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Sample records for adult hippocampal neurons

  1. Recruitment and replacement of hippocampal neurons in young and adult chickadees: an addition to the theory of hippocampal learning.

    PubMed Central

    Barnea, A; Nottebohm, F

    1996-01-01

    We used [3H]thymidine to document the birth of neurons and their recruitment into the hippocampal complex (HC) of juvenile (4.5 months old) and adult blackcapped chickadees (Parus atricapillus) living in their natural surroundings. Birds received a single dose of [3H]thymidine in August and were recaptured and killed 6 weeks later, in early October. All brains were stained with Cresyl violet, a Nissl stain. The boundaries of the HC were defined by reference to the ventricular wall, the brain surface, or differences in neuronal packing density. The HC of juveniles was as large as or larger than that of adults and packing density of HC neurons was 31% higher in juveniles than in adults. Almost all of the 3H-labeled HC neurons were found in a 350-m-wide layer of tissue adjacent to the lateral ventricle. Within this layer the fraction of 3H-labeled neurons was 50% higher in juveniles than in adults. We conclude that the HC of juvenile chickadees recruits more neurons and has more neurons than that of adults. We speculate that juveniles encounter greater environmental novelty than adults and that the greater number of HC neurons found in juveniles allows them to learn more than adults. At a more general level, we suggest that (i) long-term learning alters HC neurons irreversibly; (ii) sustained hippocampal learning requires the periodic replacement of HC neurons; (iii) memories coded by hippocampal neurons are transferred elsewhere before the neurons are replaced. Images Fig. 1 Fig. 2 PMID:11607626

  2. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    PubMed Central

    Deng, Wei; Aimone, James B.; Gage, Fred H.

    2010-01-01

    The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time. PMID:20354534

  3. Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury

    PubMed Central

    Villasana, Laura E.; Kim, Kristine N.

    2015-01-01

    Abstract Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI-induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreERT2 transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult-born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI-induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties. PMID:26478908

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

    PubMed Central

    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

  5. Trim9 Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

    PubMed Central

    Winkle, Cortney C.; Olsen, Reid H. J.; Kim, Hyojin; Moy, Sheryl S.

    2016-01-01

    During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9−/− adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9−/− mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. SIGNIFICANCE STATEMENT Appropriate generation and incorporation of adult-born neurons in the dentate gyrus are critical for spatial learning and memory and other hippocampal functions. Here we identify the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of embryonic and adult hippocampal neuron shape acquisition and hippocampal-dependent behaviors. Genetic deletion of Trim9 elevated dendritic arborization of hippocampal neurons in vitro and in vivo. Adult-born dentate granule cells lacking Trim9 similarly exhibited excessive dendritic arborization and mislocalization of cell bodies in vivo. These cellular defects were associated with severe deficits in spatial learning and memory. PMID:27147649

  6. Young adult born neurons enhance hippocampal dependent performance via influences on bilateral networks

    PubMed Central

    Zhuo, Jia-Min; Tseng, Hua-an; Desai, Mitul; Bucklin, Mark E; Mohammed, Ali I; Robinson, Nick TM; Boyden, Edward S; Rangel, Lara M; Jasanoff, Alan P; Gritton, Howard J; Han, Xue

    2016-01-01

    Adult neurogenesis supports performance in many hippocampal dependent tasks. Considering the small number of adult-born neurons generated at any given time, it is surprising that this sparse population of cells can substantially influence behavior. Recent studies have demonstrated that heightened excitability and plasticity may be critical for the contribution of young adult-born cells for certain tasks. What is not well understood is how these unique biophysical and synaptic properties may translate to networks that support behavioral function. Here we employed a location discrimination task in mice while using optogenetics to transiently silence adult-born neurons at different ages. We discovered that adult-born neurons promote location discrimination during early stages of development but only if they undergo maturation during task acquisition. Silencing of young adult-born neurons also produced changes extending to the contralateral hippocampus, detectable by both electrophysiology and fMRI measurements, suggesting young neurons may modulate location discrimination through influences on bilateral hippocampal networks. DOI: http://dx.doi.org/10.7554/eLife.22429.001 PMID:27914197

  7. Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons.

    PubMed

    Kirschen, Gregory W; Shen, Jia; Tian, Mu; Schroeder, Bryce; Wang, Jia; Man, Guoming; Wu, Song; Ge, Shaoyu

    2017-04-03

    The continuous addition of new dentate granule cells, exquisitely regulated by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to impact the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca(2+) imaging to track the real-time activity of individual dentate granule cells in freely-behaving mice. For the first time, we found that active dentate granule cells responded to a novel experience by preferentially increasing their Ca(2+) event frequency. This elevated activity, which we found to be associated with object exploration, returned to baseline by one hour in the same environment, but could be dishabituated via introduction to a novel environment. To seamlessly transition between environments, we next established a freely-controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences accumulatively increased the number of newborn neurons when compared to a single experience. Finally, optogenetic silencing of existing dentate granule cells during novel environmental exploration perturbed experience-induced neuronal addition. Together, our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active dentate granule cells.SIGNIFICANCE STATEMENTAdult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca(2+) imaging of dentate granule neurons with a novel unrestrained virtual reality system for rodents, we discovered that a new experience rapidly

  8. Cacna1c: Protecting young hippocampal neurons in the adult brain.

    PubMed

    De Jesús-Cortés, Héctor; Rajadhyaksha, Anjali M; Pieper, Andrew A

    2016-01-01

    Neuropsychiatric disease is the leading cause of disability in the United States, and fourth worldwide.(1,2) Not surprisingly, human genetic studies have revealed a common genetic predisposition for many forms of neuropsychiatric disease, potentially explaining why overlapping symptoms are commonly observed across multiple diagnostic categories. For example, the CACNA1C gene was recently identified in the largest human genome-wide association study to date as a risk loci held in common across 5 major forms of neuropsychiatric disease: bipolar disorder, schizophrenia, major depressive disorder (MDD), autism spectrum disorder and attention deficit-hyperactivity disorder.(3) This gene encodes for the Cav1.2 subunit of the L-type voltage-gated calcium channel (LTCC), accounting for 85% of LTCCs in the brain, while the Cav1.3 subunit comprises the remainder.(4) In neurons, LTCCs mediate calcium influx in response to membrane depolarization,(5) thereby regulating neurotransmission and gene expression. Here, we describe our recent finding that Cav1.2 also controls survival of young hippocampal neurons in the adult brain, which has been linked to the etiology and treatment of neuropsychiatric disease. We also describe the effective restoration of young hippocampal neuron survival in adult Cav1.2 forebrain-specific conditional knockout mice using the neuroprotective compound P7C3-A20.

  9. The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis.

    PubMed

    Boekhoorn, Karin; van Dis, Vera; Goedknegt, Erika; Sobel, André; Lucassen, Paul J; Hoogenraad, Casper C

    2014-12-01

    The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT-stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT-destabilizing proteins. Stathmin is such a MT-destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki-67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA-NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons.

  10. Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents.

    PubMed

    Cavegn, Nicole; van Dijk, R Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

    2013-01-01

    Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups.

  11. Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents

    PubMed Central

    Cavegn, Nicole; van Dijk, R. Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T.; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

    2013-01-01

    Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups. PMID:23616743

  12. Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons.

    PubMed

    Wang, Liang; Chang, Xingya; She, Liang; Xu, Duo; Huang, Wei; Poo, Mu-ming

    2015-06-03

    Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor.

  13. Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome.

    PubMed

    Gil-Mohapel, Joana; Boehme, Fanny; Patten, Anna; Cox, Adrian; Kainer, Leah; Giles, Erica; Brocardo, Patricia S; Christie, Brian R

    2011-04-12

    Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.

  14. Culturing rat hippocampal neurons.

    PubMed

    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.

  15. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies.

    PubMed

    Garthe, Alexander; Behr, Joachim; Kempermann, Gerd

    2009-01-01

    Despite enormous progress in the past few years the specific contribution of newly born granule cells to the function of the adult hippocampus is still not clear. We hypothesized that in order to solve this question particular attention has to be paid to the specific design, the analysis, and the interpretation of the learning test to be used. We thus designed a behavioral experiment along hypotheses derived from a computational model predicting that new neurons might be particularly relevant for learning conditions, in which novel aspects arise in familiar situations, thus putting high demands on the qualitative aspects of (re-)learning.In the reference memory version of the water maze task suppression of adult neurogenesis with temozolomide (TMZ) caused a highly specific learning deficit. Mice were tested in the hidden platform version of the Morris water maze (6 trials per day for 5 days with a reversal of the platform location on day 4). Testing was done at 4 weeks after the end of four cycles of treatment to minimize the number of potentially recruitable new neurons at the time of testing. The reduction of neurogenesis did not alter longterm potentiation in CA3 and the dentate gyrus but abolished the part of dentate gyrus LTP that is attributed to the new neurons. TMZ did not have any overt side effects at the time of testing, and both treated mice and controls learned to find the hidden platform. Qualitative analysis of search strategies, however, revealed that treated mice did not advance to spatially precise search strategies, in particular when learning a changed goal position (reversal). New neurons in the dentate gyrus thus seem to be necessary for adding flexibility to some hippocampus-dependent qualitative parameters of learning.Our finding that a lack of adult-generated granule cells specifically results in the animal's inability to precisely locate a hidden goal is also in accordance with a specialized role of the dentate gyrus in generating a metric

  16. Hippocampal neurons in schizophrenia

    PubMed Central

    Heckers, S.; Konradi, C.

    2014-01-01

    Summary The hippocampus is crucial for normal brain function, especially for the encoding and retrieval of multimodal sensory information. Neuropsychiatric disorders such as temporal lobe epilepsy, amnesia, and the dementias are associated with structural and functional abnormalities of specific hippocampal neurons. More recently we have also found evidence for a role of the hippocampus in the pathophysiology of schizophrenia. The most consistent finding is a subtle, yet significant volume difference in schizophrenia. Here we review the cellular and molecular basis of smaller hippocampal volume in schizophrenia. In contrast to neurodegenerative disorders, total hippocampal cell number is not markedly decreased in schizophrenia. However, the intriguing finding of a selective loss of hippocampal inter-neurons deserves further study. Two neurotransmitter receptors, the GABAA and AMPA/kainate glutamate receptors, appear to be abnormal, whereas changes of the NMDA glutamate receptor are less robust. The expression of several genes, including those related to the GABAergic system, neurodevelopment, and synaptic function, is decreased in schizophrenia. Taken together, recent studies of hippocampal cell number, protein expression, and gene regulation point towards an abnormality of hippocampal architecture in schizophrenia. PMID:12111476

  17. Updating stored memory requires adult hippocampal neurogenesis

    PubMed Central

    Suárez-Pereira, Irene; Carrión, Ángel M

    2015-01-01

    Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored memories, remains unclear. Here, using a novel fast X-ray ablation protocol to deplete neurogenic cells, we have found that adult hippocampal neurogenesis is required to update object recognition stored memory more than to reinforce it. Indeed, we show that immature neurons were selectively recruited to hippocampal circuits during the updating of stored information. Thus, our data demonstrate a new role for neurogenesis in cognitive processes, adult hippocampal neurogenesis being required for the updating of stored OR memories. These findings suggest that manipulating adult neurogenesis may have a therapeutic application in conditions associated with traumatic stored memory, for example. PMID:26358557

  18. Updating stored memory requires adult hippocampal neurogenesis.

    PubMed

    Suárez-Pereira, Irene; Carrión, Ángel M

    2015-09-11

    Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored memories, remains unclear. Here, using a novel fast X-ray ablation protocol to deplete neurogenic cells, we have found that adult hippocampal neurogenesis is required to update object recognition stored memory more than to reinforce it. Indeed, we show that immature neurons were selectively recruited to hippocampal circuits during the updating of stored information. Thus, our data demonstrate a new role for neurogenesis in cognitive processes, adult hippocampal neurogenesis being required for the updating of stored OR memories. These findings suggest that manipulating adult neurogenesis may have a therapeutic application in conditions associated with traumatic stored memory, for example.

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

    PubMed

    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.

  20. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.

    PubMed

    Veyrac, Alexandra; Gros, Alexandra; Bruel-Jungerman, Elodie; Rochefort, Christelle; Kleine Borgmann, Felix B; Jessberger, Sebastian; Laroche, Serge

    2013-04-23

    New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.

  1. Resveratrol suppresses calcium-mediated microglial activation and rescues hippocampal neurons of adult rats following acute bacterial meningitis.

    PubMed

    Sheu, Ji-Nan; Liao, Wen-Chieh; Wu, Un-In; Shyu, Ling-Yuh; Mai, Fu-Der; Chen, Li-You; Chen, Mei-Jung; Youn, Su-Chung; Chang, Hung-Ming

    2013-03-01

    Acute bacterial meningitis (ABM) is a serious disease with severe neurological sequelae. The intense calcium-mediated microglial activation and subsequently pro-inflammatory cytokine release plays an important role in eliciting ABM-related oxidative damage. Considering resveratrol possesses significant anti-inflammatory and anti-oxidative properties, the present study aims to determine whether resveratrol would exert beneficial effects on hippocampal neurons following ABM. ABM was induced by inoculating Klebsiella pneumoniae into adult rats intraventricularly. The time-of-flight secondary ion mass spectrometry (TOF-SIMS), Griffonia simplicifolia isolectin-B4 (GSA-IB4) and ionized calcium binding adaptor molecule 1 (Iba1) immunohistochemistry, enzyme-linked immunosorbent assay as well as malondialdehyde (MDA) measurement were used to examine the calcium expression, microglial activation, pro-inflammatory cytokine level, and extent of oxidative stress, respectively. In ABM rats, strong calcium signaling associated with enhanced microglial activation was observed in hippocampus. Increased microglial expression was coincided with intense production of pro-inflammatory cytokines and oxidative damage. However, in rats receiving resveratrol after ABM, the calcium intensity, microglial activation, pro-inflammatory cytokine and MDA levels were all significantly decreased. Quantitative data showed that much more hippocampal neurons were survived in resveratrol-treated rats following ABM. As resveratrol successfully rescues hippocampal neurons from ABM by suppressing the calcium-mediated microglial activation, therapeutic use of resveratrol may act as a promising strategy to counteract the ABM-induced neurological damage.

  2. Properties of GABA-mediated synaptic potentials induced by zinc in adult rat hippocampal pyramidal neurones.

    PubMed Central

    Xie, X; Smart, T G

    1993-01-01

    1. Intracellular recording techniques were used to study the actions of the transition ion, zinc, on CA1 and CA3 pyramidal neurones in adult rat hippocampal slices. 2. Zinc (300 microM) hyperpolarized pyramidal neurones, increased the membrane excitability and also induced periodic, spontaneous giant depolarizing potentials associated with a conductance increase mechanism. 3. The occurrence of spontaneous giant depolarizations was dependent on the zinc concentration (10 microM-1 mM) with an apparent dissociation constant of 98 microM. The frequency of zinc-induced depolarizations was unaffected by the membrane potential from -50 to -100 mV. 4. Stimulation of the Schaffer collaterals or mossy fibre pathways evoked an excitatory and inhibitory synaptic potential complex. In the presence of zinc, nerve fibre stimulation evoked, in an all-or-none fashion, a giant depolarizing potential with an increased membrane conductance. Both spontaneous and evoked depolarizations were inhibited by 1 microM tetrodotoxin. 5. Evoked giant depolarizations were labile with too frequent stimulation resulting in a failure of generation. A minimum time of 140 s was required between stimuli to ensure successive giant depolarizations. 6. Spontaneous and evoked zinc-induced depolarizing potentials were inhibited by bicuculline (10 microM) or picrotoxin (40 microM) and enhanced by pentobarbitone (100 microM) or flurazepam (10 microM), suggesting that these potentials are mediated by activation of gamma-aminobutyric acidA (GABAA) receptors. 7. Ionophoretic application of GABA produced biphasic responses at -60 mV membrane potential. The reversal potentials for the depolarizing and hyperpolarizing GABA responses were -56 +/- 5 and -66 +/- 8 mV respectively. The giant depolarizations induced by zinc reversed at -57 +/- 4 mV. This suggests a dendritic location for the generation of these potentials. 8. Excitatory amino acid antagonists, 2-amino-5-phosphonovalerate (APV, 40 microM) or 6-cyano-7

  3. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence

    PubMed Central

    Gould, E.; Vail, N.; Wagers, M.; Gross, C. G.

    2001-01-01

    Previously we reported that new neurons are added to the hippocampus and neocortex of adult macaque monkeys. Here we compare the production and survival of adult-generated neurons and glia in the dentate gyrus, prefrontal cortex, and inferior temporal cortex. Twelve adult macaques were injected with the thymidine analogue BrdUrd, and the phenotypes of labeled cells were examined after 2 h, 24 h, 2 wk, 5 wk, 9 wk, and 12 wk by using the following immunocytochemical markers: for immature and mature neurons, class III β-tubulin (TuJ1); for mature neurons, neuronal nuclei; for astrocytes, glial fibrillary acidic protein; and for oligodendrocytes, 2′,3′-cyclic nucleotide 3′ phosphodiesterase. We found that the dentate gyrus had many more BrdUrd-labeled cells than either neocortical area. Furthermore, a greater percentage of BrdUrd-labeled cells expressed a neuronal marker in the dentate gyrus than in either neocortical area. The number of new cells in all three areas declined by 9 wk after BrdUrd labeling, suggesting that some of the new cells have a transient existence. BrdUrd-labeled cells also were found in the subventricular zone and in the white matter between the lateral ventricle and neocortex; some of the latter cells were double-labeled for BrdUrd and TuJ1. Adult neocortical neurogenesis is not restricted to primates. Five adult rats were injected with BrdUrd, and after a 3-wk survival time, there were cells double-labeled for BrdUrd and either TuJ1 or neuronal nuclei in the anterior neocortex as well as the dentate gyrus. PMID:11526209

  4. Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice.

    PubMed

    Blanchard, Julie; Chohan, Muhammad Omar; Li, Bin; Liu, Fei; Iqbal, Khalid; Grundke-Iqbal, Inge

    2010-01-01

    A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.

  5. When are new hippocampal neurons, born in the adult brain, integrated into the network that processes spatial information?

    PubMed

    Sandoval, C Jimena; Martínez-Claros, Marisela; Bello-Medina, Paola C; Pérez, Oswaldo; Ramírez-Amaya, Víctor

    2011-03-09

    Adult-born neurons in the dentate gyrus (DG) functionally integrate into the behaviorally relevant hippocampal networks, showing a specific Arc-expression response to spatial exploration when mature. However, it is not clear when, during the 4- to 6-week interval that is critical for survival and maturation of these neurons, this specific response develops. Therefore, we characterized Arc expression after spatial exploration or cage control conditions in adult-born neurons from rats that were injected with BrdU on one day and were sacrificed 1, 7, 15, 30, and 45 days post-BrdU injection (PBI). Triple immunostaining for NeuN, Arc, and BrdU was analyzed through the different DG layers. Arc protein expression in BrdU-positive cells was observed from day 1 to day 15 PBI but was not related to behavioral stimulation. The specific Arc-expression response to spatial exploration was observed from day 30 and 45 in about 5% of the BrdU-positive cell population. Most of the BrdU-positive neurons expressing Arc in response to spatial exploration (∼90%) were located in DG layer 1, and no Arc expression was observed in cells located in the subgranular zone (SGZ). Using the current data and that obtained previously, we propose a mathematical model suggesting that new neurons are unlikely to respond to exploration by expressing Arc after they are 301 days old, and also that in a 7-month-old rat the majority (60%) of the neurons that respond to exploration must have been born during adulthood; thus, suggesting that adult neurogenesis in the DG is highly relevant for spatial information processing.

  6. When Are New Hippocampal Neurons, Born in the Adult Brain, Integrated into the Network That Processes Spatial Information?

    PubMed Central

    Sandoval, C. Jimena; Pérez, Oswaldo; Ramírez-Amaya, Víctor

    2011-01-01

    Adult-born neurons in the dentate gyrus (DG) functionally integrate into the behaviorally relevant hippocampal networks, showing a specific Arc-expression response to spatial exploration when mature. However, it is not clear when, during the 4- to 6-week interval that is critical for survival and maturation of these neurons, this specific response develops. Therefore, we characterized Arc expression after spatial exploration or cage control conditions in adult-born neurons from rats that were injected with BrdU on one day and were sacrificed 1, 7, 15, 30, and 45 days post-BrdU injection (PBI). Triple immunostaining for NeuN, Arc, and BrdU was analyzed through the different DG layers. Arc protein expression in BrdU-positive cells was observed from day 1 to day 15 PBI but was not related to behavioral stimulation. The specific Arc-expression response to spatial exploration was observed from day 30 and 45 in about 5% of the BrdU-positive cell population. Most of the BrdU-positive neurons expressing Arc in response to spatial exploration (∼90%) were located in DG layer 1, and no Arc expression was observed in cells located in the subgranular zone (SGZ). Using the current data and that obtained previously, we propose a mathematical model suggesting that new neurons are unlikely to respond to exploration by expressing Arc after they are 301 days old, and also that in a 7-month-old rat the majority (60%) of the neurons that respond to exploration must have been born during adulthood; thus, suggesting that adult neurogenesis in the DG is highly relevant for spatial information processing. PMID:21408012

  7. Trading new neurons for status: Adult hippocampal neurogenesis in eusocial Damaraland mole-rats.

    PubMed

    Oosthuizen, M K; Amrein, I

    2016-06-02

    Diversity in social structures, from solitary to eusocial, is a prominent feature of subterranean African mole-rat species. Damaraland mole-rats are eusocial, they live in colonies that are characterized by a reproductive division of labor and a subdivision into castes based on physiology and behavior. Damaraland mole-rats are exceptionally long lived and reproductive animals show delayed aging compared to non-reproductive animals. In the present study, we described the hippocampal architecture and the rate of hippocampal neurogenesis of wild-derived, adult Damaraland mole-rats in relation to sex, relative age and social status or caste. Overall, Damaraland mole-rats were found to have a small hippocampus and low rates of neurogenesis. We found no correlation between neurogenesis and sex or relative age. Social status or caste was the most prominent modulator of neurogenesis. An inverse relationship between neurogenesis and social status was apparent, with queens displaying the lowest neurogenesis while the worker mole-rats had the most. As there is no natural progression from one caste to another, social status within a colony was relatively stable and is reflected in the level of neurogenesis. Our results correspond to those found in the naked mole-rat, and may reflect an evolutionary and environmentally conserved trait within social mole-rat species.

  8. High neuronal/astroglial differentiation plasticity of adult rat hippocampal neural stem/progenitor cells in response to the effects of embryonic and adult cerebrospinal fluids

    PubMed Central

    Peirouvi, T.; Yekani, F.; Azarnia, M.; Massumi, M.

    2015-01-01

    Hippocampal neural stem/progenitor cells (hipp-NS/PCs) of the adult mammalian brain are important sources of neuronal and gial cell production. In this study, the main goal is to investigate the plasticity of these cells in neuronal/astroglial differentiations. To this end, the differentiation of the hipp-NS/PCs isolated from 3-month-old Wistar rats was investigated in response to the embryonic cerebrospinal fluid (E-CSF) including E13.5, E17-CSF and the adult cerebrospinal fluid (A-CSF), all extracted from rats. CSF samples were selected based on their effects on cell behavioral parameters. Primary cell culture was performed in the presence of either normal or high levels of KCL in a culture medium. High levels of KCL cause cell depolarization, and thus the activation of quiescent NSCs. Results from immunocytochemistry (ICC) and semi-quantitative RT-PCR (sRT-PCR) techniques showed that in E-CSF-treated groups, neuronal differentiation increased (E17>E13.5). In contrast, A-CSF decreased and increased neuronal and astroglial differentiations, respectively. Cell survivability and/or proliferation (S/P), evaluated by an MTT assay, increased by E13.5 CSF, but decreased by both E17 CSF and A-CSF. Based on the results, it is finally concluded that adult rat hippocampal proliferative cells are not restricted progenitors but rather show high plasticity in neuronal/astroglial differentiation according to the effects of CSF samples. In addition, using high concentrations of KCL in the primary cell culture led to an increase in the number of NSCs, which in turn resulted in the increase in neuronal or astroglial differentiations after CSF treatment. PMID:27175157

  9. Olfactory and cortical projections to bulbar and hippocampal adult-born neurons

    PubMed Central

    De La Rosa-Prieto, Carlos; De Moya-Pinilla, Miguel; Saiz-Sanchez, Daniel; Ubeda-banon, Isabel; Arzate, Dulce M.; Flores-Cuadrado, Alicia; Liberia, Teresa; Crespo, Carlos; Martinez-Marcos, Alino

    2015-01-01

    New neurons are continually generated in the subependymal layer of the lateral ventricles and the subgranular zone of dentate gyrus during adulthood. In the subventricular zone, neuroblasts migrate a long distance to the olfactory bulb where they differentiate into granule or periglomerular interneurons. In the hippocampus, neuroblasts migrate a short distance from the subgranular zone to the granule cell layer of the dentate gyrus to become granule neurons. In addition to the short-distance inputs, bulbar interneurons receive long-distance centrifugal afferents from olfactory-recipient structures. Similarly, dentate granule cells receive differential inputs from the medial and lateral entorhinal cortices through the perforant pathway. Little is known concerning these new inputs on the adult-born cells. In this work, we have characterized afferent inputs to 21-day old newly-born neurons. Mice were intraperitoneally injected with bromodeoxyuridine. Two weeks later, rhodamine-labeled dextran-amine was injected into the anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral and medial entorhinal cortices. One week later, animals were perfused and immunofluorescences were carried out. The data show that projection neurons from the mentioned structures, establish putative synaptic contacts onto 21-day-old neurons in the olfactory bulb and dentate gyrus, in some cases even before they start to express specific subpopulation proteins. Long-distance afferents reach middle and outer one-third portions of the molecular layer of the dentate gyrus and granule and, interestingly, periglomerular layers of the olfactory bulb. In the olfactory bulb, these fibers appear to establish presumptive axo-somatic contacts onto newly-born granule and periglomerular cells. PMID:25698936

  10. The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells

    PubMed Central

    Valente, Maria Maddalena; Allen, Megan; Bortolotto, Valeria; Lim, Seung T.; Conant, Katherine; Grilli, Mariagrazia

    2015-01-01

    Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a role in varied forms of developmental and postnatal neuroplasticity. MMP substrates include protease-activated receptor-1 (PAR-1), a G-protein coupled receptor expressed in hippocampus. We examined proliferation and differentiation of adult neural progenitor cells (aNPCs) from hippocampi of mice that overexpress the potent PAR-1 agonist MMP-1. We found that, as compared to aNPCs from littermate controls, MMP-1 tg aNPCs display enhanced proliferation. Under differentiating conditions, these cells give rise to a higher percentage of MAP-2+ neurons and a reduced number of oligodendrocyte precursors, and no change in the number of astrocytes. The fact that these results are MMP and PAR-1 dependent is supported by studies with distinct antagonists. Moreover, JSH-23, an inhibitor of NF-κB p65 nuclear translocation, counteracted both the proliferation and differentiation changes seen in MMP-1 tg-derived NPCs. In complementary studies, we found that the percentage of Sox2+ undifferentiated progenitor cells is increased in hippocampi of MMP-1 tg animals, compared to wt mice. Together, these results add to a growing body of data suggesting that MMPs are effectors of hippocampal neuroplasticity in the adult CNS and that the MMP-1/PAR-1 axis may play a role in neurogenesis following physiological and/or pathological stimuli. PMID:26783471

  11. Differential dendritic targeting of AMPA receptor subunit mRNAs in adult rat hippocampal principal neurons and interneurons.

    PubMed

    Cox, David J; Racca, Claudia

    2013-06-15

    In hippocampal neurons, AMPA receptors (AMPARs) mediate fast excitatory postsynaptic responses at glutamatergic synapses, and are involved in various forms of synaptic plasticity. Dendritic local protein synthesis of selected AMPAR subunit mRNAs is considered an additional mechanism to independently and rapidly control the strength of individual synapses. We have used fluorescent in situ hybridization and immunocytochemistry to analyze the localization of AMPAR subunit (GluA1-4) mRNAs and their relationship with the translation machinery in principal cells and interneurons of the adult rat hippocampus. The mRNAs encoding all four AMPAR subunits were detected in the somata and dendrites of CA3 and CA1 pyramidal cells and those of six classes of CA1 γ-aminobutyric acid (GABA)ergic interneurons. GluA1-4 subunit mRNAs were highly localized to the apical dendrites of pyramidal cells, whereas in interneurons they were present in multiple dendrites. In contrast, in the dentate gyrus, GluA1-4 subunit mRNAs were virtually restricted to the somata and were absent from the dendrites of granule cells. These different regional and cell type-specific labeling patterns also correlated with the localization of markers for components of the protein synthesis machinery. Our results support the local translation of GluA1-4 mRNAs in dendrites of hippocampal pyramidal cells and CA1 interneurons but not in granule cells of the dentate gyrus. Furthermore, the regional and cell type-specific differences we observed suggest that each cell type uses distinct ways of regulating the local translation of AMPAR subunits.

  12. Rit GTPase Signaling Promotes Immature Hippocampal Neuronal Survival

    PubMed Central

    Cai, Weikang; Carlson, Shaun W.; Brelsfoard, Jennifer M.; Mannon, Catherine E.; Moncman, Carole L.; Saatman, Kathryn E.; Andres, Douglas A.

    2012-01-01

    The molecular mechanisms governing the spontaneous recovery seen following brain injury remain elusive, but recent studies indicate that injury-induced stimulation of hippocampal neurogenesis contributes to the repair process. The therapeutic potential of endogenous neurogenesis is tempered by the demonstration that traumatic brain injury (TBI) results in the selective death of adult-born immature neurons, compromising the cell population poised to compensate for trauma-induced neuronal loss. Here, we identify the Ras-related GTPase, Rit, as a critical player in the survival of immature hippocampal neurons following brain injury. While Rit knockout (Rit−/−) did not alter hippocampal development, hippocampal neural cultures derived from Rit−/− mice display increased cell death and blunted MAPK cascade activation in response to oxidative stress, without affecting BDNF-dependent signaling. When compared to wild-type hippocampal cultures, Rit loss rendered immature (Dcx+) neurons susceptible to oxidative damage, without altering the survival of neural progenitor (Nestin+) cells. Oxidative stress is a major contributor to neuronal cell death following brain injury. Consistent with the enhanced vulnerability of cultured Rit−/− immature neurons, Rit−/− mice exhibited a significantly greater loss of adult-born immature neurons within the dentate gyrus after TBI. In addition, post-TBI neuronal remodeling was blunted. Taken together, these data identify a new and unexpected role for Rit in injury-induced neurogenesis, functioning as a selective survival mechanism for immature hippocampal neurons within the subgranular zone of the dentate gyrus following TBI. PMID:22815504

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

    PubMed Central

    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

  14. Altered Hippocampal Neurogenesis and Amygdalar Neuronal Activity in Adult Mice with Repeated Experience of Aggression

    PubMed Central

    Smagin, Dmitry A.; Park, June-Hee; Michurina, Tatyana V.; Peunova, Natalia; Glass, Zachary; Sayed, Kasim; Bondar, Natalya P.; Kovalenko, Irina N.; Kudryavtseva, Natalia N.; Enikolopov, Grigori

    2015-01-01

    Repeated experience of winning in a social conflict setting elevates levels of aggression and may lead to violent behavioral patterns. Here, we use a paradigm of repeated aggression and fighting deprivation to examine changes in behavior, neurogenesis, and neuronal activity in mice with positive fighting experience. We show that for males, repeated positive fighting experience induces persistent demonstration of aggression and stereotypic behaviors in daily agonistic interactions, enhances aggressive motivation, and elevates levels of anxiety. When winning males are deprived of opportunities to engage in further fights, they demonstrate increased levels of aggressiveness. Positive fighting experience results in increased levels of progenitor cell proliferation and production of young neurons in the hippocampus. This increase is not diminished after a fighting deprivation period. Furthermore, repeated winning experience decreases the number of activated (c-fos-positive) cells in the basolateral amygdala and increases the number of activated cells in the hippocampus; a subsequent no-fight period restores the number of c-fos-positive cells. Our results indicate that extended positive fighting experience in a social conflict heightens aggression, increases proliferation of neuronal progenitors and production of young neurons in the hippocampus, and decreases neuronal activity in the amygdala; these changes can be modified by depriving the winners of the opportunity for further fights. PMID:26648838

  15. Green tea compound epigallo-catechin-3-gallate (EGCG) increases neuronal survival in adult hippocampal neurogenesis in vivo and in vitro.

    PubMed

    Ortiz-López, L; Márquez-Valadez, B; Gómez-Sánchez, A; Silva-Lucero, M D C; Torres-Pérez, M; Téllez-Ballesteros, R I; Ichwan, M; Meraz-Ríos, M A; Kempermann, G; Ramírez-Rodríguez, G B

    2016-05-13

    Epigallo-catechin-3-gallate (EGCG), found in the leaves of Camellia sinensis (green tea), has antioxidant- and scavenger-functions and acts neuroprotectively. It has been publicized as anti-aging remedy but data on potential cellular mechanisms are scarce. Recent studies claimed that EGCG specifically promotes neural precursor cell proliferation in the dentate gyrus of C57Bl/6 mice, without changes at the level of immature and mature new neurons. We here analyzed the effects of EGCG on adult hippocampal neurogenesis in male Balb/C mice and saw a different pattern. Two weeks of treatment with EGCG (0, 0.625, 1.25, 2.5, 5 and 10mg/kg) showed a dose-response curve that peaked at 2.5mg/kg of EGCG with significantly increased cell survival without affecting cell proliferation but decreasing apoptotic cells. Also, EGCG increased the population of doublecortin-(DCX)-expressing cells that comprises the late intermediate progenitor cells (type-2b and -3) as well as immature neurons. After EGCG treatment, the young DCX-positive neurons showed more elaborated dendritic trees. EGCG also significantly increased net neurogenesis in the adult hippocampus and increased the hippocampal levels of phospho-Akt. Ex vivo, EGCG exerted a direct effect on survival and neuronal differentiation of adult hippocampal precursor cells, which was absent, when PI3K, a protein upstream of Akt, was blocked. Our results thus support a pro-survival and a pro-neurogenic role of EGCG. In the context of the conflicting published results, however, potential genetic modifiers must be assumed. These might help to explain the overall variability of study results with EGCG. Our data do indicate, however, that natural compounds such as EGCG can in principle modulate brain plasticity.

  16. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation.

    PubMed

    Sahay, Amar; Scobie, Kimberly N; Hill, Alexis S; O'Carroll, Colin M; Kheirbek, Mazen A; Burghardt, Nesha S; Fenton, André A; Dranovsky, Alex; Hen, René

    2011-04-28

    Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal

  17. How to make a hippocampal dentate gyrus granule neuron.

    PubMed

    Yu, Diana X; Marchetto, Maria C; Gage, Fred H

    2014-06-01

    Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.

  18. Involvement of Adult Hippocampal Neurogenesis in Learning and Forgetting

    PubMed Central

    Yau, Suk-yu; Li, Ang; So, Kwok-Fai

    2015-01-01

    Adult hippocampal neurogenesis is a process involving the continuous generation of newborn neurons in the hippocampus of adult animals. Mounting evidence has suggested that hippocampal neurogenesis contributes to some forms of hippocampus-dependent learning and memory; however, the detailed mechanism concerning how this small number of newborn neurons could affect learning and memory remains unclear. In this review, we discuss the relationship between adult-born neurons and learning and memory, with a highlight on recently discovered potential roles of neurogenesis in pattern separation and forgetting. PMID:26380120

  19. Spatial Relational Memory Requires Hippocampal Adult Neurogenesis

    PubMed Central

    Koehl, Muriel; Ichas, François; De Giorgi, Francesca; Costet, Pierre; Abrous, Djoher Nora; Piazza, Pier Vincenzo

    2008-01-01

    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. PMID:18509506

  20. TAM receptor deficiency affects adult hippocampal neurogenesis

    PubMed Central

    Ji, Rui; Meng, Lingbin; Li, Qiutang; Lu, Qingxian

    2014-01-01

    The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus. PMID:25487541

  1. Calcium Phosphate Transfection of Primary Hippocampal Neurons

    PubMed Central

    DiBona, Victoria L.; Wu, Qian; Zhang, Huaye

    2013-01-01

    Calcium phosphate precipitation is a convenient and economical method for transfection of cultured cells. With optimization, it is possible to use this method on hard-to-transfect cells like primary neurons. Here we describe our detailed protocol for calcium phosphate transfection of hippocampal neurons cocultured with astroglial cells. PMID:24300106

  2. Ventral hippocampal neurons inhibit postprandial energy intake.

    PubMed

    Hannapel, Reilly C; Henderson, Yoko H; Nalloor, Rebecca; Vazdarjanova, Almira; Parent, Marise B

    2017-03-01

    Evidence suggests that the memory of a recently ingested meal limits subsequent intake. Given that ventral hippocampal (vHC) neurons are involved in memory and energy intake, the present experiment tested the hypothesis that vHC neurons contribute to the formation of a memory of a meal and inhibit energy intake during the postprandial period. We tested (1) whether pharmacological inactivation of vHC neurons during the period following a sucrose meal, when the memory of the meal would be undergoing consolidation, accelerates the onset of the next sucrose meal and increases intake and (2) whether sucrose intake increases vHC expression of the synaptic plasticity marker activity-regulated cytoskeletal-associated protein (Arc). Adult male Sprague-Dawley rats were trained to consume a 32% sucrose solution daily at the same time and location. On the experimental day, the rats were given intra-vHC infusions of the GABAA receptor agonist muscimol or vehicle after they finished their first sucrose meal. Compared to vehicle infusions, postmeal intra-vHC muscimol infusions decreased the latency to the next sucrose meal, increased the amount of sucrose consumed during that meal, increased the total number of sucrose meals and the total amount of sucrose ingested. In addition, rats that consumed sucrose had higher levels of Arc expression in both vHC CA1 and CA3 subfields than cage control rats. Collectively, these findings are the first to show that vHC neurons inhibit energy intake during the postprandial period and support the hypothesis that vHC neurons form a memory of a meal and inhibit subsequent intake. © 2016 Wiley Periodicals, Inc.

  3. Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats.

    PubMed

    Blurton-Jones, Mathew; Tuszynski, Mark H

    2002-10-21

    Estrogen has been reported to regulate the activity of gamma-aminobutyric acid (GABA)ergic interneurons within the hippocampus, basal forebrain, and hypothalamus of adult rodents. Although estrogen receptor-alpha bearing GABAergic interneurons have been identified previously, the neurotransmitter phenotype of cells that express the more recently characterized estrogen receptor-beta (ER-beta) has not been examined in vivo. We, therefore, have used fluorescent immunohistochemistry to further characterize the phenotype of ER-beta-bearing cells by double labeling for the GABAergic-associated calcium-binding protein, parvalbumin (PV). We find that a large proportion of ER-beta-immunoreactive cells within the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized (ovx) adult rats are PV-immunoreactive. Within the infralimbic, agranular insular, primary motor, parietal association, perirhinal, and lateral entorhinal cortices, an average of 95.6% +/- 0.8% (intact) and 94.5% +/- 1.4% (ovx) of all ER-beta-immunoreactive cells coexpress parvalbumin, and this proportion is strikingly similar across these diverse cortical regions. ER-beta/PV double-labeled cells represent 23.3% +/- 1.6% (intact) and 25.8% +/- 2.0% (ovx) of all PV-labeled cells within these regions. ER-beta/PV double-labeled cells are also observed within the lateral, accessory basal, and posterior cortical nuclei of the amygdala, and periamygdaloid cortex. Within the basal forebrain, 31.0% +/- 3.1% (intact) and 26.0% +/- 5.2 % (ovx) of ER-beta-immunoreactive cells coexpress PV. Almost all ER-beta-immunoreactive cells within the subiculum, a major output region of the hippocampal formation, double label for PV (intact = 97.2% +/- 2.8%; ovx = 100% +/- 0.0%). Thus, ER-beta exhibits extensive colocalization with a subclass of inhibitory neurons, suggesting a potential mechanism whereby estrogen can regulate neuronal excitability in diverse and broad brain regions by modulating

  4. The role of microglia in adult hippocampal neurogenesis.

    PubMed

    Gemma, Carmelina; Bachstetter, Adam D

    2013-11-22

    Our view of microglia has dramatically changed in the last decade. From cells being "silent" in the healthy brain, microglia have emerged to be actively involved in several brain physiological functions including adult hippocampal neurogenesis, and cognitive and behavioral function. In light of recent discoveries revealing a role of microglia as important effectors of neuronal circuit reorganization, considerable attention has been focused on how microglia and hippocampal neurogenesis could be an interdependent phenomenon. In this review the role of microglia in the adult hippocampal neurogenesis under physiological condition is discussed.

  5. Microbats appear to have adult hippocampal neurogenesis, but post-capture stress causes a rapid decline in the number of neurons expressing doublecortin.

    PubMed

    Chawana, R; Alagaili, A; Patzke, N; Spocter, M A; Mohammed, O B; Kaswera, C; Gilissen, E; Bennett, N C; Ihunwo, A O; Manger, P R

    2014-09-26

    A previous study investigating potential adult hippocampal neurogenesis in microchiropteran bats failed to reveal a strong presence of this neural trait. As microchiropterans have a high field metabolic rate and a small body mass, it is possible that capture/handling stress may lead to a decrease in the detectable presence of adult hippocampal neurogenesis. Here we looked for evidence of adult hippocampal neurogenesis using immunohistochemical techniques for the endogenous marker doublecortin (DCX) in 10 species of microchiropterans euthanized and perfusion fixed at specific time points following capture. Our results reveal that when euthanized and perfused within 15 min of capture, abundant putative adult hippocampal neurogenesis could be detected using DCX immunohistochemistry. Between 15 and 30 min post-capture, the detectable levels of DCX dropped dramatically and after 30 min post-capture, immunohistochemistry for DCX could not reveal any significant evidence of putative adult hippocampal neurogenesis. Thus, as with all other mammals studied to date apart from cetaceans, bats, including both microchiropterans and megachiropterans, appear to exhibit substantial levels of adult hippocampal neurogenesis. The present study underscores the concept that, as with laboratory experiments, studies conducted on wild-caught animals need to be cognizant of the fact that acute stress (capture/handling) may induce major changes in the appearance of specific neural traits.

  6. Benzodiazepines do not potentiate GABA responses in neonatal hippocampal neurons.

    PubMed

    Rovira, C; Ben-Ari, Y

    1991-09-16

    Benzodiazepines (midazolam; flunitrazepam) and pentobarbital increase the response to exogenous gamma-aminobutyric acid (GABA) in adult hippocampal cells. We report in this paper that in contrast pentobarbital but not benzodiazepine potentiate the effects of exogenous (GABA) in neurons recorded from slices of less than two weeks old. This finding suggests that the functional association of benzodiazepine and GABAA receptors is changed during early postnatal life.

  7. Time course of morphine's effects on adult hippocampal subgranular zone reveals preferential inhibition of cells in S phase of the cell cycle and a subpopulation of immature neurons.

    PubMed

    Arguello, A A; Harburg, G C; Schonborn, J R; Mandyam, C D; Yamaguchi, M; Eisch, A J

    2008-11-11

    Opiates, such as morphine, decrease neurogenesis in the adult hippocampal subgranular zone (SGZ), raising the possibility that decreased neurogenesis contributes to opiate-induced cognitive deficits. However, there is an incomplete understanding of how alterations in cell cycle progression and progenitor maturation contribute to this decrease. The present study examined how morphine regulates progenitor cell cycle, cell death and immature SGZ neurons (experiment 1) as well as the progression of SGZ progenitors through key stages of maturation (experiment 2). In experiment 1, mice received sham or morphine pellets (s.c., 0 and 48 h) and bromodeoxyuridine (BrdU) 2 h prior to sacrifice (24, 72 or 96 h). Morphine decreased both the number of S phase and total cycling cells, as there were fewer cells immunoreactive (IR) for the S phase marker BrdU and the cell cycle marker Ki67. The percentage of Ki67-IR cells that were BrdU-IR was decreased after 24 but not 96 h of morphine, suggesting a disproportionate effect on S phase cells relative to all cycling cells at this time point. Cell death (activated caspase-3 counts) was increased after 24 but not 96 h. In experiment 2, nestin-green fluorescent protein (GFP) mice given BrdU 1 day prior to morphine or sham surgery (0 and 48 h, sacrifice 96 h) had fewer Ki67-IR cells, but no change in BrdU-IR cell number, suggesting that this population of BrdU-IR cells was less sensitive to morphine. Interestingly, examination of key stages of progenitor cell maturation revealed that morphine increased the percent of BrdU-IR cells that were type 2b and decreased the percent that were immature neurons. These data suggest that chronic morphine decreases SGZ neurogenesis by inhibiting dividing cells, particularly those in S phase, and progenitor cell progression to a more mature neuronal stage.

  8. Inhibitory control of hippocampal inhibitory neurons

    PubMed Central

    Chamberland, Simon; Topolnik, Lisa

    2012-01-01

    Information processing within neuronal networks is determined by a dynamic partnership between principal neurons and local circuit inhibitory interneurons. The population of GABAergic interneurons is extremely heterogeneous and comprises, in many brain regions, cells with divergent morphological and physiological properties, distinct molecular expression profiles, and highly specialized functions. GABAergic interneurons have been studied extensively during the past two decades, especially in the hippocampus, which is a relatively simple cortical structure. Different types of hippocampal inhibitory interneurons control spike initiation [e.g., axo-axonic and basket cells (BCs)] and synaptic integration (e.g., bistratified and oriens–lacunosum moleculare interneurons) within pyramidal neurons and synchronize local network activity, providing a means for functional segregation of neuronal ensembles and proper routing of hippocampal information. Thus, it is thought that, at least in the hippocampus, GABAergic inhibitory interneurons represent critical regulating elements at all stages of information processing, from synaptic integration and spike generation to large-scale network activity. However, this raises an important question: if inhibitory interneurons are fundamental for network computations, what are the mechanisms that control the activity of the interneurons themselves? Given the essential role of synaptic inhibition in the regulation of neuronal activity, it would be logical to expect that specific inhibitory mechanisms have evolved to control the operation of interneurons. Here, we review the mechanisms of synaptic inhibition of interneurons and discuss their role in the operation of hippocampal inhibitory circuits. PMID:23162426

  9. Network synchronization in hippocampal neurons.

    PubMed

    Penn, Yaron; Segal, Menahem; Moses, Elisha

    2016-03-22

    Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron's tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network's activity and dynamics, contributing to our understanding of developing neural circuits.

  10. Tau Protein and Adult Hippocampal Neurogenesis

    PubMed Central

    Fuster-Matanzo, Almudena; Llorens-Martín, María; Jurado-Arjona, Jerónimo; Avila, Jesús; Hernández, Félix

    2012-01-01

    Tau protein is a microtubule-associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10) and by presence of hyperphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis. PMID:22787440

  11. Network synchronization in hippocampal neurons

    PubMed Central

    Penn, Yaron; Segal, Menahem; Moses, Elisha

    2016-01-01

    Oscillatory activity is widespread in dynamic neuronal networks. The main paradigm for the origin of periodicity consists of specialized pacemaking elements that synchronize and drive the rest of the network; however, other models exist. Here, we studied the spontaneous emergence of synchronized periodic bursting in a network of cultured dissociated neurons from rat hippocampus and cortex. Surprisingly, about 60% of all active neurons were self-sustained oscillators when disconnected, each with its own natural frequency. The individual neuron’s tendency to oscillate and the corresponding oscillation frequency are controlled by its excitability. The single neuron intrinsic oscillations were blocked by riluzole, and are thus dependent on persistent sodium leak currents. Upon a gradual retrieval of connectivity, the synchrony evolves: Loose synchrony appears already at weak connectivity, with the oscillators converging to one common oscillation frequency, yet shifted in phase across the population. Further strengthening of the connectivity causes a reduction in the mean phase shifts until zero-lag is achieved, manifested by synchronous periodic network bursts. Interestingly, the frequency of network bursting matches the average of the intrinsic frequencies. Overall, the network behaves like other universal systems, where order emerges spontaneously by entrainment of independent rhythmic units. Although simplified with respect to circuitry in the brain, our results attribute a basic functional role for intrinsic single neuron excitability mechanisms in driving the network’s activity and dynamics, contributing to our understanding of developing neural circuits. PMID:26961000

  12. Axon specification in hippocampal neurons.

    PubMed

    Fukata, Yuko; Kimura, Toshihide; Kaibuchi, Kozo

    2002-08-01

    Neurons are the most highly polarized cells, comprised of two structurally and functionally distinct parts, axons and dendrites. This asymmetry enables a vectorial flow of signaling within neurons. One of the most fundamental questions still to be answered in neuroscience is how these two specialized processes initially develop. The first manifestation of polarization occurs when one of the immature neurites acquires axonal characteristics. We review recent advances that have highlighted the involvement of several cellular events in the initial formation of the axon, including membrane traffic and cytoskeletal rearrangement. We then discuss the molecular mechanisms underlying axon formation, focusing on the Rho family small GTPases and an axon-inducing neuronal protein, CRMP-2.

  13. Extrasynaptic vesicle recycling in mature hippocampal neurons.

    PubMed

    Ratnayaka, Arjuna; Marra, Vincenzo; Branco, Tiago; Staras, Kevin

    2011-11-08

    Fast neuronal signalling relies on highly regulated vesicle fusion and recycling at specialized presynaptic terminals. Recently, examples of non-classical neurotransmission have also been reported, where fusion of vesicles can occur at sites remote from conventional synapses. This has potentially broad biological implications, but the underlying mechanisms are not well established. Here we show that a complete vesicle recycling pathway can occur at discrete axonal sites in mature hippocampal neurons and that extrasynaptic fusion is a robust feature of native tissue. We demonstrate that laterally mobile vesicle clusters trafficking between synaptic terminals become transiently stabilized by evoked action potentials and undergo complete but delayed Ca(2+)-dependent fusion along axons. This fusion is associated with dynamic actin accumulation and, subsequently, vesicles can be locally recycled, re-acidified and re-used. Immunofluorescence and ultrastructural work demonstrates that extrasynaptic fusion sites can have apposed postsynaptic specializations, suggesting that mobile vesicle recycling may underlie highly dynamic neuron-neuron communication.

  14. New Hippocampal Neurons Are Not Obligatory for Memory Formation; Cyclin D2 Knockout Mice with No Adult Brain Neurogenesis Show Learning

    ERIC Educational Resources Information Center

    Jaholkowski, Piotr; Kiryk, Anna; Jedynak, Paulina; Abdallah, Nada M. Ben; Knapska, Ewelina; Kowalczyk, Anna; Piechal, Agnieszka; Blecharz-Klin, Kamilla; Figiel, Izabela; Lioudyno, Victoria; Widy-Tyszkiewicz, Ewa; Wilczynski, Grzegorz M.; Lipp, Hans-Peter; Kaczmarek, Leszek; Filipkowski, Robert K.

    2009-01-01

    The role of adult brain neurogenesis (generating new neurons) in learning and memory appears to be quite firmly established in spite of some criticism and lack of understanding of what the new neurons serve the brain for. Also, the few experiments showing that blocking adult neurogenesis causes learning deficits used irradiation and various drugs…

  15. High frequency stimulation induces sonic hedgehog release from hippocampal neurons

    PubMed Central

    Su, Yujuan; Yuan, Yuan; Feng, Shengjie; Ma, Shaorong; Wang, Yizheng

    2017-01-01

    Sonic hedgehog (SHH) as a secreted protein is important for neuronal development in the central nervous system (CNS). However, the mechanism about SHH release remains largely unknown. Here, we showed that SHH was expressed mainly in the synaptic vesicles of hippocampus in both young postnatal and adult rats. High, but not low, frequency stimulation, induces SHH release from the neurons. Moreover, removal of extracellular Ca2+, application of tetrodotoxin (TTX), an inhibitor of voltage-dependent sodium channels, or downregulation of soluble n-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) proteins, all blocked SHH release from the neurons in response to HFS. Our findings suggest a novel mechanism to control SHH release from the hippocampal neurons. PMID:28262835

  16. Wnt signaling in the regulation of adult hippocampal neurogenesis

    PubMed Central

    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

  17. Millisecond Timescale Synchrony among Hippocampal Neurons

    PubMed Central

    Amarasingham, Asohan; Mizuseki, Kenji; Buzsáki, György

    2014-01-01

    Inhibitory neurons in cortical circuits play critical roles in composing spike timing and oscillatory patterns in neuronal activity. These roles in turn require coherent activation of interneurons at different timescales. To investigate how the local circuitry provides for these activities, we applied resampled cross-correlation analyses to large-scale recordings of neuronal populations in the cornu ammonis 1 (CA1) and CA3 regions of the hippocampus of freely moving rats. Significant counts in the cross-correlation of cell pairs, relative to jittered surrogate spike-trains, allowed us to identify the effective couplings between neurons in CA1 and CA3 hippocampal regions on the timescale of milliseconds. In addition to putative excitatory and inhibitory monosynaptic connections, we uncovered prominent millisecond timescale synchrony between cell pairs, observed as peaks in the central 0 ms bin of cross-correlograms. This millisecond timescale synchrony appeared to be independent of network state, excitatory input, and γ oscillations. Moreover, it was frequently observed between cells of differing putative interneuronal type, arguing against gap junctions as the sole underlying source. Our observations corroborate recent in vitro findings suggesting that inhibition alone is sufficient to synchronize interneurons at such fast timescales. Moreover, we show that this synchronous spiking may cause stronger inhibition and rebound spiking in target neurons, pointing toward a potential function for millisecond synchrony of interneurons in shaping and affecting timing in pyramidal populations within and downstream from the circuit. PMID:25378164

  18. Optogenetic Activation of Septal Glutamatergic Neurons Drive Hippocampal Theta Rhythms.

    PubMed

    Robinson, Jennifer; Manseau, Frédéric; Ducharme, Guillaume; Amilhon, Bénédicte; Vigneault, Erika; El Mestikawy, Salah; Williams, Sylvain

    2016-03-09

    The medial septum and diagonal band of Broca (MS-DBB) has an essential role for theta rhythm generation in the hippocampus and is critical for learning and memory. The MS-DBB contains cholinergic, GABAergic, and recently described glutamatergic neurons, but their specific contribution to theta generation is poorly understood. Here, we examined the role of MS-DBB glutamatergic neurons in theta rhythm using optogenetic activation and electrophysiological recordings performed in in vitro preparations and in freely behaving mice. The experiments in slices suggest that MS-DBB glutamatergic neurons provide prominent excitatory inputs to a majority of local GABAergic and a minority of septal cholinergic neurons. In contrast, activation of MS-DBB glutamatergic fiber terminals in hippocampal slices elicited weak postsynaptic responses in hippocampal neurons. In the in vitro septo-hippocampal preparation, activation of MS-DBB glutamatergic neurons did increase the rhythmicity of hippocampal theta oscillations, whereas stimulation of septo-hippocampal glutamatergic fibers in the fornix did not have an effect. In freely behaving mice, activation of these neurons in the MS-DBB strongly synchronized hippocampal theta rhythms over a wide range of frequencies, whereas activation of their projections to the hippocampus through fornix stimulations had no effect on theta rhythms, suggesting that MS-DBB glutamatergic neurons played a role in theta generation through local modulation of septal neurons. Together, these results provide the first evidence that MS-DBB glutamatergic neurons modulate local septal circuits, which in turn contribute to theta rhythms in the hippocampus.

  19. Novel transient outward K+ current of mature murine hippocampal neurones.

    PubMed

    Li, X Y; McArdle, J J

    1997-06-01

    Hippocampal neurones were freshly isolated from the brain of adult mice and voltage-dependent K+ currents were recorded with whole-cell patch-clamp technique. Three components of transient K+ current (IA) were isolated when analyzing data with exponential functions or treating neurones with a variety of voltage protocols and pharmacologic agents. Subtraction of the delayed rectifier current (IK) from the K+ currents elicited after prepulses to -120 mV of varying duration revealed fast (IAf) and slow (IAs) components with decay time constants of 45 +/- 8 and 612 +/- 140 ms, respectively; the corresponding time constants for the removal of inactivation were 12.3 and 189.6 ms. both tetraethylammonium and dendrotoxin selectively inhibited IAs. 4-Aminopyridine (4-AP) specifically blocked IAf and 40% of IAs with different affinities. Therefore, the properties of a 4-AP-resistant (IAsR) and 4-AP-sensitive (IAsS) component of IAs were compared. These data suggest that three distinct subtypes of K+ currents contribute to the IA of mature murine hippocampal neurones.

