms. PMID:25263701

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

    NARCIS (Netherlands)

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

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

  4. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews

    NARCIS (Netherlands)

    Keuker, J.I.H.; de Biurrun, G.; Luiten, P.G.M.; Fuchs, E.

    2004-01-01

    Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many characteris

  5. Anterior Thalamic Lesions Alter Both Hippocampal-Dependent Behavior and Hippocampal Acetylcholine Release in the Rat

    Science.gov (United States)

    Savage, Lisa M.; Hall, Joseph M.; Vetreno, Ryan P.

    2011-01-01

    The anterior thalamic nuclei (ATN) are important for learning and memory as damage to this region produces a persistent amnestic syndrome. Dense connections between the ATN and the hippocampus exist, and importantly, damage to the ATN can impair hippocampal functioning. Acetylcholine (ACh) is a key neurotransmitter in the hippocampus, and in vivo…

  6. Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory.

    Science.gov (United States)

    Botterill, J J; Brymer, K J; Caruncho, H J; Kalynchuk, L E

    2015-06-01

    Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.

  7. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews.

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    Keuker, Jeanine I H; de Biurrun, Gabriel; Luiten, Paul G M; Fuchs, Eberhard

    2004-01-19

    Aging is associated with a decreased ability to store and retrieve information. The hippocampal formation plays a critical role in such memory processes, and its integrity is affected during normal aging. We used tree shrews (Tupaia belangeri) as an animal model of aging, because in many characteristics, tree shrews are closer to primates than they are to rodents. Young and aged male tree shrews performed a holeboard spatial memory task, which permits assessment of reference and working memory. Upon completion of the behavioral measurements, we carried out modified stereological analyses of neuronal numbers in various subdivisions of the hippocampus and used the Cavalieri method to calculate the volumes of these subfields. Results showed that the working memory of aged tree shrews was significantly impaired compared with that of young animals, whereas the hippocampus-dependent reference memory remained unchanged by aging. Estimation of the number of neurons revealed preserved neuron numbers in the subiculum, in the subregions CA1, CA2, CA3, and in the hilus of the dentate gyrus. Volume measurements showed no aging-related changes in the volume of any of these hippocampal subregions, or in the molecular and granule cell layers of the dentate gyrus of tree shrews. We conclude that the observed changes in memory performance in aging tree shrews are not accompanied by observable reductions of hippocampal neuron numbers or hippocampal volume, rather, the changes in memory performance are more likely the result of modified subcellular mechanisms that are affected by the aging process.

  8. The Impact of Sleep Loss on Hippocampal Function

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    Prince, Toni-Moi; Abel, Ted

    2013-01-01

    Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep…

  9. The Impact of Sleep Loss on Hippocampal Function

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    Prince, Toni-Moi; Abel, Ted

    2013-01-01

    Hippocampal cellular and molecular processes critical for memory consolidation are affected by the amount and quality of sleep attained. Questions remain with regard to how sleep enhances memory, what parameters of sleep after learning are optimal for memory consolidation, and what underlying hippocampal molecular players are targeted by sleep…

  10. Allopregnanolone-induced rise in intracellular calcium in embryonic hippocampal neurons parallels their proliferative potential

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    Brinton Roberta

    2008-12-01

    Full Text Available Abstract Background Factors that regulate intracellular calcium concentration are known to play a critical role in brain function and neural development, including neural plasticity and neurogenesis. We previously demonstrated that the neurosteroid allopregnanolone (APα; 5α-pregnan-3α-ol-20-one promotes neural progenitor proliferation in vitro in cultures of rodent hippocampal and human cortical neural progenitors, and in vivo in triple transgenic Alzheimer's disease mice dentate gyrus. We also found that APα-induced proliferation of neural progenitors is abolished by a calcium channel blocker, nifedipine, indicating a calcium dependent mechanism for the proliferation. Methods In the present study, we investigated the effect of APα on the regulation of intracellular calcium concentration in E18 rat hippocampal neurons using ratiometric Fura2-AM imaging. Results Results indicate that APα rapidly increased intracellular calcium concentration in a dose-dependent and developmentally regulated manner, with an EC50 of 110 ± 15 nM and a maximal response occurring at three days in vitro. The stereoisomers 3β-hydroxy-5α-hydroxy-pregnan-20-one, and 3β-hydroxy-5β-hydroxy-pregnan-20-one, as well as progesterone, were without significant effect. APα-induced intracellular calcium concentration increase was not observed in calcium depleted medium and was blocked in the presence of the broad spectrum calcium channel blocker La3+, or the L-type calcium channel blocker nifedipine. Furthermore, the GABAA receptor blockers bicuculline and picrotoxin abolished APα-induced intracellular calcium concentration rise. Conclusion Collectively, these data indicate that APα promotes a rapid, dose-dependent, stereo-specific, and developmentally regulated increase of intracellular calcium concentration in rat embryonic hippocampal neurons via a mechanism that requires both the GABAA receptor and L-type calcium channel. These data suggest that AP

  11. Chemotherapy, cognitive impairment and hippocampal toxicity.

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    Dietrich, J; Prust, M; Kaiser, J

    2015-11-19

    Cancer therapies can be associated with significant central nervous system (CNS) toxicity. While radiation-induced brain damage has been long recognized both in pediatric and adult cancer patients, CNS toxicity from chemotherapy has only recently been acknowledged. Clinical studies suggest that the most frequent neurotoxic adverse effects associated with chemotherapy include memory and learning deficits, alterations of attention, concentration, processing speed and executive function. Preclinical studies have started to shed light on how chemotherapy targets the CNS both on cellular and molecular levels to disrupt neural function and brain plasticity. Potential mechanisms include direct cellular toxicity, alterations in cellular metabolism, oxidative stress, and induction of pro-inflammatory processes with subsequent disruption of normal cellular and neurological function. Damage to neural progenitor cell populations within germinal zones of the adult CNS has been identified as one of the key mechanisms by which chemotherapy might exert long-lasting and progressive neurotoxic effects. Based on the important role of the hippocampus for maintenance of brain plasticity throughout life, several experimental studies have focused on the study of chemotherapy effects on hippocampal neurogenesis and associated learning and memory. An increasing body of literature from both animal studies and neuroimaging studies in cancer patients suggests a possible relationship between chemotherapy induced hippocampal damage and the spectrum of neurocognitive deficits and mood alterations observed in cancer patients. This review aims to briefly summarize current preclinical and neuroimaging studies that are providing a potential link between the neurotoxic effects of chemotherapy and hippocampal dysfunction, highlighting challenges and future directions in this field of investigation.

  12. Proteome Alterations of Hippocampal Cells Caused by Clostridium botulinum C3 Exoenzyme.

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    Schröder, Anke; Rohrbeck, Astrid; Just, Ingo; Pich, Andreas

    2015-11-06

    C3bot from Clostridium botulinum is a bacterial mono-ADP-ribosylating enzyme, which transfers an ADP-ribose moiety onto the small GTPases Rho A/B/C. C3bot and the catalytic inactive mutant (C3E174Q) cause axonal and dendritic growth as well as branching in primary hippocampal neurons. In cultured murine hippocampal HT22 cells, protein abundances were analyzed in response to C3bot or C3E174Q treatment using a shotgun proteomics approach. Proteome analyses were performed at four time points over 6 days. More than 4000 protein groups were identified at each time point and quantified in triplicate analyses. On day one, 46 proteins showed an altered abundance, and after 6 days, more than 700 proteins responded to C3bot with an up- or down-regulation. In contrast, C3E174Q had no provable impact on protein abundance. Protein quantification was verified for several proteins by multiple reaction monitoring. Data analysis of altered proteins revealed different cellular processes that were affected by C3bot. They are particularly involved in mitochondrial and lysosomal processes, adhesion, carbohydrate and glucose metabolism, signal transduction, and nuclear proteins of translation and ribosome biogenesis. The results of this study gain novel insights into the function of C3bot in hippocampal cells.

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

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    Gonçalves, Joana; Baptista, Sofia; Olesen, Mikkel V; Fontes-Ribeiro, Carlos; Malva, João O; Woldbye, David P; Silva, Ana P

    2012-12-01

    Methamphetamine (METH) is a psychostimulant drug that causes irreversible brain damage leading to several neurological and psychiatric abnormalities, including cognitive deficits. Neuropeptide Y (NPY) is abundant in the mammalian central nervous system (CNS) and has several important functions, being involved in learning and memory processing. It has been demonstrated that METH induces significant alteration in mice striatal NPY, Y(1) and Y(2) receptor mRNA levels. However, the impact of this drug on the hippocampal NPY system and its consequences remain unknown. Thus, in this study, we investigated the effect of METH intoxication on mouse hippocampal NPY levels, NPY receptors function, and memory performance. Results show that METH increased NPY, Y(2) and Y(5) receptor mRNA levels, as well as total NPY binding accounted by opposite up- and down-regulation of Y(2) and Y(1) functional binding, respectively. Moreover, METH-induced impairment in memory performance and AKT/mammalian target of rapamycin pathway were both prevented by the Y(2) receptor antagonist, BIIE0246. These findings demonstrate that METH interferes with the hippocampal NPY system, which seems to be associated with memory failure. Overall, we concluded that Y(2) receptors are involved in memory deficits induced by METH intoxication.

  14. Constitutive and Acquired Serotonin Deficiency Alters Memory and Hippocampal Synaptic Plasticity.

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    Fernandez, Sebastian P; Muzerelle, Aude; Scotto-Lomassese, Sophie; Barik, Jacques; Gruart, Agnès; Delgado-García, José M; Gaspar, Patricia

    2017-01-01

    Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.

  15. Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors.

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    Hill, Alexis S; Sahay, Amar; Hen, René

    2015-09-01

    Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.

  16. Alzheimer’s disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

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    Orly eLazarov

    2016-05-01

    Full Text Available New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimer’s disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimer’s disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimer’s disease. Lastly, we discuss the detectability of neurogenesis in the live mouse and human brain, as well as the therapeutic implications of enhancing neurogenesis for the treatment of cognitive deficits and Alzheimer’s disease.

  17. Transient oxytocin signaling primes the development and function of excitatory hippocampal neurons

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    Ripamonti, Silvia; Ambrozkiewicz, Mateusz C; Guzzi, Francesca; Gravati, Marta; Biella, Gerardo; Bormuth, Ingo; Hammer, Matthieu; Tuffy, Liam P; Sigler, Albrecht; Kawabe, Hiroshi; Nishimori, Katsuhiko; Toselli, Mauro; Brose, Nils; Parenti, Marco; Rhee, JeongSeop

    2017-01-01

    Beyond its role in parturition and lactation, oxytocin influences higher brain processes that control social behavior of mammals, and perturbed oxytocin signaling has been linked to the pathogenesis of several psychiatric disorders. However, it is still largely unknown how oxytocin exactly regulates neuronal function. We show that early, transient oxytocin exposure in vitro inhibits the development of hippocampal glutamatergic neurons, leading to reduced dendrite complexity, synapse density, and excitatory transmission, while sparing GABAergic neurons. Conversely, genetic elimination of oxytocin receptors increases the expression of protein components of excitatory synapses and excitatory synaptic transmission in vitro. In vivo, oxytocin-receptor-deficient hippocampal pyramidal neurons develop more complex dendrites, which leads to increased spine number and reduced γ-oscillations. These results indicate that oxytocin controls the development of hippocampal excitatory neurons and contributes to the maintenance of a physiological excitation/inhibition balance, whose disruption can cause neurobehavioral disturbances. DOI: http://dx.doi.org/10.7554/eLife.22466.001 PMID:28231043

  18. Musical Expertise Increases Top–Down Modulation Over Hippocampal Activation during Familiarity Decisions

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    Pierre Gagnepain

    2017-09-01

    Full Text Available The hippocampus has classically been associated with episodic memory, but is sometimes also recruited during semantic memory tasks, especially for the skilled exploration of familiar information. Cognitive control mechanisms guiding semantic memory search may benefit from the set of cognitive processes at stake during musical training. Here, we examined using functional magnetic resonance imaging, whether musical expertise would promote the top–down control of the left inferior frontal gyrus (LIFG over the generation of hippocampally based goal-directed thoughts mediating the familiarity judgment of proverbs and musical items. Analyses of behavioral data confirmed that musical experts more efficiently access familiar melodies than non-musicians although such increased ability did not transfer to verbal semantic memory. At the brain level, musical expertise specifically enhanced the recruitment of the hippocampus during semantic access to melodies, but not proverbs. Additionally, hippocampal activation contributed to speed of access to familiar melodies, but only in musicians. Critically, causal modeling of neural dynamics between LIFG and the hippocampus further showed that top–down excitatory regulation over the hippocampus during familiarity decision specifically increases with musical expertise – an effect that generalized across melodies and proverbs. At the local level, our data show that musical expertise modulates the online recruitment of hippocampal response to serve semantic memory retrieval of familiar melodies. The reconfiguration of memory network dynamics following musical training could constitute a promising framework to understand its ability to preserve brain functions.

  19. Extracellular calcium modulates persistent sodium current-dependent burst-firing in hippocampal pyramidal neurons.

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    Su, H; Alroy, G; Kirson, E D; Yaari, Y

    2001-06-15

    The generation of high-frequency spike bursts ("complex spikes"), either spontaneously or in response to depolarizing stimuli applied to the soma, is a notable feature in intracellular recordings from hippocampal CA1 pyramidal cells (PCs) in vivo. There is compelling evidence that the bursts are intrinsically generated by summation of large spike afterdepolarizations (ADPs). Using intracellular recordings in adult rat hippocampal slices, we show that intrinsic burst-firing in CA1 PCs is strongly dependent on the extracellular concentration of Ca(2+) ([Ca(2+)](o)). Thus, lowering [Ca(2+)](o) (by equimolar substitution with Mn(2+) or Mg(2+)) induced intrinsic bursting in nonbursters, whereas raising [Ca(2+)](o) suppressed intrinsic bursting in native bursters. The induction of intrinsic bursting by low [Ca(2+)](o) was associated with enlargement of the spike ADP. Low [Ca(2+)](o)-induced intrinsic bursts and their underlying ADPs were suppressed by drugs that reduce the persistent Na(+) current (I(NaP)), indicating that this current mediates the slow burst depolarization. Blocking Ca(2+)-activated K(+) currents with extracellular Ni(2+) or intracellular chelation of Ca(2+) did not induce intrinsic bursting. This and other evidence suggest that lowering [Ca(2+)](o) may induce intrinsic bursting by augmenting I(NaP). Because repetitive neuronal activity in the hippocampus is associated with marked decreases in [Ca(2+)](o), the regulation of intrinsic bursting by extracellular Ca(2+) may provide a mechanism for preferential recruitment of this firing mode during certain forms of hippocampal activation.

