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Sample records for adult neurogenesis modulating

  1. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors

    PubMed Central

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H.; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine’s inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3–28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1. PMID:27078155

  2. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

    PubMed

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1.

  3. Morphine Modulates Adult Neurogenesis and Contextual Memory by Impeding the Maturation of Neural Progenitors.

    PubMed

    Zhang, Yue; Xu, Chi; Zheng, Hui; Loh, Horace H; Law, Ping-Yee

    2016-01-01

    The regulation of adult neurogenesis by opiates has been implicated in modulating different addiction cycles. At which neurogenesis stage opiates exert their action remains unresolved. We attempt to define the temporal window of morphine's inhibition effect on adult neurogenesis by using the POMC-EGFP mouse model, in which newborn granular cells (GCs) can be visualized between days 3-28 post-mitotic. The POMC-EGFP mice were trained under the 3-chambers conditioned place preference (CPP) paradigm with either saline or morphine. We observed after 4 days of CPP training with saline, the number of EGFP-labeled newborn GCs in sub-granular zone (SGZ) hippocampus significantly increased compared to mice injected with saline in their homecage. CPP training with morphine significantly decreased the number of EGFP-labeled GCs, whereas no significant difference in the number of EGFP-labeled GCs was observed with the homecage mice injected with the same dose of morphine. Using cell-type selective markers, we observed that morphine reduced the number of late stage progenitors and immature neurons such as Doublecortin (DCX) and βIII Tubulin (TuJ1) positive cells in the SGZ but did not reduce the number of early progenitors such as Nestin, SOX2, or neurogenic differentiation-1 (NeuroD1) positive cells. Analysis of co-localization between different cell markers shows that morphine reduced the number of adult-born GCs by interfering with differentiation of early progenitors, but not by inducing apoptosis. In addition, when NeuroD1 was over-expressed in DG by stereotaxic injection of lentivirus, it rescued the loss of immature neurons and prolonged the extinction of morphine-trained CPP. These results suggest that under the condition of CPP training paradigm, morphine affects the transition of neural progenitor/stem cells to immature neurons via a mechanism involving NeuroD1. PMID:27078155

  4. Adult Neurogenesis and Psychiatric Disorders.

    PubMed

    Kang, Eunchai; Wen, Zhexing; Song, Hongjun; Christian, Kimberly M; Ming, Guo-Li

    2016-01-01

    Psychiatric disorders continue to be among the most challenging disorders to diagnose and treat because there is no single genetic or anatomical locus that is causative for the disease. Current treatments are often blunt tools used to ameliorate the most severe symptoms, at the risk of disrupting functional neural systems. There is a critical need to develop new therapeutic strategies that can target circumscribed functional or anatomical domains of pathology. Adult hippocampal neurogenesis may be one such domain. Here, we review the evidence suggesting that adult hippocampal neurogenesis plays a role in emotional regulation and forms of learning and memory that include temporal and spatial memory encoding and context discrimination, and that its dysregulation is associated with psychiatric disorders, such as affective disorders, schizophrenia, and drug addiction. Further, adult neurogenesis has proven to be an effective model to investigate basic processes of neuronal development and converging evidence suggests that aberrant neural development may be an etiological factor, even in late-onset diseases. Constitutive neurogenesis in the hippocampus of the mature brain reflects large-scale plasticity unique to this region and could be a potential hub for modulation of a subset of cognitive and affective behaviors that are affected by multiple psychiatric disorders. PMID:26801682

  5. Modulation of adult hippocampal neurogenesis by thyroid hormones: implications in depressive-like behavior.

    PubMed

    Montero-Pedrazuela, A; Venero, C; Lavado-Autric, R; Fernández-Lamo, I; García-Verdugo, J M; Bernal, J; Guadaño-Ferraz, A