  20. Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition

    PubMed Central

    Zhang, Run-Rui; Cui, Qing-Yan; Murai, Kiyohito; Lim, Yen Ching; Smith, Zachary D.; Jin, Shengnan; Ye, Peng; Rosa, Luis; Lee, Yew Kok; Wu, Hai-Ping; Liu, Wei; Xu, Zhi-Mei; Yang, Lu; Ding, Yu-Qiang; Tang, Fuchou; Meissner, Alexander; Ding, Chunming; Shi, Yanhong; Xu, Guo-Liang

    2015-01-01

    SUMMARY DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and down-regulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain. PMID:23770080

  1. Adult hippocampal neurogenesis in natural populations of mammals.

    PubMed

    Amrein, Irmgard

    2015-05-01

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

  2. Role of adult hippocampal neurogenesis in cognition in physiology and disease: pharmacological targets and biomarkers.

    PubMed

    Costa, Veronica; Lugert, Sebastian; Jagasia, Ravi

    2015-01-01

    Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

  3. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons123

    PubMed Central

    Lee, Anni S.; Kabir, Zeeba D.; Knobbe, Whitney; Orr, Madeline; Burgdorf, Caitlin; Huntington, Paula; McDaniel, Latisha; Britt, Jeremiah K.; Hoffmann, Franz; Brat, Daniel J.; Rajadhyaksha, Anjali M.

    2016-01-01

    Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract PMID:27066530

  4. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons.

    PubMed

    Lee, Anni S; De Jesús-Cortés, Héctor; Kabir, Zeeba D; Knobbe, Whitney; Orr, Madeline; Burgdorf, Caitlin; Huntington, Paula; McDaniel, Latisha; Britt, Jeremiah K; Hoffmann, Franz; Brat, Daniel J; Rajadhyaksha, Anjali M; Pieper, Andrew A

    2016-01-01

    Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract.

  5. Adult hippocampal neurogenesis and memory interference.

    PubMed

    Winocur, Gordon; Becker, Suzanna; Luu, Paul; Rosenzweig, Shira; Wojtowicz, J Martin

    2012-02-14

    Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory.

  6. Dendritic potassium channels in hippocampal pyramidal neurons

    PubMed Central

    Johnston, Daniel; Hoffman, Dax A; Magee, Jeffrey C; Poolos, Nicholas P; Watanabe, Shigeo; Colbert, Costa M; Migliore, Michele

    2000-01-01

    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 μm of the apical dendrites, so that action potentials recorded farther than 200 μm 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. PMID:10811726

  7. Dendritic potassium channels in hippocampal pyramidal neurons.

    PubMed

    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.

  8. Neurotrophic effects of tianeptine on hippocampal neurons: a proteomic approach.

    PubMed

    Chu, Chin-Chen; Wang, Jhi-Joung; Chen, Kuan-Ting; Shieh, Ja-Ping; Wang, Li-Kai; Shui, Hao-Ai; Ho, Shung-Tai

    2010-02-05

    Tianeptine, an atypical tricyclic antidepressant with unique characteristics, can improve memory and prevent stress-induced hippocampal damage. It has neuroplastic and neurotrophic effects on hippocampal neurons and can prevent dendritic atrophy of the hippocampus in certain pathological conditions. To obtain a better understanding of the underlying mechanisms, we performed a proteomic analysis on tianeptine-treated hippocampal neurons. Primary hippocampal neurons were prepared from fetal Sprague-Dawley rats, eliminating glia cells by addition of cytosine beta-D-arabinofuranoside at day 2 in vitro (DIV2). The neurons were treated with tianeptine (10 microg/mL) or vehicle at DIV3, then harvested at DIV4 or DIV9 for immunocytochemical analysis of, respectively, neurite outgrowth or synapse formation. A proteomics analysis was performed on DIV4 neurons and the data were confirmed by Western blot analysis. Using specific markers, we demonstrated that tianeptine can augment neurite growth and promote synaptic contacts in cultured hippocampal neurons. The proteomics analysis identified 11 differentially expressed proteins, with roles in neurite growth, metabolism of neurotrophic substances, synaptogenesis, and synaptic activity homeostasis. The data shed light on the mechanisms underlying the neurotrophic effect of tianeptine observed in both animal studies and the clinic.

  9. Transient elevation of adult hippocampal neurogenesis after dopamine depletion

    PubMed Central

    Park, June-Hee; Enikolopov, Grigori

    2010-01-01

    Degeneration of the midbrain dopaminergic neurons during Parkinson's disease (PD) may affect remote regions of the brain that are innervated by the projections of these neurons. The dentate gyrus (DG), a site of continuous production of new neurons in the adult hippocampus, receives dopaminergic inputs from the neurons of the substantia nigra (SN). Thus, depletion of the SN neurons during disease or in experimental settings may directly affect adult hippocampal neurogenesis. We show that experimental ablation of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine (MPTP) mouse model of PD results in a transient increase in cell division in the subgranular zone (SGZ) of the DG. This increase is evident for the amplifying neural progenitors and for their postmitotic progeny; our results also indicate that MPTP treatment affects division of the normally quiescent stem cells in the SGZ. We also show that L-DOPA, used in the clinical treatment of PD, while attenuating the MPTP-induced death of dopaminergic neurons, does not alter the effect of MPTP on cell division in the DG. Our results suggest that a decrease in dopaminergic signaling in the hippocampus leads to a transient activation of stem and progenitor cells in the DG. PMID:20079351

  10. PAN hollow fiber membranes elicit functional hippocampal neuronal network.

    PubMed

    Morelli, Sabrina; Piscioneri, Antonella; Salerno, Simona; Tasselli, Franco; Di Vito, Anna; Giusi, Giuseppina; Canonaco, Marcello; Drioli, Enrico; De Bartolo, Loredana

    2012-01-01

    This study focuses on the development of an advanced in vitro biohybrid culture model system based on the use of hollow fibre membranes (HFMs) and hippocampal neurons in order to promote the formation of a high density neuronal network. Polyacrylonitrile (PAN) and modified polyetheretherketone (PEEK-WC) membranes were prepared in hollow fibre configuration. The morphological and metabolic behaviour of hippocampal neurons cultured on PAN HF membranes were compared with those cultured on PEEK-WC HF. The differences of cell behaviour between HFMs were evidenced by the morphometric analysis in terms of axon length and also by the investigation of metabolic activity in terms of neurotrophin secretion. These findings suggested that PAN HFMs induced the in vitro reconstruction of very highly functional and complex neuronal networks. Thus, these biomaterials could potentially be used for the in vitro realization of a functional hippocampal tissue analogue for the study of neurobiological functions and/or neurodegenerative diseases.

  11. SIRT1 regulates dendritic development in hippocampal neurons.

    PubMed

    Codocedo, Juan F; Allard, Claudio; 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.

  12. SIRT1 Regulates Dendritic Development in Hippocampal Neurons

    PubMed Central

    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

  13. VTA neurons coordinate with the hippocampal reactivation of spatial experience

    PubMed Central

    Gomperts, Stephen N; Kloosterman, Fabian; Wilson, Matthew A

    2015-01-01

    Spatial learning requires the hippocampus, and the replay of spatial sequences during hippocampal sharp wave-ripple (SPW-R) events of quiet wakefulness and sleep is believed to play a crucial role. To test whether the coordination of VTA reward prediction error signals with these replayed spatial sequences could contribute to this process, we recorded from neuronal ensembles of the hippocampus and VTA as rats performed appetitive spatial tasks and subsequently slept. We found that many reward responsive (RR) VTA neurons coordinated with quiet wakefulness-associated hippocampal SPW-R events that replayed recent experience. In contrast, coordination between RR neurons and SPW-R events in subsequent slow wave sleep was diminished. Together, these results indicate distinct contributions of VTA reinforcement activity associated with hippocampal spatial replay to the processing of wake and SWS-associated spatial memory. DOI: http://dx.doi.org/10.7554/eLife.05360.001 PMID:26465113

  14. N-Docosahexaenoylethanolamide promotes development of hippocampal neurons

    PubMed Central

    Kim, Hee-Yong; Moon, Hyun-Seuk; Cao, Dehua; Lee, Jeongrim; Kevala, Karl; Jun, Sang Beom; Lovinger, David M.; Akbar, Mohammed; Huang, Bill X.

    2011-01-01

    DHA (docosahexaenoic acid, C22:6,n−3) has been shown to promote neurite growth and synaptogenesis in embryonic hippocampal neurons, supporting the importance of DHA known for hippocampus-related learning and memory function. In the present study, we demonstrate that DHA metabolism to DEA (N-docosahexaenoylethanolamide) is a significant mechanism for hippocampal neuronal development, contributing to synaptic function. We found that a fatty acid amide hydrolase inhibitor URB597 potentiates DHA-induced neurite growth, synaptogenesis and synaptic protein expression. Active metabolism of DHA to DEA was observed in embryonic day 18 hippocampal neuronal cultures, which was increased further by URB597. Synthetic DEA promoted hippocampal neurite growth and synaptogenesis at substantially lower concentrations in comparison with DHA. DEA-treated neurons increased the expression of synapsins and glutamate receptor subunits and exhibited enhanced glutamatergic synaptic activity, as was the case for DHA. The DEA level in mouse fetal hippocampi was altered according to the maternal dietary supply of n−3 fatty acids, suggesting that DEA formation is a relevant in vivo process responding to the DHA status. In conclusion, DHA metabolism to DEA is a significant biochemical mechanism for neurite growth, synaptogenesis and synaptic protein expression, leading to enhanced glutamatergic synaptic function. The novel DEA-dependent mechanism offers a new molecular insight into hippocampal neurodevelopment and function. PMID:21281269

  15. Strychnine-sensitive glycine responses of neonatal rat hippocampal neurones.

    PubMed Central

    Ito, S; Cherubini, E

    1991-01-01

    1. Intracellular recordings employing current and voltage clamp techniques were used to study the effects of glycine on rat CA3 hippocampal neurones during the first 3 weeks of postnatal (P) life. 2. Glycine (0.3-1 mM) depolarized neurones from rats less than 4 days old (P4). Neurones from older neonates (P5-P7) were hyperpolarized by glycine, whereas adult neurones were unaffected. 3. Both depolarizing and hyperpolarizing responses were associated with large conductance increases; they reversed polarity at a potential which changed with the extracellular chloride concentration. The responses persisted in tetrodotoxin (1 microM) or in a solution with a much reduced calcium concentration. 4. Strychnine (1 microM) but not bicuculline (10-50 microM) antagonized the effects of glycine. The action of strychnine was apparently competitive with a dissociation constant of 350 nM. 5. In voltage clamp experiments, glycine elicited a non-desensitizing outward current at -60 mV. When a maximal concentration of glycine was applied at the same time as gamma-aminobutyric acid (GABA), the conductance increase induced by the two agonists was additive, suggesting the activation of different populations of channels. 6. Concentrations of glycine lower than 100 microM did not affect membrane potential. However, at 30-50 microM glycine increased the frequency of spontaneous GABA-mediated synaptic responses; this action was not blocked by strychnine. 7. It is concluded that during the first 2 weeks of life glycine acts at strychnine-sensitive receptors to open chloride channels. PMID:1804982

  16. When is adult hippocampal neurogenesis necessary for learning? evidence from animal research.

    PubMed

    Castilla-Ortega, Estela; Pedraza, Carmen; Estivill-Torrús, Guillermo; Santín, Luis J

    2011-01-01

    The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.

  17. Natural variation and genetic covariance in adult hippocampal neurogenesis

    SciTech Connect

    Kempermann, Gerd; Chesler, Elissa J; Lu, Lu; Williams, Robert; Gage, Fred

    2006-01-01

    Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB?BXA, n ? 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1?CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis- cting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

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

    PubMed Central

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

    2015-01-01

    Recent evidence has suggested the neuroprotective effects of physical exercise on cerebral ischemic injury. However, the role of physical exercise in cerebral ischemia-induced hippocampal damage remains controversial. The aim of the present study was to evaluate the effects of pre-ischemia treadmill training on hippocampal CA1 neuronal damage after cerebral ischemia. Male adult rats were randomly divided into control, ischemia and exercise + ischemia groups. In the exercise + ischemia group, rats were subjected to running on a treadmill in a designated time schedule (5 days per week for 4 weeks). Then rats underwent cerebral ischemia induction through occlusion of common carotids followed by reperfusion. At 4 days after cerebral ischemia, rat learning and memory abilities were evaluated using passive avoidance memory test and rat hippocampal neuronal damage was detected using Nissl and TUNEL staining. Pre-ischemic exercise significantly reduced the number of TUNEL-positive cells and necrotic cell death in the hippocampal CA1 region as compared to the ischemia group. Moreover, pre-ischemic exercise significantly prevented ischemia-induced memory dysfunction. Pre-ischemic exercise mighct prevent memory deficits after cerebral ischemia through rescuing hippocampal CA1 neurons from ischemia-induced degeneration. PMID:26487851

  19. Astrocyte calcium signalling orchestrates neuronal synchronization in organotypic hippocampal slices

    PubMed Central

    Sasaki, Takuya; Ishikawa, Tomoe; Abe, Reimi; Nakayama, Ryota; Asada, Akiko; Matsuki, Norio; Ikegaya, Yuji

    2014-01-01

    Astrocytes are thought to detect neuronal activity in the form of intracellular calcium elevations; thereby, astrocytes can regulate neuronal excitability and synaptic transmission. Little is known, however, about how the astrocyte calcium signal regulates the activity of neuronal populations. In this study, we addressed this issue using functional multineuron calcium imaging in hippocampal slice cultures. Under normal conditions, CA3 neuronal networks exhibited temporally correlated activity patterns, occasionally generating large synchronization among a subset of cells. The synchronized neuronal activity was correlated with astrocyte calcium events. Calcium buffering by an intracellular injection of a calcium chelator into multiple astrocytes reduced the synaptic strength of unitary transmission between pairs of surrounding pyramidal cells and caused desynchronization of the neuronal networks. Uncaging the calcium in the astrocytes increased the frequency of neuronal synchronization. These data suggest an essential role of the astrocyte calcium signal in the maintenance of basal neuronal function at the circuit level. PMID:24710057

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

    PubMed

    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

  1. Chronic CXCL10 Alters Neuronal Properties in Rat Hippocampal Culture

    PubMed Central

    Cho, Jungsook; Nelson, Thomas E.; Bajova, Hilda; Gruol, Donna L.

    2009-01-01

    The chemokine CXCL10 is expressed in the central nervous system (CNS) during neuroinflammatory conditions. Neurons express CXCR3, the receptor for CXCL10, and neuronal function has been shown to be altered by acute exposure to CXCL10. Little is known about the effects of chronic exposure to CXCL10 on neuronal function. Results from our studies show that chronic exposure of cultured rat hippocampal neurons to CXCL10 results in altered levels of protein for GABA and glutamate receptors and altered synaptic network activity. These effects of CXCL10 may contribute to altered CNS function that occurs in some chronic neuroinflammatory conditions. PMID:19167097

  2. Casein Kinase 1 Suppresses Activation of REST in Insulted Hippocampal Neurons and Halts Ischemia-Induced Neuronal Death

    PubMed Central

    Kaneko, Naoki; Hwang, Jee-Yeon; Gertner, Michael; Pontarelli, Fabrizio

    2014-01-01

    Repressor Element-1 (RE1) Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF) is a gene-silencing factor that is widely expressed during embryogenesis and plays a strategic role in neuronal differentiation. Recent studies indicate that REST can be activated in differentiated neurons during a critical window of time in postnatal development and in adult neurons in response to neuronal insults such as seizures and ischemia. However, the mechanism by which REST is regulated in neurons is as yet unknown. Here, we show that REST is controlled at the level of protein stability via β-TrCP-dependent, ubiquitin-based proteasomal degradation in differentiated neurons under physiological conditions and identify Casein Kinase 1 (CK1) as an upstream effector that bidirectionally regulates REST cellular abundance. CK1 associates with and phosphorylates REST at two neighboring, but distinct, motifs within the C terminus of REST critical for binding of β-TrCP and targeting of REST for proteasomal degradation. We further show that global ischemia in rats in vivo triggers a decrease in CK1 and an increase in REST in selectively vulnerable hippocampal CA1 neurons. Administration of the CK1 activator pyrvinium pamoate by in vivo injection immediately after ischemia restores CK1 activity, suppresses REST expression, and rescues neurons destined to die. Our results identify a novel and previously unappreciated role for CK1 as a brake on REST stability and abundance in adult neurons and reveal that loss of CK1 is causally related to ischemia-induced neuronal death. These findings point to CK1 as a potential therapeutic target for the amelioration of hippocampal injury and cognitive deficits associated with global ischemia. PMID:24760862

  3. Characterization of NADPH Diaphorase- and Doublecortin-Positive Neurons in the Lizard Hippocampal Formation.

    PubMed

    Macedo-Lima, Matheus; Freire, Marco Aurélio M; de Carvalho Pimentel, Hugo; Rodrigues Ferreira Lins, Lívia Cristina; Amador de Lucena Medeiros, Katty Anne; Viola, Giordano Gubert; Dos Santos, José Ronaldo; Marchioro, Murilo

    2016-01-01

    The lizard cortex has remarkable similarities with the mammalian hippocampus. Both regions process memories, have similar cytoarchitectural properties, and are important neurogenic foci in adults. Lizards show striking levels of widespread neurogenesis in adulthood and can regenerate entire cortical areas after injury. Nitric oxide (NO) is an important regulatory factor of mammalian neurogenesis and hippocampal function. However, little is known about its role in nonmammalian neurogenesis. Here, we analyzed the distribution, morphology, and dendritic complexity (Neurolucida reconstructions) of NO-producing neurons through NADPH diaphorase (NADPHd) activity, and how they compare with the distribution of doublecortin-positive (DCX+) neurons in the hippocampal formation of the neotropical lizard Tropidurus hispidus. NADPHd-positive (NADPHd+) neurons in the dorsomedial cortex (DMC; putatively homologous to mammalian CA3) were more numerous and complex than the ones in the medial cortex (MC; putatively homologous to the dentate gyrus). We found that NADPHd+ DMC neurons send long projections into the MC. Interestingly, in the MC, NADPHd+ neurons existed in 2 patterns: small somata with low intensity of staining in the outer layer and large somata with high intensity of staining in the deep layer, a pattern similar to the mammalian cortex. Additionally, NADPHd+ neurons were absent in the granular cell layer of the MC. In contrast, DCX+ neurons were scarce in the DMC but highly numerous in the MC, particularly in the granular cell layer. We hypothesize that NO-producing neurons in the DMC provide important input to proliferating/migrating neurons in the highly neurogenic MC.

  4. Kalirin-7, an important component of excitatory synapses, is regulated by estradiol in hippocampal neurons.

    PubMed

    Ma, Xin-Ming; Huang, Jian-Ping; Kim, Eun-Ji; Zhu, Qing; Kuchel, George A; Mains, Richard E; Eipper, Betty A

    2011-06-01

    Estradiol enhances the formation of dendritic spines and excitatory synapses in hippocampal neurons in vitro and in vivo, but the underlying mechanisms are not fully understood. Kalirin-7 (Kal7), the major isoform of Kalirin in the adult hippocampus, is a Rho GDP/GTP exchange factor localized to postsynaptic densities. In the hippocampus, both Kal7 and estrogen receptor α (ERα) are highly expressed in a subset of interneurons. Over-expression of Kal7 caused an increase in spine density and size in hippocampal neurons. To determine whether Kalirin might play a role in the effects of estradiol on spine formation, Kal7 expression was examined in the hippocampus of ovariectomized rats. Estradiol replacement increased Kal7 staining in both CA1 pyramidal neurons and interneurons in ovariectomized rats. Estradiol treatment of cultured hippocampal neurons increased Kal7 levels at the postsynaptic side of excitatory synapses and increased the number of excitatory synapses along the dendrites of pyramidal neurons. These increases were mediated via ERα because a selective ERα agonist, but not a selective ERβ agonist, caused a similar increase in both Kal7 levels and excitatory synapse number in cultured hippocampal neurons. When Kal7 expression was reduced using a Kal7-specific shRNA, the density of excitatory synapses was reduced and estradiol was no longer able to increase synapse formation. Expression of exogenous Kal7 in hippocampal interneurons resulted in decreased levels of GAD65 staining. Inhibition of GABAergic transmission with bicuculline produced a robust increase in Kal7 expression. These studies suggest Kal7 plays a key role in the mechanisms of estradiol-mediated synaptic plasticity.

  5. Adult hippocampal neurogenesis and its role in Alzheimer's disease.

    PubMed

    Mu, Yangling; Gage, Fred H

    2011-12-22

    The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

  6. Adult hippocampal neurogenesis and its role in Alzheimer's disease

    PubMed Central

    2011-01-01

    The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD. PMID:22192775

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

    PubMed

    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.

  8. Preservation of hippocampal neuron numbers and hippocampal subfield volumes in behaviorally characterized aged tree shrews.

    PubMed

    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.

  9. Intracellular activities related to in vitro hippocampal sharp waves are altered in CA3 pyramidal neurons of aged mice.

    PubMed

    Moradi-Chameh, H; Peng, J; Wu, C; Zhang, L

    2014-09-26

    Pyramidal neurons in the hippocampal CA3 area interconnect intensively via recurrent axonal collaterals, and such CA3-to-CA3 recurrent circuitry plays important roles in the generation of hippocampal network activities. In particular, the CA3 circuitry is able to generate spontaneous sharp waves (SPWs) when examined in vitro. These in vitro SPWs are thought to result from the network activity of GABAergic inhibitory interneurons as SPW-correlating intracellular activities are featured with strong IPSPs in pyramidal neurons and EPSPs or spikes in GABAergic interneurons. In view of accumulating evidence indicating a decrease in subgroups of hippocampal GABAergic interneurons in aged animals, we test the hypothesis that the intracellular activities related to in vitro SPWs are altered in CA3 pyramidal neurons of aged mice. Hippocampal slices were prepared from adult and aged C57 black mice (ages 3-6 and 24-28months respectively). Population and single-cell activities were examined via extracellular and whole-cell patch-clamp recordings. CA3 SPW frequencies were not significantly different between the slices of adult and aged mice but SPW-correlating intracellular activities featured weaker IPSC components in aged CA3 pyramidal neurons compared to adult neurons. It was unlikely that this latter phenomenon was due to general impairments of GABAergic synapses in the aged CA3 circuitry as evoked IPSC responses and pharmacologically isolated IPSCs were observed in aged CA3 pyramidal neurons. In addition, aged CA3 pyramidal neurons displayed more positive resting potentials and had a higher propensity of burst firing than adult neurons. We postulate that alterations of GABAergic network activity may explain the reduced IPCS contributions to in vitro SPWs in aged CA3 pyramidal neurons. Overall, our present observations are supportive of the notion that excitability of hippocampal CA3 circuitry is increased in aged mice.

  10. [Electrophysiological properties of inhibitory neurones in cultured dissociated hippocampal cells].

    PubMed

    Moskaliuk, A O; Kolodin, Iu O; Kravchenko, M O; Fedulova, S A; Veselovs'kyĭ, M S

    2004-01-01

    Electrophysiological properties of inhibitory (GABAergic) neurones were studied in dissociated hippocampal culture using simultaneous whole cell recordings from pairs of monosynaptically coupled neurons. Reliable identification of GABAergic neuron was performed by presence of monosynaptic inhibitory currents at postsynaptic cell in response to action potentials at stimulated cell. It was shown that GABAergic neurons in hippocampal culture are divided in two groups by their firing characteristics: first type generates action potentials at high frequency in response to injection of current (duration 0.5 s)--fast-spiking neurons (FS), cells from second type has no ability for high-frequency action potential generation--regular spiking neurons (RS). These two groups were distinguished by kinetic characteristics of action potentials, adaptation characteristics during continuous generation of action potentials and inhibitory effect making on postsynaptic cell. Application of potassium channel blocker 4-AP to somas of FS neurons in concentration, which selectively inhibits Kv3 potassium channels evoked reversible changes in kinetic of action potentials, frequency and adaptation characteristics during continuous generation of action potentials. It was concluded that there is hight level of expression of Kv3 potassium channels in the first group of neurons.

  11. Reduced potassium currents in old rat CA1 hippocampal neurons.

    PubMed

    Alshuaib, W B; Hasan, S M; Cherian, S P; Mathew, M V; Hasan, M Y; Fahim, M A

    2001-01-15

    Potassium currents are an important factor in repolarizing the membrane potential and determining the level of neuronal excitability. We compared potassium currents in CA1 hippocampal neurons dissociated from young (2-3 months old) and old (26-30 months old) Sprague-Dawley rats. Whole-cell patch-clamp techniques were used to measure the delayed rectifier (sustained) and the A-type (transient) potassium currents. The delayed rectifier current was smaller in old (548 +/- 57 pA) than in young (1193 +/- 171 pA) neurons. In the absence of extracellular calcium, the delayed rectifier current was also smaller in old (427 +/- 41 pA) than in young (946 +/- 144 pA) neurons. The cell membrane capacitance was unchanged in old (13.3 +/- 1.2 pF) compared to young (13.6 +/- 1.2 pF). Therefore, the reduction in the delayed rectifier current was not due to a change in membrane surface area. Moreover, activation and inactivation of the delayed rectifier current were unchanged in old compared to young neurons. The slope of the current-voltage relation, however, was smaller in old (B = 5.03) than in young (B = 9.62) neurons. Similarly, the A-current was smaller in old (100 +/- 16 pA) than in young (210 +/- 44 pA) neurons in the presence of extracellular calcium. This reduction of potassium currents could account for the prolongation of action potentials reported previously for old rat CA1 hippocampal neurons. The age-related reduction in potassium current indicates plasticity in neuronal function that can impact communication in the hippocampal neural network during aging.

  12. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis

    PubMed Central

    Sierra, Amanda; Encinas, Juan M.; Deudero, Juan JP; Chancey, Jessica H.; Enikolopov, Grigori; Overstreet-Wadiche, Linda S.; Tsirka, Stella E.; Maletic-Savatic, Mirjana

    2010-01-01

    Summary In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a four-week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first one to four days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade. PMID:20887954

  13. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

    PubMed

    Steib, Kathrin; Schäffner, Iris; Jagasia, Ravi; Ebert, Birgit; Lie, D Chichung

    2014-05-07

    Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.

  14. Neuronal nitric oxide synthase contributes to pentylenetetrazole-kindling-induced hippocampal neurogenesis.

    PubMed

    Zhu, Xinjian; Dong, Jingde; Shen, Kai; Bai, Ying; Chao, Jie; Yao, Honghong

    2016-03-01

    Neuronal nitric oxide synthase (nNOS), the major nitric oxide synthase isoform in the mammalian brain, is implicated in the pathophysiology of several neurological conditions, including epilepsy. Neurogenesis in hippocampal dentate gyrus (DG) persists throughout life in the adult brain. Alterations in this process occur in many neurological diseases, including epilepsy. Few studies, however, have addressed the role of nNOS in hippocampal DG neurogenesis in epileptic brain. The present study, therefore, investigated the role of nNOS in pentylenetetrazole (PTZ)-kindling-induced neurogenesis in hippocampal DG. Our results showed that nNOS expression and enzymatic activity were significantly increased in the hippocampus of PTZ-kindled mice. Meanwhile, these PTZ-kindled mice were characterized by significant enhancement of new born cells proliferation and survival in hippocampal DG, and these survived cells are co-labeled with NeuN and GFAP. Selective inhibition of nNOS by 7-NI, however, suppressed PTZ-kindling-induced hippocampal DG new born cells proliferation and survival, suggesting that nNOS contributes to PTZ-kindling-induced hippocampal neurogenesis.

  15. Implications of adult hippocampal neurogenesis in antidepressant action

    PubMed Central

    Malberg, Jessica E.

    2004-01-01

    In the dentate gyrus of the hippocampus, cell birth and maturation into neurons, or neurogenesis, occur throughout the lifetime of animals and humans. Multiple factors have been shown to regulate adult neurogenesis, and a number of findings in this field have had a large impact on basic and clinical research in depression. It has been reported that both physical and psychosocial stress paradigms, as well as some animal models of depression, produce a decrease in hippocampal cell proliferation and neurogenesis. Conversely, long-term, but not short-term, treatment with different classes of antidepressant drug increases cell proliferation and neurogenesis. Patients with depressive disorders or post-traumatic stress disorder have reduced hippocampal volume. Given this interaction of stress, depression and neurogenesis, a current hypothesis is that reduced adult hippocampal cell proliferation or neurogenesis may be involved in the pathophysiology of depression and that reversal or prevention of the decrease in neurogenesis may be one way in which the antidepressant drugs exert their effects. Research from this emerging field will further our understanding of the effects of stress and depression on the brain and the mechanism of action of antidepressant drugs. Dans le gyrus denté de l'hippocampe, la naissance des cellules et leur maturation en neurones, ou neurogenèse, se produisent pendant toute la vie des animaux et des êtres humains. On a démontré que de multiples facteurs régularisent la neurogenèse chez l'adulte, et de nombreuses constatations dans ce domaine ont eu un effet important sur la recherche fondamentale et clinique sur la dépression. On a signalé que des paradigmes de stress à la fois physique et psychosocial, ainsi que certains modèles animaux de dépression, entraÎnent une diminution de la prolifération des cellules dans l'hippocampe et une baisse de la neurogenèse. Par ailleurs, le traitement avec différentes catégories d

  16. HIPPOCAMPAL ADULT NEUROGENESIS: ITS REGULATION AND POTENTIAL ROLE IN SPATIAL LEARNING AND MEMORY

    PubMed Central

    Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin

    2016-01-01

    Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001

  17. Adult-onset deficiency in growth hormone and insulin-like growth factor-I decreases survival of dentate granule neurons: insights into the regulation of adult hippocampal neurogenesis.

    PubMed

    Lichtenwalner, Robin J; Forbes, M Elizabeth; Sonntag, William E; Riddle, David R

    2006-02-01

    Insulin-like growth factor-I (IGF-I), long thought to provide critical trophic support during development, also has emerged as a candidate for regulating ongoing neuronal production in adulthood. Whether and how IGF-I influences each phase of neurogenesis, however, remains unclear. In the current study, we used a selective model of growth hormone (GH) and plasma IGF-I deficiency to evaluate the role of GH and IGF-I in regulating cell proliferation, survival, and neuronal differentiation in the adult dentate gyrus. GH/IGF-I-deficient dwarf rats of the Lewis strain were made GH/IGF-I replete throughout development via twice daily injections of GH, and then GH/IGF-I deficiency was initiated in adulthood by removing animals from GH treatment. Bromodeoxyuridine (BrdU) labeling revealed no effect of GH/IGF-I deficiency on cell proliferation, but adult-onset depletion of GH and plasma IGF-I significantly reduced the survival of newly generated cells in the dentate gyrus. Colabeling for BrdU and markers of immature and mature neurons revealed a selective effect of GH/IGF-I deficiency on the survival of more mature new neurons. The number of BrdU-labeled cells expressing the immature neuronal marker TUC-4 did not differ between GH/IGF-I-deficient and -replete animals, but the number expressing only the marker of maturity NeuN was lower in depleted animals. Taken together, results from the present study suggest that, under conditions of short-term GH/IGF-I deficiency during adulthood, dentate granule cells continue to be produced, to commit to a neuronal fate, and to begin the process of neuronal maturation, whereas survival of the new neurons is impaired.

  18. Rescue of Adult Hippocampal Neurogenesis in a Mouse Model of HIV Neurologic Disease

    PubMed Central

    Lee, Myoung-Hwa; Wang, Tongguang; Jang, Mi-Hyeon; Steiner, Joseph; Haughey, Norman; Ming, Guo-li; Song, Hongjun; Nath, Avindra; Venkatesan, Arun

    2011-01-01

    The prevalence of central nervous system (CNS) neurologic dysfunction associated with human immunodeficiency virus (HIV) infection continues to increase, despite the use of antiretroviral therapy. Previous work has focused on the deleterious effects of HIV on mature neurons and on development of neuroprotective strategies, which have consistently failed to show a meaningful clinical benefit. It is now well established that new neurons are continuously generated in discrete regions in the adult mammalian brain, and accumulating evidence supports important roles for these neurons in specific cognitive functions. In a transgenic mouse model of HIV neurologic disease with glial expression of the HIV envelope protein gp120, we demonstrate a significant reduction in proliferation of hippocampal neural progenitors in the dentate gyrus of adult animals, resulting in a dramatic decrease in the number of newborn neurons in the adult brain. We identify amplifying neural progenitor cells (ANPs) as the first class of progenitors affected by gp120, and we also demonstrate that newly generated neurons exhibit aberrant dendritic development. Furthermore, voluntary exercise and treatment with a selective serotonin reuptake inhibitor increase the ANP population and rescue the observed deficits in gp120 transgenic mice. Thus, during HIV infection, the envelope protein gp120 may potently inhibit adult hippocampal neurogenesis, and neurorestorative approaches may be effective in ameliorating these effects. Our study has significant implications for the development of novel therapeutic approaches for HIV-infected individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired. PMID:21146610

  19. Damage of hippocampal neurons in rats with chronic alcoholism

    PubMed Central

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

    2014-01-01

    Chronic alcoholism can damage the cytoskeleton and aggravate neurological deficits. However, the effect of chronic alcoholism on hippocampal neurons remains unclear. In this study, a model of chronic alcoholism was established in rats that were fed with 6% alcohol for 42 days. Endogenous hydrogen sulfide content and cystathionine-beta-synthase activity in the hippocampus of rats with chronic alcoholism were significantly increased, while F-actin expression was decreased. Hippocampal neurons in rats with chronic alcoholism appeared to have a fuzzy nuclear membrane, mitochondrial edema, and ruptured mitochondrial crista. These findings suggest that chronic alcoholism can cause learning and memory decline in rats, which may be associated with the hydrogen sulfide/cystathionine-beta-synthase system, mitochondrial damage and reduced expression of F-actin. PMID:25368648

  20. Hypoglycemia-activated K+ channels in hippocampal neurons.

    PubMed

    Tromba, C; Salvaggio, A; Racagni, G; Volterra, A

    1992-08-31

    Channels linking the electrical and metabolic activities of cells (KATP channels) have been described in various tissues, including some brain areas (hypothalamus, cerebral cortex and substantia nigra). Here we report the existence in hippocampal neurons of K+ permeant channels whose activity is regulated by extracellular glucose. They are open at the cell resting potential and respond to transient hypoglycemia with a reversible increase in activity. The one type so far characterized has a conductance of approximately 100 pS in isotonic K+, is inhibited by the sulphonylurea glibenclamide (1 microM), and is activated by the potassium channel opener lemakalim (0.1-1 microM). These data provide a direct demonstration of the presence, in hippocampal neurons, of glucose-sensitive channels that could belong to the KATP family.

  1. Perforated patch-clamp analysis of the passive membrane properties of three classes of hippocampal neurons.

    PubMed

    Spruston, N; Johnston, D

    1992-03-01

    1. Perforated patch-clamp recordings were made from the three major classes of hippocampal neurons in conventional in vitro slices prepared from adult guinea pigs. This technique provided experimental estimates of passive membrane properties (input resistance, RN, and membrane time constant, tau m) determined in the absence of the leak conductance associated with microelectrode impalement or the washout of cytoplasmic constituents associated with conventional whole-cell recordings. 2. To facilitate comparison of our data with previous results and to determine the passive membrane properties under conditions as physiological as possible, recordings were made at the resting potential, in physiological saline, and without any added blockers of voltage-dependent conductances. 3. Membrane-potential responses to current steps were analyzed, and four criteria were used to identify voltage responses that were the least affected by activation of voltage-dependent conductances. tau m was estimated from the slowest component (tau 0) of multiexponential fits of responses deemed passive by these criteria. RN was estimated from the slope of the linear region in the hyperpolarizing direction of the voltage-current relation. 4. It was not possible to measure purely passive membrane properties that were completely independent of membrane potential in any of the three classes of hippocampal neurons. Changing the membrane potential by constant current injection resulted in changes in RN and tau 0; subthreshold depolarization produced an increase, and hyperpolarization a decrease, in both RN and tau 0 for all three classes of hippocampal neurons. 5. Each of the three classes of hippocampal neurons also displayed a depolarizing "sag" during larger hyperpolarizing voltage transients. To evaluate the effect of the conductances underlying this sag on passive membrane properties, 2-5 mM Cs+ was added to the physiological saline. Extracellular Cs+ effectively blocked the sag in all three

  2. Stochastic and Coherence Resonance in Hippocampal Neurons

    DTIC Science & Technology

    2007-11-02

    decreases the signal to noise ratio of subthreshold synaptic inputs. Keywords - Hippocampus , neurons, stochastic resonance I. INTRODUCTION... subthreshold signals in the hippocampus ,” J. Neurophysiology , in press. [3] J. Collins C.C. Chow and T.T. Imboff, “Stochastic resonance without...nonlinear systems whereby the introduction of noise enhances the detection of subthreshold signals. Both computer simulations and experimental

  3. Immature doublecortin-positive hippocampal neurons are important for learning but not for remembering.

    PubMed

    Vukovic, Jana; Borlikova, Gilyana G; Ruitenberg, Marc J; Robinson, Gregory J; Sullivan, Robert K P; Walker, Tara L; Bartlett, Perry F

    2013-04-10

    It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.

  4. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

    PubMed

    Song, Juan; Sun, Jiaqi; Moss, Jonathan; Wen, Zhexing; Sun, Gerald J; Hsu, Derek; Zhong, Chun; Davoudi, Heydar; Christian, Kimberly M; Toni, Nicolas; Ming, Guo-Li; Song, Hongjun

    2013-12-01

    Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis.

  5. GSK-3β Overexpression Alters the Dendritic Spines of Developmentally Generated Granule Neurons in the Mouse Hippocampal Dentate Gyrus

    PubMed Central

    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

  6. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

    PubMed

    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.

  7. Intense Exercise Promotes Adult Hippocampal Neurogenesis But Not Spatial Discrimination

    PubMed Central

    So, Ji H.; Huang, Chao; Ge, Minyan; Cai, Guangyao; Zhang, Lanqiu; Lu, Yisheng; Mu, Yangling

    2017-01-01

    Hippocampal neurogenesis persists throughout adult life and plays an important role in learning and memory. Although the influence of physical exercise on neurogenesis has been intensively studied, there is controversy in regard to how the impact of exercise may vary with its regime. Less is known about how distinct exercise paradigms may differentially affect the learning behavior. Here we found that, chronic moderate treadmill running led to an increase of cell proliferation, survival, neuronal differentiation, and migration. In contrast, intense running only promoted neuronal differentiation and migration, which was accompanied with lower expressions of vascular endothelial growth factor, brain-derived neurotrophic factor, insulin-like growth factor 1, and erythropoietin. In addition, the intensely but not mildly exercised animals exhibited a lower mitochondrial activity in the dentate gyrus. Correspondingly, neurogenesis induced by moderate but not intense exercise was sufficient to improve the animal’s ability in spatial pattern separation. Our data indicate that the effect of exercise on spatial learning is intensity-dependent and may involve mechanisms other than a simple increase in the number of new neurons. PMID:28197080

  8. In Vivo AAV1 Transduction With hRheb(S16H) Protects Hippocampal Neurons by BDNF Production

    PubMed Central

    Jeon, Min-Tae; Nam, Jin Han; Shin, Won-Ho; Leem, Eunju; Jeong, Kyoung Hoon; Jung, Un Ju; Bae, Young-Seuk; Jin, Young-Ho; Kholodilov, Nikolai; Burke, Robert E; Lee, Seok-Geun; Jin, Byung Kwan; Kim, Sang Ryong

    2015-01-01

    Recent evidence has shown that Ras homolog enriched in brain (Rheb) is dysregulated in Alzheimer's disease (AD) brains. However, it is still unclear whether Rheb activation contributes to the survival and protection of hippocampal neurons in the adult brain. To assess the effects of active Rheb in hippocampal neurons in vivo, we transfected neurons in the cornu ammonis 1 (CA1) region in normal adult rats with an adeno-associated virus containing the constitutively active human Rheb (hRheb(S16H)) and evaluated the effects on thrombin-induced neurotoxicity. Transduction with hRheb(S16H) significantly induced neurotrophic effects in hippocampal neurons through activation of mammalian target of rapamycin complex 1 (mTORC1) without side effects such as long-term potentiation impairment and seizures from the alteration of cytoarchitecture, and the expression of hRheb(S16H) prevented thrombin-induced neurodegeneration in vivo, an effect that was diminished by treatment with specific neutralizing antibodies against brain-derived neurotrophic factor (BDNF). In addition, our results showed that the basal mTORC1 activity might be insufficient to mediate the level of BDNF expression, but hRheb(S16H)-activated mTORC1 stimulated BDNF production in hippocampal neurons. These results suggest that viral vector transduction with hRheb(S16H) may have therapeutic value in the treatment of neurodegenerative diseases such as AD. PMID:25502903

  9. Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis.

    PubMed

    Jang, Mi-Hyeon; Bonaguidi, Michael A; Kitabatake, Yasuji; Sun, Jiaqi; Song, Juan; Kang, Eunchai; Jun, Heechul; Zhong, Chun; Su, Yijing; Guo, Junjie U; Wang, Marie Xun; Sailor, Kurt A; Kim, Ju-Young; Gao, Yuan; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2013-02-07

    Adult neurogenesis, the process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying the activity-dependent regulation of the sequential steps of adult neurogenesis remains largely unknown. Here, we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth, and dendritic spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and the acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests an interesting activity-dependent mechanism governing adult neurogenesis via the acute release of tonic inhibition.

  10. Giant synaptic potentials in immature rat CA3 hippocampal neurones.

    PubMed

    Ben-Ari, Y; Cherubini, E; Corradetti, R; Gaiarsa, J L

    1989-09-01

    1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than -51 mV, action potentials greater than 55 mV and membrane input resistances of 117 +/- 12 M omega. An unusual characteristic of these cells was the presence of spontaneous giant depolarizing potentials (GDPs) which were observed during the first eight postnatal (P) days in over 85% of neurones. They were less frequent between P9 and P12 (48%) and disappeared after P12. 2. The GDPs were synchronously generated by a population of neurones; they reversed polarity at -27 mV when recorded with KCl-containing electrodes and at -51 mV with potassium acetate- or potassium methylsulphate-filled electrodes. 3. The GDPs were blocked by bath application of bicuculline (10 microM) or picrotoxin (100-200 microM). Exogenously applied gamma-aminobutyric acid (GABA; 0.2-1 mM) induced at resting membrane potential a bicuculline-sensitive membrane depolarization which reversed polarity at -25 and -51 mV when recorded with KCl- or potassium methylsulphate-filled electrodes respectively. 4. The GDPs were reduced in frequency or blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-7-phosphonoheptanoate (AP-7; 50 microM), D(-)2-amino-5-phosphonovalerate (AP-5, 10-50 microM) and (+-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10-50 microM) or NMDA channel blockers phencyclidine (2 microM) and ketamine (20 microM). 5. Stimulation of the hilus during the first week of life evoked a GDP followed by a hyperpolarization. The GDPs were generated by a population of synchronized neurones and reversed polarity at -27 mV with KCl-filled electrodes and at -52 mV with potassium acetate- or potassium methylsulphate-containing electrodes. 6. Bath application of bicuculline (1-10 microM) or picrotoxin (100-200 microM) reversibly blocked the evoked GDPs in the majority of cells

  11. Giant synaptic potentials in immature rat CA3 hippocampal neurones.

    PubMed Central

    Ben-Ari, Y; Cherubini, E; Corradetti, R; Gaiarsa, J L

    1989-01-01

    1. Intracellular recordings were made from rat CA3 hippocampal neurones in vitro during the first eighteen days of postnatal life. The cells had resting membrane potentials more negative than -51 mV, action potentials greater than 55 mV and membrane input resistances of 117 +/- 12 M omega. An unusual characteristic of these cells was the presence of spontaneous giant depolarizing potentials (GDPs) which were observed during the first eight postnatal (P) days in over 85% of neurones. They were less frequent between P9 and P12 (48%) and disappeared after P12. 2. The GDPs were synchronously generated by a population of neurones; they reversed polarity at -27 mV when recorded with KCl-containing electrodes and at -51 mV with potassium acetate- or potassium methylsulphate-filled electrodes. 3. The GDPs were blocked by bath application of bicuculline (10 microM) or picrotoxin (100-200 microM). Exogenously applied gamma-aminobutyric acid (GABA; 0.2-1 mM) induced at resting membrane potential a bicuculline-sensitive membrane depolarization which reversed polarity at -25 and -51 mV when recorded with KCl- or potassium methylsulphate-filled electrodes respectively. 4. The GDPs were reduced in frequency or blocked by the N-methyl-D-aspartate (NMDA) receptor antagonists DL-2-amino-7-phosphonoheptanoate (AP-7; 50 microM), D(-)2-amino-5-phosphonovalerate (AP-5, 10-50 microM) and (+-)3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10-50 microM) or NMDA channel blockers phencyclidine (2 microM) and ketamine (20 microM). 5. Stimulation of the hilus during the first week of life evoked a GDP followed by a hyperpolarization. The GDPs were generated by a population of synchronized neurones and reversed polarity at -27 mV with KCl-filled electrodes and at -52 mV with potassium acetate- or potassium methylsulphate-containing electrodes. 6. Bath application of bicuculline (1-10 microM) or picrotoxin (100-200 microM) reversibly blocked the evoked GDPs in the majority of cells

  12. GABAergic hub neurons orchestrate synchrony in developing hippocampal networks.

    PubMed

    Bonifazi, P; Goldin, M; Picardo, M A; Jorquera, I; Cattani, A; Bianconi, G; Represa, A; Ben-Ari, Y; Cossart, R

    2009-12-04

    Brain function operates through the coordinated activation of neuronal assemblies. Graph theory predicts that scale-free topologies, which include "hubs" (superconnected nodes), are an effective design to orchestrate synchronization. Whether hubs are present in neuronal assemblies and coordinate network activity remains unknown. Using network dynamics imaging, online reconstruction of functional connectivity, and targeted whole-cell recordings in rats and mice, we found that developing hippocampal networks follow a scale-free topology, and we demonstrated the existence of functional hubs. Perturbation of a single hub influenced the entire network dynamics. Morphophysiological analysis revealed that hub cells are a subpopulation of gamma-aminobutyric acid-releasing (GABAergic) interneurons possessing widespread axonal arborizations. These findings establish a central role for GABAergic interneurons in shaping developing networks and help provide a conceptual framework for studying neuronal synchrony.

  13. Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis.

    PubMed

    Ehret, Fanny; Vogler, Steffen; Pojar, Sherin; Elliott, David A; Bradke, Frank; Steiner, Barbara; Kempermann, Gerd

    2015-03-01

    Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL.

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

    PubMed

    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.

  15. Tetrahydrohyperforin increases adult hippocampal neurogenesis in wild-type and APPswe/PS1ΔE9 mice.

    PubMed

    Abbott, Ana C; Calderon Toledo, Carla; Aranguiz, Florencia C; Inestrosa, Nibaldo C; Varela-Nallar, Lorena

    2013-01-01

    Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

  16. Human Cerebrospinal Fluid Promotes Neuronal Viability and Activity of Hippocampal Neuronal Circuits In Vitro

    PubMed Central

    Perez-Alcazar, Marta; Culley, Georgia; Lyckenvik, Tim; Mobarrez, Kristoffer; Bjorefeldt, Andreas; Wasling, Pontus; Seth, Henrik; Asztely, Frederik; Harrer, Andrea; Iglseder, Bernhard; Aigner, Ludwig; Hanse, Eric; Illes, Sebastian

    2016-01-01

    For decades it has been hypothesized that molecules within the cerebrospinal fluid (CSF) diffuse into the brain parenchyma and influence the function of neurons. However, the functional consequences of CSF on neuronal circuits are largely unexplored and unknown. A major reason for this is the absence of appropriate neuronal in vitro model systems, and it is uncertain if neurons cultured in pure CSF survive and preserve electrophysiological functionality in vitro. In this article, we present an approach to address how human CSF (hCSF) influences neuronal circuits in vitro. We validate our approach by comparing the morphology, viability, and electrophysiological function of single neurons and at the network level in rat organotypic slice and primary neuronal cultures cultivated either in hCSF or in defined standard culture media. Our results demonstrate that rodent hippocampal slices and primary neurons cultured in hCSF maintain neuronal morphology and preserve synaptic transmission. Importantly, we show that hCSF increases neuronal viability and the number of electrophysiologically active neurons in comparison to the culture media. In summary, our data indicate that hCSF represents a physiological environment for neurons in vitro and a superior culture condition compared to the defined standard media. Moreover, this experimental approach paves the way to assess the functional consequences of CSF on neuronal circuits as well as suggesting a novel strategy for central nervous system (CNS) disease modeling. PMID:26973467

  17. Metabotropic suppression of excitation in murine autaptic hippocampal neurons.

    PubMed

    Straiker, Alex; Mackie, Ken

    2007-02-01

    Depolarization-induced suppression of excitation (DSE) and inhibition (DSI) are forms of short-term neuronal plasticity involving postsynaptic release of an endocannabinoid and the activation of presynaptic cannabinoid CB1 receptors. We have recently reported that CB1-dependent DSE can be elicited in autaptic cultures of excitatory hippocampal neurons of the mouse. We now report that the same preparation exhibits a parallel G(q)-coupled receptor-dependent production of endocannabinoids causing retrograde inhibition, also via CB1 receptors, which we will refer to as metabotropic suppression of excitation (MSE). We tested a spectrum of G(q)-coupled receptor agonists and found that both muscarinic and metabotropic glutamate receptors (group I) mediate retrograde inhibition via CB1 receptors in autaptic hippocampal neurons. Thus these neurons possess not only the pre- and postsynaptic machinery necessary for DSE but also that for MSE. This permitted a closer examination of MSE and its interaction with other aspects of the endocannabinoid retrograde signalling machinery: MSE mimics and occludes DSE and is itself occluded by the endocannabinoid 2-arachidonoyl glycerol (2-AG), consistent with 2-AG as a likely mediator of MSE. In contrast to DSE, MSE undergoes heterologous desensitization over the time course of minutes. In keeping with data reported for metabotropic suppression of inhibition (MSI) and DSI in the hippocampus, subthreshold MSE and DSE act synergistically. We additionally found that Delta9-tetrahydrocannabinol, which has been shown to attenuate DSE, antagonizes MSE. Finally, we have distinguished a neuronal subpopulation that exhibits DSE and a differential complement of MSE-mediating Gq-coupled receptors, making possible contrasting studies of MSE. Autaptic endocannabinoid signalling is rich, robust and complex in a deceptively simple package, including a previously unreported postsynaptic mechanism of adaptation in addition to known presynaptic CB1

  18. Hippocampal Somatostatin Interneurons Control the Size of Neuronal Memory Ensembles.

    PubMed

    Stefanelli, Thomas; Bertollini, Cristina; Lüscher, Christian; Muller, Dominique; Mendez, Pablo

    2016-03-02

    Hippocampal neurons activated during encoding drive the recall of contextual fear memory. Little is known about how such ensembles emerge during acquisition and eventually form the cellular engram. Manipulating the activity of granule cells (GCs) of the dentate gyrus (DG), we reveal a mechanism of lateral inhibition that modulates the size of the cellular engram. GCs engage somatostatin-positive interneurons that inhibit the dendrites of surrounding GCs. Our findings reveal a microcircuit within the DG that controls the size of the cellular engram and the stability of contextual fear memory.

  19. Distinct pathways for rule-based retrieval and spatial mapping of memory representations in hippocampal neurons

    PubMed Central

    Navawongse, Rapeechai; Eichenbaum, Howard

    2013-01-01

    Hippocampal neurons encode events within the context in which they occurred, a fundamental feature of episodic memory. Here we explored the sources of event and context information represented by hippocampal neurons during the retrieval of object associations in rats. Temporary inactivation of the medial prefrontal cortex differentially reduced the selectivity of rule-based object associations represented by hippocampal neuronal firing patterns but did not affect spatial firing patterns. By contrast, inactivation of the medial entorhinal cortex resulted in a pervasive reorganization of hippocampal mappings of spatial context and events. These results suggest distinct and cooperative prefrontal and medial temporal mechanisms in memory representation. PMID:23325238

  20. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C

    PubMed Central

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-01

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons. PMID:26742695

  1. Maternal immune activation produces neonatal excitability defects in offspring hippocampal neurons from pregnant rats treated with poly I:C.

    PubMed

    Patrich, Eti; Piontkewitz, Yael; Peretz, Asher; Weiner, Ina; Attali, Bernard

    2016-01-08

    Maternal immune activation (MIA) resulting from prenatal exposure to infectious pathogens or inflammatory stimuli is increasingly recognized to play an important etiological role in neuropsychiatric disorders with neurodevelopmental features. MIA in pregnant rodents induced by injection of the synthetic double-stranded RNA, Poly I:C, a mimic of viral infection, leads to a wide spectrum of behavioral abnormalities as well as structural and functional defects in the brain. Previous MIA studies using poly I:C prenatal treatment suggested that neurophysiological alterations occur in the hippocampus. However, these investigations used only juvenile or adult animals. We postulated that MIA-induced alterations could occur earlier at neonatal/early postnatal stages. Here we examined the neurophysiological properties of cultured pyramidal-like hippocampal neurons prepared from neonatal (P0-P2) offspring of pregnant rats injected with poly I:C. Offspring neurons from poly I:C-treated mothers exhibited significantly lower intrinsic excitability and stronger spike frequency adaptation, compared to saline. A similar lower intrinsic excitability was observed in CA1 pyramidal neurons from hippocampal slices of two weeks-old poly I:C offspring. Cultured hippocampal neurons also displayed lower frequency of spontaneous firing, higher charge transfer of IPSCs and larger amplitude of miniature IPSCs. Thus, maternal immune activation leads to strikingly early neurophysiological abnormalities in hippocampal neurons.

  2. Age-Dependent Glutamate Induction of Synaptic Plasticity in Cultured Hippocampal Neurons

    ERIC Educational Resources Information Center

    Ivenshitz, Miriam; Segal, Menahem; Sapoznik, Stav

    2006-01-01

    A common denominator for the induction of morphological and functional plasticity in cultured hippocampal neurons involves the activation of excitatory synapses. We now demonstrate massive morphological plasticity in mature cultured hippocampal neurons caused by a brief exposure to glutamate. This plasticity involves a slow, 70%-80% increase in…

  3. Synchronization in hybrid neuronal networks of the hippocampal formation.

    PubMed

    Netoff, Theoden I; Banks, Matthew I; Dorval, Alan D; Acker, Corey D; Haas, Julie S; Kopell, Nancy; White, John A

    2005-03-01

    Understanding the mechanistic bases of neuronal synchronization is a current challenge in quantitative neuroscience. We studied this problem in two putative cellular pacemakers of the mammalian hippocampal theta rhythm: glutamatergic stellate cells (SCs) of the medial entorhinal cortex and GABAergic oriens-lacunosum-molecular (O-LM) interneurons of hippocampal region CA1. We used two experimental methods. First, we measured changes in spike timing induced by artificial synaptic inputs applied to individual neurons. We then measured responses of free-running hybrid neuronal networks, consisting of biological neurons coupled (via dynamic clamp) to biological or virtual counterparts. Results from the single-cell experiments predicted network behaviors well and are compatible with previous model-based predictions of how specific membrane mechanisms give rise to empirically measured synchronization behavior. Both cell types phase lock stably when connected via homogeneous excitatory-excitatory (E-E) or inhibitory-inhibitory (I-I) connections. Phase-locked firing is consistently synchronous for either cell type with E-E connections and nearly anti-synchronous with I-I connections. With heterogeneous connections (e.g., excitatory-inhibitory, as might be expected if members of a given population had heterogeneous connections involving intermediate interneurons), networks often settled into phase locking that was either stable or unstable, depending on the order of firing of the two cells in the hybrid network. Our results imply that excitatory SCs, but not inhibitory O-LM interneurons, are capable of synchronizing in phase via monosynaptic mutual connections of the biologically appropriate polarity. Results are largely independent of synaptic strength and synaptic kinetics, implying that our conclusions are robust and largely unaffected by synaptic plasticity.

  4. Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors.

    PubMed

    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.

  5. Exercise Can Rescue Recognition Memory Impairment in a Model with Reduced Adult Hippocampal Neurogenesis

    PubMed Central

    Lafenêtre, Pauline; Leske, Oliver; Ma-Högemeie, Zhanlu; Haghikia, Aiden; Bichler, Zoe; Wahle, Petra; Heumann, Rolf

    2009-01-01

    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 tyrosine receptor kinase B 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. PMID:20204139

  6. Distinct stages of adult hippocampal neurogenesis are regulated by running and the running environment.

    PubMed

    Bednarczyk, Matthew R; Hacker, Lindsay C; Fortin-Nunez, Stéphanie; Aumont, Anne; Bergeron, Raynald; Fernandes, Karl J L

    2011-12-01

    Hippocampal neurogenesis continues into adulthood in mammalian vertebrates, and in experimental rodent models it is powerfully stimulated by exposure to a voluntary running wheel. In this study, we demonstrate that exposure to a running wheel environment, in the absence of running, is sufficient to regulate specific aspects of hippocampal neurogenesis. Adult mice were provided with standard housing, housing enriched with a running wheel or housing enriched with a locked wheel (i.e., an environment comparable to that of running animals, without the possibility of engaging in running). We found that mice in the running wheel and locked wheel groups exhibited equivalent increases in proliferation within the neurogenic niche of the dentate gyrus; this included comparable increases in the proliferation of radial glia-like stem cells and the number of proliferating neuroblasts. However, only running animals displayed increased numbers of postmitotic neuroblasts and mature neurons. These results demonstrate that the running wheel environment itself is sufficient for promoting proliferation of early lineage hippocampal precursors, while running per se enables newly generated neuroblasts to survive and mature into functional hippocampal neurons. Thus, both running-independent and running-dependent stimuli are integral to running wheel-induced hippocampal neurogenesis.