  20. Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses

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    Armando eRomani

    2013-01-01

    Full Text Available The role of amyloid-beta (Aβ in brain function and in the pathogenesis of Alzheimer’s disease remains elusive. Recent publications reported that an increase in Aβ concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that Aβ is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this Aβ-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz. Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced Aβ on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-Aβ condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased Aβ can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during Alzheimer’s disease.

  1. Network state-dependent inhibition of identified hippocampal CA3 axo-axonic cells in vivo.

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    Viney, Tim J; Lasztoczi, Balint; Katona, Linda; Crump, Michael G; Tukker, John J; Klausberger, Thomas; Somogyi, Peter

    2013-12-01

    Hippocampal sharp waves are population discharges initiated by an unknown mechanism in pyramidal cell networks of CA3. Axo-axonic cells (AACs) regulate action potential generation through GABAergic synapses on the axon initial segment. We found that CA3 AACs in anesthetized rats and AACs in freely moving rats stopped firing during sharp waves, when pyramidal cells fire most. AACs fired strongly and rhythmically around the peak of theta oscillations, when pyramidal cells fire at low probability. Distinguishing AACs from other parvalbumin-expressing interneurons by their lack of detectable SATB1 transcription factor immunoreactivity, we discovered a somatic GABAergic input originating from the medial septum that preferentially targets AACs. We recorded septo-hippocampal GABAergic cells that were activated during hippocampal sharp waves and projected to CA3. We hypothesize that inhibition of AACs, and the resulting subcellular redistribution of inhibition from the axon initial segment to other pyramidal cell domains, is a necessary condition for the emergence of sharp waves promoting memory consolidation.

  2. Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis

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    Pauline Lafenetre

    2010-02-01

    Full Text Available Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice. These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin-immunoreactive cells expressing TrkB BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition.

  3. Control of noradrenaline release from hippocampal synaptosomes

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    West, D.P.; Fillenz, M.

    1981-10-01

    Potassium-evoked tritiated noradrenaline (NA) release from hippocampal synaptosomes was measured with a superfusion method. A single 2-min high-K+ pulse released 39% of the vesicular NA by a Ca2+-dependent mechanism: the Ca2+-independent release was negligible. After changing the vesicular NA store size by pretreating rats with either alpha-methyl-para-tyrosine, 500 mg/kg, or tranylcypromine, 10 mg/kg, a single K+ pulse released a constant percentage of the vesicular NA. With two K+ pulses, however, there was a reduction in the percentage of vesicular NA released in response to the second pulse.

  4. Regionally specific induction of BDNF and truncated trkB.T1 receptors in the hippocampal formation after intraseptal injection of kainic acid.

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    Venero, J L; Hefti, F

    1998-04-20

    The septo-hippocampal cholinergic and GABAergic systems were lesioned with single unilateral injections of kainic acid (KA) into the septum to further characterize the role of these afferents in the regulation of hippocampal brain-derived neurotrophic factor (BDNF) expression. Nearly all cells expressing choline acetyltransferase, trkA or glutamic acid decarboxylase mRNA disappeared in the medial septum 7 days after the neurotoxin administration. The lesion resulted in a complete loss of CA3 pyramidal cells, and robust increases in BDNF mRNA levels in hippocampal granular dentate cells and in the amygdala. There were rapid transient increases of BDNF mRNA levels in the hippocampal formation and cortex. In addition, we found a strong induction of truncated trkB.T1 mRNA receptors in the stratum radiatum and stratum oriens of the CA3 subfield. The prolonged induction of BDNF mRNA levels suggests an important role of this neurotrophin, possibly mediated by truncated trkB receptors, in the regulation of hippocampal plasticity following injury.

  5. Forniceal deep brain stimulation rescues hippocampal memory in Rett syndrome mice.

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    Hao, Shuang; Tang, Bin; Wu, Zhenyu; Ure, Kerstin; Sun, Yaling; Tao, Huifang; Gao, Yan; Patel, Akash J; Curry, Daniel J; Samaco, Rodney C; Zoghbi, Huda Y; Tang, Jianrong

    2015-10-15

    Deep brain stimulation (DBS) has improved the prospects for many individuals with diseases affecting motor control, and recently it has shown promise for improving cognitive function as well. Several studies in individuals with Alzheimer disease and in amnesic rats have demonstrated that DBS targeted to the fimbria-fornix, the region that appears to regulate hippocampal activity, can mitigate defects in hippocampus-dependent memory. Despite these promising results, DBS has not been tested for its ability to improve cognition in any childhood intellectual disability disorder. Such disorders are a pressing concern: they affect as much as 3% of the population and involve hundreds of different genes. We proposed that stimulating the neural circuits that underlie learning and memory might provide a more promising route to treating these otherwise intractable disorders than seeking to adjust levels of one molecule at a time. We therefore studied the effects of forniceal DBS in a well-characterized mouse model of Rett syndrome (RTT), which is a leading cause of intellectual disability in females. Caused by mutations that impair the function of MeCP2 (ref. 6), RTT appears by the second year of life in humans, causing profound impairment in cognitive, motor and social skills, along with an array of neurological features. RTT mice, which reproduce the broad phenotype of this disorder, also show clear deficits in hippocampus-dependent learning and memory and hippocampal synaptic plasticity. Here we show that forniceal DBS in RTT mice rescues contextual fear memory as well as spatial learning and memory. In parallel, forniceal DBS restores in vivo hippocampal long-term potentiation and hippocampal neurogenesis. These results indicate that forniceal DBS might mitigate cognitive dysfunction in RTT.

  6. Environmental enrichment modifies the PKA-dependence of hippocampal LTP and improves hippocampus-dependent memory.

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    Duffy, S N; Craddock, K J; Abel, T; Nguyen, P V

    2001-01-01

    cAMP-dependent protein kinase (PKA) is critical for the expression of some forms of long-term potentiation (LTP) in area CA1 of the mouse hippocampus and for hippocampus-dependent memory. Exposure to spatially enriched environments can modify LTP and improve behavioral memory in rodents, but the molecular bases for the enhanced memory performance seen in enriched animals are undefined. We tested the hypothesis that exposure to a spatially enriched environment may alter the PKA dependence of hippocampal LTP. Hippocampal slices from enriched mice showed enhanced LTP following a single burst of 100-Hz stimulation in the Schaffer collateral pathway of area CA1. In slices from nonenriched mice, this single-burst form of LTP was less robust and was unaffected by Rp-cAMPS, an inhibitor of PKA. In contrast, the enhanced LTP in enriched mice was attenuated by Rp-cAMPS. Enriched slices expressed greater forskolin-induced, cAMP-dependent synaptic facilitation than did slices from nonenriched mice. Enriched mice showed improved memory for contextual fear conditioning, whereas memory for cued fear conditioning was unaffected following enrichment. Our data indicate that exposure of mice to spatial enrichment alters the PKA dependence of LTP and enhances one type of hippocampus-dependent memory. Environmental enrichment can transform the pharmacological profile of hippocampal LTP, possibly by altering the threshold for activity-dependent recruitment of the cAMP-PKA signaling pathway following electrical and chemical stimulation. We suggest that experience-dependent plasticity of the PKA dependence of hippocampal LTP may be important for regulating the efficacy of hippocampus-based memory.

  7. Gene expression analysis in the hippocampal formation of tree shrews chronically treated with cortisol.

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    Alfonso, Julieta; Agüero, Fernán; Sanchez, Daniel O; Flugge, Gabriele; Fuchs, Eberhard; Frasch, Alberto C C; Pollevick, Guido D

    2004-12-01

    Adrenal corticosteroids influence the function of the hippocampus, the brain structure in which the highest expression of glucocorticoid receptors is found. Chronic high levels of cortisol elicited by stress or through exogenous administration can cause irreversible damage and cognitive deficits. In this study, we searched for genes expressed in the hippocampal formation after chronic cortisol treatment in male tree shrews. Animals were treated orally with cortisol for 28 days. At the end of the experiments, we generated two subtractive hippocampal hybridization libraries from which we sequenced 2,246 expressed sequenced tags (ESTs) potentially regulated by cortisol. To validate this approach further, we selected some of the candidate clones to measure mRNA expression levels in hippocampus using real-time PCR. We found that 66% of the sequences tested (10 of 15) were differentially represented between cortisol-treated and control animals. The complete set of clones was subjected to a bioinformatic analysis, which allowed classification of the ESTs into four different main categories: 1) known proteins or genes (approximately 28%), 2) ESTs previously published in the database (approximately 16%), 3) novel ESTs matching only the reference human or mouse genome (approximately 5%), and 4) sequences that do not match any public database (50%). Interestingly, the last category was the most abundant. Hybridization assays revealed that several of these clones are indeed expressed in hippocampal tissue from tree shrew, human, and/or rat. Therefore, we discovered an extensive inventory of new molecular targets in the hippocampus that serves as a reference for hippocampal transcriptional responses under various conditions. Finally, a detailed analysis of the genomic localization in human and mouse genomes revealed a survey of putative novel splicing variants for several genes of the nervous system.

  8. Effects of inorganic lead on the differentiation and growth of cultured hippocampal and neuroblastoma cells.

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    Audesirk, T; Audesirk, G; Ferguson, C; Shugarts, D

    1991-01-01

    Lead exposure has devastating effects on the developing nervous system, and has been implicated in variety of behavioral and cognitive deficits as well as neural morphological abnormalities. Since lead impacts many calcium-dependent processes, one likely mechanism of lead toxicity is its disruption of calcium dependent processes, among which is neuronal differentiation. We investigated the effects of inorganic lead on survival and several parameters of differentiation of cultured neurons. Three different cell types were used: Rat hippocampal neurons (a primary CNS cell type), B50 rat neuroblastoma cells (a transformed CNS-derived cell line), and N1E-115 mouse neuroblastoma cells (a transformed peripherally-derived cell line). Lead concentrations ranged from low nM to 1 mM. Lead effects differed considerably among the three cell types, with B50 cells least affected. Lead effects were generally multimodal, with fewest effects observed at intermediate concentrations. Lead inhibited neurite initiation in hippocampal neurons, but stimulated initiation in N1E-115 cells. In those cells that differentiated, lead increased dendrite numbers in hippocampal neurons and neurite numbers in N1E-115 cells. Lead exposure increased both the length and the degree of branching of axons in hippocampal neurons and the length of neurites in N1E-115 cells. We hypothesize that lead impacts multiple regulatory processes that influence neuron survival and differentiation, and that its effects show differing dose-dependencies. The differing responses of the different cell types to lead suggests that differentiation may be regulated in different ways by the three types of cells. Alternatively, or additionally, the cell types may differ in their ability to compensate for, sequester, or expel lead.

  9. Topiramate protects against glutamate excitotoxicity via activating BDNF/TrkB-dependent ERK pathway in rodent hippocampal neurons.

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    Mao, Xiao-Yuan; Cao, Yong-Gang; Ji, Zhong; Zhou, Hong-Hao; Liu, Zhao-Qian; Sun, Hong-Li

    2015-07-01

    Topiramate (TPM) was previously found to have neuroprotection against neuronal injury in epileptic and ischemic models. However, whether TPM protects against glutamate-induced excitotoxicity in hippocampal neurons is elusive. Our present work aimed to evaluate the protective effect of TPM against glutamate toxicity in hippocampal neurons and further figure out the potential molecular mechanisms. The in vitro glutamate excitotoxic model was prepared with 125μM glutamate for 20min. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) analysis and Hoechst 33342 staining were conducted to detect neuronal survival. The protein expressions of brain-derived neurotrophic factor (BDNF), TrkB, mitogen-activated protein kinase (MAPK) cascade (including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 MAPK), cyclic AMP response element binding protein (CREB), Bcl-2, Bax and β-actin were detected via Western blot assay. Our results demonstrated that TPM protected hippocampal neurons from glutamate toxicity. Meanwhile, the pretreatment of TPM for 10min significantly prevented the down-regulation of BDNF and the phosphorylation of TrkB. Furthermore, the elevation of phosphorylated EKR expression was significantly inhibited after blockade of TrkB by TrkB IgG, while no alterations of phosphorylated JNK and p38 MAPK were found in the cultured hippocampal neurons. Besides, it was also found that the enhanced phosphorylation of CREB was evidently reversed under excitotoxic conditions after treating with U0126 (the selective inhibitor of ERK). The protein level of Bcl-2 was also observed to be remarkably increased after TPM treatment. In conclusion, these findings implicate that TPM exerts neuroprotective effects against glutamate excitotoxicity in hippocampal neurons and its protection may be modulated through BDNF/TrkB-dependent ERK pathway.

  10. Loss of forebrain MTCH2 decreases mitochondria motility and calcium handling and impairs hippocampal-dependent cognitive functions

    Science.gov (United States)

    Ruggiero, Antonella; Aloni, Etay; Korkotian, Eduard; Zaltsman, Yehudit; Oni-Biton, Efrat; Kuperman, Yael; Tsoory, Michael; Shachnai, Liat; Levin-Zaidman, Smadar; Brenner, Ori; Segal, Menahem; Gross, Atan

    2017-01-01

    Mitochondrial Carrier Homolog 2 (MTCH2) is a novel regulator of mitochondria metabolism, which was recently associated with Alzheimer’s disease. Here we demonstrate that deletion of forebrain MTCH2 increases mitochondria and whole-body energy metabolism, increases locomotor activity, but impairs motor coordination and balance. Importantly, mice deficient in forebrain MTCH2 display a deficit in hippocampus-dependent cognitive functions, including spatial memory, long term potentiation (LTP) and rates of spontaneous excitatory synaptic currents. Moreover, MTCH2-deficient hippocampal neurons display a deficit in mitochondria motility and calcium handling. Thus, MTCH2 is a critical player in neuronal cell biology, controlling mitochondria metabolism, motility and calcium buffering to regulate hippocampal-dependent cognitive functions. PMID:28276496

  11. Effects of hippocampal state-contingent trial presentation on hippocampus-dependent nonspatial classical conditioning and extinction.

    Science.gov (United States)

    Nokia, Miriam S; Wikgren, Jan

    2014-04-23

    Hippocampal local field potentials are characterized by two mutually exclusive states: one characterized by regular θ oscillations (∼4-8 Hz) and the other by irregular sharp-wave ripples. Presenting stimuli during dominant θ oscillations leads to expedited learning, suggesting that θ indexes a state in which encoding is most effective. However, ripple-contingent training also expedites learning, suggesting that any discrete brain state, much like the external context, can affect learning. We trained adult rabbits in trace eyeblink conditioning, a hippocampus-dependent nonspatial task, followed by extinction. Trials were delivered either in the presence or absence of θ or regardless of hippocampal state. Conditioning in the absence of θ led to more animals learning, although learning was slower compared with a yoked control group. Contrary to expectations, conditioning in the presence of θ did not affect learning. However, extinction was expedited both when it was conducted contingent on θ and when it was conducted in a state contrary to that used to trigger trials during conditioning. Strong phase-locking of hippocampal θ-band responses to the conditioned stimulus early on during conditioning predicted good learning. No such connection was observed during extinction. Our results suggest that any consistent hippocampal oscillatory state can potentially be used to regulate learning. However, the effects depend on the specific state and task at hand. Finally, much like the external environment, the ongoing neural state appears to act as a context for learning and memory retrieval.