    2006-04-01

    Hormonal imbalances are involved in many of the age-related pathologies, as neurodegenerative and psychiatric diseases. Specifically, thyroid state alterations in the adult are related to psychological changes and mood disorders as depression. The dentate gyrus of the hippocampal formation undergoes neurogenesis in adult mammals including humans. Recent evidence suggests that depressive disorders and their treatment are tightly related to the number of newly born neurons in the dentate gyrus. We have studied the effect of thyroid hormones (TH) on hippocampal neurogenesis in adult rats in vivo. A short period of adult-onset hypothyroidism impaired normal neurogenesis in the subgranular zone of the dentate gyrus with a 30% reduction in the number of proliferating cells. Hypothyroidism also reduced the number of newborn neuroblasts and immature neurons (doublecortin (DCX) immunopositive cells) which had a severely hypoplastic dendritic arborization. To correlate these changes with hippocampal function, we subjected the rats to the forced swimming and novel object recognition tests. Hypothyroid rats showed normal memory in object recognition, but displayed abnormal behavior in the forced swimming test, indicating a depressive-like disorder. Chronic treatment of hypothyroid rats with TH not only normalized the abnormal behavior but also restored the number of proliferative and DCX-positive cells, and induced growth of their dendritic trees. Therefore, hypothyroidism induced a reversible depressive-like disorder, which correlated to changes in neurogenesis. Our results indicate that TH are essential for adult hippocampal neurogenesis and suggest that mood disorders related to adult-onset hypothyroidism in humans could be due, in part, to impaired neurogenesis.

  6. Adult hippocampal neurogenesis and aging.

    PubMed

    Klempin, Friederike; Kempermann, Gerd

    2007-08-01

    The demographic changes in the foreseeable future stress the need for research on successful cognitive aging. Advancing age constitutes a primary risk factor for disease of the central nervous system most notably neurodegenerative disorders. The hippocampus is one of the brain regions that is prominently affected by neurodegeneration and functional decline even in what is still considered "normal aging". Plasticity is the basis for how the brain adapts to changes over time. The discovery of adult hippocampal neurogenesis has added a whole new dimension to research on structural plasticity in the adult and aging hippocampus. In this article, we briefly summarize and discuss recent findings on the regulation of adult neurogenesis with relevance to aging. Aging is an important co-variable for many regulatory mechanisms affecting adult neurogenesis but so far, only few studies have specifically addressed this interaction. We hypothesize that adult neurogenesis contributes to a neural reserve, i.e. the maintained potential for structural plasticity that allows compensation in situations of functional losses with aging. As such we propose that adult neurogenesis might contribute to the structural correlates of successful aging. PMID:17401726

  7. Doublecortin expression levels in adult brain reflect neurogenesis.

    PubMed

    Couillard-Despres, Sebastien; Winner, Beate; Schaubeck, Susanne; Aigner, Robert; Vroemen, Maurice; Weidner, Norbert; Bogdahn, Ulrich; Winkler, Jürgen; Kuhn, Hans-Georg; Aigner, Ludwig

    2005-01-01

    Progress in the field of neurogenesis is currently limited by the lack of tools enabling fast and quantitative analysis of neurogenesis in the adult brain. Doublecortin (DCX) has recently been used as a marker for neurogenesis. However, it was not clear whether DCX could be used to assess modulations occurring in the rate of neurogenesis in the adult mammalian central nervous system following lesioning or stimulatory factors. Using two paradigms increasing neurogenesis levels (physical activity and epileptic seizures), we demonstrate that quantification of DCX-expressing cells allows for an accurate measurement of modulations in the rate of adult neurogenesis. Importantly, we excluded induction of DCX expression during physiological or reactive gliogenesis and excluded also DCX re-expression during regenerative axonal growth. Our data validate DCX as a reliable and specific marker that reflects levels of adult neurogenesis and its modulation. We demonstrate that DCX is a valuable alternative to techniques currently used to measure the levels of neurogenesis. Importantly, in contrast to conventional techniques, analysis of neurogenesis through the detection of DCX does not require in vivo labelling of proliferating cells, thereby opening new avenues for the study of human neurogenesis under normal and pathological conditions. PMID:15654838

  8. Computational models of adult neurogenesis

    NASA Astrophysics Data System (ADS)

    Cecchi, Guillermo A.; Magnasco, Marcelo O.

    2005-10-01

    Experimental results in recent years have shown that adult neurogenesis is a significant phenomenon in the mammalian brain. Little is known, however, about the functional role played by the generation and destruction of neurons in the context of an adult brain. Here, we propose two models where new projection neurons are incorporated. We show that in both models, using incorporation and removal of neurons as a computational tool, it is possible to achieve a higher computational efficiency that in purely static, synapse-learning-driven networks. We also discuss the implication for understanding the role of adult neurogenesis in specific brain areas like the olfactory bulb and the dentate gyrus.