  7. Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy.

    PubMed

    Gao, Chunlin; Cai, Ying; Zhang, Xuebin; Huang, Huiling; Wang, Jin; Wang, Yajing; Tong, Xiaoguang; Wang, Jinhuan; Wu, Jialing

    2015-01-01

    The hippocampal CA1 region is sensitive to hypoxic and ischemic injury but can be protected by ischemic preconditioning (IPC). However, the mechanism through which IPC protects hippocampal CA1 neurons is still under investigation. Additionally, the role of autophagy in determining the fate of hippocampal neurons is unclear. Here, we examined whether IPC induced autophagy to alleviate hippocampal CA1 neuronal death in vitro and in vivo with oxygen glucose deprivation (OGD) and bilateral carotid artery occlusion (BCCAO) models. Survival of hippocampal neurons increased from 51.5% ± 6.3% in the non-IPC group (55 min of OGD) to 77.3% ± 7.9% in the IPC group (15 min of OGD, followed by 55 min of OGD 24 h later). The number of hippocampal CA1 layer neurons increased from 182 ± 26 cells/mm2 in the non-IPC group (20 min of BCCAO) to 278 ± 55 cells/mm2 in the IPC group (1 min × 3 BCCAO, followed by 20 min of BCCAO 24 h later). Akt phosphorylation and microtubule-associated protein light chain 3 (LC3)-II/LC3-I expression were increased in the preconditioning group. Moreover, the protective effects of IPC were abolished only by inhibiting the activity of autophagy, but not by blocking the activation of Akt in vitro. Using in vivo experiments, we found that LC3 expression was upregulated, accompanied by an increase in neuronal survival in hippocampal CA1 neurons in the preconditioning group. The neuroprotective effects of IPC on hippocampal CA1 neurons were completely inhibited by treatment with 3-MA. In contrast, hippocampal CA3 neurons did not show changes in autophagic activity or beneficial effects of IPC. These data suggested that IPC may attenuate ischemic injury in hippocampal CA1 neurons through induction of Akt-independent autophagy.

  8. Ischemic Preconditioning Mediates Neuroprotection against Ischemia in Mouse Hippocampal CA1 Neurons by Inducing Autophagy

    PubMed Central

    Zhang, Xuebin; Huang, Huiling; Wang, Jin; Wang, Yajing; Tong, Xiaoguang; Wang, Jinhuan; Wu, Jialing

    2015-01-01

    The hippocampal CA1 region is sensitive to hypoxic and ischemic injury but can be protected by ischemic preconditioning (IPC). However, the mechanism through which IPC protects hippocampal CA1 neurons is still under investigation. Additionally, the role of autophagy in determining the fate of hippocampal neurons is unclear. Here, we examined whether IPC induced autophagy to alleviate hippocampal CA1 neuronal death in vitro and in vivo with oxygen glucose deprivation (OGD) and bilateral carotid artery occlusion (BCCAO) models. Survival of hippocampal neurons increased from 51.5% ± 6.3% in the non-IPC group (55 min of OGD) to 77.3% ± 7.9% in the IPC group (15 min of OGD, followed by 55 min of OGD 24 h later). The number of hippocampal CA1 layer neurons increased from 182 ± 26 cells/mm2 in the non-IPC group (20 min of BCCAO) to 278 ± 55 cells/mm2 in the IPC group (1 min × 3 BCCAO, followed by 20 min of BCCAO 24 h later). Akt phosphorylation and microtubule-associated protein light chain 3 (LC3)-II/LC3-I expression were increased in the preconditioning group. Moreover, the protective effects of IPC were abolished only by inhibiting the activity of autophagy, but not by blocking the activation of Akt in vitro. Using in vivo experiments, we found that LC3 expression was upregulated, accompanied by an increase in neuronal survival in hippocampal CA1 neurons in the preconditioning group. The neuroprotective effects of IPC on hippocampal CA1 neurons were completely inhibited by treatment with 3-MA. In contrast, hippocampal CA3 neurons did not show changes in autophagic activity or beneficial effects of IPC. These data suggested that IPC may attenuate ischemic injury in hippocampal CA1 neurons through induction of Akt-independent autophagy. PMID:26325184

  9. Role of adult hippocampal neurogenesis in stress resilience

    PubMed Central

    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

  10. Channel shutdown: a response of hippocampal neurons to adverse environments.

    PubMed

    Somjen, G G; Faas, G C; Vreugdenhil, M; Wadman, W J

    1993-12-31

    Stretch-activated ion channels have been discovered in the membrane of many types of cells, but their presence in neurons is uncertain. We used freshly dissociated rat hippocampal neurons to study the effect of hypotonic swelling but, surprisingly, the isolated neurons did not swell. Voltage-dependent whole-cell membrane currents mediated by K+, Na+ and Ca2+ were rapidly and reversibly suppressed during sudden exposure to strongly hypo-osmotic, hyper-osmotic or glucose deficient solutions. The amplitudes of the sustained components of K+ and Ca2+ currents were more depressed than transient currents, but the rate of decay of transient K+ current greatly accelerated. The voltage dependence of activation and of steady state inactivation of residual K+ and Ca2+ currents were not shifted. The current holding membrane potential at -70 mV and therefore the conductance at that voltage were unchanged or somewhat decreased. Capacitive (charging) membrane current was not affected. Changes in tail current suggested moderate loss of cytosolic K+ in some but not in all cells. We conclude that channel shutdown is a uniform response of neuron somata and proximal dendrites to various adverse environments. Hypothetically we propose that swelling was prevented in anisosmotic conditions because membrane water permeability decreased.

  11. Mechanism of PAMAM Dendrimers Internalization in Hippocampal Neurons.

    PubMed

    Vidal, Felipe; Vásquez, Pilar; Díaz, Carola; Nova, Daniela; Alderete, Joel; Guzmán, Leonardo

    2016-10-03

    Polyamidoamine (PAMAM) dendrimers are hyperbranched macromolecules which have been described as one of the most promising drug nanocarrier systems. A key process to understand is their cellular internalization mechanism because of its direct influence on their intracellular distribution, association with organelles, entry kinetics, and cargo release. Despite that internalization mechanisms of dendrimers have been studied in different cell types, in the case of neurons they are not completely described. Considering the relevance of central nervous system (CNS) diseases and neuropharmacology, the aim of this report is to describe the molecular internalization mechanism of different PAMAM-based dendrimer systems in hippocampal neurons. Four dendrimers based on fourth generation PAMAM with different surface properties were studied: unmodified G4, with a positively charged surface; PP50, with a substitution of the 50% of amino surface groups with polyethylene glycol neutral groups; PAc, with a substitution of the 30% of amino surface groups with acrylate anionic groups; and PFO, decorated with folic acid groups in a 25% of total terminal groups. Confocal images show that both G4 and PFO are able to enter the neurons, but not PP50 and PAc. Colocalization study with specific endocytosis markers and specific endocytosis inhibitor assay demonstrate that clathrin-mediated endocytosis would be the main internalization mechanism for G4, whereas clathrin- and caveolae-mediated endocytosis would be implicated in PFO internalization. These results show the existence of different internalization mechanisms for PAMAM dendrimers in neurons and the possibility to control their internalization properties with specific chemical modifications.

  12. Adult newborn neurons are involved in learning acquisition and long-term memory formation: the distinct demands on temporal neurogenesis of different cognitive tasks.

    PubMed

    Suárez-Pereira, Irene; Canals, Santiago; Carrión, Angel M

    2015-01-01

    There is evidence that adult hippocampal neurogenesis influences hippocampal function, although the role these neurons fulfill in learning and consolidation processes remains unclear. Using a novel fast X-ray ablation protocol to deplete neurogenic cells, we demonstrate that immature adult hippocampal neurons are required for hippocampal learning and long-term memory formation. Moreover, we found that long-term memory formation in the object recognition and passive avoidance tests, two paradigms that involve circuits with distinct emotional components, had different temporal demands on hippocampal neurogenesis. These results reveal new and unexpected aspects of neurogenesis in cognitive processes.

  13. Leptin Counteracts the Hypoxia-Induced Inhibition of Spontaneously Firing Hippocampal Neurons: A Microelectrode Array Study

    PubMed Central

    Gavello, Daniela; Rojo-Ruiz, Jonathan; Marcantoni, Andrea; Franchino, Claudio; Carbone, Emilio; Carabelli, Valentina

    2012-01-01

    Besides regulating energy balance and reducing body-weight, the adipokine leptin has been recently shown to be neuroprotective and antiapoptotic by promoting neuronal survival after excitotoxic and oxidative insults. Here, we investigated the firing properties of mouse hippocampal neurons and the effects of leptin pretreatment on hypoxic damage (2 hours, 3% O2). Experiments were carried out by means of the microelectrode array (MEA) technology, monitoring hippocampal neurons activity from 11 to 18 days in vitro (DIV). Under normoxic conditions, hippocampal neurons were spontaneously firing, either with prevailing isolated and randomly distributed spikes (11 DIV), or with patterns characterized by synchronized bursts (18 DIV). Exposure to hypoxia severely impaired the spontaneous activity of hippocampal neurons, reducing their firing frequency by 54% and 69%, at 11 and 18 DIV respectively, and synchronized their firing activity. Pretreatment with 50 nM leptin reduced the firing frequency of normoxic neurons and contrasted the hypoxia-induced depressive action, either by limiting the firing frequency reduction (at both ages) or by increasing it to 126% (in younger neurons). In order to find out whether leptin exerts its effect by activating large conductance Ca2+-activated K+ channels (BK), as shown on rat hippocampal neurons, we applied the BK channel blocker paxilline (1 µM). Our data show that paxilline reversed the effects of leptin, both on normoxic and hypoxic neurons, suggesting that the adipokine counteracts hypoxia through BK channels activation in mouse hippocampal neurons. PMID:22848520

  14. Acute ethanol suppresses glutamatergic neurotransmission through endocannabinoids in hippocampal neurons.

    PubMed

    Basavarajappa, Balapal S; Ninan, Ipe; Arancio, Ottavio

    2008-11-01

    Ethanol exposure during fetal development is a leading cause of long-term cognitive impairments. Studies suggest that ethanol exposure have deleterious effects on the hippocampus, a brain region that is important for learning and memory. Ethanol exerts its effects, in part, via alterations in glutamatergic neurotransmission, which is critical for the maturation of neuronal circuits during development. The current literature strongly supports the growing evidence that ethanol inhibits glutamate release in the neonatal CA1 hippocampal region. However, the exact molecular mechanism responsible for this effect is not well understood. In this study, we show that ethanol enhances endocannabinoid (EC) levels in cultured hippocampal neurons, possibly through calcium pathways. Acute ethanol depresses miniature post-synaptic current (mEPSC) frequencies without affecting their amplitude. This suggests that ethanol inhibits glutamate release. The CB1 receptors (CB1Rs) present on pre-synaptic neurons are not altered by acute ethanol. The CB1R antagonist SR 141716A reverses ethanol-induced depression of mEPSC frequency. Drugs that are known to enhance the in vivo function of ECs occlude ethanol effects on mEPSC frequency. Chelation of post-synaptic calcium by EGTA antagonizes ethanol-induced depression of mEPSC frequency. The activation of CB1R with the selective agonist WIN55,212-2 also suppresses the mEPSC frequency. This WIN55,212-2 effect is similar to the ethanol effects and is reversed by SR141716A. In addition, tetani-induced excitatory post-synaptic currents (EPSCs) are depressed by acute ethanol. SR141716A significantly reverses ethanol effects on evoked EPSC amplitude in a dual recording preparation. These observations, taken together, suggest the participation of ECs as retrograde messengers in the ethanol-induced depression of synaptic activities.

  15. The Ever-Changing Morphology of Hippocampal Granule Neurons in Physiology and Pathology

    PubMed Central

    Llorens-Martín, María; Rábano, Alberto; Ávila, Jesús

    2016-01-01

    Newborn neurons are continuously added to the hippocampal dentate gyrus throughout adulthood. In this review, we analyze the maturational stages that newborn granule neurons go through, with a focus on their unique morphological features during each stage under both physiological and pathological circumstances. In addition, the influence of deleterious (such as schizophrenia, stress, Alzheimer's disease, seizures, stroke, inflammation, dietary deficiencies, or the consumption of drugs of abuse or toxic substances) and neuroprotective (physical exercise and environmental enrichment) stimuli on the maturation of these cells will be examined. Finally, the regulation of this process by proteins involved in neurodegenerative and neurological disorders such as Glycogen synthase kinase 3β, Disrupted in Schizophrenia 1 (DISC-1), Glucocorticoid receptor, pro-inflammatory mediators, Presenilin-1, Amyloid precursor protein, Cyclin-dependent kinase 5 (CDK5), among others, will be evaluated. Given the recently acquired relevance of the dendritic branch as a functional synaptic unit required for memory storage, a full understanding of the morphological alterations observed in newborn neurons may have important consequences for the prevention and treatment of the cognitive and affective alterations that evolve in conjunction with impaired adult hippocampal neurogenesis. PMID:26834550

  16. Temporal expression of neuronal connexins during hippocampal ontogeny.

    PubMed

    Rozental, R; Srinivas, M; Gökhan, S; Urban, M; Dermietzel, R; Kessler, J A; Spray, D C; Mehler, M F

    2000-04-01

    Communication through gap junction channels provides a major signaling mechanism during early brain histogenesis, a developmental time during which neural progenitor cells are inexcitable and do not express ligand-gated channel responses to the major CNS neurotransmitters. Expression of different gap junction types during neurogenesis may therefore define intercellular pathways for transmission of developmentally relevant molecules. To better understand the molecular mechanism(s) by which growth and differentiation of neurons are modulated by gap junction channels, we have been examining the developmental effects of a specific set of cytokines on differentiation and gap junction expression in a conditionally immortalized mouse embryonic hippocampal neuronal progenitor cell line (MK31). When multipotent MK31 cells are in an uncommitted state, they uniformly express the neuroepithelial intermediate filament class VI marker, nestin, are strongly coupled by gap junctions composed of connexin43 (Cx43) and express connexin45 (Cx45) at the mRNA level. As these cells undergo neuronal lineage commitment and exit from cell cycle, they begin to express the early neurofilament marker, NF66, and coupling strength and expression of Cx43 begin to decline with concurrent expression of other connexin proteins, including Cx26, Cx33, Cx36, Cx40 and Cx45. Terminal neuronal differentiation is heralded by the expression of more advanced neurofilament proteins, increased morphologic maturation, the elaboration of inward currents and action potentials that possess mature physiological properties, and changing profiles of expression of connexin subtypes, including upregulation of Cx36 expression. These important developmental transitions are regulated by a complex network of cell cycle checkpoints. To begin to examine the precise roles of gap junction proteins in traversing these developmental checkpoints and in thus regulating neurogenesis, we have focused on individual members of two

  17. Taxonomic Separation of Hippocampal Networks: Principal Cell Populations and Adult Neurogenesis

    PubMed Central

    van Dijk, R. Maarten; Huang, Shih-Hui; Slomianka, Lutz; Amrein, Irmgard

    2016-01-01

    While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis (AHN) in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates) are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non-rodent species, and

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

    PubMed

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

    2015-08-18

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

  19. Electrophysiological properties of cultured hippocampal neurons from Wistar Audiogenic Rats.

    PubMed

    Mesquita, Fernando; Aguiar, José F; Oliveira, José A; Garcia-Cairasco, Norberto; Varanda, Wamberto A

    2005-03-15

    The main goal of this work was to analyze the electrophysiological properties of cultured hippocampal neurons from a particular epileptic rat strain, called Wistar Audiogenic Rats (WAR). The whole-cell patch-clamp technique was used to record both active and passive membrane responses in an attempt to detect alterations in their characteristics in relation to controls from Wistar rats. Neurons from WARs show a significant reduction in the magnitude of the inhibitory GABAergic currents ( approximately 45%), in spite of maintaining a normal level of the excitatory glutamatergic currents. In addition, the magnitude of potassium currents, measured at +80 mV, is reduced by about 30% in comparison to controls. Surprisingly, we also found important changes in the passive cellular properties in WAR neurons such as membrane potential (-50.0 mV in WARs and -63.1 mV in controls) and input resistance (647 MOmega in WARs and 408 MOmega in controls). The changes described here, could be the basis of the neurophysiological and behavioral alterations present in these hyperexcitable animals, contributing to a better understanding of epileptogenesis in this particular animal model.

  20. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knock-in Mice

    PubMed Central

    Li, Gang; Bien-Ly, Nga; Andrews-Zwilling, Yaisa; Xu, Qin; Bernardo, Aubrey; Ring, Karen; Halabisky, Brian; Deng, Changhui; Mahley, Robert W.; Huang, Yadong

    2010-01-01

    SUMMARY Apolipoprotein (apo) E has important and diverse functions in neurobiology, and apoE4 is the major known genetic risk factor for Alzheimer’s disease. Here we report that adult neural stem/progenitor cells (NSCs) express apoE. In apoE knockout mice, neurogenesis in the hippocampus was ~60% lower than in wildtype mice, and most newborn cells developed into astrocytes rather than into neurons as in wildtype mice. This impairment was not observed in human apoE3 knock-in mice. In apoE4 knock-in mice, however, the maturation and dendritic development of newborn hippocampal neurons was significantly impaired as a result of apoE4 and its fragment-caused GABAergic interneuron dysfunction. This impairment was fully rescued by treatment with a GABAA receptor potentiator. These findings demonstrate the importance of apoE in adult hippocampal neurogenesis and show that apoE4 inhibits hippocampal neurogenesis by impairing neuronal maturation mediated by GABA signaling. PMID:19951691

  1. Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

    PubMed Central

    Ho, New Fei; Han, Siew Ping; Dawe, Gavin S

    2009-01-01

    Background Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. Results Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU). Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. Conclusion The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease. PMID:19500352

  2. Frizzled-5 receptor is involved in neuronal polarity and morphogenesis of hippocampal neurons.

    PubMed

    Slater, Paula G; Ramirez, Valerie T; Gonzalez-Billault, Christian; Varela-Nallar, Lorena; Inestrosa, Nibaldo C

    2013-01-01

    The Wnt signaling pathway plays important roles during different stages of neuronal development, including neuronal polarization and dendritic and axonal outgrowth. However, little is known about the identity of the Frizzled receptors mediating these processes. In the present study, we investigated the role of Frizzled-5 (Fzd5) on neuronal development in cultured Sprague-Dawley rat hippocampal neurons. We found that Fzd5 is expressed early in cultured neurons on actin-rich structures localized at minor neurites and axonal growth cones. At 4 DIV, Fzd5 polarizes towards the axon, where its expression is detected mainly at the peripheral zone of axonal growth cones, with no obvious staining at dendrites; suggesting a role of Fzd5 in neuronal polarization. Overexpression of Fzd5 during the acquisition of neuronal polarity induces mislocalization of the receptor and a loss of polarized axonal markers. Fzd5 knock-down leads to loss of axonal proteins, suggesting an impaired neuronal polarity. In contrast, overexpression of Fzd5 in neurons that are already polarized did not alter polarity, but decreased the total length of axons and increased total dendrite length and arborization. Fzd5 activated JNK in HEK293 cells and the effects triggered by Fzd5 overexpression in neurons were partially prevented by inhibition of JNK, suggesting that a non-canonical Wnt signaling mechanism might be involved. Our results suggest that, Fzd5 has a role in the establishment of neuronal polarity, and in the morphogenesis of neuronal processes, in part through the activation of the non-canonical Wnt mechanism involving JNK.

  3. Frizzled-5 Receptor Is Involved in Neuronal Polarity and Morphogenesis of Hippocampal Neurons

    PubMed Central

    Slater, Paula G.; Ramirez, Valerie T.; Gonzalez-Billault, Christian; Varela-Nallar, Lorena; Inestrosa, Nibaldo C.

    2013-01-01

    The Wnt signaling pathway plays important roles during different stages of neuronal development, including neuronal polarization and dendritic and axonal outgrowth. However, little is known about the identity of the Frizzled receptors mediating these processes. In the present study, we investigated the role of Frizzled-5 (Fzd5) on neuronal development in cultured Sprague-Dawley rat hippocampal neurons. We found that Fzd5 is expressed early in cultured neurons on actin-rich structures localized at minor neurites and axonal growth cones. At 4 DIV, Fzd5 polarizes towards the axon, where its expression is detected mainly at the peripheral zone of axonal growth cones, with no obvious staining at dendrites; suggesting a role of Fzd5 in neuronal polarization. Overexpression of Fzd5 during the acquisition of neuronal polarity induces mislocalization of the receptor and a loss of polarized axonal markers. Fzd5 knock-down leads to loss of axonal proteins, suggesting an impaired neuronal polarity. In contrast, overexpression of Fzd5 in neurons that are already polarized did not alter polarity, but decreased the total length of axons and increased total dendrite length and arborization. Fzd5 activated JNK in HEK293 cells and the effects triggered by Fzd5 overexpression in neurons were partially prevented by inhibition of JNK, suggesting that a non-canonical Wnt signaling mechanism might be involved. Our results suggest that, Fzd5 has a role in the establishment of neuronal polarity, and in the morphogenesis of neuronal processes, in part through the activation of the non-canonical Wnt mechanism involving JNK. PMID:24205342

  4. Apnea promotes glutamate-induced excitotoxicity in hippocampal neurons

    PubMed Central

    Fung, Simon J.; Xi, Ming-Chu; Zhang, Jian-Hua; Sampogna, Sharon; Yamuy, Jack; Morales, Francisco R.; Chase, Michael H.

    2011-01-01

    Patients with obstructive sleep apnea (OSA) exhibit hippocampal damage and cognitive deficits. To determine the effect of apnea on the synaptic transmission in the hippocampus, we performed electrophysiological studies in an in vivo guinea pig model of OSA. Specifically, we determined the cornu ammonis region 1 (CA1) field excitatory postsynaptic potential (fEPSP) response to cornu ammonis region 3 (CA3) stimulation and examined the presynaptic mechanisms underlying the changes in the fEPSP. Single episodes of apnea resulted in a maximal potentiation of the fEPSPs at one to three minutes after the termination of each episode of apnea. The mean amplitude and slope of the post-apneic fEPSP was significantly larger compared with the pre-apneic control. These changes were accompanied by a significant decrease in the paired-pulse facilitation ratio during the post-apneic period compared with the pre-apneic control. The N-methyl-D-aspartate (NMDA) glutamate receptor antagonist MK-801, when applied locally to the CA1 recording site by pressure ejection, blocked the apnea-induced potentiation of the fEPSP. In the experimental animals that were subjected to extended periods of recurrent apnea, CA1 neurons exhibited positive immunoreactivity for fragmented DNA strands, which indicates apoptotic cell death. The present results demonstrate that apnea-induced potentiation of the hippocampal CA1 fEPSP is mediated by an NMDA receptor mechanism. We therefore conclude that recurrent apnea produces abnormally high levels of glutamate that results in the apoptosis of CA1 neurons. We hypothesize that this damage is reflected by the cognitive deficits that are commonly observed in patients with breathing disorders such as OSA. PMID:17888415

  5. Anti-Nogo-A Immunotherapy Does Not Alter Hippocampal Neurogenesis after Stroke in Adult Rats

    PubMed Central

    Shepherd, Daniel J.; Tsai, Shih-Yen; O'Brien, Timothy E.; Farrer, Robert G.; Kartje, Gwendolyn L.

    2016-01-01

    Ischemic stroke is a leading cause of adult disability, including cognitive impairment. Our laboratory has previously shown that treatment with function-blocking antibodies against the neurite growth inhibitory protein Nogo-A promotes functional recovery after stroke in adult and aged rats, including enhancing spatial memory performance, for which the hippocampus is critically important. Since spatial memory has been linked to hippocampal neurogenesis, we investigated whether anti-Nogo-A treatment increases hippocampal neurogenesis after stroke. Adult rats were subject to permanent middle cerebral artery occlusion followed 1 week later by 2 weeks of antibody treatment. Cellular proliferation in the dentate gyrus was quantified at the end of treatment, and the number of newborn neurons was determined at 8 weeks post-stroke. Treatment with both anti-Nogo-A and control antibodies stimulated the accumulation of new microglia/macrophages in the dentate granule cell layer, but neither treatment increased cellular proliferation or the number of newborn neurons above stroke-only levels. These results suggest that anti-Nogo-A immunotherapy does not increase post-stroke hippocampal neurogenesis. PMID:27803646

  6. Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

    PubMed Central

    Ali, Amira A. H.; Schwarz‐Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-01-01

    Hippocampal neurogenesis undergoes dramatic age‐related changes. Mice with targeted deletion of the clock gene Bmal1 (Bmal1‐/‐) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1‐/‐ mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1‐/‐ mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70kDa and expression of the cell cycle inhibitor p21 Waf1/CIP1 were increased in adult Bmal1‐/‐ mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age‐dependent decline in adult neurogenesis presumably as a consequence of oxidative stress. PMID:26142744

  7. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

    PubMed

    Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-06-01

    Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

  8. Doublecortin (DCX) is not Essential for Survival and Differentiation of Newborn Neurons in the Adult Mouse Dentate Gyrus

    PubMed Central

    Dhaliwal, Jagroop; Xi, Yanwei; Bruel-Jungerman, Elodie; Germain, Johanne; Francis, Fiona; Lagace, Diane C.

    2016-01-01

    In the adult brain, expression of the microtubule-associated protein Doublecortin (DCX) is associated with neural progenitor cells (NPCs) that give rise to new neurons in the dentate gyrus. Many studies quantify the number of DCX-expressing cells as a proxy for the level of adult neurogenesis, yet no study has determined the effect of removing DCX from adult hippocampal NPCs. Here, we use a retroviral and inducible mouse transgenic approach to either knockdown or knockout DCX from adult NPCs in the dentate gyrus and examine how this affects cell survival and neuronal maturation. Our results demonstrate that shRNA-mediated knockdown of DCX or Cre-mediated recombination in floxed DCX mice does not alter hippocampal neurogenesis and does not change the neuronal fate of the NPCs. Together these findings show that the survival and maturation of adult-generated hippocampal neurons does not require DCX. PMID:26793044

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

    PubMed

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

    2016-05-01

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

  10. Impaired Terminal Differentiation of Hippocampal Granule Neurons and Defective Contextual Memory in PC3/Tis21 Knockout Mice

    PubMed Central

    Costanzi, Marco; Leonardi, Luca; Cinà, Irene; Micheli, Laura; Nutini, Michele; Longone, Patrizia; Oh, S. Paul; Cestari, Vincenzo; Tirone, Felice

    2009-01-01

    Neurogenesis in the dentate gyrus of the adult hippocampus has been implicated in neural plasticity and memory, but the molecular mechanisms controlling the proliferation and differentiation of newborn neurons and their integration into the synaptic circuitry are still largely unknown. To investigate this issue, we have analyzed the adult hippocampal neurogenesis in a PC3/Tis21-null mouse model. PC3/Tis21 is a transcriptional co-factor endowed with antiproliferative and prodifferentiative properties; indeed, its upregulation in neural progenitors has been shown to induce exit from cell cycle and differentiation. We demonstrate here that the deletion of PC3/Tis21 causes an increased proliferation of progenitor cells in the adult dentate gyrus and an arrest of their terminal differentiation. In fact, in the PC3/Tis21-null hippocampus postmitotic undifferentiated neurons accumulated, while the number of terminally differentiated neurons decreased of 40%. As a result, PC3/Tis21-null mice displayed a deficit of contextual memory. Notably, we observed that PC3/Tis21 can associate to the promoter of Id3, an inhibitor of proneural gene activity, and negatively regulates its expression, indicating that PC3/Tis21 acts upstream of Id3. Our results identify PC3/Tis21 as a gene required in the control of proliferation and terminal differentiation of newborn neurons during adult hippocampal neurogenesis and suggest its involvement in the formation of contextual memories. PMID:20020054

  11. Interfering of the Reelin/ApoER2/PSD95 Signaling Axis Reactivates Dendritogenesis of Mature Hippocampal Neurons.

    PubMed

    Ampuero, Estibaliz; Jury, Nur; Härtel, Steffen; Marzolo, María-Paz; van Zundert, Brigitte

    2017-05-01

    Reelin, an extracellular glycoprotein secreted in embryonic and adult brain, participates in neuronal migration and neuronal plasticity. Extensive evidence shows that reelin via activation of the ApoER2 and VLDLR receptors promotes dendrite and spine formation during early development. Further evidence suggests that reelin signaling is needed to maintain a stable architecture in mature neurons, but, direct evidence is lacking. During activity-dependent maturation of the neuronal circuitry, the synaptic protein PSD95 is inserted into the postsynaptic membrane to induce structural refinement and stability of spines and dendrites. Given that ApoER2 interacts with PSD95, we tested if reelin signaling interference in adult neurons reactivates the dendritic architecture. Unlike findings in developing cultures, the presently obtained in vitro and in vivo data show, for the first time, that reelin signaling interference robustly increase dendritogenesis and reduce spine density in mature hippocampal neurons. In particular, the expression of a mutant ApoER2 form (ApoER2-tailless), which is unable to interact with PSD95 and hence cannot transduce reelin signaling, resulted in robust dendritogenesis in mature hippocampal neurons in vitro. These results indicate that reelin/ApoER2/PSD95 signaling is important for neuronal structure maintenance in mature neurons. Mechanistically, obtained immunofluorescent data indicate that reelin signaling impairment reduced synaptic PSD95 levels, consequently leading to synaptic re-insertion of NR2B-NMDARs. Our findings underscore the importance of reelin in maintaining adult network stability and reveal a new mode for reactivating dendritogenesis in neurological disorders where dendritic arbor complexity is limited, such as in depression, Alzheimer's disease, and stroke. J. Cell. Physiol. 232: 1187-1199, 2017. © 2016 Wiley Periodicals, Inc.

  12. Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

    PubMed Central

    Hollands, Carolyn; Bartolotti, Nancy; Lazarov, Orly

    2016-01-01

    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. PMID:27199641

  13. Recruitment of hippocampal neurons to encode behavioral events in the rat: Alterations in cognitive demand and cannabinoid exposure

    PubMed Central

    Goonawardena, Anushka V; Robinson, Lianne; Riedel, Gernot; Hampson, Robert E

    2009-01-01

    Successful performance by rats of a delayed-nonmatch-to-sample (DNMS) task is hippocampal dependent. We have shown that neurons in hippocampus differentially encode task-relevant events. These responses are critical for correct DNMS performance and are diminished by exogenous cannabinoids. We therefore reasoned that hippocampal neural correlates of behavior are likely shaped during learning; however, to date, no work has examined these correlates during DNMS acquisition training. Consequently, the present study assessed the emergence of hippocampal neural encoding when (i) cognitive task demands were increased through prolongation of delay intervals between sample and nonmatch phase, and (ii) when animals are under cannabinoid treatment and performance is compromised. Adult, male Long-Evans rats were trained to perform the DNMS task without delay and then implanted with multi-electrode recording arrays directed to CA3 and CA1 sub-fields of the hippocampus. Following recovery, single units were isolated and animals divided into two treatment groups: vehicle or WIN 55,212-2 (WIN-2, 0.35 mg/kg). Ensemble firing was monitored during retraining in DNMS task at 0s, and subsequently delay intervals were progressively increased to 1–10s, 11–20s and 21–30s when animals met criterion (80% correct) at each respective interval. Hippocampal CA3 and CA1 principal cells were isolated and recorded throughout treatment. Extention of the delay led to an increase in the number of task-correlated neurons in controls. This recruitment of novel cells was reduced/prevented in the presence of WIN-2 and was paralleled by impairment in acquisition learning at longer delay intervals. Moreover, WIN-2 suppressed hippocampal ensemble firing during the sample (encoding) but not nonmatch phase of the DNMS task across all delays. These cannabinoid induced alterations in hippocampal neuronal activity may explain the observed deficits in DNMS performance. PMID:19771586

  14. Amyloid-Beta Induced Changes in Vesicular Transport of BDNF in Hippocampal Neurons

    PubMed Central

    Seifert, Bianca; Eckenstaler, Robert; Rönicke, Raik; Leschik, Julia; Lutz, Beat; Reymann, Klaus; Lessmann, Volkmar; Brigadski, Tanja

    2016-01-01

    The neurotrophin brain derived neurotrophic factor (BDNF) is an important growth factor in the CNS. Deficits in transport of this secretory protein could underlie neurodegenerative diseases. Investigation of disease-related changes in BDNF transport might provide insights into the cellular mechanism underlying, for example, Alzheimer's disease (AD). To analyze the role of BDNF transport in AD, live cell imaging of fluorescently labeled BDNF was performed in hippocampal neurons of different AD model systems. BDNF and APP colocalized with low incidence in vesicular structures. Anterograde as well as retrograde transport of BDNF vesicles was reduced and these effects were mediated by factors released from hippocampal neurons into the extracellular medium. Transport of BDNF was altered at a very early time point after onset of human APP expression or after acute amyloid-beta(1-42) treatment, while the activity-dependent release of BDNF remained unaffected. Taken together, extracellular cleavage products of APP induced rapid changes in anterograde and retrograde transport of BDNF-containing vesicles while release of BDNF was unaffected by transgenic expression of mutated APP. These early transport deficits might lead to permanently impaired brain functions in the adult brain. PMID:26881108

  15. Characterizing learning deficits and hippocampal neuron loss following transient global cerebral ischemia in rats.

    PubMed

    Hartman, Richard E; Lee, Jin M; Zipfel, Greg J; Wozniak, David F

    2005-05-10

    The 2-vessel-occlusion + hypotension (2VO + H) model of transient global cerebral ischemia results in neurodegeneration within the CA1 field of the hippocampus, but previous research has failed to demonstrate robust or reliable learning/memory deficits in rats subjected to this treatment. In the present study, sensitive behavioral protocols were developed in an effort to characterize the cognitive impairments following 2VO + H more precisely. Adult rats were exposed to 10 min of bilateral carotid occlusion with simultaneous hypotension. Following recovery, 2VO + H and control rats were subjected to a series of behavioral tests (locomotor activity, sensorimotor battery, water maze [cued, place, learning set], object recognition, and radial arm maze) over an extended recovery period followed by an assessment of neuronal loss in the dorsal hippocampus. The 2VO + H treatment was associated with long-lasting spatial learning deficits in the absence of other behavioral impairments and with neurodegeneration in dorsal hippocampal CA1. Water maze protocols that placed higher memory demands upon the rats (relatively "hard" vs. "easy") were more sensitive for detecting ischemia-induced deficits. We have shown that the use of appropriate behavioral tests (e.g., a relatively difficult place learning task) allowed for the observation of robust spatial learning deficits in a model previously shown to induce relatively subtle behavioral effects. Thus, the 2VO + H model induces both hippocampal neuronal loss and long-term learning deficits in rats, providing a potentially useful model for evaluating therapeutic efficacy.

  16. A calcium-permeable cGMP-activated cation conductance in hippocampal neurons

    NASA Technical Reports Server (NTRS)

    Leinders-Zufall, T.; Rosenboom, H.; Barnstable, C. J.; Shepherd, G. M.; Zufall, F.

    1995-01-01

    Whole-cell patch clamp recordings detected a previously unidentified cGMP-activated membrane conductance in cultured rat hippocampal neurons. This conductance is nonselectively permeable for cations and is completely but reversibly blocked by external Cd2+. The Ca2+ permeability of the hippocampal cGMP-activated conductance was examined in detail, indicating that the underlying ion channels display a high relative permeability for Ca2+. The results indicate that hippocampal neurons contain a cGMP-activated membrane conductance that has some properties similar to the cyclic nucleotide-gated channels previously shown in sensory receptor cells and retinal neurons. In hippocampal neurons this conductance similarly could mediate membrane depolarization and Ca2+ fluxes in response to intracellular cGMP elevation.

  17. Spatial gene's (Tbata) implication in neurite outgrowth and dendrite patterning in hippocampal neurons.

    PubMed

    Yammine, Miriam; Saade, Murielle; Chauvet, Sophie; Nguyen, Catherine

    2014-03-01

    The unique architecture of neurons requires the establishment and maintenance of polarity, which relies in part on microtubule-based kinesin motor transport to deliver essential cargo into axons and dendrites. In developing neurons, kinesin trafficking is essential for delivering organelles and molecules that are crucial for elongation and guidance of the growing axonal and dendritic termini. In mature neurons, kinesin cargo delivery is essential for neuron dynamic physiological functions which are critical in brain development. In this work, we followed Spatial (Tbata) gene expression during primary hippocampal neuron development and showed that it is highly expressed during dendrite formation. Spatial protein exhibits a somatodendritic distribution and we show that the kinesin motor Kif17, among other dendrite specific kinesins, is crucial for Spatial localization to dendrites of hippocampal neurons. Furthermore, Spatial down regulation in primary hippocampal cells revealed a role for Spatial in maintaining neurons' polarity by ensuring proper neurite outgrowth. This polarity is specified by intrinsic and extracellular signals that allow neurons to determine axon and dendrite fate during development. Neurotrophic factors, such as the Nerve Growth Factor (NGF), are candidate extracellular polarity-regulating cues which are proposed to accelerate neuronal polarization by enhancing dendrite growth. Here, we show that NGF treatment increases Spatial expression in hippocampal neurons. Altogether, these data suggest that Spatial, in response to NGF and through its transport by Kif17, is crucial for neuronal polarization and can be a key regulator of neurite outgrowth.

  18. Adult Hippocampal Neurogenesis in the Pathogenesis of Addiction and Dual Diagnosis Disorders

    PubMed Central

    Chambers, R. Andrew

    2013-01-01

    Background As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Methods Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. Results While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Conclusions Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders. PMID:23279925

  19. GABA mediated excitation in immature rat CA3 hippocampal neurons.

    PubMed

    Cherubini, E; Rovira, C; Gaiarsa, J L; Corradetti, R; Ben Ari, Y

    1990-01-01

    Intracellular recordings from rat hippocampal neurons in vitro during the first postnatal week revealed the presence of spontaneous giant depolarizing potentials (GDPs). These were generated by the synchronous discharge of a population of neurons. GDPs reversed polarity at -27 and -51 mV when recorded with KCl or K-methylsulphate filled electrodes, respectively. GDPs were blocked by the GABAA receptor antagonist bicuculline (10 microM). Iontophoretic or bath applications of GABA (10-300 microM) in the presence of tetrodotoxin (1 microM), induced a membrane depolarization or in voltage clamp experiments an inward current which reversed polarity at the same potential as GDPs. The response to GABA was blocked in a non-competitive manner by bicuculline (10 microM) and did not desensitize. GABA mediated GDPs were presynaptically modulated by N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Their frequency was reduced or blocked by NMDA receptor antagonists and by the rather specific non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The frequency of GDPs was enhanced by glycine and D-serine (10-30 microM) in a strychnine insensitive manner. This effect was blocked by AP-5, suggesting that it was mediated by the allosteric modulatory site of the NMDA receptor. These observations suggest that most of the 'excitatory' drive in immature neurons is mediated by GABA acting on GABAA receptors; furthermore excitatory amino acids modulate the release of GABA by a presynaptic action on GABAergic interneurons.

  20. Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

    PubMed

    Gilani, Ahmed I; Chohan, Muhammad O; Inan, Melis; Schobel, Scott A; Chaudhury, Nashid H; Paskewitz, Samuel; Chuhma, Nao; Glickstein, Sara; Merker, Robert J; Xu, Qing; Small, Scott A; Anderson, Stewart A; Ross, Margaret Elizabeth; Moore, Holly

    2014-05-20

    GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

  1. Wnt-5a Ligand Modulates Mitochondrial Fission-Fusion in Rat Hippocampal Neurons*

    PubMed Central

    Godoy, Juan A.; Arrázola, Macarena S.; Ordenes, Daniela; Silva-Alvarez, Carmen; Braidy, Nady; Inestrosa, Nibaldo C.

    2014-01-01

    The Wnt signaling pathway plays an important role in developmental processes, including embryonic patterning, cell specification, and cell polarity. Wnt components participate in the development of the central nervous system, and growing evidence indicates that this pathway also regulates the function of the adult nervous system. In this study, we report that Wnt-5a, a noncanonical Wnt ligand, is a potent activator of mitochondrial dynamics and induces acute fission and fusion events in the mitochondria of rat hippocampal neurons. The effect of Wnt-5a was inhibited in the presence of sFRP, a Wnt scavenger. Similarly, the canonical Wnt-3a ligand had no effect on mitochondrial fission-fusion events, suggesting that this effect is specific for Wnt-5a alone. We also show that the Wnt-5a effects on mitochondrial dynamics occur with an increase in both intracellular and mitochondrial calcium (Ca2+), which was correlated with an increased phosphorylation of Drp1(Ser-616) and a decrease of Ser-637 phosphorylation, both indicators of mitochondrial dynamics. Electron microscope analysis of hippocampal tissues in the CA1 region showed an increase in the number of mitochondria present in the postsynaptic region, and this finding correlated with a change in mitochondrial morphology. We conclude that Wnt-5a/Ca2+ signaling regulates the mitochondrial fission-fusion process in hippocampal neurons, a feature that might help to further understand the role of Wnt-related pathologies, including neurodegenerative diseases associated with mitochondrial dysfunction, and represents a potentially important link between impaired metabolic function and degenerative disorders. PMID:25336659

  2. Wnt-5a ligand modulates mitochondrial fission-fusion in rat hippocampal neurons.

    PubMed

    Godoy, Juan A; Arrázola, Macarena S; Ordenes, Daniela; Silva-Alvarez, Carmen; Braidy, Nady; Inestrosa, Nibaldo C

    2014-12-26

    The Wnt signaling pathway plays an important role in developmental processes, including embryonic patterning, cell specification, and cell polarity. Wnt components participate in the development of the central nervous system, and growing evidence indicates that this pathway also regulates the function of the adult nervous system. In this study, we report that Wnt-5a, a noncanonical Wnt ligand, is a potent activator of mitochondrial dynamics and induces acute fission and fusion events in the mitochondria of rat hippocampal neurons. The effect of Wnt-5a was inhibited in the presence of sFRP, a Wnt scavenger. Similarly, the canonical Wnt-3a ligand had no effect on mitochondrial fission-fusion events, suggesting that this effect is specific for Wnt-5a alone. We also show that the Wnt-5a effects on mitochondrial dynamics occur with an increase in both intracellular and mitochondrial calcium (Ca(2+)), which was correlated with an increased phosphorylation of Drp1(Ser-616) and a decrease of Ser-637 phosphorylation, both indicators of mitochondrial dynamics. Electron microscope analysis of hippocampal tissues in the CA1 region showed an increase in the number of mitochondria present in the postsynaptic region, and this finding correlated with a change in mitochondrial morphology. We conclude that Wnt-5a/Ca(2+) signaling regulates the mitochondrial fission-fusion process in hippocampal neurons, a feature that might help to further understand the role of Wnt-related pathologies, including neurodegenerative diseases associated with mitochondrial dysfunction, and represents a potentially important link between impaired metabolic function and degenerative disorders.

  3. Altered postnatal development of cortico-hippocampal neuronal electric activity in mice deficient for the mitochondrial aspartate-glutamate transporter.

    PubMed

    Gómez-Galán, Marta; Makarova, Julia; Llorente-Folch, Irene; Saheki, Takeyori; Pardo, Beatriz; Satrústegui, Jorgina; Herreras, Oscar

    2012-02-01

    The deficiency in the mitochondrial aspartate/glutamate transporter Aralar/AGC1 results in a loss of the malate-aspartate NADH shuttle in the brain neurons, hypomyelination, and additional defects in the brain metabolism. We studied the development of cortico/hippocampal local field potential (LFP) in Aralar/AGC1 knockout (KO) mice. Laminar profiles of LFP, evoked potentials, and unit activity were recorded under anesthesia in young (P15 to P22) Aralar-KO and control mice as well as control adults. While LFP power increased 3 to 7 times in both cortex and hippocampus of control animals during P15 to P22, the Aralar-KO specimens hardly progressed. The divergence was more pronounced in the CA3/hilus region. In parallel, spontaneous multiunit activity declined severely in KO mice. Postnatal growth of hippocampal-evoked potentials was delayed in KO mice, and indicated abnormal synaptic and spike electrogenesis and reduced output at P20 to P22. The lack of LFP development in KO mice was accompanied by the gradual appearance of epileptic activity in the CA3/hilus region that evolved to status epilepticus. Strikingly, CA3 bursts were poorly conducted to the CA1 field. We conclude that disturbed substrate supply to neuronal mitochondria impairs development of cortico-hippocampal LFPs. Aberrant neuronal electrogenesis and reduced neuron output may explain circuit dysfunction and phenotype deficiencies.

  4. CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation.

    PubMed

    Su, Weiping; Foster, Scott C; Xing, Rubing; Feistel, Kerstin; Olsen, Reid H J; Acevedo, Summer F; Raber, Jacob; Sherman, Larry S

    2017-03-17

    Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage, or retrieval. Here, we found that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown in vitro, suggesting that CD44 functions to regulate NSC proliferation in a cell-autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.

  5. Integrin Activation Through the Hematopoietic Adapter Molecule ADAP Regulates Dendritic Development of Hippocampal Neurons.

    PubMed

    Thiere, Marlen; Kliche, Stefanie; Müller, Bettina; Teuber, Jan; Nold, Isabell; Stork, Oliver

    2016-01-01

    Integrin-mediated cell adhesion and signaling is of critical importance for neuronal differentiation. Recent evidence suggests that an "inside-out" activation of β1-integrin, similar to that observed in hematopoietic cells, contributes to the growth and branching of dendrites. In this study, we investigated the role of the hematopoietic adaptor protein adhesion and degranulation promoting adapter protein (ADAP) in these processes. We demonstrate the expression of ADAP in the developing and adult nervous hippocampus, and in outgrowing dendrites of primary hippocampal neurons. We further show that ADAP occurs in a complex with another adaptor protein signal-transducing kinase-associated phosphoprotein-homolog (SKAP-HOM), with the Rap1 effector protein RAPL and the Hippo kinase macrophage-stimulating 1 (MST1), resembling an ADAP/SKAP module that has been previously described in T-cells and is critically involved in "inside-out" activation of integrins. Knock down of ADAP resulted in reduced expression of activated β1-integrin on dendrites. It furthermore reduced the differentiation of developing neurons, as indicated by reduced dendrite growth and decreased expression of the dendritic marker microtubule-associated protein 2 (MAP2). Our data suggest that an ADAP-dependent integrin-activation similar to that described in hematopoietic cells contributes to the differentiation of neuronal cells.

  6. Integrin Activation Through the Hematopoietic Adapter Molecule ADAP Regulates Dendritic Development of Hippocampal Neurons

    PubMed Central

    Thiere, Marlen; Kliche, Stefanie; Müller, Bettina; Teuber, Jan; Nold, Isabell; Stork, Oliver

    2016-01-01

    Integrin-mediated cell adhesion and signaling is of critical importance for neuronal differentiation. Recent evidence suggests that an “inside-out” activation of β1-integrin, similar to that observed in hematopoietic cells, contributes to the growth and branching of dendrites. In this study, we investigated the role of the hematopoietic adaptor protein adhesion and degranulation promoting adapter protein (ADAP) in these processes. We demonstrate the expression of ADAP in the developing and adult nervous hippocampus, and in outgrowing dendrites of primary hippocampal neurons. We further show that ADAP occurs in a complex with another adaptor protein signal-transducing kinase-associated phosphoprotein-homolog (SKAP-HOM), with the Rap1 effector protein RAPL and the Hippo kinase macrophage-stimulating 1 (MST1), resembling an ADAP/SKAP module that has been previously described in T-cells and is critically involved in “inside-out” activation of integrins. Knock down of ADAP resulted in reduced expression of activated β1-integrin on dendrites. It furthermore reduced the differentiation of developing neurons, as indicated by reduced dendrite growth and decreased expression of the dendritic marker microtubule-associated protein 2 (MAP2). Our data suggest that an ADAP-dependent integrin-activation similar to that described in hematopoietic cells contributes to the differentiation of neuronal cells. PMID:27746719

  7. GABAergic neurons of the medial septum lead the hippocampal network during theta activity.

    PubMed

    Hangya, Balázs; Borhegyi, Zsolt; Szilágyi, Nóra; Freund, Tamás F; Varga, Viktor

    2009-06-24

    Information processing in the hippocampus critically relies on its reciprocal interaction with the medial septum (MS). Synchronization of the septo-hippocampal system was demonstrated during both major hippocampal activity states, the regular theta rhythm and the large amplitude irregular activity. Previous experimental and modeling data suggest that the MS provides rhythmic drive to the hippocampus, and hippocampo-septal feedback synchronizes septal pacemaker units. However, this view has recently been questioned based on the possibility of intrahippocampal theta genesis. Previously, we identified putative pacemaker neurons expressing parvalbumin (PV) and/or the pacemaker hyperpolarization-activated and cyclic nucleotide-gated nonselective cation channel (HCN) in the MS. In this study, by analyzing the temporal relationship of activity between the PV/HCN-containing medial septal neurons and hippocampal local field potential, we aimed to uncover whether the sequence of events during theta formation supports the classic view of septal drive or the challenging theory of hippocampal pacing of theta. Importantly, by implementing a circular statistical method, a temporal lead of these septal neurons over the hippocampus was observed on the course of theta synchronization. Moreover, the activity of putative hippocampal interneurons also preceded hippocampal local field theta, but by a shorter time period compared with PV/HCN-containing septal neurons. Using the concept of mutual information, the action potential series of PV/HCN-containing neurons shared higher amount of information with hippocampal field oscillation than PV/HCN-immunonegative cells. Thus, a pacemaker neuron population of the MS leads hippocampal activity, presumably via the synchronization of hippocampal interneurons.

  8. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice.

    PubMed

    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.

  9. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice

    PubMed Central

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-01-01

    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. PMID:26195764

  10. Adolescent but not adult-born neurons are critical for susceptibility to chronic social defeat

    PubMed Central

    Kirshenbaum, Greer S.; Lieberman, Sophie R.; Briner, Tamara J.; Leonardo, E. David; Dranovsky, Alex

    2014-01-01

    Recent evidence implicates adult hippocampal neurogenesis in regulating behavioral and physiologic responses to stress. Hippocampal neurogenesis occurs across the lifespan, however the rate of cell birth is up to 300% higher in adolescent mice compared to adults. Adolescence is a sensitive period in development where emotional circuitry and stress reactivity undergo plasticity establishing life-long set points. Therefore neurogenesis occurring during adolescence may be particularly important for emotional behavior. However, little is known about the function of hippocampal neurons born during adolescence. In order to assess the contribution of neurons born in adolescence to the adult stress response and depression-related behavior, we transiently reduced cell proliferation either during adolescence, or during adulthood in GFAP-Tk mice. We found that the intervention in adolescence did not change adult baseline behavioral response in the forced swim test, sucrose preference test or social affiliation test, and did not change adult corticosterone responses to an acute stressor. However following chronic social defeat, adult mice with reduced adolescent neurogenesis showed a resilient phenotype. A similar transient reduction in adult neurogenesis did not affect depression-like behaviors or stress induced corticosterone. Our study demonstrates that hippocampal neurons born during adolescence, but not in adulthood are important to confer susceptibility to chronic social defeat. PMID:25221485

  11. Div-Seq: Single-nucleus RNA-Seq reveals dynamics of rare adult newborn neurons.

    PubMed

    Habib, Naomi; Li, Yinqing; Heidenreich, Matthias; Swiech, Lukasz; Avraham-Davidi, Inbal; Trombetta, John J; Hession, Cynthia; Zhang, Feng; Regev, Aviv

    2016-08-26

    Single-cell RNA sequencing (RNA-Seq) provides rich information about cell types and states. However, it is difficult to capture rare dynamic processes, such as adult neurogenesis, because isolation of rare neurons from adult tissue is challenging and markers for each phase are limited. Here, we develop Div-Seq, which combines scalable single-nucleus RNA-Seq (sNuc-Seq) with pulse labeling of proliferating cells by 5-ethynyl-2'-deoxyuridine (EdU) to profile individual dividing cells. sNuc-Seq and Div-Seq can sensitively identify closely related hippocampal cell types and track transcriptional dynamics of newborn neurons within the adult hippocampal neurogenic niche, respectively. We also apply Div-Seq to identify and profile rare newborn neurons in the adult spinal cord, a noncanonical neurogenic region. sNuc-Seq and Div-Seq open the way for unbiased analysis of diverse complex tissues.

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

    PubMed

    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.

  13. Inflammation regulates functional integration of neurons born in adult brain.

    PubMed

    Jakubs, Katherine; Bonde, Sara; Iosif, Robert E; Ekdahl, Christine T; Kokaia, Zaal; Kokaia, Merab; Lindvall, Olle

    2008-11-19

    Inflammation influences several steps of adult neurogenesis, but whether it regulates the functional integration of the new neurons is unknown. Here, we explored, using confocal microscopy and whole-cell patch-clamp recordings, whether a chronic inflammatory environment affects the morphological and electrophysiological properties of new dentate gyrus granule cells, labeled with a retroviral vector encoding green fluorescent protein. Rats were exposed to intrahippocampal injection of lipopolysaccharide, which gave rise to long-lasting microglia activation. Inflammation caused no changes in intrinsic membrane properties, location, dendritic arborization, or spine density and morphology of the new cells. Excitatory synaptic drive increased to the same extent in new and mature cells in the inflammatory environment, suggesting increased network activity in hippocampal neural circuitries of lipopolysaccharide-treated animals. In contrast, inhibitory synaptic drive was more enhanced by inflammation in the new cells. Also, larger clusters of the postsynaptic GABA(A) receptor scaffolding protein gephyrin were found on dendrites of new cells born in the inflammatory environment. We demonstrate for the first time that inflammation influences the functional integration of adult-born hippocampal neurons. Our data indicate a high degree of synaptic plasticity of the new neurons in the inflammatory environment, which enables them to respond to the increase in excitatory input with a compensatory upregulation of activity and efficacy at their afferent inhibitory synapses.

  14. Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior

    PubMed Central

    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

  15. Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory.

    PubMed

    Li, Endan; Chung, Hyunju; Kim, Yumi; Kim, Dong Hyun; Ryu, Jong Hoon; Sato, Takahiro; Kojima, Masayasu; Park, Seungjoon

    2013-01-01

    Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of bromodeoxyuridine (BrdU)-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.

  16. Dietary cholesterol modulates the excitability of rabbit hippocampal CA1 pyramidal neurons.

    PubMed

    Wang, Desheng; Schreurs, Bernard G

    2010-08-02

    Previous work has shown high dietary cholesterol can affect learning and memory including rabbit eyeblink conditioning and this effect may be due to increased membrane cholesterol and enhanced hippocampal amyloid beta production. This study investigated whether dietary cholesterol modulates rabbit hippocampal CA1 neuron membrane properties known to be involved in rabbit eyeblink conditioning. Whole-cell current clamp recordings in hippocampal neurons from rabbits fed 2 percent cholesterol or normal chow for 8 weeks revealed changes including decreased after-hyperpolarization amplitudes (AHPs) - an index of membrane excitability shown to be important for rabbit eyeblink conditioning. This index was reversed by adding copper to drinking water - a dietary manipulation that can retard rabbit eyeblink conditioning. Evidence of cholesterol effects on membrane excitability was provided by application of methyl-beta-cyclodextrin, a compound that reduces membrane cholesterol, which increased the excitability of hippocampal CA1 neurons.

  17. Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury.

    PubMed

    Hellmich, Helen L; Eidson, Kristine A; Capra, Bridget A; Garcia, Jeanna M; Boone, Deborah R; Hawkins, Bridget E; Uchida, Tatsuo; Dewitt, Douglas S; Prough, Donald S

    2007-01-05

    Hippocampal damage contributes to cognitive dysfunction after traumatic brain injury (TBI). We previously showed that Fluoro-Jade, a fluorescent stain that labels injured, degenerating brain neurons, quantifies the extent of hippocampal injury after experimental fluid percussion TBI in rats. Coincidentally, we observed that injured neurons in the rat hippocampus also stained with Newport Green, a fluorescent dye specific for free ionic zinc. Here, we show that, regardless of injury severity or therapeutic intervention, the post-TBI population of injured neurons in rat hippocampal subfields CA1, CA3 and dentate gyrus is indistinguishable, both in numbers and anatomical distribution, from the population of neurons containing high levels of zinc. Treatment with lamotrigine, which inhibits presynaptic release of glutamate and presumably zinc that is co-localized with glutamate, reduced numbers of Fluoro-Jade-positive and Newport Green-positive neurons equally as did treatment with nicardipine, which blocks voltage-gated calcium channels through which zinc enters neurons. To confirm using molecular techniques that Fluoro-Jade and Newport Green-positive neurons are equivalent populations, we isolated total RNA from 25 Fluoro-Jade-positive and 25 Newport Green-positive pyramidal neurons obtained by laser capture microdissection (LCM) from the CA3 subfield, linearly amplified the mRNA and used quantitative ribonuclease protection analysis to demonstrate similar expression of mRNA for selected TBI-induced genes. Our data suggest that therapeutic interventions aimed at reducing neurotoxic zinc levels after TBI may reduce hippocampal neuronal injury.