  12. BDNF pro-peptide actions facilitate hippocampal LTD and are altered by the common BDNF polymorphism Val66Met.

    Science.gov (United States)

    Mizui, Toshiyuki; Ishikawa, Yasuyuki; Kumanogoh, Haruko; Lume, Maria; Matsumoto, Tomoya; Hara, Tomoko; Yamawaki, Shigeto; Takahashi, Masami; Shiosaka, Sadao; Itami, Chiaki; Uegaki, Koichi; Saarma, Mart; Kojima, Masami

    2015-06-09

    Most growth factors are initially synthesized as precursor proteins and subsequently processed into their mature form by proteolytic cleavage, resulting in simultaneous removal of a pro-peptide. However, compared with that of mature form, the biological role of the pro-peptide is poorly understood. Here, we investigated the biological role of the pro-peptide of brain-derived neurotrophic factor (BDNF) and first showed that the pro-peptide is expressed and secreted in hippocampal tissues and cultures, respectively. Interestingly, we found that the BDNF pro-peptide directly facilitates hippocampal long-term depression (LTD), requiring the activation of GluN2B-containing NMDA receptors and the pan-neurotrophin receptor p75(NTR). The BDNF pro-peptide also enhances NMDA-induced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor endocytosis, a mechanism crucial for LTD expression. Thus, the BDNF pro-peptide is involved in synaptic plasticity that regulates a mechanism responsible for promoting LTD. The well-known BDNF polymorphism valine for methionine at amino acid position 66 (Val66Met) affects human memory function. Here, the BDNF pro-peptide with Met mutation completely inhibits hippocampal LTD. These findings demonstrate functional roles for the BDNF pro-peptide and a naturally occurring human BDNF polymorphism in hippocampal synaptic depression.

  13. Intercellular adhesion molecule-1 expression in the hippocampal CA1 region of hyperlipidemic rats with chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Yingying Cheng; Ying Zhang; Hongmei Song; Jiachun Feng

    2012-01-01

    Chronic cerebral ischemia is a pathological process in many cerebrovascular diseases and it is induced by long-term hyperlipidemia, hypertension and diabetes mellitus. After being fed a high-fat diet for 4 weeks, rats were subjected to permanent occlusion of bilateral common carotid arteries to establish rat models of chronic cerebral ischemia with hyperlipidemia. Intercellular adhesion molecule-1 expression in rat hippocampal CA1 region was determined to better understand the mechanism underlying the effects of hyperlipidemia on chronic cerebral ischemia. Water maze test results showed that the cognitive function of rats with hyperlipidemia or chronic cerebral ischemia, particularly in rats with hyperlipidemia combined with chronic cerebral ischemia, gradually decreased between 1 and 4 months after occlusion of the bilateral common carotid arteries. This correlated with pathological changes in the hippocampal CA1 region as detected by hematoxylin-eosin staining. Immunohistochemical staining showed that intercellular adhesion molecule-1 expression in the hippocampal CA1 region was noticeably increased in rats with hyperlipidemia or chronic cerebral ischemia, in particular in rats with hyperlipidemia combined with chronic cerebral ischemia. These findings suggest that hyperlipidemia aggravates chronic cerebral ischemia-induced neurological damage and cognitive impairment in the rat hippocampal CA1 region, which may be mediated, at least in part, by up-regulated expression of intercellular adhesion molecule-1.

  14. Modulators of cytoskeletal reorganization in CA1 hippocampal neurons show increased expression in patients at mid-stage Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Patricia F Kao

    Full Text Available During the progression of Alzheimer's disease (AD, hippocampal neurons undergo cytoskeletal reorganization, resulting in degenerative as well as regenerative changes. As neurofibrillary tangles form and dystrophic neurites appear, sprouting neuronal processes with growth cones emerge. Actin and tubulin are indispensable for normal neurite development and regenerative responses to injury and neurodegenerative stimuli. We have previously shown that actin capping protein beta2 subunit, Capzb2, binds tubulin and, in the presence of tau, affects microtubule polymerization necessary for neurite outgrowth and normal growth cone morphology. Accordingly, Capzb2 silencing in hippocampal neurons resulted in short, dystrophic neurites, seen in neurodegenerative diseases including AD. Here we demonstrate the statistically significant increase in the Capzb2 expression in the postmortem hippocampi in persons at mid-stage, Braak and Braak stage (BB III-IV, non-familial AD in comparison to controls. The dynamics of Capzb2 expression in progressive AD stages cannot be attributed to reactive astrocytosis. Moreover, the increased expression of Capzb2 mRNA in CA1 pyramidal neurons in AD BB III-IV is accompanied by an increased mRNA expression of brain derived neurotrophic factor (BDNF receptor tyrosine kinase B (TrkB, mediator of synaptic plasticity in hippocampal neurons. Thus, the up-regulation of Capzb2 and TrkB may reflect cytoskeletal reorganization and/or regenerative response occurring in hippocampal CA1 neurons at a specific stage of AD progression.

  15. Glucose deprivation activates diversity of potassium channels in cultured rat hippocampal neurons.

    Science.gov (United States)

    Velasco, Myrian; García, Esperanza; Onetti, Carlos G

    2006-05-01

    1. Glucose is one of the most important substrates for generating metabolic energy required for the maintenance of cellular functions. Glucose-mediated changes in neuronal firing pattern have been observed in the central nervous system of mammals. K(+) channels directly regulated by intracellular ATP have been postulated as a linkage between cellular energetic metabolism and excitability; the functional roles ascribed to these channels include glucose-sensing to regulate energy homeostasis and neuroprotection under energy depletion conditions. The hippocampus is highly sensitive to metabolic insults and is the brain region most sensitive to ischemic damage. Because the identity of metabolically regulated potassium channels present in hippocampal neurons is obscure, we decided to study the biophysical properties of glucose-sensitive potassium channels in hippocampal neurons. 2. The dependence of membrane potential and the sensitivity of potassium channels to glucose and ATP in rat hippocampal neurons were studied in cell-attached and excised inside-out membrane patches. 3. We found that under hypoglycemic conditions, at least three types of potassium channels were activated; their unitary conductance values were 37, 147, and 241 pS in symmetrical K(+), and they were sensitive to ATP. For K(+) channels with unitary conductance of 37 and 241, when the membrane potential was depolarized the longer closed time constant diminished and this produced an increase in the open-state probability; nevertheless, the 147-pS channels were not voltage-dependent. 4. We propose that neuronal glucose-sensitive K(+) channels in rat hippocampus include subtypes of ATP-sensitive channels with a potential role in neuroprotection during short-term or prolonged metabolic stress.

  16. Calcium current homeostasis and synaptic deficits in hippocampal neurons from Kelch-like 1 knockout mice

    Directory of Open Access Journals (Sweden)

    Paula Patricia Perissinotti

    2015-01-01

    Full Text Available Kelch-like 1 (KLHL1 is a neuronal actin-binding protein that modulates voltage-gated CaV2.1 (P/Q-type and CaV3.2 (α1H T-type calcium channels; KLHL1 knockdown experiments (KD cause down-regulation of both channel types and altered synaptic properties in cultured rat hippocampal neurons (Perissinotti et al., 2014. Here, we studied the effect of ablation of KLHL1 on calcium channel function and synaptic properties in cultured hippocampal neurons from KLHL1 knockout (KO mice. Western blot data showed the P/Q-type channel α1A subunit was less abundant in KO hippocampus compared to wildtype (WT; and PQ-type calcium currents were smaller in KO neurons than WT during early days in vitro, although this decrease was compensated for at late stages by increases in L-type calcium current. In contrast, T-type currents did not change in culture. However, biophysical properties and western blot analysis revealed a differential contribution of T-type channel isoforms in the KO, with CaV3.2 α1H subunit being down-regulated and CaV3.1 α1G up-regulated. Synapsin I levels were reduced in the KO hippocampus; cultured neurons displayed a concomitant reduction in synapsin I puncta and decreased miniature excitatory postsynaptic current (mEPSC frequency. In summary, genetic ablation of the calcium channel modulator resulted in compensatory mechanisms to maintain calcium current homeostasis in hippocampal KO neurons; however, synaptic alterations resulted in a reduction of excitatory synapse number, causing an imbalance of the excitatory-inhibitory synaptic input ratio favoring inhibition.

  17. The eIF2a Kinase PERK Limits the Expression of Hippocampal Metabotropic Glutamate Receptor-Dependent Long-Term Depression

    Science.gov (United States)

    Trinh, Mimi A.; Ma, Tao; Kaphzan, Hanoch; Bhattacharya, Aditi; Antion, Marcia D.; Cavener, Douglas R.; Hoeffer, Charles A.; Klann, Eric

    2014-01-01

    The proper regulation of translation is required for the expression of long-lasting synaptic plasticity. A major site of translational control involves the phosphorylation of eukaryotic initiation factor 2 a (eIF2a) by PKR-like endoplasmic reticulum (ER) kinase (PERK). To determine the role of PERK in hippocampal synaptic plasticity, we used the…

  18. Excitation/Inhibition Imbalance and Impaired Synaptic Inhibition in Hippocampal Area CA3 of Mecp2 Knockout Mice

    OpenAIRE

    Calfa, Gaston; Li, Wei; Rutherford, John M.; Pozzo-Miller, Lucas

    2014-01-01

    Rett syndrome (RTT) is a neurodevelopment disorder associated with intellectual disabilities and caused by loss-of-function mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding Protein-2 (MeCP2). Neuronal dysfunction and changes in cortical excitability occur in RTT individuals and Mecp2-deficient mice, including hippocampal network hyperactivity and higher frequency of spontaneous multi-unit spikes in the CA3 cell body layer. Here, we describe impaired synaptic inh...

  19. Altered Morphology of Hippocampal Dentate Granule Cell Presynaptic and Postsynaptic Terminals Following Conditional Deletion of TrkB

    OpenAIRE

    Danzer, Steve C.; Kotloski, Robert J.; Walter, Cynthia; Hughes, Maya; McNamara, James O.

    2008-01-01

    Dentate granule cells play a critical role in the function of the entorhinal-hippocampal circuitry in health and disease. Dentate granule cells are situated to regulate the flow of information into the hippocampus, a structure required for normal learning and memory. Correspondingly, impaired granule cell function leads to memory deficits, and, interestingly, altered granule cell connectivity may contribute to the hyperexcitability of limbic epilepsy. It is important, therefore, to understand...

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

    Directory of Open Access Journals (Sweden)

    Keith Daniel Sudheimer

    2014-07-01

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

  1. White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy

    Science.gov (United States)

    Manning, Emily N.; Bartlett, Jonathan W.; Cash, David M.; Malone, Ian B.; Ridgway, Gerard R.; Lehmann, Manja; Leung, Kelvin K.; Sudre, Carole H.; Ourselin, Sebastien; Biessels, Geert Jan; Carmichael, Owen T.; Fox, Nick C.; Cardoso, M. Jorge; Barnes, Josephine

    2017-01-01

    ABSTRACT This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5‐T MRI. CSF Aβ42 and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:27933676

  2. White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy.

    Science.gov (United States)

    Fiford, Cassidy M; Manning, Emily N; Bartlett, Jonathan W; Cash, David M; Malone, Ian B; Ridgway, Gerard R; Lehmann, Manja; Leung, Kelvin K; Sudre, Carole H; Ourselin, Sebastien; Biessels, Geert Jan; Carmichael, Owen T; Fox, Nick C; Cardoso, M Jorge; Barnes, Josephine

    2017-03-01

    This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial volumetric 1.5-T MRI. CSF Aβ42 and total tau were measured (n = 353). Brain and hippocampal loss were quantified from serial MRI using the boundary shift integral (BSI). Multiple linear regression models assessed the relationships between WMHs and hippocampal and brain atrophy rates. Models were refitted adjusting for (a) concurrent brain/hippocampal atrophy rates and (b) CSF Aβ42 and tau in subjects with CSF data. WMH burden was positively associated with hippocampal atrophy rate in controls (P = 0.002) and MCI subjects (P = 0.03), and with brain atrophy rate in controls (P = 0.03). The associations with hippocampal atrophy rate remained following adjustment for concurrent brain atrophy rate in controls and MCIs, and for CSF biomarkers in controls (P = 0.007). These novel results suggest that vascular damage alongside AD pathology is associated with disproportionately greater hippocampal atrophy in nondemented older adults. © 2016 The Authors Hippocampus Published by Wiley Periodicals, Inc.