  9. Effect of Opioid on Adult Hippocampal Neurogenesis

    PubMed Central

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

    2016-01-01

    During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs' effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal's opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse. PMID:27127799

  10. The Social Environment and Neurogenesis in the Adult Mammalian Brain

    PubMed Central

    Lieberwirth, Claudia; Wang, Zuoxin

    2012-01-01

    Adult neurogenesis – the formation of new neurons in adulthood – has been shown to be modulated by a variety of endogenous (e.g., trophic factors, neurotransmitters, and hormones) as well as exogenous (e.g., physical activity and environmental complexity) factors. Research on exogenous regulators of adult neurogenesis has focused primarily on the non-social environment. More recently, however, evidence has emerged suggesting that the social environment can also affect adult neurogenesis. The present review details the effects of adult–adult (e.g., mating and chemosensory interactions) and adult–offspring (e.g., gestation, parenthood, and exposure to offspring) interactions on adult neurogenesis. In addition, the effects of a stressful social environment (e.g., lack of social support and dominant–subordinate interactions) on adult neurogenesis are reviewed. The underlying hormonal mechanisms and potential functional significance of adult-generated neurons in mediating social behaviors are also discussed. PMID:22586385

  11. Adult hippocampal neurogenesis and pattern separation in DG: a role for feedback inhibition in modulating sparseness to govern population-based coding

    PubMed Central

    McAvoy, Kathleen; Besnard, Antoine; Sahay, Amar

    2015-01-01

    The dentate gyrus (DG) of mammals harbors neural stem cells that generate new dentate granule cells (DGCs) throughout life. Behavioral studies using the contextual fear discrimination paradigm have found that selectively augmenting or blocking adult hippocampal neurogenesis enhances or impairs discrimination under conditions of high, but not low, interference suggestive of a role in pattern separation. Although contextual discrimination engages population-based coding mechanisms underlying pattern separation such as global remapping in the DG and CA3, how adult hippocampal neurogenesis modulates pattern separation in the DG is poorly understood. Here, we propose a role for adult-born DGCs in re-activation coupled modulation of sparseness through feed-back inhibition to govern global remapping in the DG. PMID:26347621

  12. 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.

  13. 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

  14. Adult neurogenesis in Parkinson's disease.

    PubMed

    Marxreiter, Franz; Regensburger, Martin; Winkler, Jürgen

    2013-02-01

    Parkinson's disease (PD), the second most common neurodegenerative disorder, affects 1-2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.

  15. Adult neurogenesis and the vascular Nietzsche.

    PubMed

    Palmer, Theo D

    2002-06-13

    Adult neurogenesis is mediated by immature neural precursors that divide within the residual germinal matrices of the brain. In the paper by in this issue of Neuron, the "cause and effect" of adult neurogenesis takes a major step forward with the description of a vascular signaling network that influences neuronal precursor migration and fate.

  16. Hippocampal Memory Traces Are Differentially Modulated by Experience, Time, and Adult Neurogenesis

    PubMed Central

    Denny, Christine A.; Kheirbek, Mazen A.; Alba, Eva L.; Tanaka, Kenji F.; Brachman, Rebecca A.; Laughman, Kimberly B.; Tomm, Nicole K.; Turi, Gergely F.; Losonczy, Attila; Hen, René

    2014-01-01

    SUMMARY Memory traces are believed to be ensembles of cells used to store memories. To visualize memory traces, we created a transgenic line that allows for the comparison between cells activated during encoding and expression of a memory. Mice re-exposed to a fear-inducing context froze more and had a greater percentage of reactivated cells in the dentate gyrus (DG) and CA3 than mice exposed to a novel context. Over time, these differences disappeared, in keeping with the observation that memories become generalized. Optogenetically silencing DG or CA3 cells that were recruited during encoding of a fear-inducing context prevented expression of the corresponding memory. Mice with reduced neurogenesis displayed less contextual memory and less reactivation in CA3 but, surprisingly, normal reactivation in the DG. These studies suggest that distinct memory traces are located in the DG and in CA3 but that the strength of the memory is related to reactivation in CA3. PMID:24991962

  17. Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration

    PubMed Central

    Rusznák, Zoltán; Henskens, Willem; Schofield, Emma; Kim, Woojin S.