  18. Hippocampal neuronal subtypes develop abnormal dendritic arbors in the presence of Fragile X astrocytes.

    PubMed

    Jacobs, S; Cheng, C; Doering, L C

    2016-06-02

    Astrocytes are now recognized as key players in the neurobiology of neurodevelopmental disorders such as Fragile X syndrome. However, the nature of Fragile X astrocyte-mediated control of dendrite development in subtypes of hippocampal neurons is not yet known. We used a co-culture procedure in which wildtype primary hippocampal neurons were cultured with astrocytes from either a wildtype or Fragile X mouse, for either 7, 14 or 21 days. The neurons were processed for immunocytochemistry with the dendritic marker MAP2, classified by morphological criteria into one of five neuronal subtypes, and subjected to Sholl analyses. Both linear and semi-log methods of Sholl analyses were applied to the neurons in order to provide an in depth analysis of the dendritic arborizations. We found that Fragile X astrocytes affect the development of dendritic arborization of all subtypes of wildtype hippocampal neurons. Furthermore, we show that hippocampal neurons with spiny stellate neuron morphology exhibit the most pervasive developmental delays, with significant dendritic arbor alterations persisting at 21 days in culture. The results further dictate the critical role astrocytes play in governing neuronal morphology including altered dendrite development in Fragile X.

  19. Rhythmic coordination of hippocampal neurons during associative memory processing

    PubMed Central

    Rangel, Lara M; Rueckemann, Jon W; Riviere, Pamela D; Keefe, Katherine R; Porter, Blake S; Heimbuch, Ian S; Budlong, Carl H; Eichenbaum, Howard

    2016-01-01

    Hippocampal oscillations are dynamic, with unique oscillatory frequencies present during different behavioral states. To examine the extent to which these oscillations reflect neuron engagement in distinct local circuit processes that are important for memory, we recorded single cell and local field potential activity from the CA1 region of the hippocampus as rats performed a context-guided odor-reward association task. We found that theta (4–12 Hz), beta (15–35 Hz), low gamma (35–55 Hz), and high gamma (65–90 Hz) frequencies exhibited dynamic amplitude profiles as rats sampled odor cues. Interneurons and principal cells exhibited unique engagement in each of the four rhythmic circuits in a manner that related to successful performance of the task. Moreover, principal cells coherent to each rhythm differentially represented task dimensions. These results demonstrate that distinct processing states arise from the engagement of rhythmically identifiable circuits, which have unique roles in organizing task-relevant processing in the hippocampus. DOI: http://dx.doi.org/10.7554/eLife.09849.001 PMID:26751780

  20. Impact of nanosecond pulsed electric fields on primary hippocampal neurons

    NASA Astrophysics Data System (ADS)

    Roth, Caleb C.; Payne, Jason A.; Kuipers, Marjorie A.; Thompson, Gary L.; Wilmink, Gerald J.; Ibey, Bennett L.

    2012-02-01

    Cellular exposure to nanosecond pulsed electric fields (nsPEF) are believed to cause immediate creation of nanopores in the plasma membrane. These nanopores enable passage of small ions, but remain impermeable to larger molecules like propidium iodide. Previous work has shown that nanopores are stable for minutes after exposure, suggesting that formation of nanopores in excitable cells could lead to prolonged action potential inhibition. Previously, we measured the formation of nanopores in neuroblastoma cells by measuring the influx of extracellular calcium by preloading cells with Calcium Green-AM. In this work, we explored the impact of changing the width of a single nsPEF, at constant amplitude, on uptake of extracellular calcium ions by primary hippocampal neurons (PHN). Calcium Green was again used to measure the influx of extracellular calcium and FM1-43 was used to monitor changes in membrane conformation. The observed thresholds for nanopore formation in PHN by nsPEF were comparable to those measured in neuroblastoma. This work is the first study of nsPEF effects on PHN and strongly suggests that neurological inhibition by nanosecond electrical pulses is highly likely at doses well below irreversible damage.

  1. Early presynaptic changes during plasticity in cultured hippocampal neurons.

    PubMed

    Ninan, Ipe; Liu, Shumin; Rabinowitz, Daniel; Arancio, Ottavio

    2006-09-20

    Long-lasting increase in synaptic strength is thought to underlie learning. An explosion of data has characterized changes in postsynaptic (pstS) AMPA receptor cycling during potentiation. However, changes occurring within the presynaptic (prS) terminal remain largely unknown. We show that appearance of new release sites during potentiation between cultured hippocampal neurons is due to (a) conversion of nonrecycling sites to recycling sites, (b) formation of new releasing sites from areas containing diffuse staining for the prS marker Vesicle-Associated Membrane Protein-2 and (c) budding of new recycling sites from previously existing recycling sites. In addition, potentiation is accompanied by a release probability increase in pre-existing boutons depending upon their individual probability. These prS changes precede and regulate fluorescence increase for pstS GFP-tagged-AMPA-receptor subunit GluR1. These results suggest that potentiation involves early changes in the prS terminal including remodeling and release probability increase of pre-existing synapses.

  2. NMDA receptors and the differential ischemic vulnerability of hippocampal neurons.

    PubMed

    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.

  3. Loss of Hippocampal Neurons after Kainate Treatment Correlates with Behavioral Deficits

    PubMed Central

    Maia, Gisela H.; Quesado, José L.; Soares, Joana I.; do Carmo, Joana M.; Andrade, Pedro A.; Andrade, José P.; Lukoyanov, Nikolai V.

    2014-01-01

    Treating rats with kainic acid induces status epilepticus (SE) and leads to the development of behavioral deficits and spontaneous recurrent seizures later in life. However, in a subset of rats, kainic acid treatment does not induce overt behaviorally obvious acute SE. The goal of this study was to compare the neuroanatomical and behavioral changes induced by kainate in rats that developed convulsive SE to those who did not. Adult male Wistar rats were treated with kainic acid and tested behaviorally 5 months later. Rats that had experienced convulsive SE showed impaired performance on the spatial water maze and passive avoidance tasks, and on the context and tone retention tests following fear conditioning. In addition, they exhibited less anxiety-like behaviors than controls on the open-field and elevated plus-maze tests. Histologically, convulsive SE was associated with marked neuron loss in the hippocampal CA3 and CA1 fields, and in the dentate hilus. Rats that had not experienced convulsive SE after kainate treatment showed less severe, but significant impairments on the spatial water maze and passive avoidance tasks. These rats had fewer neurons than control rats in the dentate hilus, but not in the hippocampal CA3 and CA1 fields. Correlational analyses revealed significant relationships between spatial memory indices of rats and neuronal numbers in the dentate hilus and CA3 pyramidal field. These results show that a part of the animals that do not display intense behavioral seizures (convulsive SE) immediately after an epileptogenic treatment, later in life, they may still have noticeable structural and functional changes in the brain. PMID:24409306

  4. Plasticity-related Gene 5 Promotes Spine Formation in Murine Hippocampal Neurons*

    PubMed Central

    Coiro, Pierluca; Stoenica, Luminita; Strauss, Ulf; Bräuer, Anja Ursula

    2014-01-01

    The transmembrane protein plasticity-related genes 3 and 5 (PRG3 and PRG5) increase filopodial formation in various cell lines, independently of Cdc42. However, information on the effects of PRG5 during neuronal development is sparse. Here, we present several lines of evidence for the involvement of PRG5 in the genesis and stabilization of dendritic spines. First, PRG5 was strongly expressed during mouse brain development from embryonic day 14 (E14), peaked around the time of birth, and remained stable at least until early adult stages (i.e. P30). Second, on a subcellular level, PRG5 expression shifted from an equal distribution along all neurites toward accumulation only along dendrites during hippocampal development in vitro. Third, overexpression of PRG5 in immature hippocampal neurons induced formation of spine-like structures ahead of time. Proper amino acid sequences in the extracellular domains (D1 to D3) of PRG5 were a prerequisite for trafficking and induction of spine-like structures, as shown by mutation analysis. Fourth, at stages when spines are present, knockdown of PRG5 reduced the number but not the length of protrusions. This was accompanied by a decrease in the number of excitatory synapses and, consequently, by a reduction of miniature excitatory postsynaptic current frequencies, although miniature excitatory postsynaptic current amplitudes remained similar. In turn, overexpressing PRG5 in mature neurons not only increased Homer-positive spine numbers but also augmented spine head diameters. Mechanistically, PRG5 interacts with phosphorylated phosphatidylinositols, phospholipids involved in dendritic spine formation by different lipid-protein assays. Taken together, our data propose that PRG5 promotes spine formation. PMID:25074937

  5. Endogenous Ca2+ buffer concentration and Ca2+ microdomains in hippocampal neurons.

    PubMed

    Müller, Andreas; Kukley, Maria; Stausberg, Pia; Beck, Heinz; Müller, Wolfgang; Dietrich, Dirk

    2005-01-19

    Ca2+-binding proteins are ubiquitously expressed throughout the CNS and serve as valuable immunohistochemical markers for certain types of neurons. However, the functional role of most Ca2+-binding proteins has to date remained obscure because their concentration in central neurons is not known. In this study, we investigate the intracellular concentration of the widely expressed Ca2+-binding protein calbindin-D28k in adult hippocampal slices using patch-clamp recordings and immunohistochemistry. First, we show that calbindin-D28k freely exchanges between patch pipette and cytoplasm during whole cell patch-clamp recordings with a time constant of approximately 10 min. Substituting known concentrations of recombinant calbindin-D28k in patch pipettes enabled us to determine the endogenous calbindin-D28k concentration by postrecording immunohistochemistry. Using this calibration procedure, we find that mature granule cells (doublecortin-) contain approximately 40 microm, and newborn granule cells (doublecortin+) contain 0-20 microm calbindin-D28k. CA3 stratum radiatum interneurons and CA1 pyramidal cells enclose approximately 47 and approximately 45 microm calbindin-D28k, respectively. Numerical simulations showed that 40 microm calbindin-D28k is capable of tuning Ca2+ microdomains associated with action potentials at the mouth of single or clustered Ca2+ channels: calbindin-D28k reduces the increment in free Ca2+ at a distance of 100 and 200 nm by 20 and 35%, respectively, and strongly accelerates the collapse of the Ca2+ gradient after cessation of Ca2+ influx. These data suggest that calbindin-D28k equips hippocampal neurons with approximately 160 microm mobile, high-affinity Ca2+-binding sites (kappa(S) approximately 200) that slow and reduce global Ca2+ signals while they enhance the spatiotemporal fidelity of submicroscopic Ca2+ signals.

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

    PubMed

    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.

  7. Prospective and Episodic Memory in Relation to Hippocampal Volume in Adults with Spina Bifida Myelomeningocele

    PubMed Central

    Treble-Barna, Amery; Juranek, Jenifer; Stuebing, Karla K.; Cirino, Paul T.; Dennis, Maureen; Fletcher, Jack M.

    2014-01-01

    The present study examined prospective and episodic memory in relation to age, functional independence, and hippocampal volume in younger to middle-aged adults with spina bifida myelomeningocele (SBM) and typically developing (TD) adults. Prospective and episodic memory, as well as hippocampal volume, were reduced in adults with SBM relative to TD adults. Neither memory performance nor hippocampal volume showed greater decrements in older adults. Lower hippocampal volume was associated with reduced prospective memory in adults with SBM, and this relation was specific to the hippocampus and not to a contrast structure, the amygdala. Prospective memory mediated the relation between hippocampal volume and functional independence in adults with SBM. The results add to emerging evidence for reduced memory function in adults with SBM, and provide quantitative evidence for compromised hippocampal macrostructure as a neural correlate of reduced memory in this population. PMID:25068670

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

    PubMed Central

    2011-01-01

    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. PMID:21854604

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

    PubMed

    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.

  10. The Edible Red Alga Porphyra yezoensis Promotes Neuronal Survival and Cytoarchitecture in Primary Hippocampal Neurons.

    PubMed

    Mohibbullah, Md; Bhuiyan, Mohammad Maqueshudul Haque; Hannan, Md Abdul; Getachew, Paulos; Hong, Yong-Ki; Choi, Jae-Suk; Choi, In Soon; Moon, Il Soo

    2016-07-01

    The edible red alga Porphyra yezoensis is among the most popular marine algae and is of economic and medicinal importance. In the present study, the neurotrophic and neuroprotective activities of the ethanol extract of P. yezoensis (PYE) were investigated in primary cultures of hippocampal neurons. Results revealed that PYE significantly increased neurite outgrowth at an optimal concentration of 15 µg/mL. PYE dose-dependently increased viable cells, significantly accelerated the rate of neuronal differentiation in cultures, promoted axodendritic arborization, and eventually induced synaptogenesis. In addition to morphological development, PYE also promoted functional maturation as indicated by the staining of live cultures with FM 1-43. Moreover, PYE increased neuronal survivability, which was attributed to reduced apoptosis and its ROS scavenging activity. Taurine, a major organic acid in PYE (2.584/100 mg of dry PYE) promoted neurite outgrowth in a dose-dependent manner, and this promotion was suppressed by the taurine antagonist isethionic acid. The study indicates that PYE and its active component, taurine, facilitate neuronal development and maturation and have a neuroprotective effect.

  11. Influences of NR2B-containing NMDA receptors knockdown on neural activity in hippocampal newborn neurons.

    PubMed

    Li, Zhi-jun; Zhang, Hui-wen; Tang, Na

    2013-08-01

    Adult-born neurons undergo a transient period of plasticity during their integration into the neural circuit. This transient plasticity may involve NMDA receptors containing NR2B, the major subunit expressed at early developmental stages. The main objective of the present study was to investigate the effects of NR2B gene knockdown on the functional integration of the adult-born granule cells generated from the subgranule zone (SGZ) in the hippocampus. The small interfering RNA (siRNA) was used to knock down the NR2B gene in the adult-born hippocampal neurons. In the functional integration test, the mice were exposed to a novel environment (open field arena), and the expression of c-fos was immunohistochemically detected in the hippocampus. After exposure to the novel environment, siRNA-NR2B mice were significantly different from control mice in either the number of squares or the number of rears they crossed, showing decreased horizontal and vertical activity (P<0.05). Moreover, the c-fos expression was increased in both control and siRNA-NR2B mice after open field test. But, it was significantly lower in siRNA-NR2B neurons than in control neurons. It was concluded that the neural activity of newborn neurons is regulated by their own NR2B-containing NMDA glutamate receptors during a short, critical period after neuronal birth.

  12. Greater hippocampal neuronal recruitment in food-storing than in non-food-storing birds.

    PubMed

    Hoshooley, Jennifer S; Sherry, David F

    2007-03-01

    Previous research has shown heightened recruitment of new neurons to the chickadee hippocampus in the fall. The present study was conducted to determine whether heightened fall recruitment is associated with the seasonal onset of food-storing by comparing neurogenesis in chickadees and a non-food-storing species, the house sparrow. Chickadees and house sparrows were captured in the wild in fall and spring and received multiple injections of the cell birth marker bromodeoxyuridine (BrdU). Birds were held in captivity and the level of hippocampal neuron recruitment was assessed after 6 weeks. Chickadees showed significantly more hippocampal neuronal recruitment than house sparrows. We found no seasonal differences in hippocampal neuronal recruitment in either species. In chickadees and in house sparrows, one-third of new cells labeled for BrdU also expressed the mature neuronal protein, NeuN. In a region adjacent to the hippocampus, the hyperpallium apicale, we observed no significant differences in neuronal recruitment between species or between seasons. Hippocampal volume and total neuron number both were greater in spring than in fall in chickadees, but no seasonal differences were observed in house sparrows. Enhanced neuronal recruitment in the hippocampus of food-storing chickadees suggests a degree of neurogenic specialization that may be associated with the spatial memory requirements of food-storing behavior.

  13. Bcl-xL induces Drp1-dependent synapse formation in cultured hippocampal neurons

    PubMed Central

    Li, Hongmei; Chen, Yingbei; Jones, Adrienne F.; Sanger, Richard H.; Collis, Leon P.; Flannery, Richard; McNay, Ewan C.; Yu, Tingxi; Schwarzenbacher, Robert; Bossy, Blaise; Bossy-Wetzel, Ella; Bennett, Michael V. L.; Pypaert, Marc; Hickman, John A.; Smith, Peter J. S.; Hardwick, J. Marie; Jonas, Elizabeth A.

    2008-01-01

    Maturation of neuronal synapses is thought to involve mitochondria. Bcl-xL protein inhibits mitochondria-mediated apoptosis but may have other functions in healthy adult neurons in which Bcl-xL is abundant. Here, we report that overexpression of Bcl-xL postsynaptically increases frequency and amplitude of spontaneous miniature synaptic currents in rat hippocampal neurons in culture. Bcl-xL, overexpressed either pre or postsynaptically, increases synapse number, the number and size of synaptic vesicle clusters, and mitochondrial localization to vesicle clusters and synapses, likely accounting for the changes in miniature synaptic currents. Conversely, knockdown of Bcl-xL or inhibiting it with ABT-737 decreases these morphological parameters. The mitochondrial fission protein, dynamin-related protein 1 (Drp1), is a GTPase known to localize to synapses and affect synaptic function and structure. The effects of Bcl-xL appear mediated through Drp1 because overexpression of Drp1 increases synaptic markers, and overexpression of the dominant-negative dnDrp1-K38A decreases them. Furthermore, Bcl-xL coimmunoprecipitates with Drp1 in tissue lysates, and in a recombinant system, Bcl-xL protein stimulates GTPase activity of Drp1. These findings suggest that Bcl-xL positively regulates Drp1 to alter mitochondrial function in a manner that stimulates synapse formation. PMID:18250306

  14. Wnt-5a/JNK Signaling Promotes the Clustering of PSD-95 in Hippocampal Neurons*

    PubMed Central

    Farías, Ginny G.; Alfaro, Iván E.; Cerpa, Waldo; Grabowski, Catalina P.; Godoy, Juan A.; Bonansco, Christian; Inestrosa, Nibaldo C.

    2009-01-01

    During the formation of synapses, specific regions of pre- and postsynaptic cells associate to form a single functional transmission unit. In this process, synaptogenic factors are necessary to modulate pre- and postsynaptic differentiation. In mammals, different Wnt ligands operate through canonical and non-canonical Wnt pathways, and their precise functions to coordinate synapse structure and function in the mature central nervous system are still largely unknown. Here, we studied the effect of different Wnt ligands on postsynaptic organization. We found that Wnt-5a induces short term changes in the clustering of PSD-95, without affecting its total levels. Wnt-5a promotes the recruitment of PSD-95 from a diffuse dendritic cytoplasmic pool to form new PSD-95 clusters in dendritic spines. Moreover, Wnt-5a acting as a non-canonical ligand regulates PSD-95 distribution through a JNK-dependent signaling pathway, as demonstrated by using the TAT-TI-JIP peptide in mature hippocampal neurons. Finally, using adult rat hippocampal slices, we found that Wnt-5a modulates glutamatergic synaptic transmission through a postsynaptic mechanism. Our studies indicate that the Wnt-5a/JNK pathway modulates the postsynaptic region of mammalian synapse directing the clustering and distribution of the physiologically relevant scaffold protein, PSD-95. PMID:19332546

  15. Imipramine protects against the deleterious effects of chronic corticosterone on depression-like behavior, hippocampal reelin expression, and neuronal maturation.

    PubMed

    Fenton, Erin Y; Fournier, Neil M; Lussier, April L; Romay-Tallon, Raquel; Caruncho, Hector J; Kalynchuk, Lisa E

    2015-07-03

    We have hypothesized that a downregulation of reelin and deficient maturation of adult-born hippocampal neurons are important factors in the pathogenesis of depression. This hypothesis is based on previous work showing that depression-like behavior in rats treated with protracted corticosterone develops in concert with decreased dendritic complexity in newborn hippocampal granule neurons and decreased reelin expression in the proliferative subgranular zone of the dentate gyrus. In addition, heterozygous reeler mice with approximately 50% of normal brain levels of reelin are more vulnerable to the depressogenic effects of corticosterone than wild-type mice. The purpose of this experiment was to provide pharmacological validation for the link between reelin, neuronal maturation, and depression by examining whether the deleterious effects of corticosterone on these measures could be prevented by co-administration of the antidepressant imipramine. Rats received corticosterone injections, corticosterone injections plus either 10 or 15mg/kg imipramine injections, or vehicle injections for 21 consecutive days. They were then subjected to the forced swim test to assess depression-like behavior and sacrificed for immunohistochemical examination of immature neuron number and dendritic complexity and the presence of reelin+cells. We found that corticosterone increases depression-like behavior, decreases the number of reelin+cells in the subgranular zone, and decreases the number and complexity of immature neurons in the granule cell layer. All of these behavioral and cellular phenotypes were prevented by imipramine, providing further support for the idea that reelin is involved in the pathogenesis of depression.

  16. Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease.

    PubMed

    Krezymon, Alice; Richetin, Kevin; Halley, Hélène; Roybon, Laurent; Lassalle, Jean-Michel; Francès, Bernard; Verret, Laure; Rampon, Claire

    2013-01-01

    At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

  17. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  18. Linking adult hippocampal neurogenesis with human physiology and disease.

    PubMed

    Bowers, Megan; Jessberger, Sebastian

    2016-07-01

    We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc.

  19. Neuronal Activity Regulates Hippocampal miRNA Expression

    PubMed Central

    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

  20. Role of Wnt Signaling in the Control of Adult Hippocampal Functioning in Health and Disease: Therapeutic Implications

    PubMed Central

    Ortiz-Matamoros, Abril; Salcedo-Tello, Pamela; Avila-Muñoz, Evangelina; Zepeda, Angélica; Arias, Clorinda

    2013-01-01

    It is well recognized the role of the Wnt pathway in many developmental processes such as neuronal maturation, migration, neuronal connectivity and synaptic formation. Growing evidence is also demonstrating its function in the mature brain where is associated with modulation of axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. Proteins involved in Wnt signaling have been found expressed in the adult hippocampus suggesting that Wnt pathway plays a role in the hippocampal function through life. Indeed, Wnt ligands act locally to regulate neurogenesis, neuronal cell shape and pre- and postsynaptic assembly, events that are thought to underlie changes in synaptic function associated with long-term potentiation and with cognitive tasks such as learning and memory. Recent data have demonstrated the increased expression of the Wnt antagonist Dickkopf-1 (DKK1) in brains of Alzheimer´s disease (AD) patients suggesting that dysfunction of Wnt signaling could also contribute to AD pathology. We review here evidence of Wnt-associated molecules expression linked to physiological and pathological hippocampal functioning in the adult brain. The basic aspects of Wnt related mechanisms underlying hippocampal plasticity as well as evidence of how hippocampal dysfunction may rely on Wnt dysregulation is analyzed. This information would provide some clues about the possible therapeutic targets for developing treatments for neurodegenerative diseases associated with aberrant brain plasticity. PMID:24403870

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

    PubMed Central

    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. PMID:26389591

  2. Nuclear factor of activated T cells (NFATc4) is required for BDNF-dependent survival of adult-born neurons and spatial memory formation in the hippocampus.

    PubMed

    Quadrato, Giorgia; Benevento, Marco; Alber, Stefanie; Jacob, Carolin; Floriddia, Elisa M; Nguyen, Tuan; Elnaggar, Mohamed Y; Pedroarena, Christine M; Molkentin, Jeffrey D; Di Giovanni, Simone

    2012-06-05

    New neurons generated in the adult dentate gyrus are constantly integrated into the hippocampal circuitry and activated during encoding and recall of new memories. Despite identification of extracellular signals that regulate survival and integration of adult-born neurons such as neurotrophins and neurotransmitters, the nature of the intracellular modulators required to transduce those signals remains elusive. Here, we provide evidence of the expression and transcriptional activity of nuclear factor of activated T cell c4 (NFATc4) in hippocampal progenitor cells. We show that NFATc4 calcineurin-dependent activity is required selectively for survival of adult-born neurons in response to BDNF signaling. Indeed, cyclosporin A injection and stereotaxic delivery of the BDNF scavenger TrkB-Fc in the mouse dentate gyrus reduce the survival of hippocampal adult-born neurons in wild-type but not in NFATc4(-/-) mice and do not affect the net rate of neural precursor proliferation and their fate commitment. Furthermore, associated with the reduced survival of adult-born neurons, the absence of NFATc4 leads to selective defects in LTP and in the encoding of hippocampal-dependent spatial memories. Thus, our data demonstrate that NFATc4 is essential in the regulation of adult hippocampal neurogenesis and identify NFATc4 as a central player of BDNF-driven prosurvival signaling in hippocampal adult-born neurons.

  3. Regular theta-firing neurons in the nucleus incertus during sustained hippocampal activation.

    PubMed

    Martínez-Bellver, Sergio; Cervera-Ferri, Ana; Martínez-Ricós, Joana; Ruiz-Torner, Amparo; Luque-Garcia, Aina; Luque-Martinez, Aina; Blasco-Serra, Arantxa; Guerrero-Martínez, Juan; Bataller-Mompeán, Manuel; Teruel-Martí, Vicent

    2015-04-01

    This paper describes the existence of theta-coupled neuronal activity in the nucleus incertus (NI). Theta rhythm is relevant for cognitive processes such as spatial navigation and memory processing, and can be recorded in a number of structures related to the hippocampal activation including the NI. Strong evidence supports the role of this tegmental nucleus in neural circuits integrating behavioural activation with the hippocampal theta rhythm. Theta oscillations have been recorded in the local field potential of the NI, highly coupled to the hippocampal waves, although no rhythmical activity has been reported in neurons of this nucleus. The present work analyses the neuronal activity in the NI in conditions leading to sustained hippocampal theta in the urethane-anaesthetised rat, in order to test whether such activation elicits a differential firing pattern. Wavelet analysis has been used to better define the neuronal activity already described in the nucleus, i.e., non-rhythmical neurons firing at theta frequency (type I neurons) and fast-firing rhythmical neurons (type II). However, the most remarkable finding was that sustained stimulation activated regular-theta neurons (type III), which were almost silent in baseline conditions and have not previously been reported. Thus, we describe the electrophysiological properties of type III neurons, focusing on their coupling to the hippocampal theta. Their spike rate, regularity and phase locking to the oscillations increased at the beginning of the stimulation, suggesting a role in the activation or reset of the oscillation. Further research is needed to address the specific contribution of these neurons to the entire circuit.

  4. A critical period for experience-dependent remodeling of adult-born neuron connectivity.

    PubMed

    Bergami, Matteo; Masserdotti, Giacomo; Temprana, Silvio G; Motori, Elisa; Eriksson, Therese M; Göbel, Jana; Yang, Sung Min; Conzelmann, Karl-Klaus; Schinder, Alejandro F; Götz, Magdalena; Berninger, Benedikt

    2015-02-18

    Neurogenesis in the dentate gyrus (DG) of the adult hippocampus is a process regulated by experience. To understand whether experience also modifies the connectivity of new neurons, we systematically investigated changes in their innervation following environmental enrichment (EE). We found that EE exposure between 2-6 weeks following neuron birth, rather than merely increasing the number of new neurons, profoundly affected their pattern of monosynaptic inputs. Both local innervation by interneurons and to even greater degree long-distance innervation by cortical neurons were markedly enhanced. Furthermore, following EE, new neurons received inputs from CA3 and CA1 inhibitory neurons that were rarely observed under control conditions. While EE-induced changes in inhibitory innervation were largely transient, cortical innervation remained increased after returning animals to control conditions. Our findings demonstrate an unprecedented experience-dependent reorganization of connections impinging onto adult-born neurons, which is likely to have important impact on their contribution to hippocampal information processing.

  5. Motherhood and the hormones of pregnancy modify concentrations of hippocampal neuronal dendritic spines.

    PubMed

    Kinsley, Craig H; Trainer, Regina; Stafisso-Sandoz, Graciela; Quadros, Princy; Marcus, Lori Keyser; Hearon, Christa; Meyer, Elizabeth Ann Amory; Hester, Naomi; Morgan, Melissa; Kozub, Frederick J; Lambert, Kelly G

    2006-02-01

    Short-term fluctuations in steroid hormones such as estradiol (E2) and progesterone (P) can affect the concentration of hippocampal dendritic spines in adult, cycling nulliparous female rats. Pregnancy is characterized by a significantly longer duration of substantially elevated E2 and P compared to the estrous cycle. Thus, even greater changes than those reported during estrus may be evident. In two experiments, we examined the extent to which reproductive and hormonal state altered the concentration of apical neuronal dendritic spines of the CA1 region of the hippocampus in the following age-matched groups (N's = 7-10/group) of rats: in Exp. 1., CA1 dendritic spine density was examined in nulliparous diestrus (DES), proestrus (PRO), and estrus (ES) females, and late-pregnant (LP) (day 21) and lactating (day 5-6; LACT) females. In Exp. 2, the effects on spine density of a regimen mimicking pregnancy (and that stimulates maternal behavior) were examined, using ovariectomized, no hormone-exposed (OVX-minus) vs. sequential P&E(2)-treated (OVX + P&E2) groups. For both experiments, brains were removed, Golgi-Cox-stained and the most lateral tertiary branches of the apical dendrite of completely-stained hippocampal CA1 pyramidal neurons were traced with oil-immersion at x 1600 and dendritic spine density (# spines/10 micro dendritic segment) recorded. In Exp. 1, spine density was increased in LP and LACT females (which were not different) compared to the other virgin groups, including PRO females, who had more spines than DES and ES. In Exp. 2, OVX + P&E2 displayed significantly more dendritic spines per 10 micro than OVX-minus females (and had numbers that were similar to those of LP and LACT from Exp. 1). Pregnancy and its attendant hormonal fluctuations, therefore, may alter hippocampal neurons that regulate some non-pup-directed components of maternal behavior (e.g., nest building) or behaviors that support maternal behavior (e.g., foraging, associative memory).

  6. Cardiac arrest triggers hippocampal neuronal death through autophagic and apoptotic pathways

    PubMed Central

    Cui, Derong; Shang, Hanbing; Zhang, Xiaoli; Jiang, Wei; Jia, Xiaofeng

    2016-01-01

    The mechanism of neuronal death induced by ischemic injury remains unknown. We investigated whether autophagy and p53 signaling played a role in the apoptosis of hippocampal neurons following global cerebral ischemia-reperfusion (I/R) injury, in a rat model of 8-min asphyxial cardiac arrest (CA) and resuscitation. Increased autophagosome numbers, expression of lysosomal cathepsin B, cathepsin D, Beclin-1, and microtubule-associated protein light chain 3 (LC3) suggested autophagy in hippocampal cells. The expression of tumor suppressor protein 53 (p53) and its target genes: Bax, p53-upregulated modulator of apoptosis (PUMA), and damage-regulated autophagy modulator (DRAM) were upregulated following CA. The p53-specific inhibitor pifithrin-α (PFT-α) significantly reduced the expression of pro-apoptotic proteins (Bax and PUMA) and autophagic proteins (LC3-II and DRAM) that generally increase following CA. PFT-α also reduced hippocampal neuronal damage following CA. Similarly, 3-methyladenine (3-MA), which inhibits autophagy and bafilomycin A1 (BFA), which inhibits lysosomes, significantly inhibited hippocampal neuronal damage after CA. These results indicate that CA affects both autophagy and apoptosis, partially mediated by p53. Autophagy plays a significant role in hippocampal neuronal death induced by cerebral I/R following asphyxial-CA. PMID:27273382

  7. Argipressin(4-8) upregulate CTP: phosphocholine cytidylyltransferase in rat hippocampal neurons.

    PubMed

    Xu, Kan-Yan; Xiong, Ying; Du, Yu-Cang

    2002-07-01

    In order to study the effect of argipressin(4-8)(AVP(4-8)) on the mRNA level and activity of cytidine triphosphate: phosphocholine cytidylyltransferase(CCT) in rat hippocampal neurons, and elucidate it's possible mechanism. Rat hippocampal neurons treated with AVP(4-8) or actinomycin D were incubated with different time periods. The mRNA level of CCT was detected using RT-PCR plus Southern blot, CCT activity was determined by measuring the rate of incorporation of (14)C - phosphocholine into cytidine diphosphate-choline(CDP-choline). It was found that AVP4-8 could upregulate the CCT mRNA in rat hippocampal neurons. ZDC(C)PR, the antagonist of AVP(4-8), could greatly inhibit this upregulation. Using actinomycin D to inhibite the eucaryotic transcription, it was found that the halflife of CCT mRNA could be prolonged by coincubation with AVP(4-8). Meanwhile, AVP(4-8) could also increase CCT activity in rat hippocampal neurons. These results demonstrated that AVP(4-8) upregulated CCT mRNA level and its activity through stabilizing the CCT mRNA in rat hippocampal neurons.

  8. Coexpression of glutamate vesicular transporter (VGLUT1) and choline acetyltransferase (ChAT) proteins in fetal rat hippocampal neurons in culture.

    PubMed

    Bhargava, Neelima; Das, Mainak; Edwards, Darin; Stancescu, Maria; Kang, Jung-Fong; Hickman, James J

    2010-09-01

    A very small population of choline acetyltransferase (ChAT) immunoreactive cells is observed in all layers of the adult hippocampus. This is the intrinsic source of the hippocampal cholinergic innervation, in addition to the well-established septo-hippocampal cholinergic projection. This study aimed at quantifying and identifying the origin of this small population of ChAT-immunoreactive cells in the hippocampus at early developmental stages, by culturing the fetal hippocampal neurons in serum-free culture and on a patternable, synthetic silane substrate N-1 [3-(trimethoxysilyl) propyl] diethylenetriamine. Using this method, a large proportion of glutamatergic (glutamate vesicular transporter, VGLUT1-immunoreactive) neurons, a small fraction of GABAergic (GABA-immunoreactive) neurons, and a large proportion of cholinergic (ChAT-immunoreactive) neurons were observed in the culture. Interestingly, most of the glutamatergic neurons that expressed glutamate vesicular transporter (VGLUT1) also co-expressed ChAT proteins. On the contrary, when the cultures were double-stained with GABA and ChAT, colocalization was not observed. Neonatal and adult rat hippocampal neurons were also cultured to verify whether these more mature neurons also co-express VGLUT1 and ChAT proteins in culture. Colocalization of VGLUT1 and ChAT in these relatively more mature neurons was not observed. One possible explanation for this observation is that the neurons have the ability to synthesize multiple neurotransmitters at a very early stage of development and then with time follows a complex, combinatorial strategy of electrochemical coding to determine their final fate.

  9. Hippocampal neuron populations are reduced in vervet monkeys with fetal alcohol exposure.

    PubMed

    Burke, Mark W; Ptito, Maurice; Ervin, Frank R; Palmour, Roberta M

    2015-05-01

    Prenatal exposure to beverage alcohol is a major cause of mild mental retardation and developmental delay. In nonendangered alcohol-preferring vervet monkeys, we modeled the most common nondysmorphic form of fetal alcohol syndrome disorder with voluntary drinking during the third trimester 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 and persist through infancy (5 months) and juvenile (2 years) stages. Although the volumes of hippocampal subdivisions in FAE animals are not atypical at birth, by age 2, they are only 65-70% of those estimated in age-matched controls. These data suggest that moderate, naturalistic alcohol consumption during late pregnancy results in a stable loss of hippocampal neurons and a progressive reduction of hippocampal volume.

  10. Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

    PubMed

    Takada, Silvia Honda; Motta-Teixeira, Lívia Clemente; Machado-Nils, Aline Vilar; Lee, Vitor Yonamine; Sampaio, Carlos Alberto; Polli, Roberson Saraiva; Malheiros, Jackeline Moraes; Takase, Luiz Fernando; Kihara, Alexandre Hiroaki; Covolan, Luciene; Xavier, Gilberto Fernando; Nogueira, Maria Inês

    2016-01-01

    Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches.

  11. Epigenetic modulation of adult hippocampal neurogenesis by extremely low-frequency electromagnetic fields.

    PubMed

    Leone, Lucia; Fusco, Salvatore; Mastrodonato, Alessia; Piacentini, Roberto; Barbati, Saviana Antonella; Zaffina, Salvatore; Pani, Giovambattista; Podda, Maria Vittoria; Grassi, Claudio

    2014-06-01

    Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs' effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs' ability to improve endogenous neurogenesis, pointing to histone acetylation-related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine.

  12. Hippocampal lesion prevents spatial relational learning in adult macaque monkeys.

    PubMed

    Lavenex, Pamela Banta; Amaral, David G; Lavenex, Pierre

    2006-04-26

    The role of the hippocampus in spatial learning and memory has been extensively studied in rodents. Comparable studies in nonhuman primates, however, are few, and findings are often contradictory. This may be attributable to the failure to distinguish between allocentric and egocentric spatial representations in experimental designs. For this experiment, six adult monkeys received bilateral hippocampal ibotenic acid lesions, and six control subjects underwent sham surgery. Freely moving monkeys then foraged for food located in two arrays of three distinct locations among 18 locations distributed in an open-field arena. Multiple goals and four pseudorandomly chosen entrance points precluded the monkeys' ability to rely on an egocentric strategy to identify food locations. Monkeys were tested in two conditions. First, local visual cues marked the food locations. Second, no local cues marked the food locations, so that monkeys had to rely on an allocentric (spatial relational) representation of the environment to discriminate these locations. Both hippocampal-lesioned and control monkeys discriminated the food locations in the presence of local cues. However, in the absence of local cues, control subjects discriminated the food locations, whereas hippocampal-lesioned monkeys were unable to do so. Interestingly, histological analysis of the brain of one control monkey whose behavior was identical to that of the experimentally lesioned animals revealed a bilateral ischemic lesion restricted to the hippocampus. These findings demonstrate that the adult monkey hippocampal formation is critical for the establishment or use of allocentric spatial representations and that selective damage of the hippocampus prevents spatial relational learning in adult nonhuman primates.

  13. Functional alterations in immature cultured rat hippocampal neurons after sustained exposure to static magnetic fields.

    PubMed

    Hirai, Takao; Yoneda, Yukio

    2004-01-15

    In cultured rat hippocampal neurons, gradual increases were seen in the expression of microtubule-associated protein-2 (MAP-2), neuronal nuclei (NeuN) and growth-associated protein-43 (GAP-43), in proportion to increased duration, up to 9 days in vitro (DIV). Sustained exposure to static magnetic fields at 100 mT for up to 9 DIV significantly decreased expression of MAP-2 and NeuN in cultured rat hippocampal neurons without markedly affecting GAP-43 expression. Although a significant increase was seen in the expression of glial fibrillary acidic protein (GFAP) in hippocampal neuronal preparations cultured for 6-9 DIV under sustained magnetism, GFAP and proliferating cell nuclear antigen expression were not affected markedly in cultured astrocytes prepared from rat hippocampus and neocortex, irrespective of cellular maturity. No significant alteration was seen in cell survivability of hippocampal neurons or astrocytes cultured under sustained magnetism. In hippocampal neurons cultured for 3 DIV under sustained magnetism, marked mRNA expression was seen for N-methyl-D-aspartate (NMDA) receptor subunits, NR1, NR2A-2C, NR2D, and NR3A. In addition, significant potentiation of the ability of NMDA to increase intracellular free Ca(2+) ions was observed. Differential display analysis revealed a significant decrease in mRNA expression for the transcription factor ALF1 in response to sustained magnetism for 3 DIV. These results suggest that sustained exposure to static magnetic fields may affect cellular functionality and maturity in immature cultured rat hippocampal neurons through modulation of expression of particular NMDA receptor subunits.

  14. Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

    PubMed Central

    Lensu, Sanna; Ahtiainen, Juha P.; Johansson, Petra P.; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki

    2016-01-01

    . Furthermore, RT had no effect on proliferation (Ki67), maturation (doublecortin) or survival (bromodeoxyuridine) of new adult‐born hippocampal neurons in adult male Sprague–Dawley rats. Our results suggest that physical exercise promotes AHN most effectively if the exercise is aerobic and sustained, especially when accompanied by a heightened genetic predisposition for response to physical exercise. PMID:26844666

  15. Behavior-associated Neuronal Activation After Kainic Acid-induced Hippocampal Neurotoxicity is Modulated in Time.

    PubMed

    Aguilar-Arredondo, Andrea; López-Hernández, Fernanda; García-Velázquez, Lizbeth; Arias, Clorinda; Zepeda, Angélica

    2017-02-01

    Kainic acid-induced (KA) hippocampal damage leads to neuronal death and further synaptic plasticity. Formation of aberrant as well as of functional connections after such procedure has been documented. However, the impact of such structural plasticity on cell activation along time after damage and in face of a behavioral demand has not been explored. We evaluated if the mRNA and protein levels of plasticity-related protein synaptophysin (Syp and SYP, respectively) and activity-regulated cytoskeleton-associated protein mRNA and protein levels (Arc and Arc, respectively) in the dentate gyrus were differentially modulated in time in response to a spatial-exploratory task after KA-induced hippocampal damage. In addition, we analyzed Arc+/NeuN+ immunopositive cells in the different experimental conditions. We infused KA intrahippocampally to young-adult rats and 10 or 30 days post-lesion (dpl) animals performed a hippocampus-activating spatial-exploratory task. Our results show that Syp mRNA levels significantly increase at 10dpl and return to control levels after 30dpl, whereas SYP protein levels are diminished at 10dpl, but significantly increase at 30dpl, as compared to 10dpl. Arc mRNA and protein levels are both increased at 30dpl as compared to sham. Also the number of NeuN+/Arc+ cells significantly increases at 30dpl in the group with a spatial-exploratory demand. These results provide information on the long-term modifications associated to structural plasticity and neuronal activation in the dentate gyrus after excitotoxic damage and in face of a spatial-exploratory behavior. Anat Rec, 300:425-432, 2017. © 2016 Wiley Periodicals, Inc.

  16. Conditional overexpression of insulin-like growth factor-1 enhances hippocampal neurogenesis and restores immature neuron dendritic processes after traumatic brain injury.

    PubMed

    Carlson, Shaun W; Madathil, Sindhu K; Sama, Diana M; Gao, Xiang; Chen, Jinhui; Saatman, Kathryn E

    2014-08-01

    Traumatic brain injury (TBI) is associated with neuronal damage or neuronal death in the hippocampus, a region critical for cognitive function. Immature neurons within the hippocampal neurogenic niche are particularly susceptible to TBI. Therapeutic strategies that protect immature hippocampal neurons or enhance posttraumatic neurogenesis may be advantageous for promoting functional recovery after TBI. Insulin-like growth factor-1 (IGF-1) promotes neurogenesis in the adult brain, but its effects on neurogenesis after TBI are unknown. We used an astrocyte-specific conditional IGF-1-overexpressing mouse model to supplement IGF-1 in regions of neuronal damage and reactive astrocytosis after controlled cortical impact injury. Although early loss of immature neurons was not significantly attenuated, overexpression of IGF-1 resulted in a marked increase in immature neuron density in the subgranular zone at 10 days after injury. This delayed increase seemed to be driven by enhanced neuron differentiation rather than by increased cellular proliferation. In wild-type mice, dendrites of immature neurons exhibited significant decreases in total length and number of bifurcations at 10 days after injury versus neurons in sham-injured mice. In contrast, the morphology of immature neuron dendrites in brain-injured IGF-1-overexpressing mice was equivalent to that in sham controls. These data provide compelling evidence that IGF-1 promotes neurogenesis after TBI.

  17. Ultrastructural study of hippocampal cortex neurons in an experimental model of valproate encephalopathy.

    PubMed

    Sendrowski, Krzysztof; Sobaniec, Wojciech; Sobaniec, Piotr; Sobaniec-Lotowska, Maria E

    2013-01-01

    Valproate (VPA) is a widely used antiepileptic drug. A serious neurological-outcome defined as valproate encephalopathy (VE) may rarely occur during VPA therapy. Structural abnormalities within neurons are postulated as one of the reasons for VE. The aim of this study was to assess the ultrastructure of neurons in the hippocampal cortex during the course of chronic application of VPA to rats. VPA was chronically administered to rats, intragastrically, once daily at a dose of 200 mg/kg b.w. for 1, 3, 6, 9 and 12 months. The samples of hippocampal cortex, after routine laboratory preparation, were examined by electron microscopy. The drug induced pronounced ultrastructural changes in the population of pyramidal neurons within the hippocampal cortex after 9 and 12 months of VPA administration. The most expressed abnormalities were observed within the mitochondria and manifested by fragmentation of crests and almost complete disappearance of intramitochondrial granules. Mitochondria of numerous neurons resembled large vacuolar structures. Widening, shortening and irregular distribution of rough endoplasmic reticulum was also found. A characteristic feature of damaged neurocytes in the last two phases of the experiment was the disintegration of nuclear chromatin and the presence of numerous lipofuscin deposits within hyaloplasm. These cells assumed the look of "dark neurons" and presented the ultrastructural features of apoptosis and necrosis. Our results indicate that long-term VPA administration to rats leads to aponecrosis of hippocampal neurons.

  18. A Simplified Method for Ultra-Low Density, Long-Term Primary Hippocampal Neuron Culture.

    PubMed

    Lu, Zhongming; Piechowicz, Mariel; Qiu, Shenfeng

    2016-03-05

    Culturing primary hippocampal neurons in vitro facilitates mechanistic interrogation of many aspects of neuronal development. Dissociated embryonic hippocampal neurons can often grow successfully on glass coverslips at high density under serum-free conditions, but low density cultures typically require a supply of trophic factors by co-culturing them with a glia feeder layer, preparation of which can be time-consuming and laborious. In addition, the presence of glia may confound interpretation of results and preclude studies on neuron-specific mechanisms. Here, a simplified method is presented for ultra-low density (~2,000 neurons/cm2), long-term (>3 months) primary hippocampal neuron culture that is under serum free conditions and without glia cell support. Low density neurons are grown on poly-D-lysine coated coverslips, and flipped on high density neurons grown in a 24-well plate. Instead of using paraffin dots to create a space between the two neuronal layers, the experimenters can simply etch the plastic bottom of the well, on which the high density neurons reside, to create a microspace conducive to low density neuron growth. The co-culture can be easily maintained for >3 months without significant loss of low density neurons, thus facilitating the morphological and physiological study of these neurons. To illustrate this successful culture condition, data are provided to show profuse synapse formation in low density cells after prolonged culture. This co-culture system also facilitates the survival of sparse individual neurons grown in islands of poly-D-lysine substrates and thus the formation of autaptic connections.

  19. Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging

    PubMed Central

    Gebara, Elias; Sultan, Sebastien; Kocher-Braissant, Jacqueline; Toni, Nicolas

    2013-01-01

    Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus. PMID:23970848

  20. A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis.

    PubMed

    Castilla-Ortega, Estela; Serrano, Antonia; Blanco, Eduardo; Araos, Pedro; Suárez, Juan; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-07-01

    Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug-induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine.

  1. Role of adult hippocampal neurogenesis in persistent pain.

    PubMed

    Apkarian, A Vania; Mutso, Amelia A; Centeno, Maria V; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T; Miller, Richard J; Radulovic, Jelena; Hen, René; Kessler, John A

    2016-02-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.

  2. Role of adult hippocampal neurogenesis in persistent pain

    PubMed Central

    Apkarian, A. Vania; Mutso, Amelia A.; Centeno, Maria V.; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T.; Miller, Richard J.; Radulovic, Jelena; Hen, René; Kessler, John A.

    2016-01-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain. PMID:26313405

  3. Active dendrites support efficient initiation of dendritic spikes in hippocampal CA3 pyramidal neurons

    PubMed Central

    Kim, Sooyun; Guzman, Segundo J; Hu, Hua; Jonas, Peter

    2013-01-01

    CA3 pyramidal neurons are important for memory formation and pattern completion in the hippocampal network. It is generally thought that proximal synapses from the mossy fibers activate these neurons most efficiently, whereas distal inputs from the perforant path have a weaker modulatory influence. We used confocally targeted patch-clamp recording from dendrites and axons to map the activation of rat CA3 pyramidal neurons at the subcellular level. Our results reveal two distinct dendritic domains. In the proximal domain, action potentials initiated in the axon backpropagate actively with large amplitude and fast time course. In the distal domain, Na+ channel–mediated dendritic spikes are efficiently initiated by waveforms mimicking synaptic events. CA3 pyramidal neuron dendrites showed a high Na+-to-K+ conductance density ratio, providing ideal conditions for active backpropagation and dendritic spike initiation. Dendritic spikes may enhance the computational power of CA3 pyramidal neurons in the hippocampal network. PMID:22388958

  4. Effect of Brain-Derived Neurotrophic Factor Haploinsufficiency on Stress-Induced Remodeling of Hippocampal Neurons

    PubMed Central

    Magariños, A.M.; Li, C.J.; Toth, J. Gal; Bath, K.G.; Jing, D.; Lee, F.S.; McEwen, B.S.

    2010-01-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF±) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF± mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF± mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling. PMID:20095008

  5. Effect of brain-derived neurotrophic factor haploinsufficiency on stress-induced remodeling of hippocampal neurons.

    PubMed

    Magariños, A M; Li, C J; Gal Toth, J; Bath, K G; Jing, D; Lee, F S; McEwen, B S

    2011-03-01

    Chronic restraint stress (CRS) induces the remodeling (i.e., retraction and simplification) of the apical dendrites of hippocampal CA3 pyramidal neurons in rats, suggesting that intrahippocampal connectivity can be affected by a prolonged stressful challenge. Since the structural maintenance of neuronal dendritic arborizations and synaptic connectivity requires neurotrophic support, we investigated the potential role of brain derived neurotrophic factor (BDNF), a neurotrophin enriched in the hippocampus and released from neurons in an activity-dependent manner, as a mediator of the stress-induced dendritic remodeling. The analysis of Golgi-impregnated hippocampal sections revealed that wild type (WT) C57BL/6 male mice showed a similar CA3 apical dendritic remodeling in response to three weeks of CRS to that previously described for rats. Haploinsufficient BDNF mice (BDNF(±) ) did not show such remodeling, but, even without CRS, they presented shorter and simplified CA3 apical dendritic arbors, like those observed in stressed WT mice. Furthermore, unstressed BDNF(±) mice showed a significant decrease in total hippocampal volume. The dendritic arborization of CA1 pyramidal neurons was not affected by CRS or genotype. However, only in WT mice, CRS induced changes in the density of dendritic spine shape subtypes in both CA1 and CA3 apical dendrites. These results suggest a complex role of BDNF in maintaining the dendritic and spine morphology of hippocampal neurons and the associated volume of the hippocampal formation. The inability of CRS to modify the dendritic structure of CA3 pyramidal neurons in BDNF(±) mice suggests an indirect, perhaps permissive, role of BDNF in mediating hippocampal dendritic remodeling.

  6. Pathological involvement of the motor neuron system and hippocampal formation in motor neuron disease-inclusion dementia.

    PubMed

    Toyoshima, Yasuko; Piao, Yue-Shan; Tan, Chun-Feng; Morita, Masahiro; Tanaka, Masaharu; Oyanagi, Kiyomitsu; Okamoto, Koichi; Takahashi, Hitoshi

    2003-07-01

    We report two patients with motor neuron disease-inclusion dementia, with special reference to the pathology of the motor neuron system and hippocampal formation. The ages of the patients at death were 55 and 62 years, and the disease durations were 8 and 3 years, respectively. The two patients exhibited progressive frontotemporal dementia in the absence of motor neuron signs. At autopsy, both cases exhibited frontotemporal lobar atrophy with ubiquitin-positive, and tau- and alpha-synuclein-negative neuronal inclusions. As expected from the clinical signs, in both cases, the upper and lower motor neuron systems were well preserved: no Bunina bodies or ubiquitinated inclusions were detected in the motor neurons. However, of great importance was that when visualized immunohistochemically, the Golgi apparatus and trans-Golgi network often exhibited fragmentation in the lower motor neurons (the spinal anterior horn cells). In one of the cases, a decrease in the amount of Golgi apparatus was also a frequent feature in the upper motor neurons (Betz cells in the motor cortex). Moreover, in both cases, circumscribed degeneration affecting the CA1-subiculum border zone was evident in the hippocampal formation. These findings further strengthen the idea that, pathologically, motor neuron disease-inclusion dementia is a rare phenotype of amyotrophic lateral sclerosis.

  7. Hippocampal Neuron Number Is Unchanged 1 Year After Fractionated Whole-Brain Irradiation at Middle Age

    SciTech Connect

    Shi Lei Molina, Doris P.; Robbins, Michael E.; Wheeler, Kenneth T.; Brunso-Bechtold, Judy K.

    2008-06-01

    Purpose: To determine whether hippocampal neurons are lost 12 months after middle-aged rats received a fractionated course of whole-brain irradiation (WBI) that is expected to be biologically equivalent to the regimens used clinically in the treatment of brain tumors. Methods and Materials: Twelve-month-old Fischer 344 X Brown Norway male rats were divided into WBI and control (CON) groups (n = 6 per group). Anesthetized WBI rats received 45 Gy of {sup 137}Cs {gamma} rays delivered as 9 5-Gy fractions twice per week for 4.5 weeks. Control rats were anesthetized but not irradiated. Twelve months after WBI completion, all rats were anesthetized and perfused with paraformaldehyde, and hippocampal sections were immunostained with the neuron-specific antibody NeuN. Using unbiased stereology, total neuron number and the volume of the neuronal and neuropil layers were determined in the dentate gyrus, CA3, and CA1 subregions of hippocampus. Results: No differences in tissue integrity or neuron distribution were observed between the WBI and CON groups. Moreover, quantitative analysis demonstrated that neither total neuron number nor the volume of neuronal or neuropil layers differed between the two groups for any subregion. Conclusions: Impairment on a hippocampal-dependent learning and memory test occurs 1 year after fractionated WBI at middle age. The same WBI regimen, however, does not lead to a loss of neurons or a reduction in the volume of hippocampus.

  8. Mesenchymal Stem Cells Increase Hippocampal Neurogenesis and Neuronal Differentiation by Enhancing the Wnt Signaling Pathway in an Alzheimer's Disease Model.

    PubMed

    Oh, Se Hee; Kim, Ha Na; Park, Hyun-Jung; Shin, Jin Young; Lee, Phil Hyu

    2015-01-01

    Neurogenesis in the subgranular zone of the hippocampal dentate gyrus may act as an endogenous repair mechanism in Alzheimer's disease (AD), and the Wnt signaling pathway has been suggested to closely modulate neurogenesis in amyloid-β (Aβ)-related AD models. The present study investigated whether mesenchymal stem cells (MSCs) would modulate hippocampal neurogenesis via modulation of the Wnt signaling pathway in a model of AD. In Aβ-treated neuronal progenitor cells (NPCs), the coculture with MSCs increased significantly the expression of Ki-67, GFAP, SOX2, nestin, and HuD compared to Aβ treatment alone. In addition, MSC treatment in Aβ-treated NPCs enhanced the expression of β-catenin and Ngn1 compared to Aβ treatment alone. MSC treatment in Aβ-treated animals significantly increased the number of BrdU-ir cells in the hippocampus at 2 and 4 weeks compared to Aβ treatment alone. In addition, quantitative analysis showed that the number of BrdU and HuD double-positive cells in the dentate gyrus was significantly higher in the MSC-treated group than in controls or after Aβ treatment alone. These results demonstrate that MSC administration significantly augments hippocampal neurogenesis and enhances the differentiation of NPCs into mature neurons in AD models by augmenting the Wnt signaling pathway. The use of MSCs to modulate endogenous adult neurogenesis may have a significant impact on future strategies for AD treatment.

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

    PubMed Central

    Lonka, Liina; Aalto, Antti; Kopra, Outi; Kuronen, Mervi; Kokaia, Zaal; Saarma, Mart; Lehesjoki, Anna-Elina

    2005-01-01

    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. PMID:15826318

  10. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    PubMed

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

  11. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study

    PubMed Central

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity. PMID:27147983

  12. HERC 1 Ubiquitin Ligase Mutation Affects Neocortical, CA3 Hippocampal and Spinal Cord Projection Neurons: An Ultrastructural Study.