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

    Directory of Open Access Journals (Sweden)

    Yi ZHANG

    2014-12-01

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

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

    Directory of Open Access Journals (Sweden)

    David Dupret

    2007-08-01

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

  5. Hippocampal Sclerosis After Febrile Status Epilepticus: The FEBSTAT Study

    Science.gov (United States)

    Lewis, Darrell V.; Shinnar, Shlomo; Hesdorffer, Dale C.; Bagiella, Emilia; Bello, Jacqueline A.; Chan, Stephen; Xu, Yuan; MacFall, James; Gomes, William A.; Moshé, Solomon L.; Mathern, Gary W.; Pellock, John M.; Nordli, Douglas R.; Frank, L. Matthew; Provenzale, James; Shinnar, Ruth C.; Epstein, Leon G.; Masur, David; Litherland, Claire; Sun, Shumei

    2014-01-01

    Objective Whether febrile status epilepticus (FSE) produces hippocampal sclerosis (HS) and temporal lobe epilepsy (TLE) has long been debated. Our objective is to determine if FSE produces acute hippocampal injury that evolves to HS. Methods FEBSTAT and two affiliated studies prospectively recruited 226 children aged 1 month to 6 years with FSE and controls with simple febrile seizures. All had acute MRIs and follow-up MRIs were obtained at approximately 1 year later in the majority. Visual interpretation by two neuroradiologists informed only of subject age was augmented by hippocampal volumetrics, analysis of the intra-hippocampal distribution of T2 signal, and apparent diffusion coefficients. Results Hippocampal T2 hyperintensity, maximum in Sommer's sector, occurred acutely after FSE in 22 of 226 children in association with increased volume. Follow-up MRIs obtained on 14 of the 22 with acute T2 hyperintensity showed HS in 10 and reduced hippocampal volume in 12. In contrast, follow-up of 116 children without acute hyperintensity showed abnormal T2 signal in only 1 (following another episode of FSE). Furthermore, compared to controls with simple febrile seizures, FSE subjects with normal acute MRIs had abnormally low right to left hippocampal volume ratios, smaller hippocampi initially and reduced hippocampal growth. Interpretation Hippocampal T2 hyperintensity after FSE represents acute injury often evolving to a radiological appearance of HS after one year. Furthermore, impaired growth of normal appearing hippocampi after FSE suggests subtle injury even in the absence of T2 hyperintensity. Longer follow-up is needed to determine the relationship of these findings to TLE. PMID:24318290

  6. NMDA receptors and the differential ischemic vulnerability of hippocampal neurons.

    Science.gov (United States)

    Gee, Christine E; Benquet, Pascal; Raineteau, Olivier; Rietschin, Lotty; Kirbach, Sebastian W; Gerber, Urs

    2006-05-01

    Transient cerebral ischemia causes an inhomogeneous pattern of cell death in the brain. We investigated mechanisms, which may underlie the greater susceptibility of hippocampal CA1 vs. CA3 pyramidal cells to ischemic insult. Using an in vitro oxygen-glucose deprivation (OGD) model of ischemia, we found that N-methyl-D-aspartate (NMDA) responses were enhanced in the more susceptible CA1 pyramidal cells and transiently depressed in the resistant CA3 pyramidal cells. The long-lasting potentiation of NMDA responses in CA1 cells was associated with delayed cell death and was prevented by blocking tyrosine kinase-dependent up-regulation of NMDA receptor function. In CA3 cells, the energy deprivation-induced transient depression of NMDA responses was converted to potentiation by blocking protein phosphatase signalling. These results suggest that energy deprivation differentially shifts the intracellular equilibrium between the tyrosine kinase and phosphatase activities that modulate NMDA responses in CA1 and CA3 pyramidal cells. Therapeutic modulation of tyrosine phosphorylation may thus prove beneficial in mitigating ischemia-induced neuronal death in vulnerable brain areas.

  7. Massively augmented hippocampal dentate granule cell activation accompanies epilepsy development

    Science.gov (United States)

    Dengler, Christopher G.; Yue, Cuiyong; Takano, Hajime; Coulter, Douglas A.

    2017-01-01

    In a mouse model of temporal lobe epilepsy, multicellular calcium imaging revealed that disease emergence was accompanied by massive amplification in the normally sparse, afferent stimulation-induced activation of hippocampal dentate granule cells. Patch recordings demonstrated reductions in local inhibitory function within the dentate gyrus at time points where sparse activation was compromised. Mimicking changes in inhibitory synaptic function and transmembrane chloride regulation was sufficient to elicit the dentate gyrus circuit collapse evident during epilepsy development. Pharmacological blockade of outward chloride transport had no effect during epilepsy development, and significantly increased granule cell activation in both control and chronically epileptic animals. This apparent occlusion effect implicates reduction in chloride extrusion as a mechanism contributing to granule cell hyperactivation specifically during early epilepsy development. Glutamine plays a significant role in local synthesis of GABA in synapses. In epileptic mice, sparse granule cell activation could be restored by glutamine application, implicating compromised GABA synthesis. Glutamine had no effect on granule cell activation earlier, during epilepsy development. We conclude that compromised feedforward inhibition within the local circuit generates the massive dentate gyrus circuit hyperactivation evident in animals during and following epilepsy development. However, the mechanisms underlying this disinhibition diverge significantly as epilepsy progresses. PMID:28218241

  8. Retinoids and glucocorticoids target common genes in hippocampal HT22 cells.

    Science.gov (United States)

    Brossaud, Julie; Roumes, Hélène; Moisan, Marie-Pierre; Pallet, Véronique; Redonnet, Anabelle; Corcuff, Jean-Benoît

    2013-05-01

    Vitamin A metabolite retinoic acid (RA) plays a major role in the aging adult brain plasticity. Conversely, chronic excess of glucocorticoids (GC) elicits some deleterious effects in the hippocampus. We questioned here the involvement of RA and GC in the expression of target proteins in hippocampal neurons. We investigated proteins involved either in the signaling pathways [RA receptor β (RARβ) and glucocorticoid receptor (GR)] or in neuron differentiation and plasticity [tissue transglutaminase 2 (tTG) and brain-derived neurotrophic factor (BDNF)] in a hippocampal cell line, HT22. We applied RA and/or dexamethasone (Dex) as activators of the pathways and investigated mRNA and protein expression of their receptors and of tTG and BDNF as well as tTG activity and BDNF secretion. Our results confirm the involvement of RA- and GC-dependent pathways and their interaction in our neuronal cell model. First, both pathways regulate the transcription and expression of own and reciprocal receptors: RA and Dex increased RARβ and decreased GR expressions. Second, Dex reduces the expression of tTG when associated with RA despite stimulating its expression when used alone. Importantly, when they are combined, RA counteracts the deleterious effect of glucocorticoids on BDNF regulation and thus may improve neuronal plasticity under stress conditions. In conclusion, GC and RA both interact through regulations of the two receptors, RARβ and GR. Furthermore, they both act, synergistically or oppositely, on other target proteins critical for neuronal plasticity, tTG and BDNF.

  9. Effects of valproate sodium on extracellular signal-regulated kinase 1/2 phosphorylation after hippocampal neuronal epileptiform discharge in rats%丙戊酸钠对大鼠海马神经元癫痫样放电后细胞外信号调节激酶磷酸化水平的影响

    Institute of Scientific and Technical Information of China (English)

    徐祖才; 王学峰; 雷显泽; 徐忠祥; 徐平

    2012-01-01

    目的 细胞外信号调节激酶(extracellular signal-regulated kinase 1/2,ERK1/2)参与癫痫的发生,但其与抗癫痫药物之间的关系不明确,文中旨在观察丙戊酸钠对大鼠海马神经元癫痫样放电后磷酸化ERK1/2(p-ERK1/2)的影响.方法 取24h内新生Wistar大鼠,雌雄不拘,迅速断头取脑.建立神经元癫痫样放电模型,将神经元分为空白对照组和丙戊酸钠组,量效实验中,于神经元癫痫样放电前30min时加入不同浓度的丙戊酸钠(50mg/L、75mg/L、100mg/L),运用免疫荧光技术测定p-ERK1/2在不同浓度时的表达;时效实验中,分别于癫痫样放电前30min,放电后0min、30min、2h和6h加入50mg/L丙戊酸钠,采用 Wester blot观察p-ERK1/2的变化.结果 量效实验中,不同浓度的丙戊酸钠均能降低ERK1/2的磷酸化水平,且无显著性差异.时效实验中,于放电前30min时加入丙戊酸钠对ERK1/2的磷酸化水平抑制最明显,与以后各时间点间都有显著性差异.结论 海马神经元癫痫样放电后ERK1/2被过度持久的激活,在早期小剂量有效浓度的丙戊酸钠能显著抑制此反应中ERK1/2的磷酸化水平.%Objective Extracellular signal-regulated kinase l/2(ERKl/2) plays a role in the occurrence of epilepsy , but the mechanism of the involvement of ERK1/2 and its association with antiepileptic drugs remain unclear . The aim of this study is to investi -gate the effects of valproate sodium on ERK 1/2 phosphorylation (p-ERKl/2) after hippocampal neuronal epileptiform discharge in rats. Methods The epileptiform discharge model of the neuron was established in female and male neonate Wistar rats by rapid de -capitation. The neurons were divided into a blank control and a valproate sodium group , the latter incubated with valproate sodium at 50, 75 and 100 mg/L 30 min before epileptiform discharge in the concentration response experiment, and the expression of p-ERKl/2 at different concentrations detected using

  10. Research on Effect of α-secretase on Regulating Hippocampal APP and Aβ42 in APP/PS1 Transgenic Mice of Alzheimer’s disease after Voluntary Wheel Running%α-分泌酶在自主运动调节APP/PS1转基因小鼠海马APP与Aβ42中的作用研究

    Institute of Scientific and Technical Information of China (English)

    余锋; 徐波; 季浏

    2016-01-01

    目的:探讨α-分泌酶在16周自主跑轮运动调节 APP/PS1转基因小鼠海马 APP水解与Aβ42生成中的作用。方法:24只C57系 APP/PS1转基因小鼠,随机分为自主跑轮运动组(TE ,n=12)和对照组(TC ,n=12);同时选取C57系野生型小鼠24只,随机分为自主跑轮运动组(E ,n=12)和对照组(C ,n=12)。 TE组和 E组小鼠从3月龄开始,除给予正常饮食、饮水外,给予16周的自主跑轮运动,TC组和C组小鼠给予正常饮食、饮水,不运动。采用实时荧光定量RT-PCR实验检测各组小鼠海马α-分泌酶家族的3种主要成员ADAM 9、ADAM10和 ADAM17 mRNA表达水平,采用Western Blot实验检测各组小鼠海马 APP、AD-AM 10和 Aβ42蛋白表达水平。结果:1)16周的自主跑轮运动极显著性上调了 APP/PS1转基因小鼠海马 ADAM 10 mRNA表达水平( P<0.01),同时显著性上调了转基因小鼠海马ADAM10蛋白表达水平(P<0.05);2)16周的自主跑轮运动显著上调了 APP/PS1转基因小鼠海马 ADAM17 mRNA 表达水平(P<0.05);3)16周的自主跑轮运动显著性下调了APP/PS1转基因小鼠海马APP ( P<0.05)和Aβ42( P<0.05)的蛋白表达水平。结论:16周的自主跑轮运动可通过促进APP/PS1转基因小鼠海马α-分泌酶基因表达进而降低转基因小鼠海马 APP的水平,并抑制 APP水解产生Aβ42的水平。%Objective :To observe the effect of α-secretase on the hippocampal APP cleaving and Aβ42 deposition in transgenic mice of Alzheimer ’ s disease (AD ) after 16 weeks voluntary wheel running .Methods :24 male APP/PS1 transgenic mice of line C57 that expresses human mutant APP and PS1 in the brain were chosen and divided into wheel running group (TE ,n=12) and control group (TC ,n= 12) .Meanwhile ,24 male wild-type mice in line C57 were chose and divided into wheel running group (E ,n= 12) and control group (C ,n

  11. Hippocampal neurogenesis enhancers promote forgetting of remote fear memory after hippocampal reactivation by retrieval

    Science.gov (United States)

    Ishikawa, Rie; Fukushima, Hotaka; Frankland, Paul W; Kida, Satoshi

    2016-01-01

    Forgetting of recent fear memory is promoted by treatment with memantine (MEM), which increases hippocampal neurogenesis. The approaches for treatment of post-traumatic stress disorder (PTSD) using rodent models have focused on the extinction and reconsolidation of recent, but not remote, memories. Here we show that, following prolonged re-exposure to the conditioning context, enhancers of hippocampal neurogenesis, including MEM, promote forgetting of remote contextual fear memory. However, these interventions are ineffective following shorter re-exposures. Importantly, we find that long, but not short re-exposures activate gene expression in the hippocampus and induce hippocampus-dependent reconsolidation of remote contextual fear memory. Furthermore, remote memory retrieval becomes hippocampus-dependent after the long-time recall, suggesting that remote fear memory returns to a hippocampus dependent state after the long-time recall, thereby allowing enhanced forgetting by increased hippocampal neurogenesis. Forgetting of traumatic memory may contribute to the development of PTSD treatment. DOI: http://dx.doi.org/10.7554/eLife.17464.001 PMID:27669409

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

    Science.gov (United States)

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

    2016-12-01

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

  13. Folate deprivation modulates the expression of autophagy- and circadian-related genes in HT-22 hippocampal neuron cells through GR-mediated pathway.

    Science.gov (United States)

    Sun, Qinwei; Yang, Yang; Li, Xi; He, Bin; Jia, Yimin; Zhang, Nana; Zhao, Ruqian

    2016-08-01

    Folic acid (FA) is an extremely important nutrient for brain formation and development. FA deficiency is highly linked to brain degeneration and age-related diseases, which are also associated with autophagic activities and circadian rhythm in hippocampal neurons. However, little is known how autophagy- and circadian-related genes in hippocampal neurons are regulated under FA deficiency. Here, hippocampal neuroncells (HT-22) were employed to determine the effect of FA deprivation (FD) on the expression of relevant genes and to reveal the potential role of glucocorticoid receptor (GR). FD increased autophagic activities in HT-22 cells, associated with significantly (PGR activation indicated by higher ratio of GR phosphorylation. Out of 17 autophagy-related genes determined, 8 was significantly (PGR binding to the promoter sequence of ATG3 and Per2. Moreover, MeDIP analysis demonstrated significant (PGR-mediated pathway. Our results provide a basis for future investigations into the intracellular regulatory network in response to folate deficiency.

  14. Spatial relational memory requires hippocampal adult neurogenesis.

    Directory of Open Access Journals (Sweden)

    David Dupret

    Full Text Available The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.

  15. Staining protocol for organotypic hippocampal slice cultures.

    Science.gov (United States)

    Gogolla, Nadine; Galimberti, Ivan; DePaola, Vincenzo; Caroni, Pico

    2006-01-01

    This protocol details a method to immunostain organotypic slice cultures from mouse hippocampus. The cultures are based on the interface method, which does not require special equipment, is easy to execute and yields slice cultures that can be imaged repeatedly, from the time of isolation at postnatal day 6-9 up to 6 months in vitro. The preserved tissue architecture facilitates the analysis of defined hippocampal synapses, cells and entire projections. Time-lapse imaging is based on transgenes expressed in the mice or on constructs introduced through transfection or viral vectors; it can reveal processes that develop over periods ranging from seconds to months. Subsequent to imaging, the slices can be processed for immunocytochemistry to collect further information about the imaged structures. This protocol can be completed in 3 d.

  16. Cocaine depresses GABAA current of hippocampal neurons.

    Science.gov (United States)

    Ye, J H; Liu, P L; Wu, W H; McArdle, J J

    1997-10-01

    Although blockade of dopamine re-uptake and the resulting elevation of excitatory agonists is commonly thought the primary mechanism of cocaine-induced seizures, it is possible that other neurotransmitters such as gamma-aminobutyric acid (GABA) are involved. To examine this possibility, the effects of cocaine on the whole cell GABA current (IGABA) of freshly isolated rat hippocampal neurons were investigated with the patch-clamp technique. Preincubation or acute application of cocaine reversibly suppressed IGABA. The IC50 was 127 microM when cocaine was applied before the application of GABA. The concentration-response relations of cocaine in various GABA concentrations revealed that cocaine inhibited IGABA non-competitively. This effect of cocaine appeared to be independent of voltage. The present study suggests that the GABA receptor/channel complex is also a target for cocaine's action. The suppression of IGABA may contribute to cocaine-induced seizures.