    2016-01-01

    The subgranular zone (SGZ) and subventricular zone (SVZ) are developmental remnants of the germinal regions of the brain, hence they retain the ability to generate neuronal progenitor cells in adult life. Neurogenesis in adult brain has an adaptive function because newly produced neurons can integrate into and modify existing neuronal circuits. In contrast to the SGZ and SVZ, other brain regions have a lower capacity to produce new neurons, and this usually occurs via parenchymal and periventricular cell genesis. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration, especially in diseases associated with altered neurogenesis and/or gliogenesis, cell loss, or disturbed homeostasis of cellular constitution. The present review discusses important neuroanatomical features of adult neurogenesis and gliogenesis, aiming to explore how these processes could be modulated toward functional repair of the adult brain. PMID:27358578

  18. Adult Neurogenesis and Gliogenesis: Possible Mechanisms for Neurorestoration.

    PubMed

    Rusznák, Zoltán; Henskens, Willem; Schofield, Emma; Kim, Woojin S; Fu, YuHong

    2016-06-01

    The subgranular zone (SGZ) and subventricular zone (SVZ) are developmental remnants of the germinal regions of the brain, hence they retain the ability to generate neuronal progenitor cells in adult life. Neurogenesis in adult brain has an adaptive function because newly produced neurons can integrate into and modify existing neuronal circuits. In contrast to the SGZ and SVZ, other brain regions have a lower capacity to produce new neurons, and this usually occurs via parenchymal and periventricular cell genesis. Compared to neurogenesis, gliogenesis occurs more prevalently in the adult mammalian brain. Under certain circumstances, interaction occurs between neurogenesis and gliogenesis, facilitating glial cells to transform into neuronal lineage. Therefore, modulating the balance between neurogenesis and gliogenesis may present a new perspective for neurorestoration, especially in diseases associated with altered neurogenesis and/or gliogenesis, cell loss, or disturbed homeostasis of cellular constitution. The present review discusses important neuroanatomical features of adult neurogenesis and gliogenesis, aiming to explore how these processes could be modulated toward functional repair of the adult brain. PMID:27358578

  19. 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.

  20. 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. PMID:25977081

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

    PubMed

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

    2015-08-01

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

  2. Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

    PubMed

    Klein, C; Jonas, W; Iggena, D; Empl, L; Rivalan, M; Wiedmer, P; Spranger, J; Hellweg, R; Winter, Y; Steiner, B

    2016-05-01

    Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the

  3. Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

    PubMed

    Klein, C; Jonas, W; Iggena, D; Empl, L; Rivalan, M; Wiedmer, P; Spranger, J; Hellweg, R; Winter, Y; Steiner, B

    2016-05-01

    Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the

  4. Sex, hormones and neurogenesis in the hippocampus: hormonal modulation of neurogenesis and potential functional implications.

    PubMed

    Galea, L A M; Wainwright, S R; Roes, M M; Duarte-Guterman, P; Chow, C; Hamson, D K

    2013-11-01

    The hippocampus is an area of the brain that undergoes dramatic plasticity in response to experience and hormone exposure. The hippocampus retains the ability to produce new neurones in most mammalian species and is a structure that is targeted in a number of neurodegenerative and neuropsychiatric diseases, many of which are influenced by both sex and sex hormone exposure. Intriguingly, gonadal and adrenal hormones affect the structure and function of the hippocampus differently in males and females. Adult neurogenesis in the hippocampus is regulated by both gonadal and adrenal hormones in a sex- and experience-dependent way. Sex differences in the effects of steroid hormones to modulate hippocampal plasticity should not be completely unexpected because the physiology of males and females is different, with the most notable difference being that females gestate and nurse the offspring. Furthermore, reproductive experience (i.e. pregnancy and mothering) results in permanent changes to the maternal brain, including the hippocampus. This review outlines the ability of gonadal and stress hormones to modulate multiple aspects of neurogenesis (cell proliferation and cell survival) in both male and female rodents. The function of adult neurogenesis in the hippocampus is linked to spatial memory and depression, and the present review provides early evidence of the functional links between the hormonal modulation of neurogenesis that may contribute to the regulation of cognition and stress.