    PubMed

    Ruiz, Rocío; Pérez-Villegas, Eva María; Bachiller, Sara; Rosa, José Luis; Armengol, José Angel

    2016-01-01

    The spontaneous mutation tambaleante is caused by the Gly483Glu substitution in the highly conserved N terminal RCC1-like domain of the HERC1 protein, which leads to the increase of mutated protein levels responsible for cerebellar Purkinje cell death by autophagy. Until now, Purkinje cells have been the only central nervous neurons reported as being targeted by the mutation, and their degeneration elicits an ataxic syndrome in adult mutant mice. However, the ultrastructural analysis performed here demonstrates that signs of autophagy, such as autophagosomes, lysosomes, and altered mitochondria, are present in neocortical pyramidal, CA3 hippocampal pyramidal, and spinal cord motor neurons. The main difference is that the reduction in the number of neurons affected in the tambaleante mutation in the neocortex, the hippocampus, and the spinal cord is not so evident as the dramatic loss of cerebellar Purkinje cells. Interestingly, signs of autophagy are absent in both interneurons and neuroglia cells. Affected neurons have in common that they are projection neurons which receive strong and varied synaptic inputs, and possess the highest degree of neuronal activity. Therefore, because the integrity of the ubiquitin-proteasome system is essential for protein degradation and hence, for normal protein turnover, it could be hypothesized that the deleterious effects of the misrouting of these pathways would depend directly on the neuronal activity.

  13. Protein fucosylation regulates synapsin Ia/Ib expression and neuronal morphology in primary hippocampal neurons

    PubMed Central

    Murrey, Heather E.; Gama, Cristal I.; Kalovidouris, Stacey A.; Luo, Wen.-I.; Driggers, Edward M.; Porton, Barbara; Hsieh-Wilson, Linda C.

    2006-01-01

    Although fucose-α(1-2)-galactose [Fucα(1-2)Gal] carbohydrates have been implicated in cognitive processes such as long-term memory, the molecular mechanisms by which these sugars influence neuronal communication are not well understood. Here, we present molecular insights into the functions of Fucα(1-2)Gal sugars, demonstrating that they play a role in the regulation of synaptic proteins and neuronal morphology. We show that synapsins Ia and Ib, synapse-specific proteins involved in neurotransmitter release and synaptogenesis, are the major Fucα(1-2)Gal glycoproteins in mature cultured neurons and the adult rat hippocampus. Fucosylation has profound effects on the expression and turnover of synapsin in cells and protects synapsin from degradation by the calcium-activated protease calpain. Our studies suggest that defucosylation of synapsin has critical consequences for neuronal growth and morphology, leading to stunted neurite outgrowth and delayed synapse formation. We also demonstrate that Fucα(1-2)Gal carbohydrates are not limited to synapsin but are found on additional glycoproteins involved in modulating neuronal architecture. Together, our studies identify important roles for Fucα(1-2)Gal sugars in the regulation of neuronal proteins and morphological changes that may underlie synaptic plasticity. PMID:16373512

  14. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells

    PubMed Central

    Ables, Jessica L.; DeCarolis, Nathan A.; Johnson, Madeleine A.; Rivera, Phillip D.; Gao, Zhengliang; Cooper, Don C.; Radtke, Freddy; Hsieh, Jenny; Eisch, Amelia J.

    2010-01-01

    Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreERT2/R26R-YFP/Notch1loxP/loxP (Notch1 iKO) mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild type mice (WT; nestin-CreERT2/R26R-YFP/Notch1wt/wt) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared to WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 days post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 days post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently-amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 days of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch1- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli. PMID:20685991

  15. Study on dynamic characteristics' change of hippocampal neuron reduced models caused by the Alzheimer's disease.

    PubMed

    Peng, Yueping; Wang, Jue; Zheng, Chongxun

    2016-01-01

    In the paper, based on the electrophysiological experimental data, the Hippocampal neuron reduced model under the pathology condition of Alzheimer's disease (AD) has been built by modifying parameters' values. The reduced neuron model's dynamic characteristics under effect of AD are comparatively studied. Under direct current stimulation, compared with the normal neuron model, the AD neuron model's dynamic characteristics have obviously been changed. The neuron model under the AD condition undergoes supercritical Andronov-Hopf bifurcation from the rest state to the continuous discharge state. It is different from the neuron model under the normal condition, which undergoes saddle-node bifurcation. So, the neuron model changes into a resonator with monostable state from an integrator with bistable state under AD's action. The research reveals the neuron model's dynamic characteristics' changing under effect of AD, and provides some theoretic basis for AD research by neurodynamics theory.

  16. A viral vector expressing hypoxia-inducible factor 1 alpha inhibits hippocampal neuronal apoptosis

    PubMed Central

    Chai, Xiqing; Kong, Weina; Liu, Lingyun; Yu, Wenguo; Zhang, Zhenqing; Sun, Yimin

    2014-01-01

    Hypoxia-inducible factor 1 (HIF-1) attenuates amyloid-beta protein neurotoxicity and decreases apoptosis induced by oxidative stress or hypoxia in cortical neurons. In this study, we constructed a recombinant adeno-associated virus (rAAV) vector expressing the human HIF-1α gene (rAAV-HIF-1α), and tested the assumption that rAAV-HIF-1α represses hippocampal neuronal apoptosis induced by amyloid-beta protein. Our results confirmed that rAAV-HIF-1α significantly reduces apoptosis induced by amyloid-beta protein in primary cultured hippocampal neurons. Direct intracerebral rAAV-HIF-1α administration also induced robust and prolonged HIF-1α production in rat hippocampus. Single rAAV-HIF-1α administration resulted in decreased apoptosis of hippocampal neurons in an Alzheimer's disease rat model established by intracerebroventricular injection of aggregated amyloid-beta protein (25–35). Our in vitro and in vivo findings demonstrate that HIF-1 has potential for attenuating hippocampal neuronal apoptosis induced by amyloid-beta protein, and provides experimental support for treatment of neurodegenerative diseases using gene therapy. PMID:25206774

  17. Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

    PubMed Central

    Besnard, Antoine; Sahay, Amar

    2016-01-01

    The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)–CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal–cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD. PMID:26068726

  18. Lamina-specific synaptic connections of hippocampal neurons in vitro.

    PubMed

    Frotscher, M; Heimrich, B

    1995-03-01

    By using slice cultures as a model, we demonstrate here that different target selectivities exist among the various afferent fibers to the hippocampus. As in intact animals, septohippocampal cholinergic fibers, provided by a slice culture of septum, innervate a co-cultured slice of hippocampus diffusely, that is, without forming distinct layers of termination. As in vivo, the septal cholinergic fibers establish synapses with a variety of target cells. Conversely, fibers from an entorhinal slice co-cultured to a hippocampal slice display their normal laminar specificity. They preferentially terminate in the outer molecular layer of the fascia dentata, thereby selectively contacting peripheral dendrites of the granule cells. This preferential termination on peripheral dendritic segments is remarkable, since these fibers do not have to compete with commissural fibers, hypothalamic fibers, and septal afferents for dendritic space under these culture conditions. Moreover, in triplet cultures in which first two hippocampal slices were co-cultured and then, with a delay of 5 days, an entorhinal slice was added, the fibers from the entorhinal slice and those from the hippocampal culture terminated in their appropriate layers in the hippocampal target culture. However, in this approach the normal sequence of ingrowth of these two afferents was reversed. In normal ontogenetic development, entorhinal afferents arrive in the hippocampus before the commissural fibers. The results show that there are different degrees of target selectivity of hippocampal afferents and that the characteristic lamination of certain afferent fibers in the hippocampus is not determined by their sequential ingrowth during development.

  19. Antibiotic Supplements Affect Electrophysiological Properties and Excitability of Rat Hippocampal Pyramidal Neurons in Primary Culture

    PubMed Central

    Bahrami, Farideh; Janahmadi, Mahyar

    2013-01-01

    Introduction: Antibiotic supplements are regularly used in neuronal culture media to control contamination; however, they can interfere with the neuronal excitability and affect electrophysiological properties. Therefore, in this study, the effect of penicillin/streptomycin supplements on the spontaneous electrophysiological activity of hippocampal pyramidal neurons was examined. Methods: Electrophysiological whole-cell patch-clamp recordings from rat hippocampal pyramidal cells in primary culture were performed to investigate the effects of antibiotic supplements on the intrinsic excitability of cultured cells. Results: The present findings indicated that presence of antibiotic supplements (penicillin/streptomycin) in the culture medium altered the intrinsic electrical activity of hippocampal pyramidal neurons in primary culture. These alterations included: 1) depolarized resting membrane potential; 2) a significant enhancement in the after-hyperpolarization amplitude; 3) a significant increase in the area under the action potential and in the decay and rise time of the action potential; 4) a significant broadening of action potential and 5) a significant reduction in the firing frequency. Conclusion: These findings suggest that addition of antibiotic supplements to culture media influences the neuronal excitability and alters the electrophysiological properties of cultured neurons, possibly through changing the ionic conductance underlying neuronal excitability. PMID:23567852

  20. Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats.

    PubMed

    Methippara, Melvi; Bashir, Tariq; Suntsova, Natalia; Szymusiak, Ron; McGinty, Dennis

    2010-09-01

    The adult hippocampal dentate gyrus (DG) exhibits cell proliferation and neurogenesis throughout life. We examined the effects of daily administration of eszopiclone (Esz), a commonly used hypnotic drug and gamma-aminobutyric acid (GABA) agonist, compared with vehicle, on DG cell proliferation and neurogenesis, and on sleep-wake patterns. Esz was administered during the usual sleep period of rats, to mimic typical use in humans. Esz treatment for 7 days did not affect the rate of cell proliferation, as measured by 5-bromo-2'-deoxyuridine (BrdU) immunostaining. However, twice-daily Esz administration for 2 weeks increased survival of newborn cells by 46%. Most surviving cells exhibited a neuronal phenotype, identified as BrdU-neuronal nuclei (NeuN) double-labeling. NeuN is a marker of neurons. Non-rapid eye movement sleep was increased on day 1, but not on days 7 or 14 of Esz administration. Delta electroencephalogram activity was increased on days 1 and 7 of treatment, but not on day 14. There is evidence that enhancement of DG neurogenesis is a critical component of the effects of antidepressant treatments of major depressive disorder (MDD). Adult-born DG cells are responsive to GABAergic stimulation, which promotes cell maturation. The present study suggests that Esz, presumably acting as a GABA agonist, has pro-neurogenic effects in the adult DG. This result is consistent with evidence that Esz enhances the antidepressant treatment response of patients with MDD with insomnia.

  1. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats.

    PubMed

    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

    2011-11-01

    Microglia have neuroprotective capacities, yet chronic activation can promote neurotoxic inflammation. Neuronal fractalkine (FKN), acting on CX(3)CR1, has been shown to suppress excessive microglia activation. We found that disruption in FKN/CX(3)CR1 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 CX(3)CR1 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/CX(3)CR1 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/CX(3)CR1 interactions could provide an alternative therapeutic approach to slow age-related neurodegeneration.

  2. Neuronal implementation of hippocampal-mediated spatial behavior: a comparative evolutionary perspective.

    PubMed

    Bingman, Verner P; Sharp, Patricia E

    2006-06-01

    The hippocampal formation (HF) of mammals and birds plays a strikingly similar role in the representation of space. This evolutionarily conserved property, however, belies the contrasting spatial ecology of animals such as rats and homing pigeons, differing spatial ecologies that should have promoted the evolution of group-specific adaptations to the HF representation of space. However, the spatial response properties of pigeon and rat HF neurons reveal surprising similarity in the contribution of position, direction, and trajectory toward explaining spatial variation in firing rate. By contrast, the asymmetrical distribution of neuronal response properties in the left and right HF of homing pigeons, but not rats, indicates a difference in network organization. The authors propose that hippocampal evolution may be characterized by inertia with respect to changes in the basic spatial elements that determine the response properties of neurons but considerable plasticity in how the neuronal response elements are organized into functional networks.

  3. Investigations into neuropeptide Y-mediated presynaptic inhibition in cultured hippocampal neurones of the rat.

    PubMed Central

    Bleakman, D.; Harrison, N. L.; Colmers, W. F.; Miller, R. J.

    1992-01-01

    1. We have examined the effects of neuropeptide Y (NPY) on synaptic transmission and [Ca2+]i signals in rat hippocampal neurones grown in culture. [Ca2+]i in individual neurones displayed frequent spontaneous fluctuations often resulting in an elevated plateau [Ca2+]i. These fluctuations were reduced by tetrodotoxin (1 microM) or combinations of the excitatory amino acid antagonists 6-cyano-7-dinitro-quinoxaline (CNQX) (10 microM) and aminophosphonovalerate (APV) (50 microM), indicating that they were the result of glutamatergic transmission occurring between hippocampal neurones. 2. [Ca2+]i fluctuations were also prevented by Ni2+ (200 microM), by the GABAB receptor agonist, baclofen (10 microM) and by NPY (100 nM) or Y2 receptor-selective NPY agonists. Following treatment of cells with pertussis toxin, NPY produced only a brief decrease in [Ca2+]i fluctuations which rapidly recovered. 3. Perfusion of hippocampal neurones with 50 mM K+ produced a large rapid increase in [Ca2+]i. This increase was slightly reduced by NPY or by a combination of CNQX and APV. The effects of CNQX/APV occluded those of NPY. NPY had no effect on Ba2+ currents measured in hippocampal neurones under whole cell voltage-clamp even in the presence of intracellular GTP-gamma-S. On the other hand, Ba2+ currents were reduced by both Cd2+ (200 microM) and baclofen (10 microM). 4. Current clamp recordings from hippocampal neurones demonstrated the occurrence of spontaneous e.p.s.ps and action potential firing which were accompanied by increases in [Ca2+]i. This spontaneous activity and the accompanying [Ca2+]i signals were prevented by application of NPY (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1358389

  4. Galectin-3 expression in delayed neuronal death of hippocampal CA1 following transient forebrain ischemia, and its inhibition by hypothermia.

    PubMed

    Satoh, Kunio; Niwa, Masayuki; Goda, Wael; Binh, Nguyen Huy; Nakashima, Masaya; Takamatsu, Manabu; Hara, Akira

    2011-03-25

    The ischemic damage in the hippocampal CA1 sector following transient ischemia, delayed neuronal death, is a typical apoptosis, but the mechanism underlying the delayed neuronal death is still far from fully understood. Galectin-3 is a β-galactosidase-binding lectin which is important in cell proliferation and apoptotic regulation. Galectin-3 is expressed by microglial cells in experimental models of adult stroke. It has been reported that activated microglial cells are widely observed in the brain, including in the hippocampal CA1 region after transient ischemic insult. In the present study, time course expression of galectin-3 following transient forebrain ischemia in gerbils was examined by immunohistochemistry, combined with Iba-1 immunostaining (a specific microglial cell marker), hematoxylin and eosin staining (for morphological observation), and in situ terminal dUTP-biotin nick end labeling of DNA fragments method (for determination of cell death). Following transient ischemia, we observed a transient increase of galectin-3 expression in CA1 region, which was maximal 96h after reperfusion. Galectin-3 expression was predominately localized within CA1 region and observed only in cells which expressed Iba-1. The galectin-3-positive microglial cells emerge after the onset of neuronal cell damage. Expressions of galectin-3 and Iba-1 were strongly reduced by hypothermia during ischemic insult. Prevention of galectin-3 and Iba-1 expression in microglia by hypothermia has led us to propose that hypothermia either inhibits microglial activation or prevents delayed neuronal death itself. Our results indicate that galectin-3 might exert its effect by modulating the neuronal damage in delayed neuronal death.

  5. Inactivation characteristics of a sustained, Ca(2+)-independent K+ current of rat hippocampal neurones in vitro.

    PubMed Central

    Nistri, A; Cherubini, E

    1992-01-01

    1. Current or voltage clamp recordings from CA3 neurones of the adult rat hippocampal slice were performed to study the inactivation properties of a slow outward K+ current identified as the delayed rectifier (IK). 2. In current clamp experiments, burst firing evoked from resting membrane potential by intracellular current injection was reduced or blocked by conditioning hyperpolarizing pre-pulses of 20-40 mV amplitude. This effect was inhibited by tetraethylammonium (TEA; 20 mM) but was unaffected by Cs+ (3 mM), 4-aminopyridine (4-AP; 2 mM), carbachol (30-50 microM), mast cell degranulating peptide (MCDP; 300 nM), thyrotrophin releasing hormone (TRH; 1 microM) or by a Ca(2+)-free solution containing Mn2+ or Co2+ (2 mM). 3. Single-electrode voltage clamp experiments were carried out on neurones superfused with Ca(2+)-free solution, containing tetrodotoxin (TTX; 1 microM), Mn2+ or Co2+ (2 mM), 4-AP (2 mM), Cs+ (3 mM) and carbachol (30 microM). Step depolarizations from a holding potential of -55 mV activated an outward current which reached a plateau after 200 ms, followed by an outward tail current. Such an outward current had the characteristics of IK. 4. The outward currents were significantly potentiated by conditioning hyperpolarizing pre-pulses suggesting the IK was reduced by a voltage-dependent inactivation process. Removal of inactivation was a function of the amplitude of the conditioning hyperpolarizing pre-pulse. At a holding potential of -55 mV removal of inactivation was time dependent with a time constant of 211 ms. High K+ (12.5 or 21.5 mM) solutions did not affect the inactivation characteristics of IK. 5. Tetraethylammonium (20 mM) or low concentrations of Ba2+ (0.1 mM) readily depressed the outward current without significantly affecting the inactivation process. Dendrotoxin (200 nM) also depressed such a slow current but, in addition, increased the inactivation process of IK. 6. It is suggested that removal of inactivation of IK by

  6. The Role of Chloride Transport in Postsynaptic Inhibition of Hippocampal Neurons

    NASA Astrophysics Data System (ADS)

    Misgeld, U.; Deisz, R. A.; Dodt, H. U.; Lux, H. D.

    1986-06-01

    Hippocampal inhibitory postsynaptic potentials are depolarizing in granule cells but hyperpolarizing in CA3 neurons because the reversal potentials and membrane potentials of these cells differ. Here the hippocampal slice preparation was used to investigate the role of chloride transport in these inhibitory responses. In both cell types, increasing the intracellular chloride concentration by injection shifted the reversal potential of these responses in a positive direction, and blocking the outward transport of chloride with furosemide slowed their recovery from the injection. In addition, hyperpolarizing and depolarizing inhibitory responses and the hyperpolarizing and depolarizing responses to the inhibitory neurotransmitter γ - aminobutyric acid decreased in the presence of furosemide. These effects of furosemide suggest that the internal chloride activity of an individual hippocampal neuron is regulated by two transport processes, one that accumulates chloride and one that extrudes chloride.

  7. Metabolic syndrome causes rec ognition memory impairments and reduced the hippocampal neuronal plasticity in rats.

    PubMed

    Treviño, Samuel; Vázquez-Roque, Rubén A; López-López, Gustavo; Perez-Cruz, Claudia; Moran, Carolina; Handal-Silva, Anhabella; González-Vergara, Enrique; Flores, Gonzalo; Guevara, Jorge; Díaz, Alfonso

    2017-02-17

    Metabolic syndrome (MS) is a serious public health problem, which can promote neuronal alterations in cognitive regions related to memory processes and learning, such as the hippocampus. However, up to now there is no information of a regional segregation of this damage. In this study, we evaluate the MS effect on the neuronal morphology of the hippocampus by a regional segregation approach. Our results demonstrate that 90days of a high-calorie diet altered metabolic energy markers and caused memory impairments, as evaluated by the recognition of novel objects test (NORT). In addition, MS animals showed significant differences in dendritic order, total dendritic length and density of dendritic spines in CA1, CA3 and dentate gyrus (DG) of the hippocampal area compared to control fed rats. Furthermore, the immunoreactivity to synaptophysin (Syp) decreased in the hippocampus of MS animals compared to controls. These results indicate that metabolic alterations induced by MS affect hippocampal plasticity and hippocampal dependent memory processes.

  8. Human hippocampal neurons predict how well word pairs will be remembered.

    PubMed

    Cameron, K A; Yashar, S; Wilson, C L; Fried, I

    2001-04-01

    What is the neuronal basis for whether an experience is recalled or forgotten? In contrast to recognition, recall is difficult to study in nonhuman primates and rarely is accessible at the single neuron level in humans. We recorded 128 medial temporal lobe (MTL) neurons in patients implanted with intracranial microelectrodes while they encoded and recalled word paired associates. Neurons in the amygdala, entorhinal cortex, and hippocampus showed altered activity during encoding (9%), recall (22%), and both task phases (23%). The responses of hippocampal neurons during encoding predicted whether or not subjects later remembered the pairs successfully. Entorhinal cortex neuronal activity during retrieval was correlated with recall success. These data provide support at the single neuron level for MTL contributions to encoding and retrieval, while also suggesting there may be differences in the level of contribution of MTL regions to these memory processes.

  9. A Mechanism for the Formation of Hippocampal Neuronal Firing Patterns that Represent What Happens Where

    ERIC Educational Resources Information Center

    Tort, Adriano B. L.; Komorowski, Robert; Kopell, Nancy; Eichenbaum, Howard

    2011-01-01

    The association of specific events with the context in which they occur is a fundamental feature of episodic memory. However, the underlying network mechanisms generating what-where associations are poorly understood. Recently we reported that some hippocampal principal neurons develop representations of specific events occurring in particular…

  10. Modulation of Hippocampal Theta Oscillations and Spatial Memory by Relaxin-3 Neurons of the Nucleus Incertus

    ERIC Educational Resources Information Center

    Ma, Sherie; Olucha-Bordonau, Francisco E.; Hossain, M. Akhter; Lin, Feng; Kuei, Chester; Liu, Changlu; Wade, John D.; Sutton, Steven W.; Nunez, Angel; Gundlach, Andrew L.

    2009-01-01

    Hippocampal theta rhythm is thought to underlie learning and memory, and it is well established that "pacemaker" neurons in medial septum (MS) modulate theta activity. Recent studies in the rat demonstrated that brainstem-generated theta rhythm occurs through a multisynaptic pathway via the nucleus incertus (NI), which is the primary source of the…

  11. The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons.

    PubMed

    Alfaro, Iván E; Varela-Nallar, Lorena; Varas-Godoy, Manuel; Inestrosa, Nibaldo C

    2015-07-01

    Wnt signaling regulates synaptic development and function and contributes to the fine-tuning of the molecular and morphological differentiation of synapses. We have shown previously that Wnt5a activates non-canonical Wnt signaling to stimulate postsynaptic differentiation in excitatory hippocampal neurons promoting the clustering of the postsynaptic scaffold protein PSD-95 and the development of dendritic spines. At least three different kinds of Wnt receptors have been associated with Wnt5a signaling: seven trans-membrane Frizzled receptors and the tyrosine kinase receptors Ryk and ROR2. We report here that ROR2 is distributed in the dendrites of hippocampal neurons in close proximity to synaptic contacts and it is contained in dendritic spine protrusions. We demonstrate that ROR2 is necessary to maintain dendritic spine number and morphological distribution in cultured hippocampal neurons. ROR2 overexpression increased dendritic spine growth without affecting the density of dendritic spine protrusions in a form dependent on its extracellular Wnt binding cysteine rich domain (CRD) and kinase domain. Overexpression of dominant negative ROR2 lacking the extracellular CRD decreased spine density and the proportion of mushroom like spines, while ROR2 lacking the C-terminal and active kinase domains only affected spine morphology. Our results indicate a crucial role of the ROR2 in the formation and maturation of the postsynaptic dendritic spines in hippocampal neurons.

  12. Entorhinal-Hippocampal Neuronal Circuits Bridge Temporally Discontiguous Events

    ERIC Educational Resources Information Center

    Kitamura, Takashi; Macdonald, Christopher J.; Tonegawa, Susumu

    2015-01-01

    The entorhinal cortex (EC)-hippocampal (HPC) network plays an essential role for episodic memory, which preserves spatial and temporal information about the occurrence of past events. Although there has been significant progress toward understanding the neural circuits underlying the spatial dimension of episodic memory, the relevant circuits…

  13. GnRH analogue attenuated apoptosis of rat hippocampal neuron after ischemia-reperfusion injury.

    PubMed

    Chu, Chenyu; Xu, Bainan; Huang, Weiquan

    2010-12-01

    The expression and new functions of reproductive hormones in organs beyond hypothalamus-pituitary-gonad axis have been reported. So far, there is no report about the protective effects of GnRH analogue to hippocampal neurons suffering from ischemia-reperfusion injury. Middle cerebral artery occlusion model together with TUNEL staining were made in vivo and oxygen-glucose deprivation model together with double staining of Annexin V/PI with flow cytometer were made in vitro to observe the anti-apoptotic effects of GnRH analogue to hippocampal neurons after ischemia-reperfusion injury. The results found that the number of TUNEL positive pyramidal neurons in CA1 region in GnRH analogue experiment group was less than that in control group in vivo; the percentage of apoptotic neurons in GnRH analogue experiment group was less than that in control group in vitro. These findings suggested that pretreatment with certain concentration of GnRH analogue could attenuate apoptosis of hippocampal neurons. GnRH analogue has the protective effects to neurons.

  14. The Effect of Vitamin D Treatment On Nerve Growth Factor (NGF) Release From Hippocampal Neurons

    PubMed Central

    GEZEN-AK, Duygu; DURSUN, Erdinç; YILMAZER, Selma

    2014-01-01

    Introduction Vitamin D, the main function of which is thought to be the maintenance of calcium and phosphate homeostasis and bone structure, has been shown in recent studies to have important roles in brain development as well. A certain vitamin D receptor (VDR) gene haplotype was reported, for the first time by our group, to increase the risk of developing Alzheimer’s disease. Our studies also showed that vitamin D prevents beta amyloid-induced calcium elevation and toxicity that target nerve growth factor (NGF) release in cortical neurons; beta amyloid suppresses VDR expression and the disruption of vitamin D-VDR pathway mimics beta amyloid-induced neurodegeneration. In this study, our aim was to investigate the effects of vitamin D on the NGF release from hippocampal neurons. Method Primary hippocampal neuron cultures that were prepared from 18-day-old Sprague-Dawley rat embryos were treated with vitamin D for 48 hours. The alteration in the NGF release was determined with ELISA. Cytotoxicity tests were also performed for all groups. Results The NGF release in vitamin D-treated group was significantly higher than in untreated control group. The protective effect of vitamin D against cytotoxicity was also observed. Conclusion Our results indicated that vitamin D regulates the release of NGF, a very important molecule for neuronal survival of hippocampal neurons as well as cortical neurons.

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

    PubMed

    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.

  16. Low Proliferation and Differentiation Capacities of Adult Hippocampal Stem Cells Correlate with Memory Dysfunction in Humans

    ERIC Educational Resources Information Center

    Coras, Roland; Siebzehnrubl, Florian A.; Pauli, Elisabeth; Huttner, Hagen B.; Njunting, Marleisje; Kobow, Katja; Villmann, Carmen; Hahnen, Eric; Neuhuber, Winfried; Weigel, Daniel; Buchfelder, Michael; Stefan, Hermann; Beck, Heinz; Steindler, Dennis A.; Blumcke, Ingmar

    2010-01-01

    The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we…

  17. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

    PubMed

    Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

    2015-01-01

    Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.

  18. Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome.

    PubMed

    Godavarthi, Swetha K; Dey, Parthanarayan; Sharma, Ankit; Jana, Nihar Ranjan

    2015-09-04

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice.

  19. Visualizing hippocampal neurons with in vivo two-photon microscopy using a 1030 nm picosecond pulse laser.

    PubMed

    Kawakami, Ryosuke; Sawada, Kazuaki; Sato, Aya; Hibi, Terumasa; Kozawa, Yuichi; Sato, Shunichi; Yokoyama, Hiroyuki; Nemoto, Tomomi

    2013-01-01

    In vivo two-photon microscopy has revealed vital information on neural activity for brain function, even in light of its limitation in imaging events at depths greater than several hundred micrometers from the brain surface. We developed a novel semiconductor-laser-based light source with a wavelength of 1030 nm that can generate pulses of 5-picosecond duration with 2-W output power, and a 20-MHz repetition rate. We also developed a system to secure the head of the mouse under an upright microscope stage that has a horizontal adjustment mechanism. We examined the penetration depth while imaging the H-Line mouse brain and demonstrated that our newly developed laser successfully images not only cortex pyramidal neurons spreading to all cortex layers at a superior signal-to-background ratio, but also images hippocampal CA1 neurons in a young adult mouse.

  20. Selection for tameness, a key behavioral trait of domestication, increases adult hippocampal neurogenesis in foxes.

    PubMed

    Huang, Shihhui; Slomianka, Lutz; Farmer, Andrew J; Kharlamova, Anastasiya V; Gulevich, Rimma G; Herbeck, Yury E; Trut, Lyudmila N; Wolfer, David P; Amrein, Irmgard

    2015-08-01

    Work on laboratory and wild rodents suggests that domestication may impact on the extent of adult hippocampal neurogenesis and its responsiveness to regulatory factors. There is, however, no model of laboratory rodents and their nondomesticated conspecifics that would allow a controlled comparison of the effect of domestication. Here, we present a controlled within-species comparison of adult hippocampal neurogenesis in farm-bred foxes (Vulpes vulpes) that differ in their genetically determined degree of tameness. Quantitative comparisons of cell proliferation (Ki67) and differentiating cells of neuronal lineage (doublecortin, DCX) in the hippocampus of foxes were performed as a proxy for neurogenesis. Higher neurogenesis was observed in tameness-selected foxes, notably in an extended subgranular zone of the middle and temporal compartments of the hippocampus. Increased neurogenesis is negatively associated with aggressive behavior. Across all animals, strong septotemporal gradients were found, with higher numbers of proliferating cells and young neurons relative to resident granule cells in the temporal than in the septal hippocampus. The opposite gradient was found for the ratio of DCX/Ki67- positive cells. When tameness-selected and unselected foxes are compared with rodents and primates, proliferation is similar, while the number of young neurons is higher. The difference may be mediated by an extended period of differentiation or higher rate of survival. On the background of this species-specific neurogenic pattern, selection of foxes for a single behavioral trait key to domestication, i.e., genetic tameness, is accompanied by global and region-specific increases in neurogenesis.

  1. Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

    PubMed Central

    Klein, C.; Schreyer, S.; Kohrs, F. E.; Elhamoury, P.; Pfeffer, A.; Munder, T.; Steiner, B.

    2017-01-01

    In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3-dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL. PMID:28345617

  2. Mesenchymal stem cells enhance GABAergic transmission in co-cultured hippocampal neurons.

    PubMed

    Mauri, Mario; Lentini, Daniela; Gravati, Marta; Foudah, Dana; Biella, Gerardo; Costa, Barbara; Toselli, Mauro; Parenti, Marco; Coco, Silvia

    2012-04-01

    Bone marrow-derived mesenchymal stem cells (MSCs) are multipotent stem cells endowed with neurotrophic potential combined with immunological properties, making them a promising therapeutic tool for neurodegenerative disorders. However, the mechanisms through which MSCs promote the neurological recovery following injury or inflammation are still largely unknown, although cell replacement and paracrine mechanisms have been hypothesized. In order to find out what are the mechanisms of the trophic action of MSCs, as compared to glial cells, on CNS neurons, we set up a co-culture system where rat MSCs (or cortical astrocytes) were used as a feeding layer for hippocampal neurons without any direct contact between the two cell types. The analysis of hippocampal synaptogenesis, synaptic vesicle recycling and electrical activity show that MSCs were capable to support morphological and functional neuronal differentiation. The proliferation of hippocampal glial cells induced by the release of bioactive substance(s) from MSCs was necessary for neuronal survival. Furthermore, MSCs selectively increased hippocampal GABAergic pre-synapses. This effect was paralleled with a higher expression of the potassium/chloride KCC2 co-transporter and increased frequency and amplitude of mIPSCs and sIPSCs. The enhancement of GABA synapses was impaired by the treatment with K252a, a Trk/neurotrophin receptor blocker, and by TrkB receptor bodies hence suggesting the involvement of BDNF as a mediator of such effects. The results obtained here indicate that MSC-secreted factors induce glial-dependent neuronal survival and trigger an augmented GABAergic transmission in hippocampal cultures, highlighting a new effect by which MSCs could promote CNS repair. Our results suggest that MSCs may be useful in those neurological disorders characterized by an impairment of excitation versus inhibition balance.

  3. In Vitro Ischemia Triggers a Transcriptional Response to Down-Regulate Synaptic Proteins in Hippocampal Neurons

    PubMed Central

    Fernandes, Joana; Vieira, Marta; Carreto, Laura; Santos, Manuel A. S.; Duarte, Carlos B.; Carvalho, Ana Luísa; Santos, Armanda E.

    2014-01-01

    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. PMID:24960035

  4. Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.

    PubMed

    Albright, Benjamin; Dhaher, Roni; Wang, Helen; Harb, Roa; Lee, Tih-Shih W; Zaveri, Hitten; Eid, Tore

    2017-02-01

    Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16-43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.

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

    PubMed

    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.

  6. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons.

    PubMed

    Fujimoto, Takahiro; Itoh, Kyoko; Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH2-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

  7. Cell cycle markers have different expression and localization patterns in neuron-like PC12 cells and primary hippocampal neurons.

    PubMed

    Negis, Yesim; Unal, Aysegul Yildiz; Korulu, Sirin; Karabay, Arzu

    2011-06-01

    Neuron-like PC12 cells are extensively used in place of neurons in published studies. Aim of this paper has been to compare mRNA and protein expressions of cell cycle markers; cyclinA, B, D, E; Cdk1, 2 and 4; and p27 in post-mitotic primary hippocampal neurons, mitotically active PC12 cells and NGF-differentiated post-mitotic PC12 cells. Contrary to PC12 cells, in neurons, the presence of all these markers was detected only at mRNA level; except for cyclinA, cyclinE and Cdk4, which were detectable also at protein levels. In both NGF-treated PC12 cells and neurons, cyclinE was localized only in the nucleus. In NGF-treated PC12 cells cyclinD and Cdk4 were localized in the nucleus while, in neurons cyclinD expression was not detectable; Cdk4 was localized in the cytoplasm. In neurons, cyclinA was nuclear, whereas in NGF-treated PC12 cells, it was localized in the cell body and along the processes. These results suggest that PC12 cells and primary neurons are different in terms of cell cycle protein expressions and localizations. Thus, it may not be very appropriate to use these cells as neuronal model system in order to understand neuronal physiological activities, upstream of where may lie cell cycle activation triggered events.

  8. Alpha-conotoxin-ImI: a competitive antagonist at alpha-bungarotoxin-sensitive neuronal nicotinic receptors in hippocampal neurons.

    PubMed

    Pereira, E F; Alkondon, M; McIntosh, J M; Albuquerque, E X

    1996-09-01

    In the present study, the patch-clamp technique was applied to rat hippocampal neurons or myoballs in culture to study the actions of alpha-conotoxin-ImI on the native alpha-bungarotoxin-sensitive, presumably alpha 7-bearing, neuronal nicotinic receptor and on other ligand-gated channels. Preexposure of the neurons for 5 min to alpha-conotoxin-ImI decreased the peak amplitude of alpha-BGT-sensitive currents (referred to as type IA currents) in a concentration-dependent fashion. Several lines of evidence revealed that the inhibitory effect of alpha-conotoxin-ImI was competitive with respect to the agonist (IC50 approximately 85 nM) and reversible by washing. At 300 nM, alpha-conotoxin-ImI decreased by only 15% the peak amplitude of ACh-evoked currents in rat myoballs, did not affect the activation of currents gated by gamma-aminobutyric acid, glycine, N-methyl-D-aspartate, kainate, or quisqualate in hippocampal neurons, but reduced to approximately 60% the peak amplitude and shortened the decay phase of curare-sensitive, serotonin-gated currents in these neurons. The competitive and reversible nature of the alpha-conotoxin-ImI-induced inhibition of native alpha 7-bearing neuronal nicotinic receptors makes this peptide a valuable new tool for the functional and structural characterization of these receptors in the central nervous system.

  9. Serotonergic neuron diversity: Identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm

    PubMed Central

    Kocsis, Bernat; Varga, Viktor; Dahan, Lionel; Sik, Attila

    2006-01-01

    The serotonergic system plays a key role in the regulation of brain states, and many of the known features of serotonergic neurons appear to match this function. Midbrain raphe nuclei provide a diffuse projection to all regions of the forebrain, and raphe neurons exhibit a slow metronome-like activity that sets the ambient levels of serotonin across the sleep–wake cycle. Serotonergic cells have also been implicated, however, in a variety of more specific functions that can hardly be related to their low-rate monotonous patterns of discharges. The amazing variety of serotonergic receptors and their type-specific distribution on cortical neurons also raise the possibility of a more intimate coordination between the activity of serotonergic neurons and their target cortical circuits. Here we report an unexpected diversity in the behavior of immunohistochemically identified serotonergic neurons. Two outstanding subpopulations were identified by using the in vivo juxtacellular recording and labeling technique. The first subpopulation of serotonergic cells exhibited the classic clock-like activity with no apparent short timescale interaction with the hippocampal electroencephalogram. The other subpopulation discharged action potentials that were phase-locked to the hippocampal theta rhythm, the oscillatory pattern associated with acquisition of information and memory formation. These results indicate that the ascending serotonergic system comprises cells involved in complex information processing beyond the regulation of state transitions. The heterogeneity of serotonergic neuron behavior can also help to explain the complexity of symptoms associated with serotonergic dysfunction. PMID:16418294

  10. Serotonergic neuron diversity: identification of raphe neurons with discharges time-locked to the hippocampal theta rhythm.

    PubMed

    Kocsis, Bernat; Varga, Viktor; Dahan, Lionel; Sik, Attila

    2006-01-24

    The serotonergic system plays a key role in the regulation of brain states, and many of the known features of serotonergic neurons appear to match this function. Midbrain raphe nuclei provide a diffuse projection to all regions of the forebrain, and raphe neurons exhibit a slow metronome-like activity that sets the ambient levels of serotonin across the sleep-wake cycle. Serotonergic cells have also been implicated, however, in a variety of more specific functions that can hardly be related to their low-rate monotonous patterns of discharges. The amazing variety of serotonergic receptors and their type-specific distribution on cortical neurons also raise the possibility of a more intimate coordination between the activity of serotonergic neurons and their target cortical circuits. Here we report an unexpected diversity in the behavior of immunohistochemically identified serotonergic neurons. Two outstanding subpopulations were identified by using the in vivo juxtacellular recording and labeling technique. The first subpopulation of serotonergic cells exhibited the classic clock-like activity with no apparent short timescale interaction with the hippocampal electroencephalogram. The other subpopulation discharged action potentials that were phase-locked to the hippocampal theta rhythm, the oscillatory pattern associated with acquisition of information and memory formation. These results indicate that the ascending serotonergic system comprises cells involved in complex information processing beyond the regulation of state transitions. The heterogeneity of serotonergic neuron behavior can also help to explain the complexity of symptoms associated with serotonergic dysfunction.

  11. Developmental Changes in Hippocampal CA1 Single Neuron Firing and Theta Activity during Associative Learning

    PubMed Central

    Kim, Jangjin; Goldsberry, Mary E.; Harmon, Thomas C.; Freeman, John H.

    2016-01-01

    Hippocampal development is thought to play a crucial role in the emergence of many forms of learning and memory, but ontogenetic changes in hippocampal activity during learning have not been examined thoroughly. We examined the ontogeny of hippocampal function by recording theta and single neuron activity from the dorsal hippocampal CA1 area while rat pups were trained in associative learning. Three different age groups [postnatal days (P)17-19, P21-23, and P24-26] were trained over six sessions using a tone conditioned stimulus (CS) and a periorbital stimulation unconditioned stimulus (US). Learning increased as a function of age, with the P21-23 and P24-26 groups learning faster than the P17-19 group. Age- and learning-related changes in both theta and single neuron activity were observed. CA1 pyramidal cells in the older age groups showed greater task-related activity than the P17-19 group during CS-US paired sessions. The proportion of trials with a significant theta (4–10 Hz) power change, the theta/delta ratio, and theta peak frequency also increased in an age-dependent manner. Finally, spike/theta phase-locking during the CS showed an age-related increase. The findings indicate substantial developmental changes in dorsal hippocampal function that may play a role in the ontogeny of learning and memory. PMID:27764172

  12. Leptin regulation of neuronal morphology and hippocampal synaptic function

    PubMed Central

    Harvey, Jenni

    2013-01-01

    The central actions of the hormone leptin in regulating energy homeostasis via the hypothalamus are well documented. However, evidence is growing that this hormone can also modify the structure and function of synapses throughout the CNS. The hippocampus is a region of the forebrain that plays a crucial role in associative learning and memory and is an area also highly vulnerable to neurodegenerative processes. Recent studies indicate that leptin is a potential cognitive enhancer as it modulates the cellular processes underlying hippocampal-dependent learning and memory including dendritic morphology, glutamate receptor trafficking and activity-dependent synaptic plasticity. Here, we review the recent evidence implicating the hormone leptin as a key regulator of hippocampal synaptic function and discuss the role of leptin receptor-driven lipid signaling pathways involved in this process. PMID:23964236

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

    PubMed Central

    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

  14. Restraint stress increases hemichannel activity in hippocampal glial cells and neurons.

    PubMed

    Orellana, Juan A; Moraga-Amaro, Rodrigo; Díaz-Galarce, Raúl; Rojas, Sebastián; Maturana, Carola J; Stehberg, Jimmy; Sáez, Juan C

    2015-01-01

    Stress affects brain areas involved in learning and emotional responses, which may contribute in the development of cognitive deficits associated with major depression. These effects have been linked to glial cell activation, glutamate release and changes in neuronal plasticity and survival including atrophy of hippocampal apical dendrites, loss of synapses and neuronal death. Under neuro-inflammatory conditions, we recently unveiled a sequential activation of glial cells that release ATP and glutamate via hemichannels inducing neuronal death due to activation of neuronal NMDA/P2X7 receptors and pannexin1 hemichannels. In the present work, we studied if stress-induced glia activation is associated to changes in hemichannel activity. To this end, we compared hemichannel activity of brain cells after acute or chronic restraint stress in mice. Dye uptake experiments in hippocampal slices revealed that acute stress induces opening of both Cx43 and Panx1 hemichannels in astrocytes, which were further increased by chronic stress; whereas enhanced Panx1 hemichannel activity was detected in microglia and neurons after acute/chronic and chronic stress, respectively. Moreover, inhibition of NMDA/P2X7 receptors reduced the chronic stress-induced hemichannel opening, whereas blockade of Cx43 and Panx1 hemichannels fully reduced ATP and glutamate release in hippocampal slices from stressed mice. Thus, we propose that gliotransmitter release through hemichannels may participate in the pathogenesis of stress-associated psychiatric disorders and possibly depression.

  15. Hippocampal cannabinoid transmission modulates dopamine neuron activity: impact on rewarding memory formation and social interaction.

    PubMed

    Loureiro, Michael; Renard, Justine; Zunder, Jordan; Laviolette, Steven R

    2015-05-01

    Disturbances in cannabinoid type 1 receptor (CB1R) signaling have been linked to emotional and cognitive deficits characterizing neuropsychiatric disorders, including schizophrenia. Thus, there is growing interest in characterizing the relationship between cannabinoid transmission, emotional processing, and dopamine (DA)-dependent behavioral deficits. The CB1R is highly expressed in the mammalian nervous system, particularly in the hippocampus. Activation of the ventral hippocampal subregion (vHipp) is known to increase both the activity of DAergic neurons located in the ventral tegmental area (VTA) and DA levels in reward-related brain regions, particularly the nucleus accumbens (NAc). However, the possible functional relationship between hippocampal CB1R transmission and VTA DA neuronal activity is not currently understood. In this study, using in vivo neuronal recordings in rats, we demonstrate that activation of CB1R in the vHipp strongly increases VTA DA neuronal firing and bursting activity, while simultaneously decreasing the activity of VTA non-DA neurons. Furthermore, using a conditioned place preference procedure and a social interaction test, we report that intra-vHipp CB1R activation potentiates the reward salience of normally sub-threshold conditioning doses of opiates and induces deficits in natural sociability and social recognition behaviors. Finally, these behavioral effects were prevented by directly blocking NAc DAergic transmission. Collectively, these findings identify hippocampal CB1R transmission as a critical modulator of the mesolimbic DA pathway and in the processing of reward and social-related behavioral phenomena.

  16. Restraint stress increases hemichannel activity in hippocampal glial cells and neurons

    PubMed Central

    Orellana, Juan A.; Moraga-Amaro, Rodrigo; Díaz-Galarce, Raúl; Rojas, Sebastián; Maturana, Carola J.; Stehberg, Jimmy; Sáez, Juan C.

    2015-01-01

    Stress affects brain areas involved in learning and emotional responses, which may contribute in the development of cognitive deficits associated with major depression. These effects have been linked to glial cell activation, glutamate release and changes in neuronal plasticity and survival including atrophy of hippocampal apical dendrites, loss of synapses and neuronal death. Under neuro-inflammatory conditions, we recently unveiled a sequential activation of glial cells that release ATP and glutamate via hemichannels inducing neuronal death due to activation of neuronal NMDA/P2X7 receptors and pannexin1 hemichannels. In the present work, we studied if stress-induced glia activation is associated to changes in hemichannel activity. To this end, we compared hemichannel activity of brain cells after acute or chronic restraint stress in mice. Dye uptake experiments in hippocampal slices revealed that acute stress induces opening of both Cx43 and Panx1 hemichannels in astrocytes, which were further increased by chronic stress; whereas enhanced Panx1 hemichannel activity was detected in microglia and neurons after acute/chronic and chronic stress, respectively. Moreover, inhibition of NMDA/P2X7 receptors reduced the chronic stress-induced hemichannel opening, whereas blockade of Cx43 and Panx1 hemichannels fully reduced ATP and glutamate release in hippocampal slices from stressed mice. Thus, we propose that gliotransmitter release through hemichannels may participate in the pathogenesis of stress-associated psychiatric disorders and possibly depression. PMID:25883550

  17. Quantitative measurement of neuronal degeneration in organotypic hippocampal cultures after combined oxygen/glucose deprivation.

    PubMed

    Strasser, U; Fischer, G

    1995-04-01

    Organotypic hippocampal cultures were used to study cell degeneration during the recovery period after defined periods (30 and 60 min) of combined oxygen/glucose deprivation mimicking transient ischemic conditions. Staining with the fluorescent dye propidium iodide allowed detection of damaged cells. Fluorescence intensity was measured by an image analysis system and used to quantify cell damage at different time points during the recovery period (up to 22 h). At 30 min of oxygen/glucose deprivation cells in the CA1 area were relatively more sensitive compared to CA3 and dentate gyrus cells, with respect to the time course of degeneration and the percentage of affected cells. Expanding the oxygen/glucose deprivation period from 30 to 60 min drastically increased the percentage of cells dying in all hippocampal areas. Still, however, cells in CA1 degenerated faster compared to those in the CA3 area and dentate gyrus. A histological analysis of toluidine blue as well as MAP2-immunostained sections revealed that almost all neurons degenerated in all hippocampal areas following the 60-min deprivation period, whereas GFAP-stained astrocytes appeared to be unaffected. Therefore, neuronal degeneration could be quantified by taking the fluorescence intensity values 22 h after 60 min of oxygen/glucose deprivation as 100% neuronal damage. The possibility to quantify neuronal damage in organotypic cultures offers a useful tool for detailed studies on mechanisms of neuronal cell death in a cell culture system which is closer to in situ conditions than monolayer cell cultures.

  18. Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons

    PubMed Central

    Pizzurro, Daniella M.; Dao, Khoi; Costa, Lucio G.

    2014-01-01

    Evidence from in vivo and epidemiological studies suggests that organophosphorus insecticides (OPs) are developmental neurotoxicants, but possible underlying mechanisms are still unclear. Astrocytes are increasingly recognized for their active role in normal neuronal development. This study sought to investigate whether the widely-used OP diazinon (DZ), and its oxygen metabolite diazoxon (DZO), would affect glial-neuronal interactions as a potential mechanism of developmental neurotoxicity. Specifically, we investigated the effects of DZ and DZO on the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. The results show that both DZ and DZO adversely affect astrocyte function, resulting in inhibited neurite outgrowth in hippocampal neurons. This effect appears to be mediated by oxidative stress, as indicated by OP-induced increased reactive oxygen species production in astrocytes and prevention of neurite outgrowth inhibition by antioxidants. The concentrations of OPs were devoid of cytotoxicity, and cause limited acetylcholinesterase inhibition in astrocytes (18 and 25% for DZ and DZO, respectively). Among astrocytic neuritogenic factors, a most important one is the extracellular matrix protein fibronectin. DZ and DZO decreased levels of fibronectin in astrocytes, and this effect was also attenuated by antioxidants. Underscoring the importance of fibronectin in this context, adding exogenous fibronectin to the co-culture system successfully prevented inhibition of neurite outgrowth caused by DZ and DZO. These results indicate that DZ and DZO increase oxidative stress in astrocytes, and this in turn modulates astrocytic fibronectin, leading to impaired neurite outgrowth in hippocampal neurons. PMID:24342266

  19. Rho kinase regulates neurite outgrowth of hippocampal neurons via calcium dependent cytoskeleton regulation

    PubMed Central

    Ji, Zhisheng; Cai, Zhenbin; Zhang, Jifeng; Liu, Nannuan; Chen, Jing; Tan, Minghui; Lin, Hongsheng; Guo, Guoqing

    2017-01-01

    Objective: To investigate whether calcium is involved in downstream signal transduction in neurite outgrowth regulated by Rho kinase. Methods: In vitro primary hippocampal neurons were cultured and treated with Rho kinase agonist (LPA) or antagonist (Y-27632). Then, the cytoskeleton and neurite outgrowth were observed. After addition of calcium antagonist BAPTA/AM to reduce intracellular calcium, the cytoskeleton distribution and neurite outgrowth were observed. Results: The activation or inhibition of Rho kinase could significantly alter the number and length of neurites of hippocampal neurons. Rho kinase regulated the cytoskeleton to regulate the neurite outgrowth, and LPA could significantly increase intracellular calcium. After BAPTA/AM treatment, the length and branch number of neurites of neurons reduced markedly. BAPTA/AM was able to reduce intracellular calcium and decrease neuronal cytoskeleton. Treatment with both BAPTA/AM and LPA could stop the retraction of neurites, but the length and branch number of neurites remained unchanged after treatment with Y-27632 and LPA. Conclusion: Calcium may affect the cytoskeleton arrangement to regulate neurite outgrowth, and calcium is involved in the downstream signal transduction of Rho kinase regulated neurite outgrowth of hippocampal neurons. PMID:28337305

  20. [Effect of interrupting hippocampal connections on the neuronal activity of several midbrain nuclei].

    PubMed

    Kichigina, V F; Vinogradova, O S

    1979-01-01

    Experiments were performed on unanaesthetized rabbits with intact brain and with septo-hippocampal disconnection depriving midbrain structures of descending hippocampal influences. General characteristics of neuronal reactions in midbrain raphe (MR) and ventral tegmental nucleus (VT) did not change following deafferentation. The level of reactivity increased in VT and decreased in MR. The mean latencies of on-responses in MR became longer (15,5 msec for auditory stimuli versus 10,5 msec in intact brain); in VT they became shorter (14,5 msec versus 17 msec). Habituation of reactions, normally present in about half of neurones, disappeared. Neurones with incremental responses gradually increasing in strength and duration were observed. Complex functional relations between the hippocampus and unspecific midbrain structures are discussed.

  1. Effects of antidepressant drugs on synaptic protein levels and dendritic outgrowth in hippocampal neuronal cultures.

    PubMed

    Seo, Mi Kyoung; Lee, Chan Hong; Cho, Hye Yeon; Lee, Jung Goo; Lee, Bong Ju; Kim, Ji Eun; Seol, Wongi; Kim, Young Hoon; Park, Sung Woo

    2014-04-01

    The alteration of hippocampal plasticity has been proposed to play a critical role in both the pathophysiology and treatment of depression. In this study, the ability of different classes of antidepressant drugs (escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine) to mediate the expression of synaptic proteins and dendritic outgrowth in rat hippocampal neurons was investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. Postsynaptic density protein-95 (PSD-95), brain-derived neurotrophic factor (BDNF), and synaptophysin (SYP) levels were evaluated using Western blot analyses. Additionally, dendritic outgrowth was examined to determine whether antidepressant drugs affect the dendritic morphology of hippocampal neurons in B27-deprived cultures. Escitalopram, fluoxetine, paroxetine, sertraline, imipramine, tranylcypromine, and tianeptine significantly prevented B27 deprivation-induced decreases in levels of PSD-95, BDNF, and SYP. Moreover, the independent application of fluoxetine, paroxetine, and sertraline significantly increased levels of BDNF under normal conditions. All antidepressant drugs significantly increased the total outgrowth of hippocampal dendrites under B27 deprivation. Specific inhibitors of calcium/calmodulin kinase II (CaMKII), KN-93, protein kinase A (PKA), H-89, or phosphatidylinositol 3-kinase (PI3K), LY294002, significantly decreased the effects of antidepressant drugs on dendritic outgrowth, whereas this effect was observed only with tianeptine for the PI3K inhibitor. Taken together, these results suggest that certain antidepressant drugs can enhance synaptic protein levels and encourage dendritic outgrowth in hippocampal neurons. Furthermore, effects on dendritic outgrowth likely require CaMKII, PKA, or PI3K signaling pathways. The observed effects may be may be due to chronic treatment with antidepressant drugs.

  2. Enhancement of morphological plasticity in hippocampal neurons by a physically modified saline via phosphatidylinositol-3 kinase.

    PubMed

    Roy, Avik; Modi, Khushbu K; Khasnavis, Saurabh; Ghosh, Supurna; Watson, Richard; Pahan, Kalipada

    2014-01-01

    Increase of the density of dendritic spines and enhancement of synaptic transmission through ionotropic glutamate receptors are important events, leading to synaptic plasticity and eventually hippocampus-dependent spatial learning and memory formation. Here we have undertaken an innovative approach to upregulate hippocampal plasticity. RNS60 is a 0.9% saline solution containing charge-stabilized nanobubbles that are generated by subjecting normal saline to Taylor-Couette-Poiseuille (TCP) flow under elevated oxygen pressure. RNS60, but not NS (normal saline), PNS60 (saline containing a comparable level of oxygen without the TCP modification), or RNS10.3 (TCP-modified normal saline without excess oxygen), stimulated morphological plasticity and synaptic transmission via NMDA- and AMPA-sensitive calcium influx in cultured mouse hippocampal neurons. Using mRNA-based targeted gene array, real-time PCR, immunoblot, and immunofluorescence analyses, we further demonstrate that RNS60 stimulated the expression of many plasticity-associated genes in cultured hippocampal neurons. Activation of type IA, but not type IB, phosphatidylinositol-3 (PI-3) kinase by RNS60 together with abrogation of RNS60-mediated upregulation of plasticity-related proteins (NR2A and GluR1) and increase in spine density, neuronal size, and calcium influx by LY294002, a specific inhibitor of PI-3 kinase, suggest that RNS60 upregulates hippocampal plasticity via activation of PI-3 kinase. Finally, in the 5XFAD transgenic model of Alzheimer's disease (AD), RNS60 treatment upregulated expression of plasticity-related proteins PSD95 and NR2A and increased AMPA- and NMDA-dependent hippocampal calcium influx. These results describe a novel property of RNS60 in stimulating hippocampal plasticity, which may help AD and other dementias.

  3. Seasonal changes in neuron numbers in the hippocampal formation of a food-hoarding bird: the black-capped chickadee.

    PubMed

    Smulders, T V; Shiflett, M W; Sperling, A J; DeVoogd, T J

    2000-09-15

    The volume of the hippocampal formation (HF) in black-capped chickadees (Poecile atricapillus) varies across the seasons, in parallel with the seasonal cycle in food hoarding. In this study, we estimate cell density and total cell number in the HF across seasons in both juveniles and adults. We find that the seasonal variation in volume is due to an increase in the number of small and large cells (principally neurons) in the fall. Adults also have lower neuron densities than juveniles. Both juveniles and adults show an increase in cell density in the rostral part of the HF in August and a subsequent decrease toward October. This suggests that the net cell addition to the HF may already start in August. We discuss the implications of this early start with respect to the possibility that the seasonal change in HF volume is driven by the experience of food hoarding. We also speculate on the functional significance of the addition of neurons to the HF in the fall.

  4. Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption.

    PubMed

    Gilbert, M E; Goodman, J H; Gomez, J; Johnstone, A F M; Ramos, R L

    2017-03-01

    The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following

  5. Synaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons.

    PubMed

    Meijer, Marieke; Cijsouw, Tony; Toonen, Ruud F; Verhage, Matthijs

    2015-01-01

    The munc18-1 gene encodes two splice-variants that vary at the C-terminus of the protein and are expressed at different levels in different regions of the adult mammalian brain. Here, we investigated the expression pattern of these splice variants within the brainstem and tested whether they are functionally different. Munc18-1a is expressed in specific nuclei of the brainstem including the LRN, VII and SOC, while Munc18-1b expression is relatively low/absent in these regions. Furthermore, Munc18-1a is the major splice variant in the Calyx of Held. Synaptic transmission was analyzed in autaptic hippocampal munc18-1 KO neurons re-expressing either Munc18-1a or Munc18-1b. The two splice variants supported synaptic transmission to a similar extent, but Munc18-1b was slightly more potent in sustaining synchronous release during high frequency stimulation. Our data suggest that alternative splicing of Munc18-1 support synaptic transmission to a similar extent, but could modulate presynaptic short-term plasticity.