  17. Role of hippocampal β-adrenergic and glucocorticoid receptors in the novelty-induced enhancement of fear extinction.

    Science.gov (United States)

    Liu, Jian-Feng; Yang, Chang; Deng, Jia-Hui; Yan, Wei; Wang, Hui-Min; Luo, Yi-Xiao; Shi, Hai-Shui; Meng, Shi-Qiu; Chai, Bai-Sheng; Fang, Qin; Chai, Ning; Xue, Yan-Xue; Sun, Jia; Chen, Chen; Wang, Xue-Yi; Wang, Ji-Shi; Lu, Lin

    2015-05-27

    Fear extinction forms a new memory but does not erase the original fear memory. Exposure to novelty facilitates transfer of short-term extinction memory to long-lasting memory. However, the underlying cellular and molecular mechanisms are still unclear. Using a classical contextual fear-conditioning model, we investigated the effect of novelty on long-lasting extinction memory in rats. We found that exposure to a novel environment but not familiar environment 1 h before or after extinction enhanced extinction long-term memory (LTM) and reduced fear reinstatement. However, exploring novelty 6 h before or after extinction had no such effect. Infusion of the β-adrenergic receptor (βAR) inhibitor propranolol and glucocorticoid receptor (GR) inhibitor RU486 into the CA1 area of the dorsal hippocampus before novelty exposure blocked the effect of novelty on extinction memory. Propranolol prevented activation of the hippocampal PKA-CREB pathway, and RU486 prevented activation of the hippocampal extracellular signal-regulated kinase 1/2 (Erk1/2)-CREB pathway induced by novelty exposure. These results indicate that the hippocampal βAR-PKA-CREB and GR-Erk1/2-CREB pathways mediate the extinction-enhancing effect of novelty exposure. Infusion of RU486 or the Erk1/2 inhibitor U0126, but not propranolol or the PKA inhibitor Rp-cAMPS, into the CA1 before extinction disrupted the formation of extinction LTM, suggesting that hippocampal GR and Erk1/2 but not βAR or PKA play critical roles in this process. These results indicate that novelty promotes extinction memory via hippocampal βAR- and GR-dependent pathways, and Erk1/2 may serve as a behavioral tag of extinction.

  18. GSK-3β Overexpression Alters the Dendritic Spines of Developmentally Generated Granule Neurons in the Mouse Hippocampal Dentate Gyrus

    Science.gov (United States)

    Pallas-Bazarra, Noemí; Kastanauskaite, Asta; Avila, Jesús; DeFelipe, Javier; Llorens-Martín, María

    2017-01-01

    The dentate gyrus (DG) plays a crucial role in hippocampal-related memory. The most abundant cellular type in the DG, namely granule neurons, are developmentally generated around postnatal day P6 in mice. Moreover, a unique feature of the DG is the occurrence of adult hippocampal neurogenesis, a process that gives rise to newborn granule neurons throughout life. Adult-born and developmentally generated granule neurons share some maturational aspects but differ in others, such as in their positioning within the granule cell layer. Adult hippocampal neurogenesis encompasses a series of plastic changes that modify the function of the hippocampal trisynaptic network. In this regard, it is known that glycogen synthase kinase 3β (GSK-3β) regulates both synaptic plasticity and memory. By using a transgenic mouse overexpressing GSK-3β in hippocampal neurons, we previously demonstrated that the overexpression of this kinase has deleterious effects on the maturation of newborn granule neurons. In the present study, we addressed the effects of GSK-3β overexpression on the morphology and number of dendritic spines of developmentally generated granule neurons. To this end, we performed intracellular injections of Lucifer Yellow in developmentally generated granule neurons of wild-type and GSK-3β-overexpressing mice and analyzed the number and morphologies of dendritic spines (namely, stubby, thin and mushroom). GSK-3β overexpression led to a general reduction in the number of dendritic spines. In addition, it caused a slight reduction in the percentage, head diameter and length of thin spines, whereas the head diameter of mushroom spines was increased. PMID:28344548

  19. Different susceptibility to neurodegeneration of dorsal and ventral hippocampal dentate gyrus: a study with transgenic mice overexpressing GSK3β.

    Directory of Open Access Journals (Sweden)

    Almudena Fuster-Matanzo

    Full Text Available Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light-dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.

  20. An examination of early neural and cognitive alterations in hippocampal-spatial function of ghrelin receptor-deficient rats.

    Science.gov (United States)

    Cahill, Shaina P; Hatchard, Taylor; Abizaid, Alfonso; Holahan, Matthew R

    2014-05-01

    Ghrelin, a hormone implicated in the regulation of feeding and energy balance, has also been associated with neural function underlying learning and memory. These effects are thought to be mediated by ghrelin targeting receptors at extra hypothalamic sites such as the hippocampus. Exogenous ghrelin administration increases dendritic spine density in the hippocampal CA1 region and neurogenesis in the dentate gyrus (DG), while improving memory in rats. In the present study, we sought to determine whether rats lacking the ghrelin receptor would show early neural or cognitive decline measured via hippocampal integrity (spine density and neurogenesis) and spatial learning and memory. As such, we used young and middle-aged adult rats with mutations to the gene encoding for the ghrelin receptor (GHS-R KO) and wildtype (WT) littermates to determine differences in performance on hippocampal-dependent tasks (the water maze and radial arm maze). In addition, we examined the hippocampal dentate gyrus of these rats for differences in dendritic spine density and cell proliferation (doublecortin). Overall, results demonstrated that spine density and doublecortin staining in the dentate gyrus of the young GHS-R KO group was similar to that seen in middle-aged groups (both KO and WT) and lower than the young WT group. Middle-aged GHS-R KO and WT groups showed deficits on the radial arm maze food-motivated task but not the water maze task. These data suggest that impaired ghrelin signaling leads to an early onset decrement in hippocampal structural integrity that may manifest in non- spatial-related behavioral deficits.

  1. Hippocampal sharp waves: their origin and significance.

    Science.gov (United States)

    Buzsáki, G

    1986-11-29

    This study investigated the spatial distribution and cellular-synaptic generation of hippocampal sharp waves (SPW) in the dorsal hippocampus of the awake rat. Depth analyses of SPWs were performed by stepping the recording electrode in 82.5 microns increments. SPWs were present during slow wave sleep, awake immobility, drinking, grooming and eating (0.01-2/s). The largest negative SPWs were recorded from the middle part of the stratum radiatum of CA1, the stratum lucidum of CA3, the inner molecular layer of the dentate gyrus and from layer I of the subiculum, in that order. The polarity of the SPWs was positive in layers II-IV of the subiculum, in stratum oriens and stratum pyramidale of CA1 and CA3, and in the hilus of the dentate gyrus. The electrical gradients across the null zones of the field SPWs were as large as 8-14 mV/mm. SPWs were associated with population bursts of pyramidal cells and increased discharges of interneurons and granule cells. During the SPW the excitability of granule cells and pyramidal cells to afferent volleys increased considerably. Picrotoxin and atropine and aspiration lesion of the fimbria-fornix increased either the amplitude or the frequency of SPWs. Diazepam and Nembutal could completely abolish SPWs. It is suggested that: hippocampal SPWs are triggered by a population burst of CA3 pyramidal cells as a result of temporary disinhibition from afferent control; and field SPWs represent summed extracellular PSPs of CA1 and subicular pyramidal cells, and dentate granular cells induced by the Schaffer collaterals and the associational fibers of hilar cells, respectively. The relevance of the physiological SPWs to epileptic interictal spikes and long-term potentiation is discussed.

  2. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice.

    Science.gov (United States)

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-08-04

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell-cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.

  3. Global changes in the hippocampal proteome following exposure to an enriched environment.

    Science.gov (United States)

    McNair, K; Broad, J; Riedel, G; Davies, C H; Cobb, S R

    2007-03-16

    Exposure to an enriched environment promotes neurochemical, structural and neurophysiological changes in the brain and is associated with enhanced synaptic plasticity and improved hippocampal-dependent learning. Using a global proteomics-based approach we have now been able to reveal the altered expression of a diverse range of hippocampal proteins following exposure to an enriched environment. Male Hooded Lister rats (8 weeks) were subjected to a 6-week regimen in which they were housed in either non-enriched (open field) or enriched conditions (toys, wheels etc.). Whole protein extracts from stratum pyramidale and stratum radiatum of area CA1 were then isolated and subjected to differential gel electrophoresis [McNair K, Davies CH, Cobb SR (2006) Plasticity-related regulation of the hippocampal proteome. Eur J Neurosci 23(2):575-580]. Of the 2469 resolvable protein spots detected in this study, 42 spots (1.7% of the detectable proteome) derived from predominantly somatic fractions and 32 proteins spots from dendritic fractions (1.3% of detectable proteome) were significantly altered in abundance following exposure to an enriched environment (somatic: 14 increased/28 decreased abundance, range -1.5 to +1.4-fold change; dendritic: 16 increased, 16 decreased abundance, range -1.6 to +3.0-fold change). Following in-gel tryptic digestion and Maldi-Tof/Q-star mass spectrometry, database searching revealed the identity of 50 protein spots displaying environmental enrichment-related modulation of expression. Identified proteins belonged to a variety of functional classes with gene ontology analysis revealing the majority (>70%) of regulated proteins to be part of the energy metabolism, cytoplasmic organization/biogenesis and signal transduction processes.

  4. Converging action of alcohol consumption and cannabinoid receptor activation on adult hippocampal neurogenesis.

    Science.gov (United States)

    Alén, Francisco; Mouret, Aurélie; Viveros, Maria-Paz; Llorente, Ricardo; Lepousez, Gabriel; Lledo, Pierre-Marie; López-Moreno, José Antonio

    2010-03-01

    Alcoholism is characterized by successive periods of abstinence and relapse, resulting from long-lasting changes in various circuits of the central nervous system. Accumulating evidence points to the endocannabinoid system as one of the most relevant biochemical systems mediating alcohol addiction. The endocannabinoid system regulates adult neurogenesis, a form of long-lasting adult plasticity that occurs in a few areas of the brain, including the dentate gyrus. Because exposure to psychotropic drugs regulates adult neurogenesis, it is possible that neurogenesis might be implicated in the pathophysiology, and hence treatment, of neurobiological illnesses related to drugs of abuse. Here, we investigated the sensitivity of adult hippocampal neurogenesis to alcohol and the cannabinoid receptor agonist WIN 55,212-2 (WIN). Specifically, we analysed the potential link between alcohol relapse, cannabinoid receptor activation, and adult neurogenesis. Adult rats were exposed to subchronic alcohol binge intoxication and received the cannabinoid receptor agonist WIN. Another group of rats were subjected to an alcohol operant self-administration task. Half of these latter animals had continuous access to alcohol, while the other half were subjected to alcohol deprivation, with or without WIN administration. WIN treatment, when administered during alcohol deprivation, resulted in the greatest increase in alcohol consumption during relapse. Together, forced alcohol binge intoxication and WIN administration dramatically reduced hippocampal neurogenesis. Furthermore, adult neurogenesis inversely correlated with voluntary consumption of alcohol. These findings suggest that adult hippocampal neurogenesis is a key factor involved in drug abuse and that it may provide a new strategy for the treatment of alcohol addiction and dependence.

  5. Neurotoxicity of perfluorooctane sulfonate to hippocampal cells in adult mice.

    Directory of Open Access Journals (Sweden)

    Yan Long

    Full Text Available Perfluorooctane sulfonate (PFOS is a ubiquitous pollutant and found in the environment and in biota. The neurotoxicity of PFOS has received much concern among its various toxic effects when given during developing period of brain. However, little is known about the neurotoxic effects and potential mechanisms of PFOS in the mature brain. Our study demonstrated the neurotoxicity and the potential mechanisms of PFOS in the hippocampus of adult mice for the first time. The impairments of spatial learning and memory were observed by water maze studies after exposure to PFOS for three months. Significant apoptosis was found in hippocampal cells after PFOS exposure, accompanied with a increase of glutamate in the hippocampus and decreases of dopamine (DA and 3,4-dihydrophenylacetic acid (DOPAC in Caudate Putamen in the 10.75 mg/kg PFOS group. By two-dimensional fluorescence difference in gel electrophoresis (2D-DIGE analysis, seven related proteins in the hippocampus that responded to PFOS exposure were identified, among which, Mib1 protein (an E3 ubiquitin-protein ligase, Herc5 (hect domain and RLD 5 isoform 2 and Tyro3 (TYRO3 protein tyrosine kinase 3 were found down-regulated, while Sdha (Succinate dehydrogenase flavoprotein subunit, Gzma (Isoform HF1 of Granzyme A precursor, Plau (Urokinase-type plasminogen activator precursor and Lig4 (DNA ligase 4 were found up-regulated in the 10.75 mg/kg PFOS-treated group compare with control group. Furthermore, we also found that (i increased expression of caspase-3 protein and decreased expression of Bcl-2, Bcl-XL and survivin proteins, (ii the increased glutamate release in the hippocampus. All these might contribute to the dysfunction of hippocampus which finally account for the impairments of spatial learning and memory in adult mice.

  6. DEVELOPMENTAL LEAD (PB) CHANGES AND IN HIPPOCAMPAL FUNCTION.

    Science.gov (United States)

    Childhood lead (Pb) exposure has long been associated with reduced IQ, impaired cognitive function, and more recently increases in violence and aggression. We have studied the disruptive effects of developmental Pb exposure on an electrophysiological model of memory, hippocampal...

  7. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

    Science.gov (United States)

    Geil, Chelsea R; Hayes, Dayna M; McClain, Justin A; Liput, Daniel J; Marshall, S Alex; Chen, Kevin Y; Nixon, Kimberly

    2014-10-03

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology. Alcohol is a pharmacologically promiscuous drug capable of interfering with adult neurogenesis through multiple mechanisms. This review will discuss the primary mechanisms underlying alcohol-induced changes in adult hippocampal neurogenesis including alcohol's effects on neurotransmitters, CREB and its downstream effectors, and the neurogenic niche.

  8. Segmentation of the mouse hippocampal formation in magnetic resonance images.

    Science.gov (United States)

    Richards, Kay; Watson, Charles; Buckley, Rachel F; Kurniawan, Nyoman D; Yang, Zhengyi; Keller, Marianne D; Beare, Richard; Bartlett, Perry F; Egan, Gary F; Galloway, Graham J; Paxinos, George; Petrou, Steven; Reutens, David C

    2011-10-01

    The hippocampal formation plays an important role in cognition, spatial navigation, learning, and memory. High resolution magnetic resonance (MR) imaging makes it possible to study in vivo changes in the hippocampus over time and is useful for comparing hippocampal volume and structure in wild type and mutant mice. Such comparisons demand a reliable way to segment the hippocampal formation. We have developed a method for the systematic segmentation of the hippocampal formation using the perfusion-fixed C57BL/6 mouse brain for application in longitudinal and comparative studies. Our aim was to develop a guide for segmenting over 40 structures in an adult mouse brain using 30 μm isotropic resolution images acquired with a 16.4 T MR imaging system and combined using super-resolution reconstruction.