  5. Detection and Phenotypic Characterization of Adult Neurogenesis.

    PubMed

    Kuhn, H Georg; Eisch, Amelia J; Spalding, Kirsty; Peterson, Daniel A

    2016-03-01

    Studies of adult neurogenesis have greatly expanded in the last decade, largely as a result of improved tools for detecting and quantifying neurogenesis. In this review, we summarize and critically evaluate detection methods for neurogenesis in mammalian and human brain tissue. Besides thymidine analog labeling, cell-cycle markers are discussed, as well as cell stage and lineage commitment markers. Use of these histological tools is critically evaluated in terms of their strengths and limitations, as well as possible artifacts. Finally, we discuss the method of radiocarbon dating for determining cell and tissue turnover in humans.

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

    PubMed

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

    2016-04-01

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

  7. Exercise modulates insulin-like growth factor 1-dependent and -independent effects on adult hippocampal neurogenesis and behaviour.

    PubMed

    Llorens-Martín, María; Torres-Alemán, Ignacio; Trejo, José Luis

    2010-06-01

    While physical exercise clearly has beneficial effects on the brain, fomenting neuroprotection as well as promoting neural plasticity and behavioural modifications, the cellular and molecular mechanisms mediating these effects are not yet fully understood. We have analyzed sedentary and exercised animals to examine the effects of activity on behaviour (spatial memory and anxiety--as measured by a fear/exploration conflict test), as well as on adult hippocampal neurogenesis (a well-known form of neural plasticity). We have found that the difference in activity between sedentary and exercised animals induced a decrease in the fear/exploration conflict scores (a measure usually accepted as an anxiolytic effect), while no changes are evident in terms of spatial memory learning. The short-term anxiolytic-like effect of exercise was IGF1-dependent and indeed, the recall of hippocampus-dependent spatial memory is impaired by blocking serum IGF1 (as observed by measuring serum IGF levels in the same animals used to analyze the behaviour), irrespective of the activity undertaken by the animals. On the other hand, activity affected neurogenesis as reflected by counting the numbers of several cell populations, while the dependence of this effect on IGF1 varied according to the differentiation state of the new neurons. Hence, while proliferating precursors and postmitotic immature neurons (measured by means of doublecortin and calretinin) are influenced by serum IGF1 levels in both sedentary and exercised animals, premitotic immature neurons (an intermediate stage) respond to exercise independently of serum IGF1. Therefore, we conclude that physical exercise has both serum IGF1-independent and -dependent effects on neural plasticity. Furthermore, several effects mediated by serum IGF1 are induced by physical activity while others are not (both in terms of behaviour and neural plasticity). These findings help to delimit the role of serum IGF1 as a mediator of the effects of

  8. Adult neurogenesis and the ischemic forebrain.

    PubMed

    Lichtenwalner, Robin J; Parent, Jack M

    2006-01-01

    The recent identification of endogenous neural stem cells and persistent neuronal production in the adult brain suggests a previously unrecognized capacity for self-repair after brain injury. Neurogenesis not only continues in discrete regions of the adult mammalian brain, but new evidence also suggests that neural progenitors form new neurons that integrate into existing circuitry after certain forms of brain injury in the adult. Experimental stroke in adult rodents and primates increases neurogenesis in the persistent forebrain subventricular and hippocampal dentate gyrus germinative zones. Of greater relevance for regenerative potential, ischemic insults stimulate endogenous neural progenitors to migrate to areas of damage and form neurons in otherwise dormant forebrain regions, such as the neostriatum and hippocampal pyramidal cell layer, of the mature brain. This review summarizes the current understanding of adult neurogenesis and its regulation in vivo, and describes evidence for stroke-induced neurogenesis and neuronal replacement in the adult. Current strategies used to modify endogenous neurogenesis after ischemic brain injury also will be discussed, as well as future research directions with potential for achieving regeneration after stroke and other brain insults. PMID:15959458

  9. The role of cannabinoids in adult neurogenesis.

    PubMed

    Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

    2015-08-01

    The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain.

  10. The role of cannabinoids in adult neurogenesis

    PubMed Central

    Prenderville, Jack A; Kelly, Áine M; Downer, Eric J

    2015-01-01

    The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, probably through activation of both CB1 and CB2 receptors. In recent years, a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarizes the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall, these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. PMID:25951750

  11. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus

    PubMed Central

    Varela-Nallar, Lorena; Arredondo, Sebastian B.; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C.