  6. Synaptic Effects of Munc18-1 Alternative Splicing in Excitatory Hippocampal Neurons

    PubMed Central

    Toonen, Ruud F.; Verhage, Matthijs

    2015-01-01

    The munc18-1 gene encodes two splice-variants that vary at the C-terminus of the protein and are expressed at different levels in different regions of the adult mammalian brain. Here, we investigated the expression pattern of these splice variants within the brainstem and tested whether they are functionally different. Munc18-1a is expressed in specific nuclei of the brainstem including the LRN, VII and SOC, while Munc18-1b expression is relatively low/absent in these regions. Furthermore, Munc18-1a is the major splice variant in the Calyx of Held. Synaptic transmission was analyzed in autaptic hippocampal munc18-1 KO neurons re-expressing either Munc18-1a or Munc18-1b. The two splice variants supported synaptic transmission to a similar extent, but Munc18-1b was slightly more potent in sustaining synchronous release during high frequency stimulation. Our data suggest that alternative splicing of Munc18-1 support synaptic transmission to a similar extent, but could modulate presynaptic short-term plasticity. PMID:26407320

  7. Diazinon and diazoxon impair the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons

    SciTech Connect

    Pizzurro, Daniella M.; Dao, Khoi; Costa, Lucio G.

    2014-02-01

    Evidence from in vivo and epidemiological studies suggests that organophosphorus insecticides (OPs) are developmental neurotoxicants, but possible underlying mechanisms are still unclear. Astrocytes are increasingly recognized for their active role in normal neuronal development. This study sought to investigate whether the widely-used OP diazinon (DZ), and its oxygen metabolite diazoxon (DZO), would affect glial–neuronal interactions as a potential mechanism of developmental neurotoxicity. Specifically, we investigated the effects of DZ and DZO on the ability of astrocytes to foster neurite outgrowth in primary hippocampal neurons. The results show that both DZ and DZO adversely affect astrocyte function, resulting in inhibited neurite outgrowth in hippocampal neurons. This effect appears to be mediated by oxidative stress, as indicated by OP-induced increased reactive oxygen species production in astrocytes and prevention of neurite outgrowth inhibition by antioxidants. The concentrations of OPs were devoid of cytotoxicity, and cause limited acetylcholinesterase inhibition in astrocytes (18 and 25% for DZ and DZO, respectively). Among astrocytic neuritogenic factors, the most important one is the extracellular matrix protein fibronectin. DZ and DZO decreased levels of fibronectin in astrocytes, and this effect was also attenuated by antioxidants. Underscoring the importance of fibronectin in this context, adding exogenous fibronectin to the co-culture system successfully prevented inhibition of neurite outgrowth caused by DZ and DZO. These results indicate that DZ and DZO increase oxidative stress in astrocytes, and this in turn modulates astrocytic fibronectin, leading to impaired neurite outgrowth in hippocampal neurons. - Highlights: • DZ and DZO inhibit astrocyte-mediated neurite outgrowth in rat hippocampal neurons. • Oxidative stress is involved in inhibition of neuritogenesis by DZ and DZO. • DZ and DZO decrease expression of the neuritogenic

  8. Somatodendritic and excitatory postsynaptic distribution of neuron-type dystrophin isoform, Dp40, in hippocampal neurons

    SciTech Connect

    Fujimoto, Takahiro; Itoh, Kyoko Yaoi, Takeshi; Fushiki, Shinji

    2014-09-12

    Highlights: • Identification of dystrophin (Dp) shortest isoform, Dp40, is a neuron-type Dp. • Dp40 expression is temporally and differentially regulated in comparison to Dp71. • Somatodendritic and nuclear localization of Dp40. • Dp40 is localized to excitatory postsynapses. • Dp40 might play roles in dendritic and synaptic functions. - Abstract: The Duchenne muscular dystrophy (DMD) gene produces multiple dystrophin (Dp) products due to the presence of several promoters. We previously reported the existence of a novel short isoform of Dp, Dp40, in adult mouse brain. However, the exact biochemical expression profile and cytological distribution of the Dp40 protein remain unknown. In this study, we generated a polyclonal antibody against the NH{sub 2}-terminal region of the Dp40 and identified the expression profile of Dp40 in the mouse brain. Through an analysis using embryonic and postnatal mouse cerebrums, we found that Dp40 emerged from the early neonatal stages until adulthood, whereas Dp71, an another Dp short isoform, was highly detected in both prenatal and postnatal cerebrums. Intriguingly, relative expressions of Dp40 and Dp71 were prominent in cultured dissociated neurons and non-neuronal cells derived from mouse hippocampus, respectively. Furthermore, the immunocytological distribution of Dp40 was analyzed in dissociated cultured neurons, revealing that Dp40 is detected in the soma and its dendrites, but not in the axon. It is worthy to note that Dp40 is localized along the subplasmalemmal region of the dendritic shafts, as well as at excitatory postsynaptic sites. Thus, Dp40 was identified as a neuron-type Dp possibly involving dendritic and synaptic functions.

  9. LTP Induction Modifies Functional Relationship among Hippocampal Neurons

    ERIC Educational Resources Information Center

    Yun, Sung H.; Lee, Deok S.; Lee, Hyunjung; Baeg, Eun H.; Kim, Yun B.; Jung, Min W.

    2007-01-01

    To obtain evidence linking long-term potentiation (LTP) and memory, we examined whether LTP induction modifies functional relationship among neurons in the rat hippocampus. In contrast to neurons in low-frequency stimulated or AP5-treated slices, LTP induction altered "functional connectivity," as defined by the degree of synchronous firing, among…

  10. The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition.

    PubMed

    Morais, Mónica; Santos, Paulo A R; Mateus-Pinheiro, António; Patrício, Patrícia; Pinto, Luísa; Sousa, Nuno; Pedroso, Pedro; Almeida, Susana; Filipe, Augusto; Bessa, João M

    2014-12-01

    There is accumulating evidence that adult neurogenesis and dendritic plasticity in the hippocampus are neuroplastic phenomena, highly sensitive to the effects of chronic stress and treatment with most classes of antidepressant drugs, being involved in the onset and recovery from depression. However, the effects of antidepressants that act through the selective inhibition of monoamine oxidase subtype A (MAO-A) in these phenomena are still largely unknown. In the present study, adult neurogenesis and neuronal morphology were examined in the hippocampus of rats exposed to chronic mild stress (CMS) and treated with the selective reversible MAO-A inhibitor (RIMA) drug, pirlindole and the selective serotonin reuptake inhibitor (SSRI), fluoxetine. The results provide the first demonstration that selective MAO-A inhibition with pirlindole is able to revert the behavioural effects of stress exposure while promoting hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons.

  11. Pretreatment with apoaequorin protects hippocampal CA1 neurons from oxygen-glucose deprivation.

    PubMed

    Detert, Julia A; Adams, Erin L; Lescher, Jacob D; Lyons, Jeri-Anne; Moyer, James R

    2013-01-01

    Ischemic stroke affects ∼795,000 people each year in the U.S., which results in an estimated annual cost of $73.7 billion. Calcium is pivotal in a variety of neuronal signaling cascades, however, during ischemia, excess calcium influx can trigger excitotoxic cell death. Calcium binding proteins help neurons regulate/buffer intracellular calcium levels during ischemia. Aequorin is a calcium binding protein isolated from the jellyfish Aequorea victoria, and has been used for years as a calcium indicator, but little is known about its neuroprotective properties. The present study used an in vitro rat brain slice preparation to test the hypothesis that an intra-hippocampal infusion of apoaequorin (the calcium binding component of aequorin) protects neurons from ischemic cell death. Bilaterally cannulated rats received an apoaequorin infusion in one hemisphere and vehicle control in the other. Hippocampal slices were then prepared and subjected to 5 minutes of oxygen-glucose deprivation (OGD), and cell death was assayed by trypan blue exclusion. Apoaequorin dose-dependently protected neurons from OGD--doses of 1% and 4% (but not 0.4%) significantly decreased the number of trypan blue-labeled neurons. This effect was also time dependent, lasting up to 48 hours. This time dependent effect was paralleled by changes in cytokine and chemokine expression, indicating that apoaequorin may protect neurons via a neuroimmunomodulatory mechanism. These data support the hypothesis that pretreatment with apoaequorin protects neurons against ischemic cell death, and may be an effective neurotherapeutic.

  12. Neuronal zinc stores are modulated by non-steroidal anti-inflammatory drugs: an optical analysis in cultured hippocampal neurons.

    PubMed

    Love, Rachal; Salazar, Gloria; Faundez, Victor

    2005-11-02

    Zinc chelation and non-steroidal anti-inflammatory drugs (NSAIDs) have been explored as potential neuroprotective agents. However, it remains unknown whether NSAIDs and zinc chelation may converge on a similar cellular process. Using two-photon microscopy to observe hippocampal neurons labeled with a zinc-sensitive dye, we provide evidence that three chemically unrelated NSAIDs, niflumic acid, ibuprofen, and naproxen, acutely increase intracellular zinc stores from extracellular metal pools. Phospholipase A2 inhibitors triggered similar responses, suggesting that NSAIDs likely control zinc stores by their activity as cyclooxygenase inhibitors. These results provide evidence for a new link between cyclooxygenase metabolites and the mechanisms controlling neuronal zinc pools.

  13. Time-dependent enhancement of hippocampus-dependent memory after treatment with memantine: Implications for enhanced hippocampal adult neurogenesis.

    PubMed

    Ishikawa, Rie; Kim, Ryang; Namba, Takashi; Kohsaka, Shinichi; Uchino, Shigeo; Kida, Satoshi

    2014-07-01

    Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high-dose treatment with the N-methyl-d-aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus-dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus-dependent spatial and social recognition memories when they were trained and tested at 3-6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM-treated mice, but not saline-treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus-dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old.

  14. The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways

    PubMed Central

    2017-01-01

    Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects. PMID:28191274

  15. The Neuroprotective Effects of Carvacrol on Ethanol-Induced Hippocampal Neurons Impairment via the Antioxidative and Antiapoptotic Pathways.

    PubMed

    Wang, Peng; Luo, Qian; Qiao, Hui; Ding, Hui; Cao, Yonggang; Yu, Juan; Liu, Ruxia; Zhang, Qianlong; Zhu, Hui; Qu, Lihui

    2017-01-01

    Chronic alcohol consumption causes hippocampal neuronal impairment, which is associated with oxidative stress and apoptosis. Carvacrol is a major monoterpenic phenol found in essential oils from the family Labiatae and has antioxidative stress and antiapoptosis actions. However, the protective effects of carvacrol in ethanol-induced hippocampal neuronal impairment have not been fully understood. We explored the neuroprotective effects of carvacrol in vivo and in vitro. Male C57BL/6 mice were exposed to 35% ethanol for 4 weeks to establish ethanol model in vivo, and hippocampal neuron injury was simulated by 200 mM ethanol in vitro. Morris water maze test was performed to evaluate the cognitive dysfunction. The oxidative stress injury of hippocampal neurons was evaluated by measuring the levels of oxidative stress biomarkers. Histopathological examinations and western blot were performed to evaluate the apoptosis of neurons. The results showed that carvacrol attenuates the cognitive dysfunction, oxidative stress, and apoptosis of the mice treated with ethanol and decreases hippocampal neurons apoptosis induced by ethanol in vitro. In addition, western blot analysis revealed that carvacrol modulates the protein expression of Bcl-2, Bax, caspase-3, and p-ERK, without influence of p-JNK and p-p38. Our results suggest that carvacrol alleviates ethanol-mediated hippocampal neuronal impairment by antioxidative and antiapoptotic effects.

  16. Thrombin modulates persistent sodium current in CA1 pyramidal neurons of young and adult rat hippocampus.

    PubMed

    Lunko, O O; Isaev, D S; Krishtal, O O; Isaeva, E V

    2015-01-01

    Serine protease thrombin, a key factor of blood coagulation, participates in many neuronal processes important for normal brain functioning and during pathological conditions involving abnormal neuronal synchronization, neurodegeneration and inflammation. Our previous study on CA3 pyramidal neurons showed that application ofthrombin through the activation of specific protease-activated receptor 1 (PAR1) produces a significant hyperpolarizing shift of the activation of the TTX-sensitive persistent voltage-gated Na+ current (I(Nap)) thereby affecting membrane potential and seizure threshold at the network level. It was shown that PAR1 is also expressed in CA1 area of hippocampus and can be implicated in neuronal damage in this area after status epilepticus. The aim of the present study was to evaluate the effect of thrombin on I(NaP) in CA1 pyramidal neurons from adult and young rats. Using whole cell patch-clamp technique we demonstrate that thrombin application results in the hyperpolarization shift of I(NaP) activation as well as increase in the I(NaP) amplitude in both age groups. We have found that I(NaP) in pyramidal neurons of hippocampal CA 1 region is more vulnerable to the thrombin action than I(NaP) in pyramidal neurons of hippocampal CA3 region. We have also found that the immature hippocampus is more sensitive to thrombin action which emphasizes the contribution of thrombin-dependent pathway to the regulation of neuronal activity in immature brain.

  17. Activator protein-1 complex expressed by magnetism in cultured rat hippocampal neurons.

    PubMed

    Hirai, Takao; Nakamichi, Noritaka; Yoneda, Yukio

    2002-03-22

    Brief exposure for 15 min to static magnetic filed at 100 mT led to marked but transient potentiation of binding of a radiolabeled probe for activator protein-1 (AP1) in immature cultured rat hippocampal neurons with high expression of growth-associated protein-43. Immunoblotting and supershift analyses revealed that brief exposure to static magnetic field increased AP1 DNA binding through expression of Fra-2, c-Jun, and Jun-D proteins in immature cultured hippocampal neurons. Significantly less potent increases were seen in both intracellular free Ca(2+) concentration and AP1 binding following the addition of N-methyl-d-aspartate in these immature neurons exposed to magnetism 24 h before. These results suggest that brief exposure to weak static magnetic field may lead to desensitization of NMDA receptor channels through modulation of de novo synthesis of particular inducible target proteins at the level of gene transcription by the AP1 complex expressed in the nucleus of immature cultured rat hippocampal neurons.

  18. Regulation of dendrite growth by the Cdc42 activator Zizimin1/Dock9 in hippocampal neurons.

    PubMed

    Kuramoto, Kazuya; Negishi, Manabu; Katoh, Hironori

    2009-06-01

    Rho family small GTPases are key regulators of morphological changes in neurons. Cdc42, one of the most characterized members of the Rho family of proteins, is involved in axon and dendrite outgrowth through cytoskeletal reorganization. Recent studies have identified Zizimin1, a member of the Dock180-related family of proteins [also called CDM (Ced-5/Dock180/Myoblast city)-zizimin homology (CZH) proteins], as a specific guanine-nucleotide exchange factor (GEF) for Cdc42. However, the physiological function of Zizimin1 is totally unknown. In this study, we investigated the role of Zizimin1 in dendrite development in rat hippocampal neurons. In situ hybridization and Western blot analysis showed that Zizimin1 is strongly expressed in the developing brain including in the hippocampus and cerebral cortex in late developmental stages. Overexpression of wild-type Zizimin1 promoted dendrite growth, whereas knockdown of Zizimin1 by short hairpin RNA or expression of a mutant Zizimin1 lacking Cdc42 GEF activity suppressed dendrite growth in primary cultured rat hippocampal neurons. Both the N-terminal CZH1 domain, which is conserved among CZH proteins, and the Pleckstrin homology domain of Zizimin1 are involved in membrane localization, Cdc42 activation, and regulation of dendrite growth. Thus, these results suggest that Zizimin1 plays an important role in dendrite growth in hippocampal neurons through activation of Cdc42.

  19. Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

    PubMed Central

    Clark, Peter J.; Kohman, Rachel A.; Miller, Daniel S.; Bhattacharya, Tushar K.; Brzezinska, Weronika J.; Rhodes, Justin S.

    2011-01-01

    New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into pre-existing circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large versus small increases in neurogenesis in response to wheel running so the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. The first 10 days mice received daily injections of BrdU to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Further, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline versus exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise. PMID:21223504

  20. Hippocampal pyramidal neurons comprise two distinct cell types that are countermodulated by metabotropic receptors

    PubMed Central

    Graves, Austin R; Moore, Shannon J; Bloss, Erik B; Mensh, Brett D; Kath, William L; Spruston, Nelson

    2012-01-01

    Summary Relating the function of neuronal cell types to information processing and behavior is a central goal of neuroscience. In the hippocampus, pyramidal cells in CA1 and the subiculum process sensory and motor cues to form a cognitive map encoding spatial, contextual, and emotional information, which they transmit throughout the brain. Do these cells constitute a single class, or are there multiple cell types with specialized functions? Using unbiased cluster analysis, we show that there are two morphologically and electrophysiologically distinct principal cell types that carry hippocampal output. We show further that these two cell types are inversely modulated by the synergistic action of glutamate and acetylcholine acting on metabotropic receptors that are central to hippocampal function. Combined with prior connectivity studies, our results support a model of hippocampal processing in which the two pyramidal cell types are predominantly segregated into two parallel pathways that process distinct modalities of information. PMID:23177962

  1. Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones.

    PubMed

    Mueller, Anka D; Pollock, Michael S; Lieblich, Stephanie E; Epp, Jonathan R; Galea, Liisa A M; Mistlberger, Ralph E

    2008-05-01

    Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.

  2. Activities of visual cortical and hippocampal neurons co-fluctuate in freely moving rats during spatial behavior

    PubMed Central

    Haggerty, Daniel Christopher; Ji, Daoyun

    2015-01-01

    Visual cues exert a powerful control over hippocampal place cell activities that encode external spaces. The functional interaction of visual cortical neurons and hippocampal place cells during spatial navigation behavior has yet to be elucidated. Here we show that, like hippocampal place cells, many neurons in the primary visual cortex (V1) of freely moving rats selectively fire at specific locations as animals run repeatedly on a track. The V1 location-specific activity leads hippocampal place cell activity both spatially and temporally. The precise activities of individual V1 neurons fluctuate every time the animal travels through the track, in a correlated fashion with those of hippocampal place cells firing at overlapping locations. The results suggest the existence of visual cortical neurons that are functionally coupled with hippocampal place cells for spatial processing during natural behavior. These visual neurons may also participate in the formation and storage of hippocampal-dependent memories. DOI: http://dx.doi.org/10.7554/eLife.08902.001 PMID:26349031

  3. Novel Nuclear Protein Complexes of Dystrophin 71 Isoforms in Rat Cultured Hippocampal GABAergic and Glutamatergic Neurons.

    PubMed

    Rodríguez-Muñoz, Rafael; Cárdenas-Aguayo, María Del Carmen; Alemán, Víctor; Osorio, Beatriz; Chávez-González, Oscar; Rendon, Alvaro; Martínez-Rojas, Dalila; Meraz-Ríos, Marco Antonio

    2015-01-01

    The precise functional role of the dystrophin 71 in neurons is still elusive. Previously, we reported that dystrophin 71d and dystrophin 71f are present in nuclei from cultured neurons. In the present work, we performed a detailed analysis of the intranuclear distribution of dystrophin 71 isoforms (Dp71d and Dp71f), during the temporal course of 7-day postnatal rats hippocampal neurons culture for 1h, 2, 4, 10, 15 and 21 days in vitro (DIV). By immunofluorescence assays, we detected the highest level of nuclear expression of both dystrophin Dp71 isoforms at 10 DIV, during the temporal course of primary culture. Dp71d and Dp71f were detected mainly in bipolar GABAergic (≥60%) and multipolar Glutamatergic (≤40%) neurons, respectively. We also characterized the existence of two nuclear dystrophin-associated protein complexes (DAPC): dystrophin 71d or dystrophin 71f bound to β-dystroglycan, α1-, β-, α2-dystrobrevins, α-syntrophin, and syntrophin-associated protein nNOS (Dp71d-DAPC or Dp71f-DAPC, respectively), in the hippocampal neurons. Furthermore, both complexes were localized in interchromatin granule cluster structures (nuclear speckles) of neuronal nucleoskeleton preparations. The present study evinces that each Dp71's complexes differ slightly in dystrobrevins composition. The results demonstrated that Dp71d-DAPC was mainly localized in bipolar GABAergic and Dp71f-DAPC in multipolar Glutamatergic hippocampal neurons. Taken together, our results show that dystrophin 71d, dystrophin 71f and DAP integrate protein complexes, and both complexes were associated to nuclear speckles structures.

  4. Novel Nuclear Protein Complexes of Dystrophin 71 Isoforms in Rat Cultured Hippocampal GABAergic and Glutamatergic Neurons

    PubMed Central

    Alemán, Víctor; Osorio, Beatriz; Chávez-González, Oscar; Rendon, Alvaro; Martínez-Rojas, Dalila; Meraz-Ríos, Marco Antonio

    2015-01-01

    The precise functional role of the dystrophin 71 in neurons is still elusive. Previously, we reported that dystrophin 71d and dystrophin 71f are present in nuclei from cultured neurons. In the present work, we performed a detailed analysis of the intranuclear distribution of dystrophin 71 isoforms (Dp71d and Dp71f), during the temporal course of 7-day postnatal rats hippocampal neurons culture for 1h, 2, 4, 10, 15 and 21 days in vitro (DIV). By immunofluorescence assays, we detected the highest level of nuclear expression of both dystrophin Dp71 isoforms at 10 DIV, during the temporal course of primary culture. Dp71d and Dp71f were detected mainly in bipolar GABAergic (≥60%) and multipolar Glutamatergic (≤40%) neurons, respectively. We also characterized the existence of two nuclear dystrophin-associated protein complexes (DAPC): dystrophin 71d or dystrophin 71f bound to β-dystroglycan, α1-, β-, α2-dystrobrevins, α-syntrophin, and syntrophin-associated protein nNOS (Dp71d-DAPC or Dp71f-DAPC, respectively), in the hippocampal neurons. Furthermore, both complexes were localized in interchromatin granule cluster structures (nuclear speckles) of neuronal nucleoskeleton preparations. The present study evinces that each Dp71’s complexes differ slightly in dystrobrevins composition. The results demonstrated that Dp71d-DAPC was mainly localized in bipolar GABAergic and Dp71f-DAPC in multipolar Glutamatergic hippocampal neurons. Taken together, our results show that dystrophin 71d, dystrophin 71f and DAP integrate protein complexes, and both complexes were associated to nuclear speckles structures. PMID:26378780

  5. Mechanisms of transport and exocytosis of dense-core granules containing tissue plasminogen activator in developing hippocampal neurons.

    PubMed

    Silverman, Michael A; Johnson, Scooter; Gurkins, Dmitri; Farmer, Meredith; Lochner, Janis E; Rosa, Patrizia; Scalettar, Bethe A

    2005-03-23

    Dense-core granules (DCGs) are organelles found in specialized secretory cells, including neuroendocrine cells and neurons. Neuronal DCGs facilitate many critical processes, including the transport and secretion of proteins involved in learning, and yet their transport and exocytosis are poorly understood. We have used wide-field and total internal reflection fluorescence microscopy, in conjunction with transport theory, to visualize the transport and exocytosis of DCGs containing a tissue plasminogen activator-green fluorescent protein hybrid in cell bodies, neurites, and growth cones of developing hippocampal neurons and to quantify the roles that diffusion, directed motion, and immobility play in these processes. Our results demonstrate that shorter-ranged transport of DCGs near sites of exocytosis in hippocampal neurons and neuroendocrine cells differs markedly. Specifically, the immobile fraction of DCGs within growth cones and near the plasma membrane of hippocampal neurons is small and relatively unaltered by actin disruption, unlike in neuroendocrine cells. Moreover, transport of DCGs in these domains of hippocampal neurons is unusually heterogeneous, being significantly rapid and directed as well as slow and diffusive. Our results also demonstrate that exocytosis is preceded by substantial movement and heterogeneous transport; this movement may facilitate delivery of DCG cargo in hippocampal neurons, given the relatively low abundance of neuronal DCGs. In addition, the extensive mobility of DCGs in hippocampal neurons argues strongly against the hypothesis that cortical actin is a major barrier to membrane-proximal DCGs in these cells. Instead, our results suggest that extended release of DCG cargo from hippocampal neurons arises from heterogeneity in DCG mobility.

  6. Graph Theoretic and Motif Analyses of the Hippocampal Neuron Type Potential Connectome

    PubMed Central

    White, Charise M.; Komendantov, Alexander O.

    2016-01-01

    Abstract We computed the potential connectivity map of all known neuron types in the rodent hippocampal formation by supplementing scantly available synaptic data with spatial distributions of axons and dendrites from the open-access knowledge base Hippocampome.org. The network that results from this endeavor, the broadest and most complete for a mammalian cortical region at the neuron-type level to date, contains more than 3200 connections among 122 neuron types across six subregions. Analyses of these data using graph theory metrics unveil the fundamental architectural principles of the hippocampal circuit. Globally, we identify a highly specialized topology minimizing communication cost; a modular structure underscoring the prominence of the trisynaptic loop; a core set of neuron types serving as information-processing hubs as well as a distinct group of particular antihub neurons; a nested, two-tier rich club managing much of the network traffic; and an innate resilience to random perturbations. At the local level, we uncover the basic building blocks, or connectivity patterns, that combine to produce complex global functionality, and we benchmark their utilization in the circuit relative to random networks. Taken together, these results provide a comprehensive connectivity profile of the hippocampus, yielding novel insights on its functional operations at the computationally crucial level of neuron types. PMID:27896314

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

    PubMed

    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.

  8. Transmembrane Agrin Regulates Dendritic Filopodia and Synapse Formation in Mature Hippocampal Neuron Cultures

    PubMed Central

    McCroskery, Seumas; Bailey, Allison; Lin, Lin; Daniels, Mathew P.

    2009-01-01

    The transmembrane isoform of agrin (Tm-agrin) is the predominant form expressed in the brain but its putative roles in brain development are not well understood. Recent reports have implicated Tm-agrin in the formation and stabilization of filopodia on neurites of immature central and peripheral neurons in culture. In maturing central neurons, dendritic filopodia are believed to facilitate synapse formation. In the present study we have investigated the role of Tm-agrin in regulation of dendritic filopodia and synaptogenesis in maturing cultures of hippocampal neurons. We did this by infecting the neurons with an RNAi lentivirus to deplete endogenous agrin during the developmental period when filopodia density on the dendritic arbor was high, and synapse formation was rapid. We found that dendritic filopodia density was markedly reduced, as was synapse density along dendrites. Moreover, synapse formation was more sharply reduced on dendrites of infected neurons contacted by uninfected axons than on uninfected dendrites contacted by infected axons. The results are consistent with a physiological role for Tm-agrin in the maturation of hippocampal neurons involving positive regulation of dendritic filopodia and consequent promotion of synaptogenesis, but also suggest a role for axonal agrin in synaptogenesis. PMID:19524020

  9. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

    PubMed Central

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C. M.; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2′-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  10. Wnt-5a occludes Aβ oligomer-induced depression of glutamatergic transmission in hippocampal neurons

    PubMed Central

    2010-01-01

    Background Soluble amyloid-β (Aβ;) oligomers have been recognized to be early and key intermediates in Alzheimer's disease (AD)-related synaptic dysfunction. Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Wnt signaling plays an important role in neural development, including synaptic differentiation. Results We report here that the Wnt signaling activation prevents the synaptic damage triggered by Aβ oligomers. Electrophysiological analysis of Schaffer collaterals-CA1 glutamatergic synaptic transmission in hippocampal slices indicates that Wnt-5a increases the amplitude of field excitatory postsynaptic potentials (fEPSP) and both AMPA and NMDA components of the excitatory postsynaptic currents (EPSCs), without modifying the paired pulse facilitation (PPF). Conversely, in the presence of Aβ oligomers the fEPSP and EPSCs amplitude decreased without modification of the PPF, while the postsynaptic scaffold protein (PSD-95) decreased as well. Co-perfusion of hippocampal slices with Wnt-5a and Aβ oligomers occludes against the synaptic depression of EPSCs as well as the reduction of PSD-95 clusters induced by Aβ oligomers in neuronal cultures. Taken together these results indicate that Wnt-5a and Aβ oligomers inversely modulate postsynaptic components. Conclusion These results indicate that post-synaptic damage induced by Aβ oligomers in hippocampal neurons is prevented by non-canonical Wnt pathway activation. PMID:20205789

  11. Sleep deprivation and hippocampal vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function.

    PubMed

    Kreutzmann, J C; Havekes, R; Abel, T; Meerlo, P

    2015-11-19

    Despite the ongoing fundamental controversy about the physiological function of sleep, there is general consensus that sleep benefits neuronal plasticity, which ultimately supports brain function and cognition. In agreement with this are numerous studies showing that sleep deprivation (SD) results in learning and memory impairments. Interestingly, such impairments appear to occur particularly when these learning and memory processes require the hippocampus, suggesting that this brain region may be particularly sensitive to the consequences of sleep loss. Although the molecular mechanisms underlying sleep and memory formation remain to be investigated, available evidence suggests that SD may impair hippocampal neuronal plasticity and memory processes by attenuating intracellular cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) signaling which may lead to alterations in cAMP response element binding protein (CREB)-mediated gene transcription, neurotrophic signaling, and glutamate receptor expression. When restricted sleep becomes a chronic condition, it causes a reduction of hippocampal cell proliferation and neurogenesis, which may eventually lead to a reduction in hippocampal volume. Ultimately, by impairing hippocampal plasticity and function, chronically restricted and disrupted sleep contributes to cognitive disorders and psychiatric diseases.

  12. Hippocampal Neuron Populations Are Reduced in Vervet Monkeys With Fetal Alcohol Exposure

    PubMed Central

    Burke, Mark W; Ptito, Maurice; Ervin, Frank R; Palmour, Roberta M

    2015-01-01

    Prenatal exposure to beverage alcohol is a major cause of mild mental retardation and developmental delay. In nonendangered alcohol-preferring vervet monkeys, we modeled the most common nondysmorphic form of fetal alcohol syndrome disorder with voluntary drinking during the third trimester 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 and persist through infancy (5 months) and juvenile (2 years) stages. Although the volumes of hippocampal subdivisions in FAE animals are not atypical at birth, by age 2, they are only 65–70% of those estimated in age-matched controls. These data suggest that moderate, naturalistic alcohol consumption during late pregnancy results in a stable loss of hippocampal neurons and a progressive reduction of hippocampal volume. © 2015 The Authors. Developmental Psychobiology Published by Wiley Periodicals, Inc. Dev Psychobiol 57:470–485, 2015. PMID:25913787

  13. Conditional Reduction of Adult Born Doublecortin-Positive Neurons Reversibly Impairs Selective Behaviors

    PubMed Central

    Garrett, Lillian; Zhang, Jingzhong; Zimprich, Annemarie; Niedermeier, Kristina M.; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabě de Angelis, Martin; Vogt Weisenhorn, Daniela; Wurst, Wolfgang; Hölter, Sabine M.

    2015-01-01

    Adult neurogenesis occurs in the adult mammalian subventricular zone (SVZ) along the walls of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. While a burgeoning body of research implicates adult neurogenesis in olfactory bulb (OB)- and hippocampal-related behaviors, the precise function continues to elude. To further assess the behavioral importance of adult neurogenesis, we herein generated a novel inducible transgenic mouse model of adult neurogenesis reduction where mice with CreERT2 under doublecortin (DCX) promoter control were crossed with mice where diphtheria toxin A (DTA) was driven by the Rosa26 promoter. Activation of DTA, through the administration of tamoxifen (TAM), results in a specific reduction of DCX+ immature neurons in both the hippocampal dentate gyrus and OB. We show that the decrease of DCX+ cells causes impaired social discrimination ability in both young adult (from 3 months) and middle aged (from 10 months) mice. Furthermore, these animals showed an age-independent altered coping behavior in the Forced Swim Test without clear changes in anxiety-related behavior. Notably, these behavior changes were reversible on repopulating the neurogenic zones with DCX+ cells on cessation of the TAM treatment, demonstrating the specificity of this effect. Overall, these results support the notion that adult neurogenesis plays a role in social memory and in stress coping but not necessarily in anxiety-related behavior. PMID:26617501

  14. Conditional Reduction of Adult Born Doublecortin-Positive Neurons Reversibly Impairs Selective Behaviors.

    PubMed

    Garrett, Lillian; Zhang, Jingzhong; Zimprich, Annemarie; Niedermeier, Kristina M; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabě de Angelis, Martin; Vogt Weisenhorn, Daniela; Wurst, Wolfgang; Hölter, Sabine M

    2015-01-01

    Adult neurogenesis occurs in the adult mammalian subventricular zone (SVZ) along the walls of the lateral ventricles and the subgranular zone (SGZ) of the hippocampal dentate gyrus. While a burgeoning body of research implicates adult neurogenesis in olfactory bulb (OB)- and hippocampal-related behaviors, the precise function continues to elude. To further assess the behavioral importance of adult neurogenesis, we herein generated a novel inducible transgenic mouse model of adult neurogenesis reduction where mice with CreER(T2) under doublecortin (DCX) promoter control were crossed with mice where diphtheria toxin A (DTA) was driven by the Rosa26 promoter. Activation of DTA, through the administration of tamoxifen (TAM), results in a specific reduction of DCX+ immature neurons in both the hippocampal dentate gyrus and OB. We show that the decrease of DCX+ cells causes impaired social discrimination ability in both young adult (from 3 months) and middle aged (from 10 months) mice. Furthermore, these animals showed an age-independent altered coping behavior in the Forced Swim Test without clear changes in anxiety-related behavior. Notably, these behavior changes were reversible on repopulating the neurogenic zones with DCX+ cells on cessation of the TAM treatment, demonstrating the specificity of this effect. Overall, these results support the notion that adult neurogenesis plays a role in social memory and in stress coping but not necessarily in anxiety-related behavior.

  15. Rat Hippocampal Neurons Express Genes for Both Rod Retinal and Olfactory Cyclic Nucleotide-Gated Channels: Novel Targets for cAMP/cGMP Function

    NASA Astrophysics Data System (ADS)

    Kingston, Paul A.; Zufall, Frank; Barnstable, Colin J.

    1996-09-01

    Cyclic nucleotide-gated (CNG) channels are Ca2+-permeable, nonspecific cation channels that can be activated through direct interaction with cAMP and/or cGMP. Recent electrophysiological evidence for these channels in cultured hippocampal neurons prompted us to investigate the expression of CNG channel genes in hippocampus. PCR amplification detected the expression of transcripts for subunit 1 of both the rod photoreceptor (RCNGC1) and the olfactory receptor cell (OCNGC1) subtype of CNG channel in adult rat hippocampus. In situ hybridization detected expression of both channel subtypes in most principal neurons, including pyramidal cells of the CA1 through CA3 regions and granule cells of the dentate gyrus. From the hybridization patterns, we conclude that the two genes are colocalized in individual neurons. Comparison of the patterns of expression of type 1 cGMP-dependent protein kinase and the CNG channels suggests that hippocampal neurons can respond to changes in cGMP levels with both rapid changes in CNG channel activity and slower changes induced by phosphorylation. Future models of hippocampal function should include CNG channels and their effects on both electrical responses and intracellular Ca2+ levels.

  16. Neuronal nicotinic acetylcholine receptor activation modulates gamma-aminobutyric acid release from CA1 neurons of rat hippocampal slices.

    PubMed

    Alkondon, M; Pereira, E F; Barbosa, C T; Albuquerque, E X

    1997-12-01

    In the present study we investigated electrophysiologically the nicotinic responses of pyramidal neurons and interneurons visualized by infrared-assisted videomicroscopy and fluorescence in the CA1 field of hippocampal slices obtained from 8- to 24-day-old rats. Application of nicotinic agonists to CA1 neurons evoked at least four types of nicotinic responses. Of major interest was the ability of these agonists to induce the release of gamma-aminobutyric acid (GABA) from interneurons. Slowly decaying ACh whole-cell currents and GABA-mediated postsynaptic currents could be recorded from pyramidal neurons and interneurons, whereas fast-decaying nicotinic currents and fast current transients were recorded only from interneurons. Nicotinic responses were sensitive to blockade by d-tubocurarine (10 microM), which indicated that they were mediated by nicotinic acetylcholine receptors (nAChRs). The slowly decaying currents, the postsynaptic currents and the fast current transients were insensitive to blockade by the alpha-7 nAChR-specific antagonist methyllycaconitine (up to 1 microM) or alpha-bungarotoxin (100 nM). On the other hand, the slowly decaying nicotinic currents recorded from the interneurons were blocked by the alpha4beta2 nAChR-specific antagonist dihydro-beta-erythroidine, and the fast-desensitizing nicotinic currents were evoked by the alpha-7 nAChR-specific agonist choline. In experimental conditions similar to those used to record nicotinic responses from neurons in slice (i. e., in the absence of tetrodotoxin), we observed that nicotinic agonists can also induce the release of GABA from hippocampal neurons in culture. In summary, these results provide direct evidence for more than one subtype of functional nAChR in CA1 neurons and suggest that activation of nAChRs present in GABAergic interneurons can evoke inhibitory activity in CA1 pyramidal neurons, thereby modulating processing of information in the hippocampus.

  17. Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons and causes cognitive deficits

    PubMed Central

    Zamboni, Valentina; Armentano, Maria; Sarò, Gabriella; Ciraolo, Elisa; Ghigo, Alessandra; Germena, Giulia; Umbach, Alessandro; Valnegri, Pamela; Passafaro, Maria; Carabelli, Valentina; Gavello, Daniela; Bianchi, Veronica; D’Adamo, Patrizia; de Curtis, Ivan; El-Assawi, Nadia; Mauro, Alessandro; Priano, Lorenzo; Ferri, Nicola; Hirsch, Emilio; Merlo, Giorgio R.

    2016-01-01

    During brain development, the small GTPases Rac1/Rac3 play key roles in neuronal migration, neuritogenesis, synaptic formation and plasticity, via control of actin cytoskeleton dynamic. Their activity is positively and negatively regulated by GEFs and GAPs molecules, respectively. However their in vivo roles are poorly known. The ArhGAP15 gene, coding for a Rac-specific GAP protein, is expressed in both excitatory and inhibitory neurons of the adult hippocampus, and its loss results in the hyperactivation of Rac1/Rac3. In the CA3 and dentate gyrus (DG) regions of the ArhGAP15 mutant hippocampus the CR+, PV+ and SST+ inhibitory neurons are reduced in number, due to reduced efficiency and directionality of their migration, while pyramidal neurons are unaffected. Loss of ArhGAP15 alters neuritogenesis and the balance between excitatory and inhibitory synapses, with a net functional result consisting in increased spike frequency and bursts, accompanied by poor synchronization. Thus, the loss of ArhGAP15 mainly impacts on interneuron-dependent inhibition. Adult ArhGAP15−/− mice showed defective hippocampus-dependent functions such as working and associative memories. These findings indicate that a normal architecture and function of hippocampal inhibitory neurons is essential for higher hippocampal functions, and is exquisitely sensitive to ArhGAP15-dependent modulation of Rac1/Rac3. PMID:27713499

  18. Disruption of ArhGAP15 results in hyperactive Rac1, affects the architecture and function of hippocampal inhibitory neurons and causes cognitive deficits.

    PubMed

    Zamboni, Valentina; Armentano, Maria; Sarò, Gabriella; Ciraolo, Elisa; Ghigo, Alessandra; Germena, Giulia; Umbach, Alessandro; Valnegri, Pamela; Passafaro, Maria; Carabelli, Valentina; Gavello, Daniela; Bianchi, Veronica; D'Adamo, Patrizia; de Curtis, Ivan; El-Assawi, Nadia; Mauro, Alessandro; Priano, Lorenzo; Ferri, Nicola; Hirsch, Emilio; Merlo, Giorgio R

    2016-10-07

    During brain development, the small GTPases Rac1/Rac3 play key roles in neuronal migration, neuritogenesis, synaptic formation and plasticity, via control of actin cytoskeleton dynamic. Their activity is positively and negatively regulated by GEFs and GAPs molecules, respectively. However their in vivo roles are poorly known. The ArhGAP15 gene, coding for a Rac-specific GAP protein, is expressed in both excitatory and inhibitory neurons of the adult hippocampus, and its loss results in the hyperactivation of Rac1/Rac3. In the CA3 and dentate gyrus (DG) regions of the ArhGAP15 mutant hippocampus the CR+, PV+ and SST+ inhibitory neurons are reduced in number, due to reduced efficiency and directionality of their migration, while pyramidal neurons are unaffected. Loss of ArhGAP15 alters neuritogenesis and the balance between excitatory and inhibitory synapses, with a net functional result consisting in increased spike frequency and bursts, accompanied by poor synchronization. Thus, the loss of ArhGAP15 mainly impacts on interneuron-dependent inhibition. Adult ArhGAP15(-/-) mice showed defective hippocampus-dependent functions such as working and associative memories. These findings indicate that a normal architecture and function of hippocampal inhibitory neurons is essential for higher hippocampal functions, and is exquisitely sensitive to ArhGAP15-dependent modulation of Rac1/Rac3.

  19. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis.

    PubMed

    Garthe, Alexander; Roeder, Ingo; Kempermann, Gerd

    2016-02-01

    We here show that living in a stimulus-rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss-of-function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals' behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro-neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end-point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences.

  20. Correlation of hippocampal theta rhythm with changes in cutaneous temperature. [evoked neuron response in thermoregulation

    NASA Technical Reports Server (NTRS)

    Horowitz, J. M.; Saleh, M. A.; Karem, R. D.

    1974-01-01

    A possible role for the hippocampus in alerting an animal to changes in cutaneous temperature was examined. Following local warming or cooling of the ears of unanesthetized, loosely restrained rabbits, theta waves (4-7 Hz EEG waves) were recorded from electrodes straddling the hippocampus. The onset of the hippocampal theta rhythm was correlated with changes in cutaneous temperature, an observation consistent with studies indicating that the theta rhythm is a nonspecific response evoked by stimulation of several sensory modalities. Additional data from cats and rabbits were correlated with specific neurons within the hippocampus, namely pyramidal cells. Post stimulus time histograms obtained by excitation of the dorsal fornix were interpreted in terms of excitatory and inhibitory inputs to pyramidal cells. Thus, the theta rhythm, which appears to be evoked by changes in cutaneous temperature, can be related to a specific type of hippocampal neuron which is in turn connected with other areas of the brain involved in temperature regulation.

  1. Robust conjunctive item-place coding by hippocampal neurons parallels learning what happens where

    PubMed Central

    Komorowski, Robert W.; Manns, Joseph R.; Eichenbaum, Howard

    2009-01-01

    Previous research indicates a critical role of the hippocampus in memory for events in the context in which they occur. However, studies to date have not provided compelling evidence that hippocampal neurons encode event-context conjunctions directly associated with this kind of learning. Here we report that, as animals learn different meanings for items in distinct contexts, individual hippocampal neurons develop responses to specific stimuli in the places where they have differential significance. Furthermore, this conjunctive coding evolves in the form of enhanced item-specific responses within a subset of the pre-existing spatial representation. These findings support the view that conjunctive representations in the hippocampus underlie the acquisition of context specific memories. PMID:19657042

  2. Chronic exposure to alcohol alters network activity and morphology of cultured hippocampal neurons.

    PubMed

    Korkotian, Eduard; Botalova, Alena; Odegova, Tatiana; Segal, Menahem

    2015-03-01

    The effects of chronic exposure to moderate concentrations of ethanol were studied in cultured hippocampal neurons. Network activity, assessed by imaging of [Ca(2+)]i variations, was markedly suppressed following 5 days of exposure to 0.25-1% ethanol. The reduced activity was sustained following extensive washout of ethanol, but the activity recovered by blockade of inhibition with bicuculline. This reduction of network activity was associated with a reduction in rates of mEPSCs, but not in a change in inhibitory synaptic activity. Chronic exposure to ethanol caused a significant reduction in the density of mature dendritic spines, without an effect on dendritic length or arborization. These results indicate that chronic exposure to ethanol causes a reduction in excitatory network drive in hippocampal neurons adding another dimension to the chronic effects of alcohol abuse.

  3. The Nuclear Receptor REV-ERBα Regulates Fabp7 and Modulates Adult Hippocampal Neurogenesis

    PubMed Central

    Schnell, Anna; Chappuis, Sylvie; Schmutz, Isabelle; Brai, Emanuele; Ripperger, Jürgen A.; Schaad, Olivier; Welzl, Hans; Descombes, Patrick; Alberi, Lavinia; Albrecht, Urs

    2014-01-01

    The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer. PMID:24932636

  4. Dendritic remodeling of hippocampal neurons is associated with altered NMDA receptor expression in alcohol dependent rats

    PubMed Central

    Staples, Miranda C.; Kim, Airee; Mandyam, Chitra D.

    2015-01-01

    Prolonged alcohol exposure has been previously shown to impair the structure and function of the hippocampus, although the underlying structural and biochemical alterations contributing to these deleterious effects are unclear. Also unclear is whether these changes persist into prolonged periods of abstinence. Previous work from our lab utilizing a clinically relevant rodent model of alcohol consumption demonstrated that alcohol dependence (induced by chronic intermittent ethanol vapor exposure or CIE) decreases proliferation and survival of neural stem cells in the hippocampal subgranular zone and hippocampal neurogenesis in the dentate gyrus, implicating this region of the cortex as particularly sensitive to the toxic effects of prolonged ethanol exposure. For this study, we investigated seven weeks of CIE-induced morphological changes (dendritic complexity and dendritic spine density) of dentate gyrus (DG) granule cell neurons, CA3, and CA1 pyramidal neurons and the associated alterations in biochemical markers of synaptic plasticity and toxicity (NMDA receptors and PSD-95) in the hippocampus in ethanol-experienced Wistar rats 3h (CIE) and 21 days (protracted abstinence) after the last ethanol vapor exposure. CIE reduced dendritic arborization of DG neurons and this effect persisted into protracted abstinence. CIE enhanced dendritic arborization of pyramidal neurons and this effect did not persist into protracted abstinence. The architectural changes in dendrites did not correlate with alterations in dendritic spine density, however, they were associated with increases in the expression of pNR2B, total NR2B, and total NR2A immediately following CIE with expression levels returning to control levels in prolonged abstinence. Overall, these data provide the evidence that CIE produces profound changes in hippocampal structural plasticity and in molecular tools that maintain hippocampal structural plasticity, and these alterations may underlie cognitive dysfunction

  5. Distinct electrophysiological properties of glutamatergic, cholinergic and GABAergic rat septohippocampal neurons: novel implications for hippocampal rhythmicity

    PubMed Central

    Sotty, F; Danik, M; Manseau, F; Laplante, F; Quirion, R; Williams, S

    2003-01-01

    The medial septum-diagonal band complex (MSDB) contains cholinergic and non-cholinergic neurons known to play key roles in learning and memory processing, and in the generation of hippocampal theta rhythm. Electrophysiologically, several classes of neurons have been described in the MSDB, but their chemical identity remains to be fully established. By combining electrophysiology with single-cell RT-PCR, we have identified four classes of neurons in the MSDB in vitro. The first class displayed slow-firing and little or no Ih, and expressed choline acetyl-transferase mRNA (ChAT). The second class was fast-firing, had a substantial Ih and expressed glutamic acid decarboxylase 67 mRNA (GAD67), sometimes co-localized with ChAT mRNAs. A third class exhibited fast- and burst-firing, had an important Ih and expressed GAD67 mRNA also occasionally co-localized with ChAT mRNAs. The ionic mechanism underlying the bursts involved a low-threshold spike and a prominent Ih current, conductances often associated with pacemaker activity. Interestingly, we identified a fourth class that expressed transcripts solely for one or two of the vesicular glutamate transporters (VGLUT1 and VGLUT2), but not ChAT or GAD. Some putative glutamatergic neurons displayed electrophysiological properties similar to ChAT-positive slow-firing neurons such as the occurrence of a very small Ih, but nearly half of glutamatergic neurons exhibited cluster firing with intrinsically generated voltage-dependent subthreshold membrane oscillations. Neurons belonging to each of the four described classes were found among septohippocampal neurons by retrograde labelling. We provide results suggesting that slow-firing cholinergic, fast-firing and burst-firing GABAergic, and cluster-firing glutamatergic neurons, may each uniquely contribute to hippocampal rhythmicity in vivo. PMID:12865506

  6. Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus

    PubMed Central

    Groves, Natalie J.; Bradford, DanaKai; Sullivan, Robert K. P.; Conn, Kyna-Anne; Aljelaify, Rasha Fahad; McGrath, John J.; Burne, Thomas H. J.

    2016-01-01

    Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2’-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis. PMID:27043014

  7. Behavioural Effects of Adult Vitamin D Deficiency in BALB/c Mice Are not Associated with Proliferation or Survival of Neurons in the Adult Hippocampus.

    PubMed

    Groves, Natalie J; Bradford, DanaKai; Sullivan, Robert K P; Conn, Kyna-Anne; Aljelaify, Rasha Fahad; McGrath, John J; Burne, Thomas H J

    2016-01-01

    Epidemiological studies have shown that up to one third of adults have insufficient levels of vitamin D and there is an association between low vitamin D concentrations and adverse brain outcomes, such as depression. Vitamin D has been shown to be involved in processes associated with neurogenesis during development. Therefore, the aim of this study was to test the hypothesis that adult vitamin D (AVD) deficiency in BALB/c mice was associated with (a) adult hippocampal neurogenesis at baseline, b) following 6 weeks of voluntary wheel running and (c) a depressive-like phenotype on the forced swim test (FST), which may be linked to alterations in hippocampal neurogenesis. We assessed proliferation and survival of adult born hippocampal neurons by counting the number of cells positive for Ki67 and doublecortin (DCX), and incorporation of 5-Bromo-2'-Deoxyuridine (BrdU) within newly born mature neurons using immunohistochemistry. There were no significant effects of diet on number of Ki67+, DCX+ or BrdU+ cells in the dentate gyrus. All mice showed significantly increased number of Ki67+ cells and BrdU incorporation, and decreased immobility time in the FST, after voluntary wheel running. A significant correlation was found in control mice between immobility time in the FST and level of hippocampal neurogenesis, however, no such correlation was found for AVD-deficient mice. We conclude that AVD deficiency was not associated with impaired proliferation or survival of adult born neurons in BALB/c mice and that the impact on rodent behaviour may not be due to altered neurogenesis per se, but to altered function of new hippocampal neurons or processes independent of adult neurogenesis.

  8. Inositol hexakisphosphate suppresses excitatory neurotransmission via synaptotagmin-1 C2B domain in the hippocampal neuron.

    PubMed

    Yang, Shao-Nian; Shi, Yue; Yang, Guang; Li, Yuxin; Yu, Lina; Shin, Ok-Ho; Bacaj, Taulant; Südhof, Thomas C; Yu, Jia; Berggren, Per-Olof

    2012-07-24

    Inositol hexakisphosphate (InsP(6)) levels rise and fall with neuronal excitation and silence, respectively, in the hippocampus, suggesting potential signaling functions of this inositol polyphosphate in hippocampal neurons. We now demonstrate that intracellular application of InsP(6) caused a concentration-dependent inhibition of autaptic excitatory postsynaptic currents (EPSCs) in cultured hippocampal neurons. The treatment did not alter the size and replenishment rate of the readily releasable pool in autaptic neurons. Intracellular exposure to InsP(6) did not affect spontaneous EPSCs or excitatory amino acid-activated currents in neurons lacking autapses. The InsP(6)-induced inhibition of autaptic EPSCs was effectively abolished by coapplication of an antibody to synaptotagmin-1 C2B domain. Importantly, preabsorption of the antibody with a GST-WT synaptotagmin-1 C2B domain fragment but not with a GST-mutant synaptotagmin-1 C2B domain fragment that poorly reacted with the antibody impaired the activity of the antibody on the InsP(6)-induced inhibition of autaptic EPSCs. Furthermore, K(+) depolarization significantly elevated endogenous levels of InsP(6) and occluded the inhibition of autaptic EPSCs by exogenous InsP(6). These data reveal that InsP(6) suppresses excitatory neurotransmission via inhibition of the presynaptic synaptotagmin-1 C2B domain-mediated fusion via an interaction with the synaptotagmin Ca(2+)-binding sites rather than via interference with presynaptic Ca(2+) levels, synaptic vesicle trafficking, or inactivation of postsynaptic ionotropic glutamate receptors. Therefore, elevated InsP(6) in activated neurons serves as a unique negative feedback signal to control hippocampal excitatory neurotransmission.

  9. Large-scale phenotyping links adult hippocampal neurogenesis to the reaction to novelty.

    PubMed

    van Dijk, R Maarten; Lazic, Stanley E; Slomianka, Lutz; Wolfer, David P; Amrein, Irmgard

    2016-05-01

    The discovery of adult-born neurons in the hippocampus has triggered a wide range of studies that link the new neurons to various behavioral functions. However, the role of new neurons in behavior is still equivocal. Conflicting results may be due to the difficulty in manipulating neurogenesis without off-target effects as well as the statistical approach used, which fail to account for neurogenesis-independent effects of experimental manipulations on behavior. In this study, we apply a more comprehensive statistical and conceptual approach. Instead of between-group analyses, we consider the within-group relationships between neurogenesis and behavior (ANCOVA and mediation analysis) in a large-scale experiment, in which distinct age- (3 and 5 months) and strain- (DBA and C57) related differences in basal levels of neurogenesis in mice are compared with a large number (∼1,500) of behavioral read outs. The analysis failed to detect any association between anxiety and motor impulsivity with neurogenesis. However, within-group adult hippocampal neurogenesis is associated with the reaction to novelty. Specifically, more neurogenesis is associated with a longer latency to explore and a lower frequency of exploratory actions, overall indicative of a phenotype where animals with more neurogenesis were slower to explore a novel environment. This effect is observed in 5-months-old, but not in 3-months-old mice of both strains. An association between the reaction to novelty and adult neurogenesis can have a major impact on results from previous studies using classical behavioral experiments, in which animals are tested in a--for the animal--novel experimental set-up. The neurogenesis-novelty association found here is also a necessary link in the relation that has been suggested to exist between neurogenesis and psychiatric disorders marked by a failure to cope with novelty.

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

    PubMed Central

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

    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. PMID:25767499

  11. Maternal creatine supplementation affects the morpho-functional development of hippocampal neurons in rat offspring.

    PubMed

    Sartini, S; Lattanzi, D; Ambrogini, P; Di Palma, M; Galati, C; Savelli, D; Polidori, E; Calcabrini, C; Rocchi, M B L; Sestili, P; Cuppini, R

    2016-01-15

    Creatine supplementation has been shown to protect neurons from oxidative damage due to its antioxidant and ergogenic functions. These features have led to the hypothesis of creatine supplementation use during pregnancy as prophylactic treatment to prevent CNS damage, such as hypoxic-ischemic encephalopathy. Unfortunately, very little is known on the effects of creatine supplementation during neuron differentiation, while in vitro studies revealed an influence on neuron excitability, leaving the possibility of creatine supplementation during the CNS development an open question. Using a multiple approach, we studied the hippocampal neuron morphological and functional development in neonatal rats born by dams supplemented with 1% creatine in drinking water during pregnancy. CA1 pyramidal neurons of supplemented newborn rats showed enhanced dendritic tree development, increased LTP maintenance, larger evoked-synaptic responses, and higher intrinsic excitability in comparison to controls. Moreover, a faster repolarizing phase of action potential with the appearance of a hyperpolarization were recorded in neurons of the creatine-treated group. Consistently, CA1 neurons of creatine exposed pups exhibited a higher maximum firing frequency than controls. In summary, we found that creatine supplementation during pregnancy positively affects morphological and electrophysiological development of CA1 neurons in offspring rats, increasing neuronal excitability. Altogether, these findings emphasize the need to evaluate the benefits and the safety of maternal intake of creatine in humans.

  12. Soluble cpg15 from Astrocytes Ameliorates Neurite Outgrowth Recovery of Hippocampal Neurons after Mouse Cerebral Ischemia.