  9. White matter hyperintensities are associated with disproportionate progressive hippocampal atrophy

    NARCIS (Netherlands)

    Fiford, Cassidy M.; Manning, Emily N.; Bartlett, Jonathan W.; Cash, David M.; Malone, Ian B.; Ridgway, Gerard R.; Lehmann, Manja; Leung, Kelvin K.; Sudre, Carole H.; Ourselin, Sebastien; Biessels, Geert Jan; Carmichael, Owen T.; Fox, Nick C.; Cardoso, M. Jorge; Barnes, Josephine

    This study investigates relationships between white matter hyperintensity (WMH) volume, cerebrospinal fluid (CSF) Alzheimer's disease (AD) pathology markers, and brain and hippocampal volume loss. Subjects included 198 controls, 345 mild cognitive impairment (MCI), and 154 AD subjects with serial

  10. Rhinal-hippocampal EEG coherence is reduced during human sleep.

    NARCIS (Netherlands)

    Fell, J.; Staedtgen, M.; Burr, W.; Kockelmann, E.; Helmstaedter, C.; Schaller, C.; Elger, C.E.; Fernandez, G.S.E.

    2003-01-01

    The deficiency of declarative memory compared with waking state is an often overlooked characteristic of sleep. Here, we investigated whether rhinal-hippocampal coherence, an electrophysiological correlate of declarative memory formation, is significantly altered during sleep as compared with waking

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2015-05-01

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

  12. Alcohol and adult hippocampal neurogenesis: Promiscuous drug, wanton effects

    OpenAIRE

    Geil, Chelsea R.; Hayes, Dayna M.; McClain, Justin A.; Liput, Daniel J.; Marshall, S. Alex; Chen, Kevin Y.; Nixon, Kimberly

    2014-01-01

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may...

  13. Hippocampal Theta Dysfunction after Lateral Fluid Percussion Injury

    OpenAIRE

    2010-01-01

    Chronic memory deficits are a major cause of morbidity following traumatic brain injury (TBI). In the rat, the hippocampal theta rhythm is a well-studied correlate of memory function. This study sought to investigate disturbances in hippocampal theta rhythm following lateral fluid percussion injury in the rat. A total of 13 control rats and 12 TBI rats were used. Electrodes were implanted in bilateral hippocampi and an electroencephalogram (EEG) was recorded while the rats explored a new envi...

  14. Adult hippocampal neurogenesis of mammals: evolution and life history

    OpenAIRE

    Amrein, I.; Lipp, H. P.

    2009-01-01

    Substantial production of new neurons in the adult mammalian brain is restricted to the olfactory system and the hippocampal formation. Its physiological and behavioural role is still debated. By comparing adult hippocampal neurogenesis (AHN) across many mammalian species, one might recognize a common function. AHN is most prominent in rodents, but shows considerable variability across species, being lowest or missing in primates and bats. The latter finding argues against a critical role of ...

  15. The hippocampal response to psychosocial stress varies with salivary uric acid level.

    Science.gov (United States)

    Goodman, Adam M; Wheelock, Muriah D; Harnett, Nathaniel G; Mrug, Sylvie; Granger, Douglas A; Knight, David C

    2016-12-17

    Uric acid is a naturally occurring, endogenous compound that impacts mental health. In particular, uric acid levels are associated with emotion-related psychopathology (e.g., anxiety and depression). Therefore, understanding uric acid's impact on the brain would provide valuable new knowledge regarding neural mechanisms that mediate the relationship between uric acid and mental health. Brain regions including the prefrontal cortex, amygdala, and hippocampus underlie stress reactivity and emotion regulation. Thus, uric acid may impact emotion by modifying the function of these brain regions. The present study used functional magnetic resonance imaging (fMRI) during a psychosocial stress task to investigate the relationship between baseline uric acid levels (in saliva) and brain function. Results demonstrate that activity within the bilateral hippocampal complex varied with uric acid concentrations. Specifically, activity within the hippocampus and surrounding cortex increased as a function of uric acid level. The current findings suggest that uric acid levels modulate stress-related hippocampal activity. Given that the hippocampus has been implicated in emotion regulation during psychosocial stress, the present findings offer a potential mechanism by which uric acid impacts mental health. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  16. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance.

    Science.gov (United States)

    McNay, Ewan C; Ong, Cecilia T; McCrimmon, Rory J; Cresswell, James; Bogan, Jonathan S; Sherwin, Robert S

    2010-05-01

    Insulin regulates glucose uptake and storage in peripheral tissues, and has been shown to act within the hypothalamus to acutely regulate food intake and metabolism. The machinery for transduction of insulin signaling is also present in other brain areas, particularly in the hippocampus, but a physiological role for brain insulin outside the hypothalamus has not been established. Recent studies suggest that insulin may be able to modulate cognitive functions including memory. Here we report that local delivery of insulin to the rat hippocampus enhances spatial memory, in a PI-3-kinase dependent manner, and that intrahippocampal insulin also increases local glycolytic metabolism. Selective blockade of endogenous intrahippocampal insulin signaling impairs memory performance. Further, a rodent model of type 2 diabetes mellitus produced by a high-fat diet impairs basal cognitive function and attenuates both cognitive and metabolic responses to hippocampal insulin administration. Our data demonstrate that insulin is required for optimal hippocampal memory processing. Insulin resistance within the telencephalon may underlie the cognitive deficits commonly reported to accompany type 2 diabetes.

  17. Alpha-bungarotoxin binding to hippocampal interneurons: immunocytochemical characterization and effects on growth factor expression.

    Science.gov (United States)

    Freedman, R; Wetmore, C; Strömberg, I; Leonard, S; Olson, L

    1993-05-01

    The nicotinic cholinergic antagonist alpha-bungarotoxin (alpha-BT) binds throughout the rat hippocampal formation. The binding is displaceable by d-tubocurarine. The most heavily labeled cells are GABA-containing interneurons in the dentate and in Ammon's horn. These neurons have several different morphologies and contain several neuropeptides. alpha-BT-labeled interneurons in the dentate are small cells between the granular and molecular layers that often contain neuropeptide Y. alpha-BT-labeled interneurons in CA1 are medium-sized interneurons, occasionally found in stratum pyramidale, but more often found in stratum radiatum and stratum lacunosum moleculare. These neurons often contain cholecystokinin. The largest alpha-BT-labeled interneurons are found in CA3, in both stratum radiatum and stratum lucidum. These neurons are multipolar and frequently are autofluorescent. They often contain somatostatin or cholecystokinin. These large interneurons have been found to receive medial septal innervation and may also have projections that provide inhibitory feedback directly to the medial septal nucleus. The cholinergic innervation of the hippocampus from the medial septal nucleus is under the trophic regulation of NGF and brain-derived neurotrophic factor, even in adult life. Expression of mRNA for both these factors is increased in CA3 and the dentate after intraventricular administration of alpha-BT, but not after administration of the muscarinic antagonist atropine. alpha-BT-sensitive cholinergic receptors on inhibitory interneurons may be critical to medial septal regulation of the hippocampal activity, including the habituation of response to sensory input.

  18. EEA1 restores homeostatic synaptic plasticity in hippocampal neurons from Rett syndrome mice.

    Science.gov (United States)

    Xu, Xin; Pozzo-Miller, Lucas

    2017-08-15

    Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Mecp2 deletion in mice results in an imbalance of excitation and inhibition in hippocampal neurons, which affects 'Hebbian' synaptic plasticity. We show that Mecp2-deficient neurons also lack homeostatic synaptic plasticity, likely due to reduced levels of EEA1, a protein involved in AMPA receptor endocytosis. Expression of EEA1 restored homeostatic synaptic plasticity in Mecp2-deficient neurons, providing novel targets of intervention in Rett syndrome. Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in MECP2, the gene encoding the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2). Deletion of Mecp2 in mice results in an imbalance of synaptic excitation and inhibition in hippocampal pyramidal neurons, which affects 'Hebbian' long-term synaptic plasticity. Since the excitatory-inhibitory balance is maintained by homeostatic mechanisms, we examined the role of MeCP2 in homeostatic synaptic plasticity (HSP) at excitatory synapses. Negative feedback HSP, also known as synaptic scaling, maintains the global synaptic strength of individual neurons in response to sustained alterations in neuronal activity. Hippocampal neurons from Mecp2 knockout (KO) mice do not show the characteristic homeostatic scaling up of the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and of synaptic levels of the GluA1 subunit of AMPA-type glutamate receptors after 48 h silencing with the Na(+) channel blocker tetrodotoxin. This deficit in HSP is bidirectional because Mecp2 KO neurons also failed to scale down mEPSC amplitudes and GluA1 synaptic levels after 48 h blockade of type A GABA receptor (GABAA R)-mediated inhibition with bicuculline. Consistent with the role of synaptic trafficking of AMPA-type of glutamate receptors in HSP, Mecp2 KO neurons

  19. Hippocampal sclerosis in dementia, epilepsy, and ischemic injury: differential vulnerability of hippocampal subfields.

    Science.gov (United States)

    Hatanpaa, Kimmo J; Raisanen, Jack M; Herndon, Emily; Burns, Dennis K; Foong, Chan; Habib, Amyn A; White, Charles L

    2014-02-01

    Severe neuronal loss in the hippocampus, that is, hippocampal sclerosis (HS), can be seen in 3 main clinical contexts: dementia (particularly frontotemporal lobar degeneration [FTLD]), temporal lobe epilepsy (TLE), and hippocampal ischemic injury (H-I). It has been suggested that shared pathogenetic mechanisms may underlie selective vulnerability of the hippocampal subfields such as the CA1 in these conditions. We determined the extent of neuronal loss in cases of HS-FTLD (n=14), HS-TLE (n=35), and H-I (n=20). Immunohistochemistry for zinc transporter 3 was used to help define the CA3/CA2 border in the routinely processed human autopsy tissue samples. The subiculum was involved in 57% of HS-FTLD, 10% of H-I, and 0% of HS-TLE cases (p<0.0001). The CA regions other than CA1 were involved in 57% of HS-TLE, 30% of H-I, and 0% of HS-FTLD cases (p=0.0003). The distal third of CA1 was involved in 79% of HS-FTLD, 35% of H-I, and 37% of HS-TLE cases (p=0.02). The distal third of CA1 was the only area involved in 29% of HS-FTLD, 3% of HS-TLE, and 0% of H-I cases (p=0.019). The proximal-middle CA1 was the only area affected in 50% of H-I, 29% of HS-TLE, and 0% of HS-FTLD cases (p=0.004). These findings support heterogeneity in the pathogenesis of HS.

  20. HIPPOCAMPAL SCLEROSIS, HIPPOCAMPAL NEURON LOSS PATTERNS AND TDP-43 IN THE AGED POPULATION.

    Science.gov (United States)

    Hokkanen, Suvi R K; Hunter, Sally; Polvikoski, Tuomo M; Keage, Hannah A D; Minett, Thais; Matthews, Fiona E; Brayne, Carol

    2017-08-18

    Hippocampal neuron loss is a common neuropathological feature in old age with various underlying aetiologies. Hippocampal sclerosis of aging (HS-Aging) is neuropathologically characterized by severe CA1 neuronal loss and frequent presence of transactive response DNA-binding protein of 43kDa (TDP-43) aggregations. Its aetiology is unclear and currently no standardized approaches to measure HS-Aging exist. We developed a semi-quantitative protocol, which captures various hippocampal neuron loss patterns, and compared their occurrence in the context of HS-Aging, TDP-43, vascular and tau pathology in 672 brains (TDP-43 staining n=642/672, 96%) donated for the population-based Cambridge City over-75s Cohort and the Cognitive Function and Ageing Study. HS-Aging was first evaluated independently from the protocol using the most common criteria defined in literature, and then described in detail through examination of neuron loss patterns and associated pathologies. 34 (5%) cases were identified, with a maximum of five pyramidal neurons in each of over half CA1 fields-of-view (x200 magnification), no vascular damage, no neuron loss in CA2-CA4, but consistent TDP-43 neuronal solid inclusions and neurites. We also report focal CA1 neuron loss with vascular pathology to affect predominantly CA1 bordering CA2 (Fisher's exact, p=0.009), whereas neuron loss in the subicular end of CA1 was associated with TDP-43 inclusions (Fisher's exact, pTDP-43. We conclude that hippocampal neuron loss patterns are associated with different aetiologies within CA1, and propose that these patterns can be used to form objective criteria for HS-Aging diagnosis. Finally, based on our results we hypothesize that neuron loss leading to HS-Aging starts from the subicular end of CA1 when it is associated with TDP-43 pathology, and that this neurodegenerative process is likely to be significantly more common than "end-stage" HS-Aging only. This article is protected by copyright. All rights reserved.

  1. Amyloid β-protein differentially affects NMDA receptor- and GABAA receptor-mediated currents in rat hippocampal CA1 neurons

    Institute of Scientific and Technical Information of China (English)

    Junfang Zhang; Lei Hou; Xiuping Gao; Fen Guo; Wei Jing; Jinshun Qi; Jiantian Qiao

    2009-01-01

    Although the aggregated amyloid β-protein (Aβ) in senile plaques is one of the key neuropathological features of Alzheimer's disease (AD), soluble forms of Aβ also interfere with synaptic plasticity at the early stage of AD. The suppressive action of acute application of Aβ on hippocampal long-term potentiation (LTP) has been reported widely, whereas the mechanism underlying the effects of Aβ is still mostly unknown. The present study, using the whole-cell patch clamp technique, investigated the effects of Aβ fragments (Aβ25-35 and Aβ31-35) on the LTP induction-related postsynaptic ligand-gated channel currents in isolated hippocampal CA1 neurons. The results showed a rapid but opposite action of both peptides on excitatory and inhibitory receptor currents. Glutamate application-induced currents were suppressed by A β25-35 in a dose-dependent manner, and further N-methyl-I>aspartate (NMDA) receptor-mediated currents were selec-tively inhibited. In contrast, pretreatment with Aβ fragments potentiated γ-aminobutyric acid (GABA)-induced whole-cell currents. As a control, Aβ35-31 the reversed sequence of Aβ35-31 showed no effect on the currents induced by glutamate, NMDA or GABA. These results may partly explain the impaired effects of Aβ on hippocampal LTP, and suggest that the functional down-regulation of N M DA receptors and up-regulation of GABAA receptors may play an important role in remodeling the hippocampal synaptic plasticity in early AD.