    PubMed

    Zhao, Jing-Jing; Hu, Jie-Xian; Lu, De-Xin; Ji, Chun-Xia; Qi, Yao; Liu, Xiao-Yan; Sun, Feng-Yan; Huang, Fang; Xu, Ping; Chen, Xian-Hua

    2017-02-08

    The present study focuses on the function of cpg15, a neurotrophic factor, in ischemic neuronal recovery using transient global cerebral ischemic (TGI) mouse model and oxygen-glucose deprivation (OGD)-treated primary cultured cells. The results showed that expression of cpg15 proteins in astrocytes, predominantly the soluble form, was significantly increased in mouse hippocampus after TGI and in the cultured astrocytes after OGD. Addition of the medium from the cpg15-overexpressed astrocytic culture into the OGD-treated hippocampal neuronal cultures reduces the neuronal injury, whereas the recovery of neurite outgrowths of OGD-injured neurons was prevented when cpg15 in the OGD-treated astrocytes was knocked down, or the OGD-treated-astrocytic medium was immunoadsorbed by cpg15 antibody. Furthermore, lentivirus-delivered knockdown of cpg15 expression in mouse hippocampal astrocytes diminishes the dendritic branches and exacerbates injury of neurons in CA1 region after TGI. In addition, treatment with inhibitors of MEK1/2, PI3K, and TrkA decreases, whereas overexpression of p-CREB, but not dp-CREB, increases the expression of cpg15 in U118 or primary cultured astrocytes. Also, it is observed that the Flag-tagged soluble cpg15 from the astrocytes transfected with Flag-tagged cpg15-expressing plasmids adheres to the surface of neuronal bodies and the neurites. In conclusion, our results suggest that the soluble cpg15 from astrocytes induced by ischemia could ameliorate the recovery of the ischemic-injured hippocampal neurons via adhering to the surface of neurons. The upregulated expression of cpg15 in astrocytes may be activated via MAPK and PI3K signal pathways, and regulation of CREB phosphorylation.SIGNIFICANCE STATEMENT Neuronal plasticity plays a crucial role in the amelioration of neurological recovery of ischemic injured brain, which remains a challenge for clinic treatment of cerebral ischemia. cpg15 as a synaptic plasticity-related factor may participate in

  13. Odours stimulate neuronal activity in the dorsolateral area of the hippocampal formation during path integration

    PubMed Central

    Jorge, P. E.; Phillips, J. B.; Gonçalves, A.; Marques, P. A. M.; Nĕmec, P.

    2014-01-01

    The dorsolateral area of the hippocampal formation of birds is commonly assumed to play a central role in processing information needed for geographical positioning and homing. Previous work has interpreted odour-induced activity in this region as evidence for an ‘olfactory map’. Here, we show, using c-Fos expression as a marker, that neuronal activation in the dorsolateral area of the hippocampal formation of pigeons is primarily a response to odour novelty, not to the spatial distribution of odour sources that would be necessary for an olfactory map. Pigeons exposed to odours had significantly more neurons activated in this area of the brain than pigeons exposed to filtered air with odours removed. This increased activity was observed only in response to unfamiliar odours. No change in activity was observed when pigeons were exposed to home odours. These findings are consistent with non-home odours activating non-olfactory components of the pigeon's navigation system. The pattern of neuronal activation in the triangular and dorsomedial areas of the hippocampal formation was, by contrast, consistent with the possibility that odours play a role in providing spatial information. PMID:24671977

  14. Odours stimulate neuronal activity in the dorsolateral area of the hippocampal formation during path integration.

    PubMed

    Jorge, P E; Phillips, J B; Gonçalves, A; Marques, P A M; Nĕmec, P

    2014-05-22

    The dorsolateral area of the hippocampal formation of birds is commonly assumed to play a central role in processing information needed for geographical positioning and homing. Previous work has interpreted odour-induced activity in this region as evidence for an 'olfactory map'. Here, we show, using c-Fos expression as a marker, that neuronal activation in the dorsolateral area of the hippocampal formation of pigeons is primarily a response to odour novelty, not to the spatial distribution of odour sources that would be necessary for an olfactory map. Pigeons exposed to odours had significantly more neurons activated in this area of the brain than pigeons exposed to filtered air with odours removed. This increased activity was observed only in response to unfamiliar odours. No change in activity was observed when pigeons were exposed to home odours. These findings are consistent with non-home odours activating non-olfactory components of the pigeon's navigation system. The pattern of neuronal activation in the triangular and dorsomedial areas of the hippocampal formation was, by contrast, consistent with the possibility that odours play a role in providing spatial information.

  15. Dietary cholesterol concentration affects synaptic plasticity and dendrite spine morphology of rabbit hippocampal neurons.

    PubMed

    Wang, Desheng; Zheng, Wen

    2015-10-05

    Previous studies have shown dietary cholesterol can enhance learning but retard memory which may be partly due to increased cholesterol levels in hippocampus and reduced afterhyperpolarization (AHP) amplitude of hippocampal CA1 neurons. This study explored the dose-dependent effect of dietary cholesterol on synaptic plasticity of rabbit hippocampal CA1 neurons and spine morphology, the postsynaptic structures responsible for synaptic plasticity. Field potential recordings revealed a low concentration of dietary cholesterol increased long-term potentiation (LTP) expression while high concentrations produced a pronounced reduction in LTP expression. Dietary cholesterol facilitated basal synaptic transmission but did not influence presynaptic function. DiI staining showed dietary cholesterol induced alterations in dendrite spine morphology characterized by increased mushroom spine density and decreased thin spine density, two kinds of dendritic spines that may be linked to memory consolidation and learning acquisition. Dietary cholesterol also modulated the geometric measures of mushroom spines. Therefore, dietary cholesterol dose-dependently modulated both synaptic plasticity and dendrite spine morphologies of hippocampal CA1 neurons that could mediate learning and memory changes previously seen to result from feeding a cholesterol diet.

  16. New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats.

    PubMed

    Soumier, Amelie; Carter, Rayna M; Schoenfeld, Timothy J; Cameron, Heather A

    2016-01-01

    Virtually all antidepressant agents increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours, far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, and BrdU, respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally mature young granule neurons within 2 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis.

  17. New Hippocampal Neurons Mature Rapidly in Response to Ketamine But Are Not Required for Its Acute Antidepressant Effects on Neophagia in Rats123

    PubMed Central

    Soumier, Amelie; Carter, Rayna M.; Schoenfeld, Timothy J.

    2016-01-01

    Abstract Virtually all antidepressant agents increase the birth of granule neurons in the adult dentate gyrus in rodents, providing a key basis for the neurogenesis hypothesis of antidepressant action. The novel antidepressant ketamine, however, shows antidepressant activity in humans within hours, far too rapid for a mechanism involving neuronal birth. Ketamine could potentially act more rapidly by enhancing maturation of new neurons born weeks earlier. To test this possibility, we assessed the effects of S-ketamine (S-(+)-ketamine hydrochloride) injection on maturation, as well as birth and survival, of new dentate gyrus granule neurons in rats, using the immediate-early gene zif268, proliferating cell nuclear antigen, and BrdU, respectively. We show that S-ketamine has rapid effects on new neurons, increasing the proportion of functionally mature young granule neurons within 2 h. A single injection of S-ketamine also increased cell proliferation and functional maturation, and decreased depressive-like behavior, for at least 4 weeks in rats treated with long-term corticosterone administration (a depression model) and controls. However, the behavioral effects of S-ketamine on neophagia were unaffected by elimination of adult neurogenesis. Together, these results indicate that ketamine has surprisingly rapid and long-lasting effects on the recruitment of young neurons into hippocampal networks, but that ketamine has antidepressant-like effects that are independent of adult neurogenesis. PMID:27066531

  18. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons.

    PubMed

    Hoffman, D A; Magee, J C; Colbert, C M; Johnston, D

    1997-06-26

    Pyramidal neurons receive tens of thousands of synaptic inputs on their dendrites. The dendrites dynamically alter the strengths of these synapses and coordinate them to produce an output in ways that are not well understood. Surprisingly, there turns out to be a very high density of transient A-type potassium ion channels in dendrites of hippocampal CA1 pyramidal neurons. These channels prevent initiation of an action potential in the dendrites, limit the back-propagation of action potentials into the dendrites, and reduce excitatory synaptic events. The channels act to prevent large, rapid dendritic depolarizations, thereby regulating orthograde and retrograde propagation of dendritic potentials.

  19. Effect of enteropeptidase on survival of cultured hippocampal neurons under conditions of glutamate toxicity.

    PubMed

    Makarova, A M; Gorbacheva, L R; Savinkova, I V; Mikhailova, A G; Rumsh, L D; Pinelis, V G; Strukova, S M

    2010-09-01

    The effects of full-size bovine enteropeptidase (BEK) and of human recombinant light chain enteropeptidase (L-HEP) on survival of cultured hippocampal neurons were studied under conditions of glutamate excitotoxicity. Low concentrations of L-HEP or BEK (0.1-1 and 0.1-0.5 nM, respectively) protected hippocampal neurons against the death caused by 100 µM glutamate. Using the PAR1 (proteinase-activated receptor) antagonist SCH 79797, we revealed a PAR1-dependent mechanism of neuroprotective action of low concentrations of enteropeptidase. The protective effect of full-size enteropeptidase was not observed at the concentrations of 1 and 10 nM; moreover, 10 nM of BEK caused death of 88.9% of the neurons, which significantly exceeded the cell death caused by glutamate (31.9%). Under conditions of glutamate cytotoxicity the survival of neurons was 26.8% higher even in the presence of 10 nM of L-HEP than in the presence of 10 nM BEK. Pretreatment of cells with 10 nM of either form of enteropeptidase abolished the protective effect of 10 nM thrombin under glutamate cytotoxicity. High concentrations of BEK and L-HEP caused the death of neurons mainly through necrosis.

  20. Comparative Effects of Heterologous TRPV1 and TRPM8 Expression in Rat Hippocampal Neurons

    PubMed Central

    Crawford, Devon C.; Moulder, Krista L.; Gereau, Robert W.; Story, Gina M.; Mennerick, Steven

    2009-01-01

    Heterologous channel expression can be used to control activity in select neuronal populations, thus expanding the tools available to modern neuroscience. However, the secondary effects of exogenous channel expression are often left unexplored. We expressed two transient receptor potential (TRP) channel family members, TRPV1 and TRPM8, in cultured hippocampal neurons. We compared functional expression levels and secondary effects of channel expression and activation on neuronal survival and signaling. We found that activation of both channels with appropriate agonist caused large depolarizing currents in voltage-clamped hippocampal neurons, exceeding the amplitude responses to a calibrating 30 mM KCl stimulation. Both TRPV1 and TRPM8 currents were reduced but not eliminated by 4 hr incubation in saturating agonist concentration. In the case of TRPV1, but not TRPM8, prolonged agonist exposure caused strong calcium-dependent toxicity. In addition, TRPV1 expression depressed synaptic transmission dramatically without overt signs of toxicity, possibly due to low-level TRPV1 activation in the absence of exogenous agonist application. Despite evidence of expression at presynaptic sites, in addition to somatodendritic sites, TRPM8 expression alone exhibited no effects on synaptic transmission. Therefore, by a number of criteria, TRPM8 proved the superior choice for control over neuronal membrane potential. This study also highlights the need to explore potential secondary effects of long-term expression and activation of heterologously introduced channels. PMID:19997638

  1. Endoplasmic reticulum stress-mediated hippocampal neuron apoptosis involved in diabetic cognitive impairment.

    PubMed

    Zhang, Xiaoming; Xu, Linhao; He, Daqiang; Ling, Shucai

    2013-01-01

    Poor management of DM causes cognitive impairment while the mechanism is still unconfirmed. The aim of the present study was to investigate the activation of C/EBP Homology Protein (CHOP), the prominent mediator of the endoplasmic reticulum (ER) stress-induced apoptosis under hyperglycemia. We employed streptozotocin- (STZ-) induced diabetic rats to explore the ability of learning and memory by the Morris water maze test. The ultrastructure of hippocampus in diabetic rats and cultured neurons in high glucose medium were observed by transmission electron microscopy and scanning electron microscopy. TUNEL staining was also performed to assess apoptotic cells while the expression of CHOP was assayed by immunohistochemistry and Western blot assay in these hippocampal neurons. Six weeks after diabetes induction, the escape latency increased and the average frequency in finding the platform decreased in diabetic rats (P < 0.05). The morphology of neuron and synaptic structure was impaired; the number of TUNEL-positive cells and the expression of CHOP in hippocampus of diabetic rats and high glucose medium cultured neurons were markedly altered (P < 0.05). The present results suggested that the CHOP-dependent endoplasmic reticulum (ER) stress-mediated apoptosis may be involved in hyperglycemia-induced hippocampal synapses and neurons impairment and promote the diabetic cognitive impairment.

  2. Differential regulation of amyloid-. beta. -protein mRNA expression within hippocampal neuronal subpopulations in Alzheimer disease

    SciTech Connect

    Higgins, G.A.; Lewis, D.A.; Bahmanyar, S.; Goldgaber, D.; Gajdusek, D.C.; Young, W.G.; Morrison, J.H.; Wilson, M.C.

    1988-02-01

    The authors have mapped the neuroanatomical distribution of amyloid-..beta..-protein mRNA within neuronal subpopulations of the hippocampal formation in the cynomolgus monkey (Macaca fascicularis), normal aged human, and patients with Alzheimer disease. Amyloid-..beta..-protein mRNA appears to be expressed in all hippocampal neurons, but at different levels of abundance. In the central nervous system of monkey and normal aged human, image analysis shows that neurons of the dentate gyrus and cornu Ammonis fields contain a 2.5-times-greater hybridization signal than is present in neurons of the subiculum and entorhinal cortex. In contrast, in the Alzheimer disease hippocampal formation, the levels of amyloid-..beta..-protein mRNA in the cornu Ammonis field 3 and parasubiculum are equivalent. These findings suggest that within certain neuronal subpopulations cell type-specific regulation of amyloid-..beta..-protein gene expression may be altered in Alzheimer disease.

  3. Stochastic fluctuations in gene expression in aging hippocampal neurons could be exacerbated by traumatic brain injury.

    PubMed

    Shearer, Joseph; Boone, Deborah; Weisz, Harris; Jennings, Kristofer; Uchida, Tatsuo; Parsley, Margaret; DeWitt, Douglas; Prough, Donald; Hellmich, Helen

    2016-04-01

    Traumatic brain injury (TBI) is a risk factor for age-related dementia and development of neurodegenerative disorders such as Alzheimer's disease that are associated with cognitive decline. The exact mechanism for this risk is unknown but we hypothesized that TBI is exacerbating age-related changes in gene expression. Here, we present evidence in an animal model that experimental TBI increases age-related stochastic gene expression. We compared the variability in expression of several genes associated with cell survival or death, among three groups of laser capture microdissected hippocampal neurons from aging rat brains. TBI increased stochastic fluctuations in gene expression in both dying and surviving neurons compared to the naïve neurons. Increases in random, stochastic fluctuations in prosurvival or prodeath gene expression could potentially alter cell survival or cell death pathways in aging neurons after TBI which may lead to age-related cognitive decline.

  4. Assay of Rab17 and its guanine nucleotide exchange factor Rabex-5 in the dendrites of hippocampal neurons.

    PubMed

    Mori, Yasunori; Fukuda, Mitsunori

    2015-01-01

    Neurons are functionally and morphologically compartmentalized into axons and dendrites, and the localization of specific proteins within these compartments is critical to the proper formation of neuronal networks, which includes neurite morphogenesis and synapse formation. The small GTPase Rab17 is specifically localized in dendrites and is not found in axons, and it regulates the dendrite morphogenesis and postsynaptic development of mouse hippocampal neurons. However, the spatiotemporal regulation of Rab17 is poorly understood. We recently identified Rabex-5, originally described as a Rab5-guanine nucleotide exchange factor (GEF), as a physiological Rab17-GEF that promotes translocation of Rab17 from the cell body to the dendrites of developing hippocampal neurons. Knockdown of Rab17 in mouse hippocampal neurons resulted in reductions in dendrite growth, branch numbers, filopodium density, and active synapse numbers. Knockdown of Rab17-GEF Rabex-5 in hippocampal neurons resulted in decreased targeting of Rab17 to the dendrites, which led to a reduction in dendrite growth. In this chapter we describe the assay procedures for analyzing Rab17 and Rabex-5 in cultured mouse hippocampal neurons, and we particularly focus on the measurement of total dendrite (or axon) length and total dendrite (or axon) branch numbers, filopodium density, number of active synapses, and dendritic Rab17 signals.

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

    PubMed Central

    2014-01-01

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

  6. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

    PubMed

    Wagner, Gerd; Herbsleb, Marco; de la Cruz, Feliberto; Schumann, Andy; Brünner, Franziska; Schachtzabel, Claudia; Gussew, Alexander; Puta, Christian; Smesny, Stefan; Gabriel, Holger W; Reichenbach, Jürgen R; Bär, Karl-Jürgen

    2015-10-01

    Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

  7. Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis.

    PubMed

    Encinas, Juan M; Sierra, Amanda

    2012-02-14

    Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.

  8. Prolactin mediates neuroprotection against excitotoxicity in primary cell cultures of hippocampal neurons via its receptor.

    PubMed

    Vergara-Castañeda, E; Grattan, D R; Pasantes-Morales, H; Pérez-Domínguez, M; Cabrera-Reyes, E A; Morales, T; Cerbón, M

    2016-04-01

    Recently it has been reported that prolactin (PRL) exerts a neuroprotective effect against excitotoxicity in hippocampus in the rat in vivo models. However, the exact mechanism by which PRL mediates this effect is not completely understood. The aim of our study was to assess whether prolactin exerts neuroprotection against excitotoxicity in an in vitro model using primary cell cultures of hippocampal neurons, and to determine whether this effect is mediated via the prolactin receptor (PRLR). Primary cell cultures of rat hippocampal neurons were used in all experiments, gene expression was evaluated by RT-qPCR, and protein expression was assessed by Western blot analysis and immunocytochemistry. Cell viability was assessed by using the MTT method. The results demonstrated that PRL treatment of neurons from primary cultures did not modify cell viability, but that it exerted a neuroprotective effect, with cells treated with PRL showing a significant increase of viability after glutamate (Glu)--induced excitotoxicity as compared with neurons treated with Glu alone. Cultured neurons expressed mRNA for both PRL and its receptor (PRLR), and both PRL and PRLR expression levels changed after the excitotoxic insult. Interestingly, the PRLR protein was detected as two main isoforms of 100 and 40 kDa as compared with that expressed in hypothalamic cells, which was present only as a 30 kDa variant. On the other hand, PRL was not detected in neuron cultures, either by western blot or by immunohistochemistry. Neuroprotection induced by PRL was significantly blocked by specific oligonucleotides against PRLR, thus suggesting that the PRL role is mediated by its receptor expressed in these neurons. The overall results indicated that PRL induces neuroprotection in neurons from primary cell cultures.

  9. Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression After Whole-Brain Irradiation

    PubMed Central

    Wong-Goodrich, Sarah J.E.; Pfau, Madeline L.; Flores, Catherine T.; Fraser, Jennifer A.; Williams, Christina L.; Jones, Lee W.

    2010-01-01

    Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention, and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to four months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting one month after sham- or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdU) immunolabeling and ELISA indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdU+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor, and occurred despite irradiation-induced elevations in hippocampal pro-inflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. PMID:20884629

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

    PubMed Central

    Grüter, Thomas; Wiescholleck, Valentina; Dubovyk, Valentyna; Aliane, Verena; Manahan-Vaughan, Denise

    2015-01-01

    Psychosis is accompanied by severe attentional deficits, and impairments in associational-memory processing and sensory information processing that are ascribed to dysfunctions in prefrontal and hippocampal function. Disruptions of glutamatergic signaling may underlie these alterations: Antagonism of the N-methyl-D-aspartate receptor (NMDAR) results in similar molecular, cellular, cognitive and behavioral changes in rodents and/or humans as those that occur in psychosis, raising the question as to whether changes in glutamatergic transmission may be intrinsic to the pathophysiology of the disease. In an animal model of psychosis that comprises treatment with the irreversible NMDAR-antagonist, MK801, we explored the cellular mechanisms that may underlie hippocampal dysfunction in psychosis. MK801-treatment resulted in a profound loss of hippocampal LTP that was evident 4 weeks after treatment. Whereas neuronal expression of the immediate early gene, Arc, was enhanced in the hippocampus by spatial learning in controls, MK801-treated animals failed to show activity-dependent increases in Arc expression. By contrast, a significant increase in basal Arc expression in the absence of learning was evident compared to controls. Paired-pulse (PP) facilitation was increased at the 40 ms interval indicating that NMDAR and/or fast GABAergic-mediated neurotransmission was disrupted. In line with this, MK801-treatment resulted in a significant decrease in GABA(A), and increase in GABA(B)-receptor-expression in PFC, along with a significant increase of GABA(B)- and NMDAR-GluN2B expression in the dentate gyrus. NMDAR-GluN1 or GluN2A subunit expression was unchanged. These data suggest that in psychosis, deficits in hippocampus-dependent memory may be caused by a loss of hippocampal LTP that arises through enhanced hippocampal neuronal excitability, altered GluN2B and GABA receptor expression and an uncoupling of the hippocampus-prefrontal cortex circuitry. PMID:26042007

  11. Glucose deprivation activates diversity of potassium channels in cultured rat hippocampal neurons.

    PubMed

    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.

  12. Amyloid beta oligomers induce neuronal elasticity changes in age-dependent manner: a force spectroscopy study on living hippocampal neurons

    PubMed Central

    Ungureanu, Andreea-Alexandra; Benilova, Iryna; Krylychkina, Olga; Braeken, Dries; De Strooper, Bart; Van Haesendonck, Chris; Dotti, Carlos G.; Bartic, Carmen

    2016-01-01

    Small soluble species of amyloid-beta (Aβ) formed during early peptide aggregation stages are responsible for several neurotoxic mechanisms relevant to the pathology of Alzheimer’s disease (AD), although their interaction with the neuronal membrane is not completely understood. This study quantifies the changes in the neuronal membrane elasticity induced by treatment with the two most common Aβ isoforms found in AD brains: Aβ40 and Aβ42. Using quantitative atomic force microscopy (AFM), we measured for the first time the static elastic modulus of living primary hippocampal neurons treated with pre-aggregated Aβ40 and Aβ42 soluble species. Our AFM results demonstrate changes in the elasticity of young, mature and aged neurons treated for a short time with the two Aβ species pre-aggregated for 2 hours. Neurons aging under stress conditions, showing aging hallmarks, are the most susceptible to amyloid binding and show the largest decrease in membrane stiffness upon Aβ treatment. Membrane stiffness defines the way in which cells respond to mechanical forces in their environment and has been shown to be important for processes such as gene expression, ion-channel gating and neurotransmitter vesicle transport. Thus, one can expect that changes in neuronal membrane elasticity might directly induce functional changes related to neurodegeneration. PMID:27173984

  13. Bcl-xL Is Necessary for Neurite Outgrowth in Hippocampal Neurons

    PubMed Central

    Park, Han-A; Licznerski, Pawel; Alavian, Kambiz N.; Shanabrough, Marya

    2015-01-01

    Abstract Aims: B-cell lymphoma-extra large (Bcl-xL) protects survival in dividing cells and developing neurons, but was not known to regulate growth. Growth and synapse formation are indispensable for neuronal survival in development, inextricably linking these processes. We have previously shown that, during synaptic plasticity, Bcl-xL produces changes in synapse number, size, activity, and mitochondrial metabolism. In this study, we determine whether Bcl-xL is required for healthy neurite outgrowth and whether neurite outgrowth is necessary for survival in developing neurons in the presence or absence of stress. Results: Depletion of endogenous Bcl-xL impairs neurite outgrowth in hippocampal neurons followed by delayed cell death which is dependent on upregulation of death receptor 6 (DR6), a molecule that regulates axonal pruning. Under hypoxic conditions, Bcl-xL-depleted neurons demonstrate increased vulnerability to neuronal process loss and to death compared with hypoxic controls. Endogenous DR6 expression and upregulation during hypoxia are associated with worsened neurite damage; depletion of DR6 partially rescues neuronal process loss, placing DR6 downstream of the effects of Bcl-xL on neuronal process outgrowth and protection. In vivo ischemia produces early increases in DR6, suggesting a role for DR6 in brain injury. Innovation: We suggest that DR6 levels are usually suppressed by Bcl-xL; Bcl-xL depletion leads to upregulation of DR6, failure of neuronal outgrowth in nonstressed cells, and exacerbation of hypoxia-induced neuronal injury. Conclusion: Bcl-xL regulates neuronal outgrowth during development and protects neurites from hypoxic insult, as opposed by DR6. Factors that enhance neurite formation may protect neurons against hypoxic injury or neurodegenerative stimuli. Antioxid. Redox Signal. 22, 93–108. PMID:24787232

  14. Cyclin E marks quiescent neural stem cells and caspase-3-positive newborn cells during adult hippocampal neurogenesis in mice.

    PubMed

    Ikeda, Yayoi; Ikeda, Masa-Aki

    2015-10-21

    Cyclin E is a key regulator of progression through the G1-phase of the cell cycle. Recently, a cell cycle-independent role for cyclin E in the adult mouse central nervous system has been suggested. In the present study, we examined expression of cyclin E in the mouse hippocampal dentate gyrus (DG), a region of neurogenesis in adulthood, using immunofluorescence. In the adult DG, cyclin E-immunoreactive (cyclin E+) cells was limited to postmitotic cells. In the subgranular zone, cyclin E was detected in the vertical process of radial glia-like cells, which were marked by the neural stem cell markers nestin and GFAP. Cyclin E was also detected in the nucleus of cells, which were labeled with stage-specific neuronal cell markers, including Pax6, Sox2, NeuroD, doublecortin, and NeuN. The densities of cyclin E+ cells in the DG reduced and increased with age and running, respectively. Furthermore, the majority of cyclin E+ cells co-expressed active caspase-3, a marker of apoptosis. Together, the results indicate that cyclin E is expressed in the process of quiescent neural stem cells and in the nucleus of active caspase-3+ cells during neuronal cell differentiation, suggesting that cyclin E has a Cdk-independent function, which might be important for the mechanisms regulating adult hippocampal neurogenesis.

  15. Discharge correlates of hippocampal complex spike neurons in behaving rats passively displaced on a mobile robot.

    PubMed

    Gavrilov, V V; Wiener, S I; Berthoz, A

    1998-01-01

    This study investigated location-, movement-, and directional-selectivity of action potential discharges of hippocampal neurons in awake rats subjected to passive displacements in order to estimate vestibular contributions to this activity. Water-deprived rats were habituated to being restrained in a sling mounted on a moving robot. The extracellular activity of single complex-spike cells in area CA1 of the hippocampus was recorded with glass micropipettes in the rats during passive translations, rotations, and immobility. The robot made a standardized series of trajectories starting from each of four corners of a square enclosure surrounded by black curtains. A drop of water was delivered to the rat each time the robot arrived at one designated corner of the arena. The activities of 29 neurons were investigated in 45 recording sessions (16 of which were in total darkness) in four rats. Hippocampal neurons recorded in 31 sessions (9 sessions in the dark) had significant location-selective increases or decreases in firing rate as the rat was passively displaced or immobile within the experimental arena. In 20 sessions (6 in the dark) direction-selective discharges were found when the rat was in the corners. In six sessions, cells discharged selectively during movement initiation or termination. These data suggest that information essential for path integration is present in the hippocampus and that inertial cues could play a vital role in hippocampal spatial functions. These results resemble those of O'Mara et al. ([1994] J Neurosci 14:6511) using the same protocol in macaques, suggesting similarities in hippocampal processing and function.

  16. Misoprostol Reverse Hippocampal Neuron Cyclooxygenase-2 Downstream Signaling Imbalance in Aluminum-Overload Rats

    PubMed Central

    Guo, Yuanxin; Lei, Wenjuan; Wang, Jianfeng; Hu, Xinyue; Wei, Yuling; Ji, Chaonan; Yang, Junqing

    2016-01-01

    Although COX-2 inhibition in animal models of neurodegenerative diseases has shown neuroprotection, recent studies have revealed some serious side effects (ulcers, bleeding, fatal cerebrovascular diseases etc.) and the limited benefits of COX-2 inhibitors. A more focused approach is necessary to explore the therapeutic effect of the COX downstream signaling pathway in neurological research. The aim of this study was to explore the alterations of the PGES-PGE2-EP signal pathway and the effect of misoprostol on neurodegeneration by chronic aluminum-overload in rats. Adult rats were treated by intragastric administration of aluminum gluconate. The PGE2 content and expression of PGES and EPs in the hippocampi of rats were detected using ELISA, q-PCR and Western blot analysis, respectively. The content of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD) in the rat hippocampi were also detected. The misoprostol treatment dose-dependently improved spatial learning and memory function as well as healing after hippocampal neuron damage induced by chronic aluminum-overload in rats. Meanwhile, the administration of misoprostol resulted in a decrease in the PGE2 level and down-regulation of the mPGES-1, EP2 and EP4 expression levels, while there was a dose-dependent up-regulation of EP3 expression. These results suggest that misoprostol possesses a neuroprotective property, and the mechanism involves affecting the EP3 level and reducing the endogenous production of PGE2 through a negative feedback mechanism, increasing the EP3 expression level, decreasing the EP2 and EP4 expression levels, and rebuilding the mPGES-1-PGE2-EP1-4 signal pathway balance. In this way, misoprostol has a counteractive effect on oxidant stress and inflammation in the central nervous system. The PGES-PGE2-EPs signaling pathway is a potential therapeutic strategy for treating neurodegeneration in patients. PMID:27033056

  17. Seamless Reconstruction of Intact Adult-Born Neurons by Serial End-Block Imaging Reveals Complex Axonal Guidance and Development in the Adult Hippocampus

    PubMed Central

    Sun, Gerald J.; Sailor, Kurt A.; Mahmood, Qasim A.; Chavali, Nikhil; Christian, Kimberly M.; Song, Hongjun

    2013-01-01

    In the adult mammalian hippocampus, newborn dentate granule cells are continuously integrated into the existing circuitry and contribute to specific brain functions. Little is known about the axonal development of these newborn neurons in the adult brain due to technological challenges that have prohibited large-scale reconstruction of long, thin, and complex axonal processes within the mature nervous system. Here, using a new serial end-block imaging (SEBI) technique, we seamlessly reconstructed axonal and dendritic processes of intact individual retrovirus-labeled newborn granule cells at different developmental stages in the young adult mouse hippocampus. We found that adult-born dentate granule cells exhibit tortuous, yet highly stereotyped, axonal projections to CA3 hippocampal subregions. Primary axonal projections of cohorts of new neurons born around the same time organize into laminar patterns with staggered terminations that stack along the septo-temporal hippocampal axis. Analysis of individual newborn neuron development further defined an initial phase of rapid axonal and dendritic growth within 21 d after newborn neuron birth, followed by minimal growth of primary axonal and whole dendritic processes through the last time point examined at 77 d. Our results suggest that axonal development and targeting is a highly orchestrated, precise process in the adult brain. These findings demonstrate a striking regenerative capacity of the mature CNS to support long-distance growth and guidance of neuronal axons. Our SEBI approach can be broadly applied for analysis of intact, complex neuronal projections in limitless tissue volume. PMID:23843512

  18. Seamless reconstruction of intact adult-born neurons by serial end-block imaging reveals complex axonal guidance and development in the adult hippocampus.

    PubMed

    Sun, Gerald J; Sailor, Kurt A; Mahmood, Qasim A; Chavali, Nikhil; Christian, Kimberly M; Song, Hongjun; Ming, Guo-li

    2013-07-10

    In the adult mammalian hippocampus, newborn dentate granule cells are continuously integrated into the existing circuitry and contribute to specific brain functions. Little is known about the axonal development of these newborn neurons in the adult brain due to technological challenges that have prohibited large-scale reconstruction of long, thin, and complex axonal processes within the mature nervous system. Here, using a new serial end-block imaging (SEBI) technique, we seamlessly reconstructed axonal and dendritic processes of intact individual retrovirus-labeled newborn granule cells at different developmental stages in the young adult mouse hippocampus. We found that adult-born dentate granule cells exhibit tortuous, yet highly stereotyped, axonal projections to CA3 hippocampal subregions. Primary axonal projections of cohorts of new neurons born around the same time organize into laminar patterns with staggered terminations that stack along the septo-temporal hippocampal axis. Analysis of individual newborn neuron development further defined an initial phase of rapid axonal and dendritic growth within 21 d after newborn neuron birth, followed by minimal growth of primary axonal and whole dendritic processes through the last time point examined at 77 d. Our results suggest that axonal development and targeting is a highly orchestrated, precise process in the adult brain. These findings demonstrate a striking regenerative capacity of the mature CNS to support long-distance growth and guidance of neuronal axons. Our SEBI approach can be broadly applied for analysis of intact, complex neuronal projections in limitless tissue volume.

  19. Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

    PubMed Central

    Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

    2015-01-01

    Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression. PMID:25875952

  20. Agonist-Dependent Postsynaptic Effects of Opioids on Miniature Excitatory Postsynaptic Currents in Cultured Hippocampal Neurons

    PubMed Central

    Liao, Dezhi; Grigoriants, Olga O.; Loh, Horace H.; Law, Ping-Yee

    2006-01-01

    Although chronic treatment with morphine is known to alter the function and morphology of excitatory synapses, the effects of other opioids on these synapses are not clear. Here we report distinct effects of several opioids (morphine, DAMGO and etorphine) on miniature excitatory postsynaptic currents (mEPSCs) in cultured hippocampal neurons: (1) Chronic treatment with morphine for > 3 days decreased the amplitude, frequency, rise time and decay time of mEPSCs. In contrast, “internalizing” opioids such as etorphine and DAMGO increased the frequency of mEPSCs and had no significant effect on the amplitude and kinetics of mEPSCs. These results demonstrate that different opioids can have distinct effects on the function of excitatory synapses. (2) MOR-GFP is clustered in dendritic spines in most hippocampal neurons but is concentrated in axon-like processes in striatal and corticostriatal non-spiny neurons. It suggests that MORs might mediate pre- or post-synaptic effects depending upon cell types. (3) Neurons were cultured from MOR knock-out mice and were exogenously transfected with GFP-tagged MORs (MOR-GFP). Chronic treatment with morphine suppressed mEPSCs only in neurons that contained postsynaptic MOR-GFP, indicating thatopioids can modulate excitatory synaptic transmission postsynaptically. (4) Morphine acutely decreased mEPSC amplitude in neurons expressing exogenous MOR-GFP, but had no effect on neurons expressing GFP. It indicates that the low level of endogenous MORs could only allow slow opioid-induced plasticity of excitatory synapses under normal conditions. (5) A theoretical model suggests that morphine might affect the function of spines by decreasing the electrotonic distance from synaptic inputs to the soma. PMID:17122315

  1. Differential Tiam1/Rac1 activation in hippocampal and cortical neurons mediates differential spine shrinkage in response to oxygen/glucose deprivation

    PubMed Central

    Blanco-Suárez, Elena; Fiuza, Maria; Liu, Xun; Chakkarapani, Elavazhagan; Hanley, Jonathan G

    2014-01-01

    Distinct neuronal populations show differential sensitivity to global ischemia, with hippocampal CA1 neurons showing greater vulnerability compared to cortical neurons. The mechanisms that underlie differential vulnerability are unclear, and we hypothesize that intrinsic differences in neuronal cell biology are involved. Dendritic spine morphology changes in response to ischemic insults in vivo, but cell type-specific differences and the molecular mechanisms leading to such morphologic changes are unexplored. To directly compare changes in spine size in response to oxygen/glucose deprivation (OGD) in cortical and hippocampal neurons, we used separate and equivalent cultures of each cell type. We show that cortical neurons exhibit significantly greater spine shrinkage compared to hippocampal neurons. Rac1 is a Rho-family GTPase that regulates the actin cytoskeleton and is involved in spine dynamics. We show that Rac1 and the Rac guanine nucleotide exchange factor (GEF) Tiam1 are differentially activated by OGD in hippocampal and cortical neurons. Hippocampal neurons express more Tiam1 than cortical neurons, and reducing Tiam1 expression in hippocampal neurons by shRNA enhances OGD-induced spine shrinkage. Tiam1 knockdown also reduces hippocampal neuronal vulnerability to OGD. This work defines fundamental differences in signalling pathways that regulate spine morphology in distinct neuronal populations that may have a role in the differential vulnerability to ischemia. PMID:25248834

  2. Tetramethyl Pyrazine Protects Hippocampal Neurons Against Anoxia/Reoxygenation Injury Through Inhibiting Apoptosis Mediated by JNK/MARK Signal Pathway

    PubMed Central

    Zhong, Ming; Ma, Wuhua; Zhang, Xiong; Wang, Yong; Gao, Xiaoqiu

    2016-01-01

    Background Tetramethyl pyrazine (TMP) is a typical biologically active alkaloid isolated from the Chinese herb Ligusticum walliichi. It has been reported that TMP shows neuroprotective and stroke injury reductive properties in cerebral ischemia/reperfusion (I/R) animal models. In the present study we sought to investigate the effect and potential intervention mechanism of TMP in anoxia/reoxygenation (A/R) rat hippocampal neurons. Material/Methods After being cultured for 7 days, primary hippocampal neurons were randomly assigned into a normal control group (N), a TMP group (C: 0 ug/ml, L: 60 ug/ml, M: 200ug/ml and H: 800 ug/ml), and a JNK inhibitor group (S: SP600125, 10 μmol/L). A hypoxia/reoxygenation model were prepared 1 h after incubation. Hippocampal neurons were incubated in 90% N2 and 10% CO2 for 2 h, and then reoxygenated for 24 h in an incubator with 5%CO2 at the temperature of 37°C. The apoptosis rate, MKK4 and MKK7 mRNA and JNK kinase protein levels (C-fos, c-jun, and P-JNK) of hippocampal neurons were detected. Results The apoptosis rates of hippocampal neurons induced by A/R showed significant reduction after being pre-treated with JNK inhibitor, TMP 60 μg/ml, 200 μg/ml, and 800 μg/ml. The JNK kinase MKK4mRNA and MKK7mRNA levels, as well as the expressions of C-fos, C-jun, and P-JNK protein levels, were also be reduced. Conclusions TMP may produce a protective effect in anoxia/reoxygenation-induced primary hippocampal neuronal injury by inhibiting the apoptosis of the hippocampal neurons; the possible mechanism may be inhibition of the JNK signal pathway. PMID:28009855

  3. Diverse impact of neuronal activity at θ frequency on hippocampal long-term plasticity.

    PubMed

    Wójtowicz, Tomasz; Mozrzymas, Jerzy W

    2015-09-01

    Brain oscillatory activity is considered an essential aspect of brain function, and its frequency can vary from <1 Hz to >200 Hz, depending on the brain states and projection. Episodes of rhythmic activity accompany hippocampus-dependent learning and memory in vivo. Therefore, long-term synaptic potentiation (LTP) and long-term depression, which are considered viable substrates of learning and memory, are often experimentally studied in paradigms of patterned high-frequency (>50 Hz) and low-frequency (<5 Hz) stimulation. However, the impact of intermediate frequencies on neuronal plasticity remains less well understood. In particular, hippocampal neurons are specifically tuned for activity at θ frequency (4-8 Hz); this band contributes significantly to electroencephalographic signals, and it is likely to be involved in shaping synaptic strength in hippocampal circuits. Here, we review in vitro and in vivo studies showing that variation of θ-activity duration may affect long-term modification of synaptic strength and neuronal excitability in the hippocampus. Such θ-pulse-induced neuronal plasticity 1) is long-lasting, 2) may be built on previously stabilized potentiation in the synapse, 3) may produce opposite changes in synaptic strength, and 4) requires complex molecular machinery. Apparently innocuous episodes of low-frequency synaptic activity may have a profound impact on network signaling, thereby contributing to information processing in the hippocampus and beyond. In addition, θ-pulse-induced LTP might be an advantageous protocol in studies of specific molecular mechanisms of synaptic plasticity.

  4. NGF and BDNF signaling control amyloidogenic route and Abeta production in hippocampal neurons.

    PubMed

    Matrone, Carmela; Ciotti, Maria Teresa; Mercanti, Delio; Marolda, Roberta; Calissano, Pietro

    2008-09-02

    Here, we report that interruption of NGF or BDNF signaling in hippocampal neurons rapidly activates the amyloidogenic pathway and causes neuronal apoptotic death. These events are associated with an early intracellular accumulation of PS1 N-terminal catalytic subunits and of APP C-terminal fragments and a progressive accumulation of intra- and extracellular Abeta aggregates partly released into the culture medium. The released pool of Abeta induces an increase of APP and PS1 holoprotein levels, creating a feed-forward toxic loop that might also cause the death of healthy neurons. These events are mimicked by exogenously added Abeta and are prevented by exposure to beta- and gamma-secretase inhibitors and by antibodies directed against Abeta peptides. The same cultured neurons deprived of serum die, but APP and PS1 overexpression does not occur, Abeta production is undetectable, and cell death is not inhibited by anti-Abeta antibodies, suggesting that hippocampal amyloidogenesis is not a simple consequence of an apoptotic trigger but is due to interruption of neurotrophic signaling.

  5. The tyrosine phosphatase inhibitor orthovanadate mimics NGF-induced neuroprotective signaling in rat hippocampal neurons.

    PubMed

    Gerling, Norbert; Culmsee, Carsten; Klumpp, Susanne; Krieglstein, Josef

    2004-06-01

    Activation of the high affinity neurotrophin receptor tropomyosin-related kinase A (TrkA) by nerve growth factor (NGF) leads to phosphorylation of intracellular tyrosine residues of the receptor with subsequent activation of signaling pathways involved in neuronal survival such as the phosphoinositide-3-kinase (PI3-K)/protein kinase B (PKB/Akt) pathway and the mitogen-activated protein kinase (MAPK) cascade. In the present study, we tested whether inhibition of protein-tyrosine phosphatases (PTP) by orthovanadate could enhance tyrosine phosphorylation of TrkA thereby stimulating NGF-like survival signaling in embryonic hippocampal neurons. We found that the PTP inhibitor orthovanadate (1 microM) enhanced TrkA phosphorylation and protected neurons against staurosporine (STS)-induced apoptosis in a time-and concentration-dependent manner. Inhibition of PTP enhanced TrkA phosphorylation also in the presence of NGF antibodies indicating that NGF binding to TrkA was not required for the effects of orthovanadate. Moreover, orthovanadate enhanced phosphorylation of Akt and the MAPK Erk1/2 suggesting that the signaling pathways involved in the protective effect were similar to those activated by NGF. Accordingly, inhibition of PI3-K by wortmannin and MAPK-kinase (MEK) inhibition by UO126 abolished the neuroprotective effects. In conclusion, the results indicate that orthovanadate mimics the effect of NGF on survival signaling pathways in hippocampal neurons. Thus, PTP inhibition appears to be an appropriate strategy to trigger neuroprotective signaling pathways downstream of neurotrophin receptors.

  6. Active Summation of Excitatory Postsynaptic Potentials in Hippocampal CA3 Pyramidal Neurons

    NASA Astrophysics Data System (ADS)

    Urban, Nathaniel N.; Barrionuevo, German

    1998-09-01

    The manner in which the thousands of synaptic inputs received by a pyramidal neuron are summed is critical both to our understanding of the computations that may be performed by single neurons and of the codes used by neurons to transmit information. Recent work on pyramidal cell dendrites has shown that subthreshold synaptic inputs are modulated by voltage-dependent channels, raising the possibility that summation of synaptic responses is influenced by the active properties of dendrites. Here, we use somatic and dendritic whole-cell recordings to show that pyramidal cells in hippocampal area CA3 sum distal and proximal excitatory postsynaptic potentials sublinearly and actively, that the degree of nonlinearity depends on the magnitude and timing of the excitatory postsynaptic potentials, and that blockade of transient potassium channels linearizes summation. Nonlinear summation of synaptic inputs could have important implications for the computations performed by single neurons and also for the role of the mossy fiber and perforant path inputs to hippocampal area CA3.

  7. Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3.

    PubMed

    Scala, Federico; Fusco, Salvatore; Ripoli, Cristian; Piacentini, Roberto; Li Puma, Domenica Donatella; Spinelli, Matteo; Laezza, Fernanda; Grassi, Claudio; D'Ascenzo, Marcello

    2015-02-01

    Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K(+) currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K(+) currents, at Ser-616. In acute hippocampal slices derived from an adult triple-transgenic Alzheimer's mouse model, characterized by endogenous intracellular accumulation of Aβ42, CA1 pyramidal neurons exhibit hyperexcitability accompanied by increased phosphorylation of Kv4.2 at Ser-616. Collectively, these data suggest that intraneuronal Aβ42 accumulation leads to an intracellular cascade culminating into caspases activation and GSK-3-dependent phosphorylation of Kv4.2 channels. These findings provide new insights into the toxic mechanisms triggered by intracellular Aβ42 and offer potentially new therapeutic targets for Alzheimer's disease treatment.

  8. Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K+ current inhibition mediated by activation of caspases and GSK-3

    PubMed Central

    Scala, Federico; Fusco, Salvatore; Ripoli, Cristian; Piacentini, Roberto; Li Puma, Domenica Donatella; Spinelli, Matteo; Laezza, Fernanda; Grassi, Claudio; D’Ascenzo, Marcello

    2016-01-01

    Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K+ currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K+ currents, at Ser-616. In acute hippocampal slices derived from an adult triple-transgenic Alzheimer’s mouse model, characterized by endogenous intracellular accumulation of Aβ42, CA1 pyramidal neurons exhibit hyperexcitability accompanied by increased phosphorylation of Kv4.2 at Ser-616. Collectively, these data suggest that intraneuronal Aβ42 accumulation leads to an intracellular cascade culminating into caspases activation and GSK-3-dependent phosphorylation of Kv4.2 channels. These findings provide new insights into the toxic mechanisms triggered by intracellular Aβ42 and offer potentially new therapeutic targets for Alzheimer’s disease treatment. PMID:25541422

  9. Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.

    PubMed

    Kronenberg, Golo; Gertz, Karen; Baldinger, Tina; Kirste, Imke; Eckart, Sarah; Yildirim, Ferah; Ji, Shengbo; Heuser, Isabella; Schröck, Helmut; Hörtnagl, Heide; Sohr, Reinhard; Djoufack, Pierre Chryso; Jüttner, René; Glass, Rainer; Przesdzing, Ingo; Kumar, Jitender; Freyer, Dorette; Hellweg, Rainer; Kettenmann, Helmut; Fink, Klaus Benno; Endres, Matthias

    2010-03-03

    Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

  10. Effects of long-term malnutrition and rehabilitation on the hippocampal formation of the adult rat. A morphometric study.

    PubMed Central

    Andrade, J P; Madeira, M D; Paula-Barbosa, M M

    1995-01-01

    We have previously shown that the numerical density of dentate granule and CA3 pyramidal cells of adult rats is reduced after lengthy periods of low-protein diet. In this study, the total number of these neurons was estimated, together with those for the hilar and CA1 pyramidal cells in order to obtain a complete and unbiased insight into the effects of malnutrition and rehabilitation from malnutrition on the structure of the hippocampal formation. Groups of 2-month-old rats were fed a low protein diet (8% casein) for 6, 12 and 18 months and compared with age-matched control and recovery rats. The recovery group was fed a low protein diet for 6 months and then switched to normal diet during the same period. Total numbers of neurons of each hippocampal region were calculated from their numerical density, estimated with the physical disector, and from the volume of the respective cell layers, after correction for the tissue shrinkage factor. The total number of granule, hilar, CA1 and CA3 pyramidal cells was reduced in all groups of malnourished rats including the recovery group. No differences were found between malnourished and recovery groups. These findings indicate that a prolonged low protein diet, started in adult life, leads to a deficit in neuronal numbers in the hippocampal formation, and that it may also disrupt the normal process of cell acquisition in the dentate gyrus. Moreover, our data support the view that the morphological alterations induced by a low protein intake are irreversible. Images Fig. 1 Fig. 2 Fig. 3 PMID:7592001

  11. Pericellular innervation of neurons expressing abnormally hyperphosphorylated tau in the hippocampal formation of Alzheimer's disease patients.

    PubMed

    Blazquez-Llorca, Lidia; Garcia-Marin, Virginia; Defelipe, Javier

    2010-01-01

    Neurofibrillary tangles (NFT) represent one of the main neuropathological features in the cerebral cortex associated with Alzheimer's disease (AD). This neurofibrillary lesion involves the accumulation of abnormally hyperphosphorylated or abnormally phosphorylated microtubule-associated protein tau into paired helical filaments (PHF-tau) within neurons. We have used immunocytochemical techniques and confocal microscopy reconstructions to examine the distribution of PHF-tau-immunoreactive (ir) cells, and their perisomatic GABAergic and glutamatergic innervations in the hippocampal formation and adjacent cortex of AD patients. Furthermore, correlative light and electron microscopy was employed to examine these neurons and the perisomatic synapses. We observed two patterns of staining in PHF-tau-ir neurons, pattern I (without NFT) and pattern II (with NFT), the distribution of which varies according to the cortical layer and area. Furthermore, the distribution of both GABAergic and glutamatergic terminals around the soma and proximal processes of PHF-tau-ir neurons does not seem to be altered as it is indistinguishable from both control cases and from adjacent neurons that did not contain PHF-tau. At the electron microscope level, a normal looking neuropil with typical symmetric and asymmetric synapses was observed around PHF-tau-ir neurons. These observations suggest that the synaptic connectivity around the perisomatic region of these PHF-tau-ir neurons was apparently unaltered.

  12. Pericellular Innervation of Neurons Expressing Abnormally Hyperphosphorylated Tau in the Hippocampal Formation of Alzheimer's Disease Patients

    PubMed Central

    Blazquez-Llorca, Lidia; Garcia-Marin, Virginia; DeFelipe, Javier

    2010-01-01

    Neurofibrillary tangles (NFT) represent one of the main neuropathological features in the cerebral cortex associated with Alzheimer's disease (AD). This neurofibrillary lesion involves the accumulation of abnormally hyperphosphorylated or abnormally phosphorylated microtubule-associated protein tau into paired helical filaments (PHF-tau) within neurons. We have used immunocytochemical techniques and confocal microscopy reconstructions to examine the distribution of PHF-tau-immunoreactive (ir) cells, and their perisomatic GABAergic and glutamatergic innervations in the hippocampal formation and adjacent cortex of AD patients. Furthermore, correlative light and electron microscopy was employed to examine these neurons and the perisomatic synapses. We observed two patterns of staining in PHF-tau-ir neurons, pattern I (without NFT) and pattern II (with NFT), the distribution of which varies according to the cortical layer and area. Furthermore, the distribution of both GABAergic and glutamatergic terminals around the soma and proximal processes of PHF-tau-ir neurons does not seem to be altered as it is indistinguishable from both control cases and from adjacent neurons that did not contain PHF-tau. At the electron microscope level, a normal looking neuropil with typical symmetric and asymmetric synapses was observed around PHF-tau-ir neurons. These observations suggest that the synaptic connectivity around the perisomatic region of these PHF-tau-ir neurons was apparently unaltered. PMID:20631843

  13. NRSF causes cAMP-sensitive suppression of sodium current in cultured hippocampal neurons

    NASA Technical Reports Server (NTRS)

    Nadeau, H.; Lester, H. A.

    2002-01-01

    The neuron restrictive silencer factor (NRSF/REST) has been shown to bind to the promoters of many neuron-specific genes and is able to suppress transcription of Na(+) channels in PC12 cells, although its functional effect in terminally differentiated neurons is unknown. We constructed lentiviral vectors to express NRSF as a bicistronic message with green fluorescent protein (GFP) and followed infected hippocampal neurons in culture over a period of 1-2 wk. NRSF-expressing neurons showed a time-dependent suppression of Na(+) channel function as measured by whole cell electrophysiology. Suppression was reversed or prevented by the addition of membrane-permeable cAMP analogues and enhanced by cAMP antagonists but not affected by increasing protein expression with a viral enhancer. Secondary effects, including altered sensitivity to glutamate and GABA and reduced outward K(+) currents, were duplicated by culturing GFP-infected control neurons in TTX. The striking similarity of the phenotypes makes NRSF potentially useful as a genetic "silencer" and also suggests avenues of further exploration that may elucidate the transcription factor's in vivo role in neuronal plasticity.

  14. Tech: a RhoA GEF selectively expressed in hippocampal and cortical neurons.

    PubMed

    Marx, Ruth; Henderson, Jennifer; Wang, James; Baraban, Jay M

    2005-02-01

    Recent studies implicating the Rho family of small G proteins in the regulation of neuronal morphology have focused attention on identifying key components of Rho signaling pathways in neurons. To this end, we have conducted studies aimed at defining the localization and function of Tech, a Rho guanine nucleotide exchange factor (GEF) family member that is highly enriched in brain. We have found that Tech is selectively expressed in cortical and hippocampal neurons with prominent Tech immunostaining apparent in the cell bodies and dendrites of these cells. In vitro studies with prototypical members of the major Rho subfamilies, RhoA, Rac1 and Cdc42, indicate that Tech binds selectively to and activates RhoA. To assess whether Tech may be involved in the regulation of neuronal morphology, we examined the effects of Tech constructs on the morphology of cortical neurons grown in primary culture. We found that a constitutively active Tech construct, Tech 245DeltaC, decreases the number of dendritic processes present on these neurons. This reduction appears to be mediated by activation of RhoA as it is blocked by insertion of a point mutation into the DH domain of Tech which blocks its ability to activate RhoA or coexpression of a dominant negative RhoA construct. As Tech protein levels increase during post-natal development and remain at peak levels into adulthood, these results indicate that Tech regulates RhoA signaling pathways in developing and mature forebrain neurons.

  15. Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: Dependence on synaptic androgen receptor and kinase networks.

    PubMed

    Hatanaka, Yusuke; Hojo, Yasushi; Mukai, Hideo; Murakami, Gen; Komatsuzaki, Yoshimasa; Kim, Jonghyuk; Ikeda, Muneki; Hiragushi, Ayako; Kimoto, Tetsuya; Kawato, Suguru

    2015-09-24

    Rapid modulation of hippocampal synaptic plasticity by locally synthesized androgen is important in addition to circulating androgen. Here, we investigated the rapid changes of dendritic spines in response to the elevation of dihydrotestosterone (DHT) and testosterone (T), by using hippocampal slices from adult male rats, in order to clarify whether these signaling processes include synaptic/extranuclear androgen receptor (AR) and activation of kinases. We found that the application of 10nM DHT and 10nM T increased the total density of spines by approximately 1.3-fold within 2h, by imaging Lucifer Yellow-injected CA1 pyramidal neurons. Interestingly, DHT and T increased different head-sized spines. While DHT increased middle- and large-head spines, T increased small-head spines. Androgen-induced spinogenesis was suppressed by individually blocking Erk MAPK, PKA, PKC, p38 MAPK, LIMK or calcineurin. On the other hand, blocking CaMKII did not inhibit spinogenesis. Blocking PI3K altered the spine head diameter distribution, but did not change the total spine density. Blocking mRNA and protein synthesis did not suppress the enhancing effects induced by DHT or T. The enhanced spinogenesis by androgens was blocked by AR antagonist, which AR was localized postsynaptically. Taken together, these results imply that enhanced spinogenesis by DHT and T is mediated by synaptic/extranuclear AR which rapidly drives the kinase networks. This article is part of a Special Issue entitled SI: Brain and Memory.

  16. Glutamatergic neurons of the mouse medial septum and diagonal band of Broca synaptically drive hippocampal pyramidal cells: relevance for hippocampal theta rhythm.

    PubMed

    Huh, Carey Y L; Goutagny, Romain; Williams, Sylvain

    2010-11-24

    Neurons of the medial septum and diagonal band of Broca (MS-DBB) provide an important input to the hippocampus and are critically involved in learning and memory. Although cholinergic and GABAergic MS-DBB neurons are known to modulate hippocampal activity, the role of recently described glutamatergic MS-DBB neurons is unknown. Here, we examined the electrophysiological properties of glutamatergic MS-DBB neurons and tested whether they provide a functional synaptic input to the hippocampus. To visualize the glutamatergic neurons, we used MS-DBB slices from transgenic mice in which the green fluorescent protein is expressed specifically by vesicular glutamate transporter 2-positive neurons and characterized their properties using whole-cell patch-clamp technique. For assessing the function of the glutamatergic projection, we used an in vitro septohippocampal preparation, electrically stimulated the fornix or chemically activated the MS-DBB using NMDA microinfusions and recorded postsynaptic responses in CA3 pyramidal cells. We found that glutamatergic MS-DBB neurons as a population display a highly heterogeneous set of firing patterns including fast-, cluster-, burst-, and slow-firing. Remarkably, a significant proportion exhibited fast-firing properties, prominent I(h), and rhythmic spontaneous firing at theta frequencies similar to those found in GABAergic MS-DBB neurons. Activation of the MS-DBB led to fast, AMPA receptor-mediated glutamatergic responses in CA3 pyramidal cells. These results describe for the first time the electrophysiological signatures of glutamatergic MS-DBB neurons, their rhythmic firing properties, and their capacity to drive hippocampal principal neurons. Our findings suggest that the glutamatergic septohippocampal pathway may play an important role in hippocampal theta oscillations and relevant cognitive functions.