  2. Hypermethylation of Hippocampal Synaptic Plasticity-Related genes is Involved in Neonatal Sevoflurane Exposure-Induced Cognitive Impairments in Rats.

    Science.gov (United States)

    Ju, Ling-sha; Jia, Min; Sun, Jie; Sun, Xiao-ru; Zhang, Hui; Ji, Mu-huo; Yang, Jian-jun; Wang, Zhong-yun

    2016-02-01

    General anesthetics given to immature rodents cause delayed neurobehavioral abnormalities via incompletely understood mechanisms. DNA methylation, one of the epigenetic modifications, is essential for the modulation of hippocampal synaptic plasticity through regulating the related genes. Therefore, we investigated whether abnormalities in the hippocampal DNA methylation of synaptic plasticity-related genes are involved in neonatal sevoflurane exposure-induced cognitive impairments in rats. Male Sprague-Dawley rats were exposed to 3 % sevoflurane or 30 % oxygen/air for 2 h daily from postnatal day 7 (P7) to P9 and were treated with DNA methyltransferases (DNMTs) inhibitor 5-aza-2-deoxycytidine (5-AZA) or vehicle 1 h before the first sevoflurane exposure on P7. The rats were euthanized 1, 6, 24 h, and 30 days after the last sevoflurane exposure, and the brain tissues were harvested for biochemical analysis. Cognitive functions were evaluated by the open field, fear conditioning, and Morris water maze (MWM) tests on P39, P41-43, and P50-57, respectively. In the present study, repeated neonatal sevoflurane exposure resulted in hippocampus-dependent cognitive impairments as assessed by fear conditioning and MWM tests. The cognitive impairments were associated with the increased DNMTs and hypermethylation of brain-derived neurotrophic factor (BDNF) and Reelin genes, and subsequent down-regulation of BDNF and Reelin genes, which finally led to the decrease of dendritic spines in the hippocampal pyramidal neurons in adolescent rats. Notably, pretreatment with 5-AZA reversed these sevoflurane-induced abnormalities. In conclusion, our results suggest that hypermethylation of hippocampal BDNF and Reelin is involved in neonatal sevoflurane exposure-induced cognitive impairments.

  3. Hippocampal Hyperactivation in Presymptomatic Familial Alzheimer’s Disease

    Science.gov (United States)

    Quiroz, Yakeel T.; Budson, Andrew E.; Celone, Kim; Ruiz, Adriana; Newmark, Randall; Castrillón, Gabriel; Lopera, Francisco; Stern, Chantal E.

    2011-01-01

    Objective The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimer’s disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively-intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin-1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms. Methods Twenty carriers of the Alzheimer’s-associated E280A PS1 mutation and 19 PS1-negative control subjects participated. Both groups were matched for age, sex, education level, and neuropsychological test performance. All participants performed a face-name associative encoding task while in a Philips 1.5T fMRI scanner. Analysis focused on the hippocampal system. Results Despite identical behavioral performance, presymptomatic PS1 mutation carriers exhibited increased activation of the right anterior hippocampus during encoding of novel face-name associations compared to matched controls. Interpretation Our results demonstrate that functional changes within the hippocampal memory system occur years before cognitive decline in FAD. These presymptomatic changes in hippocampal physiology in FAD suggest that hippocampal fMRI patterns during associative encoding may also provide a preclinical biomarker in sporadic AD. PMID:21194156

  4. Role of adult hippocampal neurogenesis in stress resilience

    Directory of Open Access Journals (Sweden)

    Brunno R. Levone

    2015-01-01

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

  5. Role of adult hippocampal neurogenesis in stress resilience

    Science.gov (United States)

    Levone, Brunno R.; Cryan, John F.; O'Leary, Olivia F.

    2014-01-01

    There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders. PMID:27589664

  6. Nonlinear dynamical analysis of carbachol induced hippocampal oscillations in mice

    Institute of Scientific and Technical Information of China (English)

    Metin AKAY; Kui WANG; Yasemin M AKAY; Andrei DRAGOMIR; Jie WU

    2009-01-01

    Aim: Hippocampal neuronal network and synaptic impairment underlie learning and memory deficit in Alzheimer's disease (AD) patients and animal models. In this paper, we analyzed the dynamics and complexity of hippocampal neuronal network synchronization induced by acute exposure to carbachol, a nicotinic and muscarinic receptor co-agonist, using the nonlinear dynamical model based on the Lempel-Ziv estimator. We compared the dynamics of hippocampal oscillations between wild-type (WT) and triple-transgenic (3xTg) mice, as an AD animal model. We also compared these dynamic alterations between different age groups (5 and 10 months). We hypothesize that there is an impairment of complexity of CCh-induced hippocampal oscillations in 3xTg AD mice compared to WT mice, and that this impairment is age-dependent. Methods: To test this hypothesis, we used electrophysiological recordings (field potential) in hippocampal slices. Results: Acute exposure to 100 nmol/L CCh induced field potential oscillations in hippocampal CA1 region, which exhibited three distinct patterns: (1) continuous neural firing, (2) repeated burst neural firing and (3) the mixed (continuous and burst) pattern in both WT and 3xTg AD mice. Based on Lempel-Ziv estimator, pattern (2) was significantly lower than patterns (1) and (3) in 3xTg AD mice compared to WT mice (P<0.001), and also in 10-month old WT mice compared to those in 5-month old WT mice (P<0.01).Conclusion: These results suggest that the burst pattern (theta oscillation) of hippocampal network is selectively impaired in 3xTg AD mouse model, which may reflect a learning and memory deficit in the AD patients.

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

    Science.gov (United States)

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

    2016-09-01

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

  8. NADPH oxidase mediates β-amyloid peptide-induced activation of ERK in hippocampal organotypic cultures

    Science.gov (United States)

    Serrano, Faridis; Chang, Angela; Hernandez, Caterina; Pautler, Robia G; Sweatt, J David; Klann, Eric

    2009-01-01

    Background Previous studies have shown that beta amyloid (Aβ) peptide triggers the activation of several signal transduction cascades in the hippocampus, including the extracellular signal-regulated kinase (ERK) cascade. In this study we sought to characterize the cellular localization of phosphorylated, active ERK in organotypic hippocampal cultures after acute exposure to either Aβ (1-42) or nicotine. Results We observed that Aβ and nicotine increased the levels of active ERK in distinct cellular localizations. We also examined whether phospho-ERK was regulated by redox signaling mechanisms and found that increases in active ERK induced by Aβ and nicotine were blocked by inhibitors of NADPH oxidase. Conclusion Our findings indicate that NADPH oxidase-dependent redox signaling is required for Aβ-induced activation of ERK, and suggest a similar mechanism may occur during early stages of Alzheimer's disease. PMID:19804648

  9. Surveillance, phagocytosis, and inflammation: how never-resting microglia influence adult hippocampal neurogenesis.

    Science.gov (United States)

    Sierra, Amanda; Beccari, Sol; Diaz-Aparicio, Irune; Encinas, Juan M; Comeau, Samuel; Tremblay, Marie-Ève

    2014-01-01

    Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

  10. Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

    Directory of Open Access Journals (Sweden)

    Amanda Sierra

    2014-01-01

    Full Text Available Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory.

  11. Lithium improves hippocampal neurogenesis, neuropathology and cognitive functions in APP mutant mice.

    Directory of Open Access Journals (Sweden)

    Anna Fiorentini

    Full Text Available BACKGROUND: Alzheimer's disease (AD is a neurodegenerative disorder characterized by progressive deterioration of cognitive functions, extracellular β-amyloid (Aβ plaques and intracellular neurofibrillary tangles within neocortex and hippocampus. Adult hippocampal neurogenesis plays an important role in learning and memory processes and its abnormal regulation might account for cognitive impairments associated with AD. METHODOLOGY/PRINCIPAL FINDINGS: The double transgenic (Tg CRND8 mice (overexpressing the Swedish and Indiana mutations in the human amyloid precursor protein, aged 2 and 6 months, were used to examine in vivo the effects of 5 weeks lithium treatment. BrdU labelling showed a decreased neurogenesis in the subgranular zone of Tg mice compared to non-Tg mice. The decrease of hippocampal neurogenesis was accompanied by behavioural deficits and worsened with age and pathology severity. The differentiation into neurons and maturation of the proliferating cells were also markedly impaired in the Tg mice. Lithium treatment to 2-month-old Tg mice significantly stimulated the proliferation and neuron fate specification of newborn cells and fully counteracted the transgene-induced impairments of cognitive functions. The drug, by the inhibition of GSK-3β and subsequent activation of Wnt/ß-catenin signalling promoted hippocampal neurogenesis. Finally, the data show that the lithium's ability to stimulate neurogenesis and cognitive functions was lost in the aged Tg mice, thus indicating that the lithium-induced facilitation of neurogenesis and cognitive functions declines as brain Aβ deposition and pathology increases. CONCLUSIONS: Lithium, when given on time, stimulates neurogenesis and counteracts AD-like pathology.

  12. Neonatal isoflurane exposure induces neurocognitive impairment and abnormal hippocampal histone acetylation in mice.

    Directory of Open Access Journals (Sweden)

    Tao Zhong

    Full Text Available Neonatal exposure to isoflurane may induce long-term memory impairment in mice. Histone acetylation is an important form of chromatin modification that regulates the transcription of genes required for memory formation. This study investigated whether neonatal isoflurane exposure-induced neurocognitive impairment is related to dysregulated histone acetylation in the hippocampus and whether it can be attenuated by the histone deacetylase (HDAC inhibitor trichostatin A (TSA.C57BL/6 mice were exposed to 0.75% isoflurane three times (each for 4 h at postnatal days 7, 8, and 9. Contextual fear conditioning (CFC was tested at 3 months after anesthesia administration. TSA was intraperitoneally injected 2 h before CFC training. Hippocampal histone acetylation levels were analyzed following CFC training. Levels of the neuronal activation and synaptic plasticity marker c-Fos were investigated at the same time point.Mice that were neonatally exposed to isoflurane showed significant memory impairment on CFC testing. These mice also exhibited dysregulated hippocampal H4K12 acetylation and decreased c-Fos expression following CFC training. TSA attenuated isoflurane-induced memory impairment and simultaneously increased histone acetylation and c-Fos levels in the hippocampal cornu ammonis (CA1 area 1 h after CFC training.Memory impairment induced by repeated neonatal exposure to isoflurane is associated with dysregulated histone H4K12 acetylation in the hippocampus, which probably affects downstream c-Fos gene expression following CFC training. The HDAC inhibitor TSA successfully rescued impaired contextual fear memory, presumably by promoting histone acetylation and histone acetylation-mediated gene expression.

  13. Amphetamine withdrawal differentially affects hippocampal and peripheral corticosterone levels in response to stress.

    Science.gov (United States)

    Bray, Brenna; Scholl, Jamie L; Tu, Wenyu; Watt, Michael J; Renner, Kenneth J; Forster, Gina L

    2016-08-01

    Amphetamine withdrawal is associated with heightened anxiety-like behavior, which is directly driven by blunted stress-induced glucocorticoid receptor-dependent serotonin release in the ventral hippocampus. This suggests that glucocorticoid availability in the ventral hippocampus during stress may be reduced during amphetamine withdrawal. Therefore, we tested whether amphetamine withdrawal alters either peripheral or hippocampal corticosterone stress responses. Adult male rats received amphetamine (2.5mg/kg, ip) or saline for 14 days followed by 2 weeks of withdrawal. Contrary to our prediction, microdialysis samples from freely-moving rats revealed that restraint stress-induced corticosterone levels in the ventral hippocampus are enhanced by amphetamine withdrawal relative to controls. In separate groups of rats, plasma corticosterone levels increased immediately after 20min of restraint and decreased to below stress-naïve levels after 1h, indicating negative feedback regulation of corticosterone following stress. However, plasma corticosterone responses were similar in amphetamine-withdrawn and control rats. Neither amphetamine nor stress exposure significantly altered protein expression or enzyme activity of the steroidogenic enzymes 11β-hydroxysteroid dehydrogenase (11β-HSD1) or hexose-6-phosphate dehydrogenase (H6PD) in the ventral hippocampus. Our findings demonstrate for the first time that amphetamine withdrawal potentiates stress-induced corticosterone in the ventral hippocampus, which may contribute to increased behavioral stress sensitivity previously observed during amphetamine withdrawal. However, this is not mediated by either changes in plasma corticosterone or hippocampal steroidogenic enzymes. Establishing enhanced ventral hippocampal corticosterone as a direct cause of greater stress sensitivity may identify the glucocorticoid system as a novel target for treating behavioral symptoms of amphetamine withdrawal. Copyright © 2016 Elsevier B

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

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    Daniela Hartl

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

  15. Dendritic potassium channels in hippocampal pyramidal neurons.

    Science.gov (United States)

    Johnston, D; Hoffman, D A; Magee, J C; Poolos, N P; Watanabe, S; Colbert, C M; Migliore, M

    2000-05-15

    Potassium channels located in the dendrites of hippocampal CA1 pyramidal neurons control the shape and amplitude of back-propagating action potentials, the amplitude of excitatory postsynaptic potentials and dendritic excitability. Non-uniform gradients in the distribution of potassium channels in the dendrites make the dendritic electrical properties markedly different from those found in the soma. For example, the influence of a fast, calcium-dependent potassium current on action potential repolarization is progressively reduced in the first 150 micrometer of the apical dendrites, so that action potentials recorded farther than 200 micrometer from the soma have no fast after-hyperpolarization and are wider than those in the soma. The peak amplitude of back-propagating action potentials is also progressively reduced in the dendrites because of the increasing density of a transient potassium channel with distance from the soma. The activation of this channel can be reduced by the activity of a number of protein kinases as well as by prior depolarization. The depolarization from excitatory postsynaptic potentials (EPSPs) can inactivate these A-type K+ channels and thus lead to an increase in the amplitude of dendritic action potentials, provided the EPSP and the action potentials occur within the appropriate time window. This time window could be in the order of 15 ms and may play a role in long-term potentiation induced by pairing EPSPs and back-propagating action potentials.

  16. Ultrafast endocytosis at mouse hippocampal synapses

    Science.gov (United States)

    Watanabe, Shigeki; Rost, Benjamin R.; Camacho-Pérez, Marcial; Davis, M. Wayne; Söhl-Kielczynski, Berit; Rosenmund, Christian; Jorgensen, Erik M.

    2013-12-01

    To sustain neurotransmission, synaptic vesicles and their associated proteins must be recycled locally at synapses. Synaptic vesicles are thought to be regenerated approximately 20s after fusion by the assembly of clathrin scaffolds or in approximately 1s by the reversal of fusion pores via `kiss-and-run' endocytosis. Here we use optogenetics to stimulate cultured hippocampal neurons with a single stimulus, rapidly freeze them after fixed intervals and examine the ultrastructure using electron microscopy--`flash-and-freeze' electron microscopy. Docked vesicles fuse and collapse into the membrane within 30ms of the stimulus. Compensatory endocytosis occurs within 50 to 100ms at sites flanking the active zone. Invagination is blocked by inhibition of actin polymerization, and scission is blocked by inhibiting dynamin. Because intact synaptic vesicles are not recovered, this form of recycling is not compatible with kiss-and-run endocytosis; moreover, it is 200-fold faster than clathrin-mediated endocytosis. It is likely that `ultrafast endocytosis' is specialized to restore the surface area of the membrane rapidly.

  17. Neuroprotection against diisopropylfluorophosphate in acute hippocampal slices

    Science.gov (United States)

    Ferchmin, P. A.; Pérez, Dinely; Cuadrado, Brenda L.; Carrasco, Marimée; Martins, Antonio H.; Eterović, Vesna A.

    2015-01-01

    Diisopropylfluorophosphate (DFP) is an irreversible inhibitor of acetylcholine esterase (AChE) and a surrogate of the organophosphorus (OP) nerve agent sarin. The neurotoxicity of DFP was assessed as a reduction of population spike (PS) area elicited by synaptic stimulation in acute hippocampal slices. Two classical antidotes, atropine, and pralidoxime, and two novel antidotes, 4R-cembranotriene-diol (4R) and a caspase 9 inhibitor, were tested. Atropine, pralidoxime, and 4R significantly protected when applied 30 min after DFP. The caspase inhibitor was neuroprotective when applied 5–10 min before or after DFP, suggesting that early synaptic apoptosis is responsible for the loss of PSs. It is likely that apoptosis starts at the synapses and, if antidotes are not applied, descends to the cell bodies, causing death. The acute slice is a reliable tool for mechanistic studies, and the assessment of neurotoxicity and neuroprotection with PS areas is, in general, pharmacologically congruent with in vivo results and predicts the effect of drugs in vivo. 4R was first found to be neuroprotective in slices and later we demonstrated that 4R is neuroprotective in vivo. The mechanism of neurotoxicity of OPs is not well understood, and there is a need for novel antidotes that could be discovered using acute slices. PMID:26438150

  18. Hippocampal transcriptional and neurogenic changes evoked by combination yohimbine and imipramine treatment.

    Science.gov (United States)

    Husain, Basma Fatima Anwar; Nanavaty, Ishira N; Marathe, Swananda V; Rajendran, Rajeev; Vaidya, Vidita A

    2015-08-03

    Adjunct α2-adrenoceptor antagonism is a potential strategy to accelerate the behavioral effects of antidepressants. Co-administration of the α2-adrenoceptor antagonist yohimbine hastens the behavioral and neurogenic effects of the antidepressant imipramine. We examined the transcriptional targets of short duration (7days), combination treatment of yohimbine and imipramine (Y+I) within the adult rat hippocampus. Using microarray and qPCR analysis we observed functional enrichment of genes involved in intracellular signaling cascades, plasma membrane, cellular metal ion homeostasis, multicellular stress responses and neuropeptide signaling pathways in the Y+I transcriptome. We noted reduced expression of the α2A-adrenoceptor (Adra2a), serotonin 5HT2C receptor (Htr2c) and the somatostatin receptor 1 (Sstr1), which modulate antidepressant action. Further, we noted a regulation of signaling pathway genes like inositol monophosphatase 2 (Impa2), iodothyronine deiodinase 3 (Dio3), regulator of G-protein signaling 4 (Rgs4), alkaline ceramidase 2 (Acer2), doublecortin-like kinase 2 (Dclk2), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (Nfkbia) and serum/glucocorticoid-regulated kinase 1 (Sgk1), several of which are implicated in the pathophysiology of mood disorders. Comparative analysis revealed an overlap in the hippocampal regulation of Acer2, Nfkbia, Sgk1 and Impa2 between Y+I treatment, the fast-acting electroconvulsive seizure (ECS) paradigm, and the slow-onset chronic (21days) imipramine treatment. Further, Y+I treatment enhanced the quiescent neural progenitor pool in the hippocampal neurogenic niche similar to ECS, and distinct from chronic imipramine treatment. Taken together, our results provide insight into the molecular and cellular targets of short duration Y+I treatment, and identify potential leads for the development of rapid-action antidepressants.

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

    Science.gov (United States)

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

    2014-09-01

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

  20. Hippocampal functional connectivity and episodic memory in early childhood

    Directory of Open Access Journals (Sweden)

    Tracy Riggins

    2016-06-01

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

  1. The Form and Function of Hippocampal Context Representations

    Science.gov (United States)

    Smith, David M.; Bulkin, David A.

    2014-01-01

    Context is an essential component of learning and memory processes, and the hippocampus is critical for encoding contextual information. However, connecting hippocampal physiology with its role in context and memory has only recently become possible. It is now clear that contexts are represented by coherent ensembles of hippocampal neurons and new optogenetic stimulation studies indicate that activity in these ensembles can trigger the retrieval of context appropriate memories. We interpret these findings in light of recent evidence that the hippocampus is critically involved in using contextual information to prevent interference, and propose a theoretical framework for understanding contextual influence of memory retrieval. When a new context is encountered, a unique hippocampal ensemble is recruited to represent it. Memories for events that occur in the context become associated with the hippocampal representation. Revisiting the context causes the hippocampal context code to be re-expressed and the relevant memories are primed. As a result, retrieval of appropriate memories is enhanced and interference from memories belonging to other contexts is minimized. PMID:24462752

  2. Altered hippocampal morphology in unmedicated patients with major depressive illness

    Directory of Open Access Journals (Sweden)

    Carrie E Bearden

    2009-11-01

    Full Text Available Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2±11.9 years; 77% female and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1 subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

  3. Impaired cognitive performance and hippocampal atrophy in Parkinson disease.

    Science.gov (United States)

    Yildiz, Demet; Erer, Sevda; Zarifoğlu, Mehmet; Hakyemez, Bahattin; Bakar, Mustafa; Karli, Necdet; Varlibaş, Zeynep Nigar; Tufan, Fatih

    2015-01-01

    Dementia is common in Parkinson disease (PD). Since magnetic resonance imaging has been used, hippocampal atrophy has been shown in PD patients with or without dementia. In this study we sought the correlation of cognitive decline with bilateral hippocampal volume in PD patients. Thirty-three patients with diagnosis of idiopathic PD and 16 healthy subjects were included in this study. PD patients were divided into two groups as normal cognitive function and mild cognitive impairment (MCI). The Mini-Mental State Examination and detailed cognitive assessment tests were performed for all patients for cognitive analyses. Depression was excluded by the Geriatric Depression Scale. The mean onset age of disease was 55 years for PD patients without dementia and 59 for PD patients with MCI. According to the Hoehn-Yahr scales, 24% of patients had grade 1, 58% had grade 2, and 18% had grade 3 disease. Right and left hippocampal volumes decreased along with cognitive test scores in PD patients. Increased right hippocampal volume was correlated with forward number test in the MCI-PD group. These findings suggest that memory deficit is associated with hippocampal atrophy in PD patients.

  4. Amyloid Beta Peptide Slows Down Sensory-Induced Hippocampal Oscillations

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    Fernando Peña-Ortega

    2012-01-01

    Full Text Available Alzheimer’s disease (AD progresses with a deterioration of hippocampal function that is likely induced by amyloid beta (Aβ oligomers. Hippocampal function is strongly dependent on theta rhythm, and disruptions in this rhythm have been related to the reduction of cognitive performance in AD. Accordingly, both AD patients and AD-transgenic mice show an increase in theta rhythm at rest but a reduction in cognitive-induced theta rhythm. We have previously found that monomers of the short sequence of Aβ (peptide 25–35 reduce sensory-induced theta oscillations. However, considering on the one hand that different Aβ sequences differentially affect hippocampal oscillations and on the other hand that Aβ oligomers seem to be responsible for the cognitive decline observed in AD, here we aimed to explore the effect of Aβ oligomers on sensory-induced theta rhythm. Our results show that intracisternal injection of Aβ1–42 oligomers, which has no significant effect on spontaneous hippocampal activity, disrupts the induction of theta rhythm upon sensory stimulation. Instead of increasing the power in the theta band, the hippocampus of Aβ-treated animals responds to sensory stimulation (tail pinch with an increase in lower frequencies. These findings demonstrate that Aβ alters induced theta rhythm, providing an in vivo model to test for therapeutic approaches to overcome Aβ-induced hippocampal and cognitive dysfunctions.

  5. Hippocampal Neurogenesis, Cognitive Deficits and Affective Disorder in Huntington's Disease

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    Mark I. Ransome

    2012-01-01

    Full Text Available Huntington’s disease (HD is a neurodegenerative disorder caused by a tandem repeat expansion encoding a polyglutamine tract in the huntingtin protein. HD involves progressive psychiatric, cognitive, and motor symptoms, the selective pathogenesis of which remains to be mechanistically elucidated. There are a range of different brain regions, including the cerebral cortex and striatum, known to be affected in HD, with evidence for hippocampal dysfunction accumulating in recent years. In this review we will focus on hippocampal abnormalities, in particular, deficits of adult neurogenesis. We will discuss potential molecular mechanisms mediating disrupted hippocampal neurogenesis, and how this deficit of cellular plasticity may in turn contribute to specific cognitive and affective symptoms that are prominent in HD. The generation of transgenic animal models of HD has greatly facilitated our understanding of disease mechanisms at molecular, cellular, and systems levels. Transgenic HD mice have been found to show progressive behavioral changes, including affective, cognitive, and motor abnormalities. The discovery, in multiple transgenic lines of HD mice, that adult hippocampal neurogenesis and synaptic plasticity is disrupted, may help explain specific aspects of cognitive and affective dysfunction. Furthermore, these mouse models have provided insight into potential molecular mediators of adult neurogenesis deficits, such as disrupted serotonergic and neurotrophin signaling. Finally, a number of environmental and pharmacological interventions which are known to enhance adult hippocampal neurogenesis have been found to have beneficial affective and cognitive effects in mouse models, suggesting common molecular targets which may have therapeutic utility for HD and related diseases.

  6. Qualitative and Quantitative Hippocampal MRI Assessments in Intractable Epilepsy

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    Paramdeep Singh

    2013-01-01

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

  7. Influence of Ginkgo Biloba extract on beta-secretase in rat hippocampal neuronal cultures following chronic hypoxic and hypoglycemic conditions

    Institute of Scientific and Technical Information of China (English)

    Xueneng Guan; Fuling Yan

    2008-01-01

    BACKGROUND: Preparation of Ginkgo leaf has been widely used to improve cognitive deficits and dementia, in particular in Alzheimer's disease patients. However, the precise mechanism of action of Ginkgo leaf remains unclear.OBJECTIVE: To explore the effect of Ginkgo Biloba extract (Egb761), Ginaton, on β-secretase expression in rat hippocampal neuronal cultures following chronic hypoxic and hypoglycemic conditions.DESIGN, TIME AND SETTNG: Completely by randomized, grouping study. The experiment was performed at the Laboratory of Molecular Imaging, Southeast University between August 2006 and August 2007.MATERIALS: A total of 128 Wistar rats aged 24 hours were selected, and hippocampal neurons were harvested for primary cultures.METHODS: On day 7, primary hippocampal neuronal cultures were treated with Egb761 (0, 25, 50, 100, 150, and 200 μ g/mL) under hypoxic/hypoglycemic or hypoglycemic culture conditions for 12, 24, and 36 hours, respectively. Hippocampal neurons cultured in primary culture medium served as control.MAIN OUTCOME MEASURES: Cell viability was assayed using 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT); fluorescence detection of β-secretase activity was performed; Western Blot was used to measure β -secretase expression.RESULTS: Cell viability under hypoxic/hypoglycemic or hypoglycemic culture conditions was significantly less than control cells (P 25 μ g/mL Egb761 induced greater cell viability (P 0.05). Α -secretase activity was increased after 12 hours in hypoxic/hypoglycemic culture (P 0.05). Β -secretase activity was greater after 12, 24, and 36 hours in hypoxic/hypoglycemic culture conditions, compared with control conditions (P < 0.05). Β-secretase activity was significantly decreased in neurons treated with Egb761 for 12, 24, or 36 hours, compared with the hypoxic/hypoglycemic group (P < 0.05).β-secretase protein expression was significantly up-regulated in neurons cultured in hypoxic/hypoglycemic conditions for

  8. Hippocampal neuron populations are reduced in vervet monkeys with fetal alcohol exposure

    DEFF Research Database (Denmark)

    Burke, Mark W; Ptito, Maurice; Ervin, Frank R

    2015-01-01

    of pregnancy. Here, we report significant numerical reductions in the principal hippocampal neurons of fetal alcohol-exposed (FAE) offspring, as compared to age-matched, similarly housed conspecifics with isocaloric sucrose exposure. These deficits, particularly marked in CA1 and CA3, are present neonatally...... late pregnancy results in a stable loss of hippocampal neurons and a progressive reduction of hippocampal volume....

  9. MR-determined hippocampal asymmetry in full-term and preterm neonates.

    Science.gov (United States)

    Thompson, Deanne K; Wood, Stephen J; Doyle, Lex W; Warfield, Simon K; Egan, Gary F; Inder, Terrie E

    2009-02-01

    Hippocampi are asymmetrical in children and adults, where the right hippocampus is larger. To date, no literature has confirmed that hippocampal asymmetry is evident at birth. Furthermore, gender differences have been observed in normal hippocampal asymmetry, but this has not been examined in neonates. Stress, injury, and lower IQ have been associated with alterations to hippocampal asymmetry. These same factors often accompany preterm birth. Therefore, prematurity is possibly associated with altered hippocampal asymmetry. There were three aims of this study: First, we assessed whether hippocampi were asymmetrical at birth, second whether there was a gender effect on hippocampal asymmetry, and third whether the stress of preterm birth altered hippocampal asymmetry. This study utilized volumetric magnetic resonance imaging to compare left and right hippocampal volumes in 32 full-term and 184 preterm infants at term. Full-term infants demonstrated rightward hippocampal asymmetry, as did preterm infants. In the case of preterm infants, hippocampal asymmetry was proportional to total hemispheric asymmetry. This study is the first to demonstrate that the normal pattern of hippocampal asymmetry is present this early in development. We did not find gender differences in hippocampal asymmetry at term. Preterm infants tended to have less asymmetrical hippocampi than full-term infants, a difference which became significant after correcting for hemispheric brain tissue volumes. This study may suggest that hippocampal asymmetry develops in utero and is maintained into adulthood in infants with a normal neurological course.

  10. Active Dentate Granule Cells Encode Experience to Promote the Addition of Adult-Born Hippocampal Neurons.