  17. Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death

    PubMed Central

    Vereczki, Viktoria; Martin, Erica; Rosenthal, Robert E; Hof, Patrick R; Hoffman, Gloria E; Fiskum, Gary

    2008-01-01

    Resuscitation and prolonged ventilation using 100% oxygen after cardiac arrest is standard clinical practice despite evidence from animal models indicating that neurologic outcome is improved using normoxic compared with hyperoxic resuscitation. This study tested the hypothesis that normoxic ventilation during the first hour after cardiac arrest in dogs protects against prelethal oxidative stress to proteins, loss of the critical metabolic enzyme pyruvate dehydrogenase complex (PDHC), and minimizes subsequent neuronal death in the hippocampus. Anesthetized beagles underwent 10 mins ventricular fibrillation cardiac arrest, followed by defibrillation and ventilation with either 21% or 100% O2. At 1 h after resuscitation, the ventilator was adjusted to maintain normal blood gas levels in both groups. Brains were perfusion-fixed at 2 h reperfusion and used for immunohistochemical measurements of hippocampal nitrotyrosine, a product of protein oxidation, and the E1α subunit of PDHC. In hyperoxic dogs, PDHC immunostaining diminished by approximately 90% compared with sham-operated dogs, while staining in normoxic animals was not significantly different from nonischemic dogs. Protein nitration in the hippocampal neurons of hyperoxic animals was 2–3 times greater than either sham-operated or normoxic resuscitated animals at 2 h reperfusion. Stereologic quantification of neuronal death at 24 h reperfusion showed a 40% reduction using normoxic compared with hyperoxic resuscitation. These results indicate that postischemic hyperoxic ventilation promotes oxidative stress that exacerbates prelethal loss of pyruvate dehydrogenase and delayed hippocampal neuronal cell death. Moreover, these findings indicate the need for clinical trials comparing the effects of different ventilatory oxygen levels on neurologic outcome after cardiac arrest. PMID:16251887

  18. Zbtb20 defines a hippocampal neuronal identity through direct repression of genes that control projection neuron development in the isocortex.

    PubMed

    Nielsen, Jakob V; Thomassen, Mads; Møllgård, Kjeld; Noraberg, Jens; Jensen, Niels A

    2014-05-01

    Hippocampal pyramidal neurons are important for encoding and retrieval of spatial maps and episodic memories. While previous work has shown that Zbtb20 is a cell fate determinant for CA1 pyramidal neurons, the regulatory mechanisms governing this process are not known. In this study, we demonstrate that Zbtb20 binds to genes that control neuronal subtype specification in the developing isocortex, including Cux1, Cux2, Fezf2, Foxp2, Mef2c, Rorb, Satb2, Sox5, Tbr1, Tle4, and Zfpm2. We show that Zbtb20 represses these genes during ectopic CA1 pyramidal neuron development in transgenic mice. These data reveal a novel regulatory mechanism by which Zbtb20 suppresses the acquisition of an isocortical fate during archicortical neurogenesis to ensure commitment to a CA1 pyramidal neuron fate. We further show that the expression pattern of Zbtb20 is evolutionary conserved in the fetal human hippocampus, where it is complementary to the expression pattern of the Zbtb20 target gene Tbr1. Therefore, the disclosed Zbtb20-mediated transcriptional repressor mechanism may be involved in development of the human archicortex.

  19. Subthreshold membrane-potential oscillations in immature rat CA3 hippocampal neurones.

    PubMed

    Psarropoulou, C; Avoli, M

    1995-12-15

    Subthreshold membrane potential oscillations (MPOs) were recorded intracellularly in 31 of 43 (>70%) immature CA3 hippocampal neurones (from 3-17 days postnatally). MPOs (3-5 mV, 3-15 Hz) occurred at resting membrane potential (RMP) in 20 of 31 neurones, or following depolarization (11 of 31 neurones); with sufficient depolarization spontaneous action potentials (APs) were generated from the positive-going phase of MPOs. In all cells, MPOs were blocked by steady membrane hyperpolarization. Tetrodotoxin abolished MPOs (n = 4); Co(2+) markedly reduced them (n = 3), and tetraethylammonium, added in the presence of TTX, revealed lower frequency oscillatory activity (n = 2). We conclude that subthreshold MPOs in immature hippocampus, possibly linked to theta rhythm generation and memory acquisition, depend on voltage-dependent Na+ electrogenesis and they might be additionally controlled by Ca(2+) and K+ conductances.

  20. Temporal integration by a slowly inactivating K+ current in hippocampal neurons.

    PubMed

    Storm, J F

    1988-11-24

    A central aspect of neuronal function is how each nerve cell translated synaptic input into a sequence of action potentials that carry information along the axon, coded as spike frequency. When transduction from a graded depolarizing input to spikes is studied by injecting a depolarizing current, there is often a remarkably long delay to the first action potential, both in mammalian and molluscan neurons. Here, I report that the delayed excitation in rat hippocampal neurons is due to a slowly inactivating potassium current, ID. ID co-exists with other voltage-gated K+ currents, including a fast A current and a slow delayed rectifier current. As ID activates in the subthreshold range, and takes tens of seconds to recover from inactivation, it enables the cell to integrate separate depolarizing inputs over long times. ID also makes the encoding properties of the cell exceedingly sensitive to the prevailing membrane potential.

  1. Membrane Potential Dynamics of CA1 Pyramidal Neurons During Hippocampal Ripples in Awake Mice

    PubMed Central

    Hulse, Brad K.; Moreaux, Laurent C.; Lubenov, Evgueniy V.; Siapas, Athanassios G.

    2016-01-01

    Ripples are high-frequency oscillations associated with population bursts in area CA1 of the hippocampus that play a prominent role in theories of memory consolidation. While spiking during ripples has been extensively studied, our understanding of the subthreshold behavior of hippocampal neurons during these events remains incomplete. Here, we combine in vivo whole-cell and multisite extracellular recordings to characterize the membrane potential dynamics of identified CA1 pyramidal neurons during ripples. We find that the subthreshold depolarization during ripples is uncorrelated with the net excitatory input to CA1, while the post-ripple hyperpolarization varies proportionately. This clarifies the circuit mechanism keeping most neurons silent during ripples. On a finer time scale, the phase delay between intracellular and extracellular ripple oscillations varies systematically with membrane potential. Such smoothly varying delays are inconsistent with models of intracellular ripple generation involving perisomatic inhibition alone. Instead, they suggest that ripple-frequency excitation leading inhibition shapes intracellular ripple oscillations. PMID:26889811

  2. Transplanted embryonic neurons integrate into adult neocortical circuits.

    PubMed

    Falkner, Susanne; Grade, Sofia; Dimou, Leda; Conzelmann, Karl-Klaus; Bonhoeffer, Tobias; Götz, Magdalena; Hübener, Mark

    2016-11-10

    The ability of the adult mammalian brain to compensate for neuronal loss caused by injury or disease is very limited. Transplantation aims to replace lost neurons, but the extent to which new neurons can integrate into existing circuits is unknown. Here, using chronic in vivo two-photon imaging, we show that embryonic neurons transplanted into the visual cortex of adult mice mature into bona fide pyramidal cells with selective pruning of basal dendrites, achieving adult-like densities of dendritic spines and axonal boutons within 4-8 weeks. Monosynaptic tracing experiments reveal that grafted neurons receive area-specific, afferent inputs matching those of pyramidal neurons in the normal visual cortex, including topographically organized geniculo-cortical connections. Furthermore, stimulus-selective responses refine over the course of many weeks and finally become indistinguishable from those of host neurons. Thus, grafted neurons can integrate with great specificity into neocortical circuits that normally never incorporate new neurons in the adult brain.

  3. Wogonin Attenuates Hippocampal Neuronal Loss and Cognitive Dysfunction in Trimethyltin-Intoxicated Rats

    PubMed Central

    Lee, Bombi; Sur, Bongjun; Cho, Seong-Guk; Yeom, Mijung; Shim, Insop; Lee, Hyejung; Hahm, Dae-Hyun

    2016-01-01

    We examined whether wogonin (WO) improved hippocampal neuronal activity, behavioral alterations and cognitive impairment, in rats induced by administration of trimethyltin (TMT), an organotin compound that is neurotoxic to these animals. The ability of WO to improve cognitive efficacy in the TMT-induced neurodegenerative rats was investigated using a passive avoidance test, and the Morris water maze test, and using immunohistochemistry to detect components of the acetylcholinergic system, brain-derived neurotrophic factor (BDNF), and cAMP-response element-binding protein (CREB) expression. Rats injected with TMT showed impairments in learning and memory and daily administration of WO improved memory function, and reduced aggressive behavior. Administration of WO significantly alleviated the TMT-induced loss of cholinergic immunoreactivity and restored the hippocampal expression levels of BDNF and CREB proteins and their encoding mRNAs to normal levels. These findings suggest that WO might be useful as a new therapy for treatment of various neurodegenerative diseases. PMID:27133262

  4. Super-Resolution Microscopy Reveals Presynaptic Localization of the ALS/FTD Related Protein FUS in Hippocampal Neurons

    PubMed Central

    Schoen, Michael; Reichel, Jochen M.; Demestre, Maria; Putz, Stefan; Deshpande, Dhruva; Proepper, Christian; Liebau, Stefan; Schmeisser, Michael J.; Ludolph, Albert C.; Michaelis, Jens; Boeckers, Tobias M.

    2016-01-01

    Fused in Sarcoma (FUS) is a multifunctional RNA-/DNA-binding protein, which is involved in the pathogenesis of the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A common hallmark of these disorders is the abnormal accumulation of mutated FUS protein in the cytoplasm. Under normal conditions FUS is confined to the nuclear compartment, in neurons, however, additional somatodendritic localization can be observed. In this study, we carefully analyzed the subcellular localization of endogenous FUS at synaptic sites of hippocampal neurons which are among the most affected cell types in FTD with FUS pathology. We could confirm a strong nuclear localization of FUS as well as its prominent and widespread neuronal expression throughout the adult and developing rat brain, particularly in the hippocampus, the cerebellum and the outer layers of the cortex. Intriguingly, FUS was also consistently observed at synaptic sites as detected by neuronal subcellular fractionation as well as by immunolabeling. To define a pre- and/or postsynaptic localization of FUS, we employed super-resolution fluorescence localization microscopy. FUS was found to be localized within the axon terminal in close proximity to the presynaptic vesicle protein Synaptophysin1 and adjacent to the active zone protein Bassoon, but well separated from the postsynaptic protein PSD-95. Having shown the presynaptic localization of FUS in the nervous system, a novel extranuclear role of FUS at neuronal contact sites has to be considered. Since there is growing evidence that local presynaptic translation might also be an important mechanism for plasticity, FUS – like the fragile X mental retardation protein FMRP – might act as one of the presynaptic RNA-binding proteins regulating this machinery. Our observation of presynaptic FUS should foster further investigations to determine its role in neurodegenerative diseases such as ALS and FTD. PMID:26834559

  5. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations.

    PubMed

    Larimore, Jennifer L; Chapleau, Christopher A; Kudo, Shinichi; Theibert, Anne; Percy, Alan K; Pozzo-Miller, Lucas

    2009-05-01

    The expression of the methylated DNA-binding protein MeCP2 increases during neuronal development, which suggests that this epigenetic factor is crucial for neuronal terminal differentiation. We evaluated dendritic and axonal development in embryonic day-18 hippocampal neurons in culture by measuring total length and counting branch point numbers at 4 days in vitro, well before synapse formation. Pyramidal neurons transfected with a plasmid encoding a small hairpin RNA (shRNA) to knockdown endogenous Mecp2 had shorter dendrites than control untransfected neurons, without detectable changes in axonal morphology. On the other hand, overexpression of wildtype (wt) human MECP2 increased dendritic branching, in addition to axonal branching and length. Consistent with reduced neuronal growth and complexity in Rett syndrome (RTT) brains, overexpression of human MECP2 carrying missense mutations common in RTT individuals (R106W or T158M) reduced dendritic and axonal length. One of the targets of MeCP2 transcriptional control is the Bdnf gene. Indeed, endogenous Mecp2 knockdown increased the intracellular levels of BDNF protein compared to untransfected neurons, suggesting that MeCP2 represses Bdnf transcription. Surprisingly, overexpression of wt MECP2 also increased BDNF levels, while overexpression of RTT-associated MECP2 mutants failed to affect BDNF levels. The extracellular BDNF scavenger TrkB-Fc prevented dendritic overgrowth in wt MECP2-overexpressing neurons, while overexpression of the Bdnf gene reverted the dendritic atrophy caused by Mecp2-knockdown. However, this effect was only partial, since Bdnf increased dendritic length only to control levels in mutant MECP2-overexpressing neurons, but not as much as in Bdnf-transfected cells. Our results demonstrate that MeCP2 plays varied roles in dendritic and axonal development during neuronal terminal differentiation, and that some of these effects are mediated by autocrine actions of BDNF.

  6. Recovery of network-driven glutamatergic activity in rat hippocampal neurons during chronic glutamate receptor blockade.

    PubMed

    Leininger, Eric; Belousov, Andrei B

    2009-01-28

    Previous studies indicated that a long-term decrease in the activity of ionotropic glutamate receptors induces cholinergic activity in rat and mouse hypothalamic neuronal cultures. Here we studied whether a prolonged inactivation of ionotropic glutamate receptors also induces cholinergic activity in hippocampal neurons. Receptor activity was chronically suppressed in rat hippocampal primary neuronal cultures with two proportionally increasing sets of concentrations of NMDA plus non-NMDA receptor antagonists: 100 microM/10 microM AP5/CNQX (1X cultures) and 200 microM/20 microM AP5/CNQX (2X cultures). Using calcium imaging we demonstrate that cholinergic activity does not develop in these cultures. Instead, network-driven glutamate-dependent activity, that normally is detected in hyper-excitable conditions, reappears in each culture group in the presence of these antagonists and can be reversibly suppressed by higher concentrations of AP5/CNQX. This activity is mediated by non-NMDA receptors and is modulated by NMDA receptors. Further, non-NMDA receptors, the general level of glutamate receptor activity and CaMK-dependent signaling are critical for development of this network-driven glutamatergic activity in the presence of receptor antagonists. Using electrophysiology, western blotting and calcium imaging we show that some neuronal parameters are either reduced or not affected by chronic glutamate receptor blockade. However, other parameters (including neuronal excitability, mEPSC frequency, and expression of GluR1, NR1 and betaCaMKII) become up-regulated and, in some cases, proportionally between the non-treated, 1X and 2X cultures. Our data suggest recovery of the network-driven glutamatergic activity after chronic glutamate receptor blockade. This recovery may represent a form of neuronal plasticity that compensates for the prolonged suppression of the activity of glutamate receptors.

  7. Dendritic atrophy constricts functional maps in resonance and impedance properties of hippocampal model neurons

    PubMed Central

    Dhupia, Neha; Rathour, Rahul K.; Narayanan, Rishikesh

    2015-01-01

    A gradient in the density of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels is necessary for the emergence of several functional maps within hippocampal pyramidal neurons. Here, we systematically analyzed the impact of dendritic atrophy on nine such functional maps, related to input resistance and local/transfer impedance properties, using conductance-based models of hippocampal pyramidal neurons. We introduced progressive dendritic atrophy in a CA1 pyramidal neuron reconstruction through a pruning algorithm, measured all functional maps in each pruned reconstruction, and arrived at functional forms for the dependence of underlying measurements on dendritic length. We found that, across frequencies, atrophied neurons responded with higher efficiency to incoming inputs, and the transfer of signals across the dendritic tree was more effective in an atrophied reconstruction. Importantly, despite the presence of identical HCN-channel density gradients, spatial gradients in input resistance, local/transfer resonance frequencies and impedance profiles were significantly constricted in reconstructions with dendritic atrophy, where these physiological measurements across dendritic locations converged to similar values. These results revealed that, in atrophied dendritic structures, the presence of an ion channel density gradient alone was insufficient to sustain homologous functional maps along the same neuronal topograph. We assessed the biophysical basis for these conclusions and found that this atrophy-induced constriction of functional maps was mediated by an enhanced spatial spread of the influence of an HCN-channel cluster in atrophied trees. These results demonstrated that the influence fields of ion channel conductances need to be localized for channel gradients to express themselves as homologous functional maps, suggesting that ion channel gradients are necessary but not sufficient for the emergence of functional maps within single neurons

  8. Lead increases tetrodotoxin-insensitive spontaneous release of glutamate and GABA from hippocampal neurons.

    PubMed

    Braga, M F; Pereira, E F; Marchioro, M; Albuquerque, E X

    1999-04-24

    This study was aimed at investigating the effects of the environmental pollutant lead (Pb2+) on the tetrodotoxin (TTX)-insensitive release of neurotransmitters from hippocampal neurons. Evidence is provided that Pb2+ (>/=100 nM) increases the frequency of gamma-aminobutyric acid (GABA)- and glutamate-mediated miniature postsynaptic currents (MPSCs) recorded by means of the patch-clamp technique from cultured hippocampal neurons. Because Pb2+ changed neither the amplitude nor the decay-time constant of the MPSCs, Pb2+-induced changes in MPSC frequency are exclusively due to a presynaptic action of this heavy metal. Increase by Pb2+ of the action potential-independent release of GABA and glutamate was concentration dependent and was only partially reversible upon washing of the neurons with nominally Pb2+-free external solution. This effect was also Ca2+ independent and began approximately after 1-2-min exposure of the neurons to Pb2+. The latency for the onset of the Pb2+'s effect on the MPSC frequency and the inability of the chelator ethylenediaminetetraacetic acid (100 microM) to reverse the effect that remained after washing of the neurons with external solution suggested that Pb2+ acted via an intracellular mechanism. Of interest also was the finding that Pb2+ simultaneously increased the release of GABA and glutamate, overriding the ability of these neurotransmitters to decrease the release of one another. Given that synaptic activity is a key mechanism for the establishment of stable synaptic connections early in the development, it is possible that, by interfering with spontaneous transmitter release, Pb2+ has lasting effects on neuronal maturation and plasticity.

  9. Dendritic atrophy constricts functional maps in resonance and impedance properties of hippocampal model neurons.

    PubMed

    Dhupia, Neha; Rathour, Rahul K; Narayanan, Rishikesh

    2014-01-01

    A gradient in the density of hyperpolarization-activated cyclic-nucleotide gated (HCN) channels is necessary for the emergence of several functional maps within hippocampal pyramidal neurons. Here, we systematically analyzed the impact of dendritic atrophy on nine such functional maps, related to input resistance and local/transfer impedance properties, using conductance-based models of hippocampal pyramidal neurons. We introduced progressive dendritic atrophy in a CA1 pyramidal neuron reconstruction through a pruning algorithm, measured all functional maps in each pruned reconstruction, and arrived at functional forms for the dependence of underlying measurements on dendritic length. We found that, across frequencies, atrophied neurons responded with higher efficiency to incoming inputs, and the transfer of signals across the dendritic tree was more effective in an atrophied reconstruction. Importantly, despite the presence of identical HCN-channel density gradients, spatial gradients in input resistance, local/transfer resonance frequencies and impedance profiles were significantly constricted in reconstructions with dendritic atrophy, where these physiological measurements across dendritic locations converged to similar values. These results revealed that, in atrophied dendritic structures, the presence of an ion channel density gradient alone was insufficient to sustain homologous functional maps along the same neuronal topograph. We assessed the biophysical basis for these conclusions and found that this atrophy-induced constriction of functional maps was mediated by an enhanced spatial spread of the influence of an HCN-channel cluster in atrophied trees. These results demonstrated that the influence fields of ion channel conductances need to be localized for channel gradients to express themselves as homologous functional maps, suggesting that ion channel gradients are necessary but not sufficient for the emergence of functional maps within single neurons.

  10. Moderate increases in intracellular calcium activate neuroprotective signals in hippocampal neurons.

    PubMed

    Bickler, P E; Fahlman, C S

    2004-01-01

    Although large increases in neuronal intracellular calcium concentrations ([Ca(2+)](i)) are lethal, moderate increases in [Ca(2+)](i) of 50-200 nM may induce immediate or long-term tolerance of ischemia or other stresses. In neurons in rat hippocampal slice cultures, we determined the relationship between [Ca(2+)](i), cell death, and Ca(2+)-dependent neuroprotective signals before and after a 45 min period of oxygen and glucose deprivation (OGD). Thirty minutes before OGD, [Ca(2+)](i) was increased in CA1 neurons by 40-200 nM with 1 nM-1 microM of a Ca(2+)-selective ionophore (calcimycin or ionomycin-"Ca(2+) preconditioning"). Ca(2+) preconditioning greatly reduced cell death in CA1, CA3 and dentate during the following 7 days, even though [Ca(2+)](i) was similar (approximately 2 microM) in preconditioned and control neurons 1 h after the OGD. When pre-OGD [Ca(2+)](i) was lowered to 25 nM (10 nM ionophore in Ca(2+)-free medium) or increased to 8 microM (10 microM ionophore), more than 90% of neurons died. Increased levels of the anti-apoptotic protein protein kinase B (Akt) and the MAP kinase ERK (p42/44) were present in preconditioned slices after OGD. Reducing Ca(2+) influx, inhibiting calmodulin, and preventing Akt or MAP kinase p42/44 upregulation prevented Ca(2+) preconditioning, supporting a specific role for Ca(2+) in the neuroprotective process. Further, in continuously oxygenated cultured hippocampal/cortical neurons, preconditioning for 30 min with 10 nM ionomycin reduced cell death following a 4 microM increase in [Ca(2+)](i) elicited by 1 microM ionomycin. Thus, a zone of moderately increased [Ca(2+)](i) before a potentially lethal insult promotes cell survival, uncoupling subsequent large increases in [Ca(2+)](i) from initiating cell death processes.

  11. Ischemic insults promote epigenetic reprogramming of μ opioid receptor expression in hippocampal neurons

    PubMed Central

    Formisano, Luigi; Noh, Kyung-Min; Miyawaki, Takahiro; Mashiko, Toshihiro; Bennett, Michael V. L.; Zukin, R. Suzanne

    2007-01-01

    Transient global ischemia is a neuronal insult that induces delayed, selective death of hippocampal CA1 pyramidal neurons. A mechanism underlying ischemia-induced cell death is activation of the gene silencing transcription factor REST (repressor element-1 silencing transcription factor)/NRSF (neuron-restrictive silencing factor) and REST-dependent suppression of the AMPA receptor subunit GluR2 in CA1 neurons destined to die. Here we show that REST regulates an additional gene target, OPRM1 (μ opioid receptor 1 or MOR-1). MORs are abundantly expressed by basket cells and other inhibitory interneurons of CA1. Global ischemia induces a marked decrease in MOR-1 mRNA and protein expression that is specific to the selectively vulnerable area CA1, as assessed by quantitative real-time RT-PCR, Western blotting, and ChIP. We further show that OPRM1 gene silencing is REST-dependent and occurs via epigenetic modifications. Ischemia promotes deacetylation of core histone proteins H3 and H4 and dimethylation of histone H3 at lysine-9 (H3-K9) over the MOR-1 promoter, an signature of epigenetic gene silencing. Acute knockdown of MOR-1 gene expression by administration of antisense oligodeoxynucleotides to hippocampal slices in vitro or injection of the MOR antagonist naloxone to rats in vivo affords protection against ischemia-induced death of CA1 pyramidal neurons. These findings implicate MORs in ischemia-induced death of CA1 pyramidal neurons and document epigenetic remodeling of expression of OPRM1 in CA1 inhibitory interneurons. PMID:17360495

  12. Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage.

    PubMed

    Amrein, Irmgard; Isler, Karin; Lipp, Hans-Peter

    2011-09-01

    Adult hippocampal neurogenesis is a prominent event in rodents. In species with longer life expectancies, newly born cells in the adult dentate gyrus of the hippocampal formation are less abundant or can be completely absent. Several lines of evidence indicate that the regulatory mechanisms of adult neurogenesis differ between short- and long-lived mammals. After a critical appraisal of the factors and problems associated with comparing different species, we provide a quantitative comparison derived from seven laboratory strains of mice (BALB, C57BL/6, CD1, outbred) and rats (F344, Sprague-Dawley, Wistar), six other rodent species of which four are wild-derived (wood mouse, vole, spiny mouse and guinea pig), three non-human primate species (marmoset and two macaque species) and one carnivore (red fox). Normalizing the number of proliferating cells to total granule cell number, we observe an overall exponential decline in proliferation that is chronologically equal between species and orders and independent of early developmental processes and life span. Long- and short-lived mammals differ with regard to major life history stages; at the time points of weaning, age at first reproduction and average life expectancy, long-lived primates and foxes have significantly fewer proliferating cells than rodents. Although the database for neuronal differentiation is limited, we find indications that the extent of neuronal differentiation is subject to species-specific selective adaptations. We conclude that absolute age is the critical factor regulating cell genesis in the adult hippocampus of mammals. Ontogenetic and ecological factors primarily influence the regulation of neuronal differentiation rather than the rate of cell proliferation.

  13. NaHS Protects against the Impairments Induced by Oxygen-Glucose Deprivation in Different Ages of Primary Hippocampal Neurons

    PubMed Central

    Yu, Qian; Wang, Binrong; Zhao, Tianzhi; Zhang, Xiangnan; Tao, Lei; Shi, Jinshan; Sun, Xude; Ding, Qian

    2017-01-01

    Brain ischemia leads to poor oxygen supply, and is one of the leading causes of brain damage and/or death. Neuroprotective agents are thus in great need for treatment purpose. Using both young and aged primary cultured hippocampal neurons as in vitro models, we investigated the effect of sodium hydrosulfide (NaHS), an exogenous donor of hydrogen sulfide, on oxygen-glucose deprivation (OGD) damaged neurons that mimick focal cerebral ischemia/reperfusion (I/R) induced brain injury. NaHS treatment (250 μM) protected both young and aged hippocampal neurons, as indicated by restoring number of primary dendrites by 43.9 and 68.7%, number of dendritic end tips by 59.8 and 101.1%, neurite length by 36.8 and 66.7%, and spine density by 38.0 and 58.5% in the OGD-damaged young and aged neurons, respectively. NaHS treatment inhibited growth-associated protein 43 downregulation, oxidative stress in both young and aged hippocampal neurons following OGD damage. Further studies revealed that NaHS treatment could restore ERK1/2 activation, which was inhibited by OGD-induced protein phosphatase 2 (PP2A) upregulation. Our results demonstrated that NaHS has potent protective effects against neuron injury induced by OGD in both young and aged hippocampal neurons. PMID:28326019

  14. Deep Sequencing and High-Resolution Imaging Reveal Compartment-Specific Localization of Bdnf mRNA in Hippocampal Neurons

    PubMed Central

    Will, Tristan J.; Tushev, Georgi; Kochen, Lisa; Nassim-Assir, Belquis; Cajigas, Ivan J.; tom Dieck, Susanne; Schuman, Erin M.

    2016-01-01

    Brain-derived neurotrophic factor (BDNF) is a small protein of the neurotrophin family that regulates various brain functions. Although much is known about how its transcription is regulated, the abundance of endogenous BDNF mRNA and its subcellular localization pattern are matters of debate. We used next-generation sequencing and high-resolution in situ hybridization in the rat hippocampus to reexamine this question. We performed 3′ end sequencing on rat hippocampal slices and detected two isoforms of Bdnf containing either a short or a long 3′ untranslated region (3′UTR). Most of the Bdnf transcripts contained the short 3′UTR isoform and were present in low amounts relative to other neuronal transcripts. Bdnf mRNA was present in the somatic compartment of rat hippocampal slices or the somata of cultured rat hippocampal neurons but was rarely detected in the dendritic processes. Pharmacological stimulation of hippocampal neurons induced Bdnf expression but did not change the ratio of Bdnf isoform abundance. The findings indicate that endogenous Bdnf mRNA, although weakly abundant, is primarily localized to the somatic compartment of hippocampal neurons. Both Bdnf mRNA isoforms have shorter half-lives compared with other neuronal mRNAs. Furthermore, the findings show that using complementary high-resolution techniques can provide sensitive measures of endogenous transcript abundance. PMID:24345682

  15. Hippocampal pyramidal neurons switch from a multipolar migration mode to a novel "climbing" migration mode during development.

    PubMed

    Kitazawa, Ayako; Kubo, Ken-ichiro; Hayashi, Kanehiro; Matsunaga, Yuki; Ishii, Kazuhiro; Nakajima, Kazunori

    2014-01-22

    The hippocampus plays important roles in brain functions. Despite the importance of hippocampal functions, recent analyses of neuronal migration have mainly been performed on the cerebral neocortex, and the cellular mechanisms responsible for the formation of the hippocampus are not yet completely understood. Moreover, why a prolonged time is required for hippocampal neurons to complete their migration has been unexplainable for several decades. We analyzed the migratory profile of neurons in the developing mouse hippocampal CA1 region and found that the hippocampal pyramidal neurons generated near the ventricle became postmitotic multipolar cells and accumulated in the multipolar cell accumulation zone (MAZ) in the late stage of development. The hippocampal neurons passed through the pyramidal layer by a unique mode of migration. Their leading processes were highly branched and made contact with many radial fibers. Time-lapse imaging revealed that the migrating cells changed their scaffolds from the original radial fibers to other radial fibers, and as a result they proceed in a zigzag manner, with long intervals. The migrating cells in the hippocampus reminded us of "rock climbers" that instead of using their hands to pull up their bodies were using their leading processes to pull up their cell bodies. Because this mode of migration had never been described, we called it the "climbing" mode. The change from the "climbing" mode in the hippocampus to the "locomotion" mode in the neocortex may have contributed to the brain expansion during evolution.

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

    PubMed

    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. Hippocampal EEG and Unit Activity Responses to Modulation of Serotonergic Median Raphe Neurons in the Freely Behaving Rat

    PubMed Central

    Nitz, Douglas A.; McNaughton, Bruce L.

    1999-01-01

    Hippocampal EEG, GABAergic interneurons, and principal cells were recorded simultaneously as rats foraged within one of three environments both before and after modulation of serotonergic inputs to the hippocampus. Median raphe microinjections of the 5-HT1a receptor agonist 8-OH-DPAT were made to produce inhibition of serotonergic neurons in this region. Such microinjections produced behavioral arousal and increases in the amplitude of hippocampal EEG theta. Consistent with the pattern of serotonergic innervation of the hippocampus, the GABAergic interneuron population was affected differentially by the microinjections. Principal cells were generally unaffected by the manipulation and maintained robust spatial firing correlates within the foraging environment. The results provide basic data on the relationship between serotonergic median raphe neurons and hippocampal activity in a behaving animal. The data suggest that behavioral responses to manipulation of the serotonergic system are mediated by brain regions other than the hippocampus or are mediated through changes in the activity of hippocampal interneurons. PMID:10327240

  18. GSK-3β-induced Tau pathology drives hippocampal neuronal cell death in Huntington's disease: involvement of astrocyte–neuron interactions

    PubMed Central

    L'Episcopo, F; Drouin-Ouellet, J; Tirolo, C; Pulvirenti, A; Giugno, R; Testa, N; Caniglia, S; Serapide, M F; Cisbani, G; Barker, R A; Cicchetti, F; Marchetti, B

    2016-01-01

    Glycogen synthase kinase-3β (GSK-3β) has emerged as a critical factor in several pathways involved in hippocampal neuronal maintenance and function. In Huntington's disease (HD), there are early hippocampal deficits both in patients and transgenic mouse models, which prompted us to investigate whether disease-specific changes in GSK-3β expression may underlie these abnormalities. Thirty-three postmortem hippocampal samples from HD patients (neuropathological grades 2–4) and age- and sex-matched normal control cases were analyzed using real-time quantitative reverse transcription PCRs (qPCRs) and immunohistochemistry. In vitro and in vivo studies looking at hippocampal pathology and GSK-3β were also undertaken in transgenic R6/2 and wild-type mice. We identified a disease and stage-dependent upregulation of GSK-3β mRNA and protein levels in the HD hippocampus, with the active isoform pGSK-3β-Tyr216 being strongly expressed in dentate gyrus (DG) neurons and astrocytes at a time when phosphorylation of Tau at the AT8 epitope was also present in these same neurons. This upregulation of pGSK-3β-Tyr216 was also found in the R6/2 hippocampus in vivo and linked to the increased vulnerability of primary hippocampal neurons in vitro. In addition, the increased expression of GSK-3β in the astrocytes of R6/2 mice appeared to be the main driver of Tau phosphorylation and caspase3 activation-induced neuronal death, at least in part via an exacerbated production of major proinflammatory mediators. This stage-dependent overactivation of GSK-3β in HD-affected hippocampal neurons and astrocytes therefore points to GSK-3β as being a critical factor in the pathological development of this condition. As such, therapeutic targeting of this pathway may help ameliorate neuronal dysfunction in HD. PMID:27124580

  19. Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis.

    PubMed

    Malik, Ruchi; Dougherty, Kelly Ann; Parikh, Komal; Byrne, Connor; Johnston, Daniel

    2016-03-01

    Differences in behavioral roles, anatomical connectivity, and gene expression patterns in the dorsal, intermediate, and ventral regions of the hippocampus are well characterized. Relatively fewer studies have, however, focused on comparing the physiological properties of neurons located at different dorsoventral extents of the hippocampus. Recently, we reported that dorsal CA1 neurons are less excitable than ventral neurons. There is little or no information for how neurons in the intermediate hippocampus compare to those from the dorsal and ventral ends. Also, it is not known whether the transition of properties along the dorsoventral axis is gradual or segmented. In this study, we developed a statistical model to predict the dorsoventral position of transverse hippocampal slices. Using current clamp recordings combined with this model, we found that CA1 neurons in dorsal, intermediate, and ventral hippocampus have distinct electrophysiological and morphological properties and that the transition in most (but not all) of these properties from the ventral to dorsal end is gradual. Using linear and segmented regression analyses, we found that input resistance and resting membrane potential changed linearly along the V-D axis. Interestingly, the transition in resonance frequency, rebound slope, dendritic branching in stratum radiatum, and action potential properties was segmented along the V-D axis. Together, the findings from this study highlight the heterogeneity in CA1 neuronal properties along the entire longitudinal axis of hippocampus.

  20. Mapping the electrophysiological and morphological properties of CA1 pyramidal neurons along the longitudinal hippocampal axis

    PubMed Central

    Ruchi, Malik; Ann, Dougherty Kelly; Komal, Parikh; Connor, Byrne; Daniel, Johnston

    2015-01-01

    Differences in behavioral roles, anatomical connectivity and gene expression patterns in the dorsal, intermediate and ventral regions of the hippocampus are well characterized. Relatively fewer studies have, however, focused on comparing the physiological properties of neurons located at different dorsoventral extents of the hippocampus. Recently we reported that dorsal CA1 neurons are less excitable than ventral neurons. There is little or no information for how neurons in the intermediate hippocampus compare to those from the dorsal and ventral ends. Also, it is not known whether the transition of properties along the dorsoventral axis is gradual or segmented. In this study, we developed a statistical model to predict the dorsoventral position of transverse hippocampal slices. Using current clamp recordings combined with this model, we found that CA1 neurons in dorsal, intermediate and ventral hippocampus have distinct electrophysiological and morphological properties and that the transition in most (but not all) of these properties from the ventral to dorsal end is gradual. Using linear and segmented regression analyses, we found that input resistance and resting membrane potential changed linearly along the V–D axis. Interestingly, the transition in resonance frequency, rebound slope, dendritic branching in stratum radiatum and action potential properties was segmented along the V–D axis. Together, the findings from this study highlight the heterogeneity in CA1 neuronal properties along the entire longitudinal axis of hippocampus. PMID:26333017

  1. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death

    PubMed Central

    Noh, Kyung-Min; Yokota, Hidenori; Mashiko, Toshihiro; Castillo, Pablo E.; Zukin, R. Suzanne; Bennett, Michael V. L.

    2005-01-01

    Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn2+ in CA1 neurons just before the onset of histologically detectable cell death. Here we show that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca2+/Zn2+-permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn2+ and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn2+ in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn2+ and death of CA1 neurons, although a direct action at the time of the rise in Zn2+ is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans. PMID:16093311

  2. Chronic exposure to GSM 1800-MHz microwaves reduces excitatory synaptic activity in cultured hippocampal neurons.

    PubMed

    Xu, Shujun; Ning, Wei; Xu, Zhengping; Zhou, Suya; Chiang, Huai; Luo, Jianhong

    2006-05-08

    The world wide proliferation of mobile phones raises the concern about the health effects of 1800-MHz microwaves on the brain. The present study assesses the effects of microwave exposure on the function of cultured hippocampal neurons of rats using whole cell patch-clamp analysis combined with immunocytochemistry. We showed that chronic exposure (15 min per day for 8 days) to Global System for Mobile Communication (GSM) 1800-MHz microwaves at specific absorption rate (SAR) of 2.4 W/kg induced a selective decrease in the amplitude of alpha-amino-3-hydroxy-5-methyl-4-soxazole propionic acid (AMPA) miniature excitatory postsynaptic currents (mEPSCs), whereas the frequency of AMPA mEPSCs and the amplitude of N-methyl-D-aspartate (NMDA) mEPSCs did not change. Furthermore, the GSM microwave treatment decreased the expression of postsynaptic density 95 (PSD95) in cultured neurons. Our results indicated that 2.4 W/kg GSM 1800-MHz microwaves may reduce excitatory synaptic activity and the number of excitatory synapses in cultured rat hippocampal neurons.

  3. Interaction of Acetylcholinesterase with Neurexin-1β regulates Glutamatergic Synaptic stability in Hippocampal neurons

    PubMed Central

    2014-01-01

    Background Excess expression of acetylcholinesterase (AChE) in the cortex and hippocampus causes a decrease in the number of glutamatergic synapses and alters the expression of neurexin and neuroligin, trans-synaptic proteins that control synaptic stability. The molecular sequence and three-dimensional structure of AChE are homologous to the corresponding aspects of the ectodomain of neuroligin. This study investigated whether excess AChE interacts physically with neurexin to destabilize glutamatergic synapses. Results The results showed that AChE clusters colocalized with neurexin assemblies in the neurites of hippocampal neurons and that AChE co-immunoprecipitated with neurexin from the lysate of these neurons. Moreover, when expressed in human embryonic kidney 293 cells, N-glycosylated AChE co-immunoprecipitated with non-O–glycosylated neurexin-1β, with N-glycosylation of the AChE being required for this co-precipitation to occur. Increasing extracellular AChE decreased the association of neurexin with neuroligin and inhibited neuroligin-induced synaptogenesis. The number and activity of excitatory synapses in cultured hippocampal neurons were reduced by extracellular catalytically inactive AChE. Conclusions Excessive glycosylated AChE could competitively disrupt a subset of the neurexin–neuroligin junctions consequently impairing the integrity of glutamatergic synapses. This might serve a molecular mechanism of excessive AChE induced neurodegeneration. PMID:24594013

  4. Undaria pinnatifida Promotes Spinogenesis and Synaptogenesis and Potentiates Functional Presynaptic Plasticity in Hippocampal Neurons.

    PubMed

    Maqueshudul Haque Bhuiyan, Mohammad; Mohibbullah, Md; Hannan, Md Abdul; Hong, Yong-Ki; Choi, Jae-Suk; Choi, In Soon; Moon, Il Soo

    2015-01-01

    Reductions in neurotrophic factors are implicated in synaptic dysfunction in the central nervous system, but exogenous neurotrophic factors with potential effects on neuritic regeneration and synaptic reconstruction could offer therapeutic and preventive strategies for treating memory-related neurological disorders. In an earlier effort to identify natural neurotrophic agents, we found that the ethanol extract of the edible marine alga Undaria pinnatifida (UPE) had promising effects on the neuritogenesis of cultured hippocampal neurons. Here, we further investigated the ability of UPE to promote spinogenesis and synaptogenesis in primary cultures of hippocampal neurons. It was found that UPE triggered significant increase in numbers of dendritic filopodia and spines, promoted the formation of excitatory and inhibitory synapses, and potentiated synaptic transmission by increasing the sizes of reserve vesicle pools at presynaptic terminals. These findings indicate a substantial role for UPE in the morphological and functional maturation of neurons and suggest that UPE is a possible therapeutic preventative measure and treatment for neurodegenerative diseases, such as those involving cognitive disorders and memory impairments.

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

    PubMed

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

    2015-05-01

    Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low-intensity walking activity, which may be related to leisure-time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher-intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low-intensity walking activity, independent of moderate- to vigorous-intensity activity and self-reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings

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

    PubMed Central

    HATALSKI, C. G.; BRUNSON, K. L.; TANTAYANUBUTR, B.; CHEN, Y.; BARAM, T. Z.

    2011-01-01

    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 abundance in CNS regions involved with the neuroendocrine responses to stress has been forthcoming, the mechanisms regulating the peptide’s levels in the hippocampus have not yet been determined. Here we tested the hypothesis that, in the immature rat hippocampus, neuronal stimulation, rather than neuroendocrine challenge, influences the peptide’s expression. Messenger RNA levels of corticotropin-releasing hormone in hippocampal CA1, CA3 and the dentate gyrus, as well as in the hypothalamic paraventricular nucleus, were determined after cold, a physiological challenge that activates the hypothalamic pituitary adrenal system in immature rats, and after activation of hippocampal neurons by hyperthermia. These studies demonstrated that, while cold challenge enhanced corticotropin-releasing hormone messenger RNA levels in the hypothalamus, hippocampal expression of this neuropeptide was unchanged. Secondly, hyperthermia stimulated expression of hippocampal immediate-early genes, as well as of corticotropin-releasing hormone. Finally, the mechanism of hippocampal corticotropin-releasing hormone induction required neuronal stimulation and was abolished by barbiturate administration. Taken together, these results indicate that neuronal stimulation may regulate hippocampal corticotropin-releasing hormone expression in the immature rat, whereas the peptide’s expression in the hypothalamus is influenced by neuroendocrine challenges. PMID:11113306

  7. Gene expression levels assessed by CA1 pyramidal neuron and regional hippocampal dissections in Alzheimer’s disease

    PubMed Central

    Ginsberg, Stephen D.; Alldred, Melissa J.; Che, Shaoli

    2011-01-01

    To evaluate molecular signatures of an individual cell type in comparison to the associated region relevant towards understanding the pathogenesis of Alzheimer’s disease (AD), CA1 pyramidal neurons and the surrounding hippocampal formation were microaspirated via laser capture microdissection (LCM) from neuropathologically confirmed AD and age-matched control (CTR) subjects as well as from wild type mouse brain using single population RNA amplification methodology coupled with custom-designed microarray analysis with real-time quantitative polymerase-chain reaction (qPCR) validation. CA1 pyramidal neurons predominantly displayed downregulation of classes of transcripts related to synaptic transmission in AD versus CTR. Regional hippocampal dissections displayed downregulation of several overlapping genes found in the CA1 neuronal population related to neuronal expression, as well as upregulation of select transcripts indicative of admixed cell types including glial-associated markers and immediate-early and cell death genes. Gene level distributions observed in CA1 neurons and regional hippocampal dissections in wild type mice paralleled expression mosaics seen in postmortem human tissue. Microarray analysis was validated in qPCR studies using human postmortem brain tissue and CA1 sector and regional hippocampal dissections obtained from a mouse model of AD/Down syndrome (Ts65Dn mice) and normal disomic (2N) littermates. Classes of transcripts that have a greater percentage of the overall hybridization signal intensity within single neurons tended to be genes related to neuronal communication. The converse was also found, as classes of transcripts such as glial-associated markers were under represented in CA1 pyramidal neuron expression profiles relative to regional hippocampal dissections. These observations highlight a dilution effect that is likely to occur in conventional regional microarray and qPCR studies. Thus, single population studies of specific

  8. Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the Kv2.1 potassium channel

    PubMed Central

    Mohapatra, Durga P.; Misonou, Hiroaki; Pan, Sheng-Jun; Held, Joshua E.; Surmeier, D. James; Trimmer, James S.

    2009-01-01

    Kv2.1 is the prominent somatodendritic sustained or delayed rectifier voltage-gated potassium (Kv) channel in mammalian central neurons, and is a target for activity-dependent modulation via calcineurin-dependent dephosphorylation. Using hanatoxin-mediated block of Kv2.1 we show that, in cultured rat hippocampal neurons, glutamate stimulation leads to significant hyperpolarizing shifts in the voltage-dependent activation and inactivation gating properties of the Kv2.1-component of delayed rectifier K+ (IK) currents. In computer models of hippocampal neurons, these glutamate-stimulated shifts in the gating of the Kv2.1-component of IK lead to a dramatic suppression of action potential firing frequency. Current-clamp experiments in cultured rat hippocampal neurons showed glutamate-stimulation induced a similar suppression of neuronal firing frequency. Membrane depolarization also resulted in similar hyperpolarizing shifts in the voltage-dependent gating properties of neuronal IK currents, and suppression of neuronal firing. The glutamate-induced effects on neuronal firing were eliminated by hanatoxin, but not by dendrotoxin-K, a blocker of Kv1.1-containing channels. These studies together demonstrate a specific contribution of modulation of Kv2.1 channels in the activity-dependent regulation of intrinsic neuronal excitability. PMID:19276663

  9. NMDAR-Mediated Hippocampal Neuronal Death is Exacerbated by Activities of ASIC1a

    PubMed Central

    Gao, Su; Yu, Yang; Ma, Zhi-Yuan; Sun, Hui; Zhang, Yong-Li; Wang, Xing-Tao; Wang, Chaoyun; Fan, Wei-Ming; Zheng, Qing-Yin

    2015-01-01

    NMDARs and ASIC1a both exist in central synapses and mediate important physiological and pathological conditions, but the functional relationship between them is unclear. Here we report several novel findings that may shed light on the functional relationship between these two ion channels in the excitatory postsynaptic membrane of mouse hippocampus. Firstly, NMDAR activation induced by either NMDA or OGD led to increased [Ca2+]i and greater apoptotic and necrotic cell deaths in cultured hippocampal neurons; these cell deaths were prevented by application of NMDAR antagonists. Secondly, ASIC1a activation induced by pH 6.0 extracellular solution (ECS) showed similar increases in apoptotic and necrotic cell deaths; these cell deaths were prevented by ASIC1a antagonists, and also by NMDAR antagonists. Since increased [Ca2+]i leads to increased cell deaths and since NMDAR exhibits much greater calcium permeability than ASIC1a, these data suggest that ASIC1a-induced neuronal death is mediated through activation of NMDARs. Thirdly, treatment of hippocampal cultures with both NMDA and acidic ECS induced greater degrees of cell deaths than either NMDA or acidic ECS treatment alone. These results suggest that ASIC1a activation up-regulates NMDAR function. Additional data supporting the functional relationship between ASIC1a and NMDAR are found in our electrophysiology experiments in hippocampal slices, where stimulation of ASIC1a induced a marked increase in NMDAR EPSC amplitude, and inhibition of ASIC1a resulted in a decrease in NMDAR EPSC amplitude. In summary, we present evidence that ASIC1a activity facilitates NMDAR function and exacerbates NMDAR-mediated neuronal death in pathological conditions. These findings are invaluable to the search for novel therapeutic targets in the treatment of brain ischemia. PMID:25947342

  10. Blocking brain-derived neurotrophic factor inhibits injury-induced hyperexcitability of hippocampal CA3 neurons.

    PubMed

    Gill, Raminder; Chang, Philip K-Y; Prenosil, George A; Deane, Emily C; McKinney, Rebecca A

    2013-12-01

    Brain trauma can disrupt synaptic connections, and this in turn can prompt axons to sprout and form new connections. If these new axonal connections are aberrant, hyperexcitability can result. It has been shown that ablating tropomyosin-related kinase B (TrkB), a receptor for brain-derived neurotrophic factor (BDNF), can reduce axonal sprouting after hippocampal injury. However, it is unknown whether inhibiting BDNF-mediated axonal sprouting will reduce hyperexcitability. Given this, our purpose here was to determine whether pharmacologically blocking BDNF inhibits hyperexcitability after injury-induced axonal sprouting in the hippocampus. To induce injury, we made Schaffer collateral lesions in organotypic hippocampal slice cultures. As reported by others, we observed a 50% reduction in axonal sprouting in cultures treated with a BDNF blocker (TrkB-Fc) 14 days after injury. Furthermore, lesioned cultures treated with TrkB-Fc were less hyperexcitable than lesioned untreated cultures. Using electrophysiology, we observed a two-fold decrease in the number of CA3 neurons that showed bursting responses after lesion with TrkB-Fc treatment, whereas we found no change in intrinsic neuronal firing properties. Finally, evoked field excitatory postsynaptic potential recordings indicated an increase in network activity within area CA3 after lesion, which was prevented with chronic TrkB-Fc treatment. Taken together, our results demonstrate that blocking BDNF attenuates injury-induced hyperexcitability of hippocampal CA3 neurons. Axonal sprouting has been found in patients with post-traumatic epilepsy. Therefore, our data suggest that blocking the BDNF-TrkB signaling cascade shortly after injury may be a potential therapeutic target for the treatment of post-traumatic epilepsy.

  11. Ethanol exposure in early adolescence inhibits intrinsic neuronal plasticity via sigma-1 receptor activation in hippocampal CA1 neurons

    PubMed Central

    Sabeti, Jilla

    2011-01-01

    Background We demonstrated previously that rats exposed to chronic intermittent ethanol (CIE) vapors in early adolescence show increased magnitudes of long-term potentiation (LTP) of excitatory transmission when recorded at dendritic synapses in hippocampus. Large amplitude LTP following CIE exposure is mediated by sigma-1 receptors; however, not yet addressed is the role of sigma-1 receptors in modulating the intrinsic properties of neurons to alter their action potential firing during LTP. Methods Activity-induced plasticity of spike firing was investigated using rat hippocampal slice recordings to measure changes in both field excitatory postsynaptic potentials (fEPSPs) and population spikes (pop. spikes) concomitantly at dendritic inputs and soma of CA1 pyramidal neurons, respectively. Results We observed unique modifications in plasticity of action potential firing in hippocampal slices from CIE exposed adolescent rats, where the induction of large amplitude LTP by 100 Hz stimulations was accompanied by reduced CA1 neuronal excitability—reflected as decreased pop. spike efficacy and impaired activity-induced fEPSP-to-spike (E-S) potentiation. By contrast, LTP induction in ethanol-naïve control slices resulted in increased spike efficacy and robust E-S potentiation. E-S potentiation impairments emerged at 24 hr after CIE treatment cessation, but not before the alcohol withdrawal period, and were restored with bath-application of the sigma-1 receptor selective antagonist BD1047, but not the NMDA receptor antagonist D-AP5. Further evidence revealed a significantly shortened somatic fEPSP time course in adolescent CIE-withdrawn hippocampal slices during LTP; however, paired-pulse data show no apparent correspondence between E-S dissociation and altered recurrent feedback inhibition. Conclusions Results here suggest that acute withdrawal from adolescent CIE exposure triggers sigma-1 receptors that act to depress the efficacy of excitatory inputs in triggering

  12. Glutamate-mediated excitotoxicity in neonatal hippocampal neurons is mediated by mGluR-induced release of Ca++ from intracellular stores and is prevented by estradiol

    PubMed Central

    Hilton, Genell D.; Nunez, Joseph L.; Bambrick, Linda; Thompson, Scott M.; McCarthy, Margaret M.

    2008-01-01

    Hypoxic/ischemic (HI) brain injury in newborn full-term and premature infants is a common and pervasive source of life time disabilities in cognitive and locomotor function. In the adult, HI induces glutamate release and excitotoxic cell death dependent on NMDA receptor activation. In animal models of the premature human infant, glutamate is also released following HI, but neurons are largely insensitive to NMDA or AMPA/kainic acid (KA) receptor-mediated damage. Using primary cultured hippocampal neurons we have determined that glutamate increases intracellular calcium much more than kainic acid. Moreover, glutamate induces cell death by activating Type I metabotropic glutamate receptors (mGluRs). Pretreatment of neurons with the gonadal steroid estradiol reduces the level of the Type I metabotropic glutamate receptors and completely prevents cell death, suggesting a novel therapeutic approach to excitotoxic brain damage in the neonate. PMID:17156362

  13. Oppositional Effects of Serotonin Receptors 5-HT1a, 2, and 2c in the Regulation of Adult Hippocampal Neurogenesis

    PubMed Central

    Klempin, Friederike; Babu, Harish; Tonelli, Davide De Pietri; Alarcon, Edson; Fabel, Klaus; Kempermann, Gerd

    2009-01-01

    Serotonin (5-HT) appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lacked acute effects on adult neurogenesis in many studies, which suggested a surprisingly long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late-stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT receptors. PMID

  14. Early postnatal stress suppresses the developmental trajectory of hippocampal pyramidal neurons: the role of CRHR1.

    PubMed

    Liu, Rui; Yang, Xiao-Dun; Liao, Xue-Mei; Xie, Xiao-Meng; Su, Yun-Ai; Li, Ji-Tao; Wang, Xiao-Dong; Si, Tian-Mei

    2016-12-01

    Adverse experiences early in life hamper the development and maturation of the hippocampus, but how early-life stress perturbs the developmental trajectory of the hippocampus across various life stages and the underlying molecular mechanisms remain to be investigated. In this study, we stressed male mice from postnatal day 2 (P2) to P9, and examined the potential role of CRHR1 in postnatal stress-induced structural remodeling of hippocampal CA3 pyramidal neurons directly after stress (P9), in mid-adolescence (P35) and in adulthood (P90). We found that early-life stress exposure significantly reduced apical dendritic arborization and spine density in CA3 neurons on P9 and P90. Moreover, postnatally stressed neurons underwent increased pruning of spines, especially thin spines, between P35 and P90. These stress-induced immediate and long-term structural abnormalities could be abolished by daily systemic administration of the CRHR1 antagonist antalarmin (20 µg/g of body weight) during stress exposure. However, such treatment strategy failed to attenuate the deleterious stress effects in mid-adolescence on P35. We then extended antalarmin treatment until the end of the second postnatal week, and found that prolonged blockade of CRHR1 could prevent the mid-term impact of early postnatal stress on structural remodeling of CA3 neurons. Our study characterized the influences of early-life stress on the developmental trajectory of hippocampal pyramidal neurons, and highlighted the critical role of CRHR1 in modulating these negative outcomes evoked by early-life stress.

  15. Astaxanthin Protects Primary Hippocampal Neurons against Noxious Effects of Aβ-Oligomers

    PubMed Central

    Lobos, Pedro; Bruna, Barbara; Cordova, Alex; Barattini, Pablo; Galáz, Jose Luis; Adasme, Tatiana; Hidalgo, Cecilia; Muñoz, Pablo

    2016-01-01

    Increased reactive oxygen species (ROS) generation and the ensuing oxidative stress contribute to Alzheimer's disease pathology. We reported previously that amyloid-β peptide oligomers (AβOs) produce aberrant Ca2+ signals at sublethal concentrations and decrease the expression of type-2 ryanodine receptors (RyR2), which are crucial for hippocampal synaptic plasticity and memory. Here, we investigated whether the antioxidant agent astaxanthin (ATX) protects neurons from AβOs-induced excessive mitochondrial ROS generation, NFATc4 activation, and RyR2 mRNA downregulation. To determine mitochondrial H2O2 production or NFATc4 nuclear translocation, neurons were transfected with plasmids coding for HyperMito or NFATc4-eGFP, respectively. Primary hippocampal cultures were incubated with 0.1 μM ATX for 1.5 h prior to AβOs addition (500 nM). We found that incubation with ATX (≤10 μM) for ≤24 h was nontoxic to neurons, evaluated by the live/dead assay. Preincubation with 0.1 μM ATX also prevented the neuronal mitochondrial H2O2 generation induced within minutes of AβOs addition. Longer exposures to AβOs (6 h) promoted NFATc4-eGFP nuclear translocation and decreased RyR2 mRNA levels, evaluated by detection of the eGFP-tagged fluorescent plasmid and qPCR, respectively. Preincubation with 0.1 μM ATX prevented both effects. These results indicate that ATX protects neurons from the noxious effects of AβOs on mitochondrial ROS production, NFATc4 activation, and RyR2 gene expression downregulation. PMID:27034843

  16. Bursting Neurons in the Hippocampal Formation Encode Features of LFP Rhythms

    PubMed Central

    Constantinou, Maria; Gonzalo Cogno, Soledad; Elijah, Daniel H.; Kropff, Emilio; Gigg, John; Samengo, Inés; Montemurro, Marcelo A.

    2016-01-01

    Burst spike patterns are common in regions of the hippocampal formation such as the subiculum and medial entorhinal cortex (MEC). Neurons in these areas are immersed in extracellular electrical potential fluctuations often recorded as the local field potential (LFP). LFP rhythms within different frequency bands are linked to different behavioral states. For example, delta rhythms are often associated with slow-wave sleep, inactivity and anesthesia; whereas theta rhythms are prominent during awake exploratory behavior and REM sleep. Recent evidence suggests that bursting neurons in the hippocampal formation can encode LFP features. We explored this hypothesis using a two-compartment model of a bursting pyramidal neuron driven by time-varying input signals containing spectral peaks at either delta or theta rhythms. The model predicted a neural code in which bursts represented the instantaneous value, phase, slope and amplitude of the driving signal both in their timing and size (spike number). To verify whether this code is employed in vivo, we examined electrophysiological recordings from the subiculum of anesthetized rats and the MEC of a behaving rat containing prevalent delta or theta rhythms, respectively. In both areas, we found bursting cells that encoded information about the instantaneous voltage, phase, slope and/or amplitude of the dominant LFP rhythm with essentially the same neural code as the simulated