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected. PMID:26798521

  12. Andrographolide Stimulates Neurogenesis in the Adult Hippocampus.

    PubMed

    Varela-Nallar, Lorena; Arredondo, Sebastian B; Tapia-Rojas, Cheril; Hancke, Juan; Inestrosa, Nibaldo C

    2015-01-01

    Andrographolide (ANDRO) is a labdane diterpenoid component of Andrographis paniculata widely used for its anti-inflammatory properties. We have recently determined that ANDRO is a competitive inhibitor of glycogen synthase kinase-3β (GSK-3β), a key enzyme of the Wnt/β-catenin signaling cascade. Since this signaling pathway regulates neurogenesis in the adult hippocampus, we evaluated whether ANDRO stimulates this process. Treatment with ANDRO increased neural progenitor cell proliferation and the number of immature neurons in the hippocampus of 2- and 10-month-old mice compared to age-matched control mice. Moreover, ANDRO stimulated neurogenesis increasing the number of newborn dentate granule neurons. Also, the effect of ANDRO was evaluated in the APPswe/PS1ΔE9 transgenic mouse model of Alzheimer's disease. In these mice, ANDRO increased cell proliferation and the density of immature neurons in the dentate gyrus. Concomitantly with the increase in neurogenesis, ANDRO induced the activation of the Wnt signaling pathway in the hippocampus of wild-type and APPswe/PS1ΔE9 mice determined by increased levels of β-catenin, the inactive form of GSK-3β, and NeuroD1, a Wnt target gene involved in neurogenesis. Our findings indicate that ANDRO stimulates neurogenesis in the adult hippocampus suggesting that this drug could be used as a therapy in diseases in which neurogenesis is affected. PMID:26798521

  13. Genetic control of adult neurogenesis: interplay of differentiation, proliferation and survival modulates new neurons function, and memory circuits

    PubMed Central

    Tirone, Felice; Farioli-Vecchioli, Stefano; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca

    2013-01-01

    Within the hippocampal circuitry, the basic function of the dentate gyrus is to transform the memory input coming from the enthorinal cortex into sparse and categorized outputs to CA3, in this way separating related memory information. New neurons generated in the dentate gyrus during adulthood appear to facilitate this process, allowing a better separation between closely spaced memories (pattern separation). The evidence underlying this model has been gathered essentially by ablating the newly adult-generated neurons. This approach, however, does not allow monitoring of the integration of new neurons into memory circuits and is likely to set in motion compensatory circuits, possibly leading to an underestimation of the role of new neurons. Here we review the background of the basic function of the hippocampus and of the known properties of new adult-generated neurons. In this context, we analyze the cognitive performance in mouse models generated by us and others, with modified expression of the genes Btg2 (PC3/Tis21), Btg1, Pten, BMP4, etc., where new neurons underwent a change in their differentiation rate or a partial decrease of their proliferation or survival rate rather than ablation. The effects of these modifications are equal or greater than full ablation, suggesting that the architecture of circuits, as it unfolds from the interaction between existing and new neurons, can have a greater functional impact than the sheer number of new neurons. We propose a model which attempts to measure and correlate the set of cellular changes in the process of neurogenesis with the memory function. PMID:23734097

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

    SciTech Connect

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

    2009-07-31

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

  15. 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.

  16. Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis.

    PubMed

    Valero, Jorge; Paris, Iñaki; Sierra, Amanda

    2016-04-20

    Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging. PMID:26971802

  17. Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis.

    PubMed

    Valero, Jorge; Paris, Iñaki; Sierra, Amanda

    2016-04-20

    Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging.

  18. Decreased adult neurogenesis in hibernating Syrian hamster.

    PubMed

    León-Espinosa, Gonzalo; García, Esther; Gómez-Pinedo, Ulises; Hernández, Félix; DeFelipe, Javier; Ávila, Jesús

    2016-10-01

    Generation of new neurons from adult neural stem cells occurs in the dentate gyrus (DG) of the hippocampus and the lateral walls of the lateral ventricles. In this article, we study the neurogenesis that takes place during the hibernation of the Syrian hamster (Mesocricetus auratus). Using a variety of standard neurogenesis markers and 5-bromo-2-deoxyuridine (BrdU) incorporation, we describe a preferential decrease in the proliferation of newborn neurons in the subventricular zone (SVZ) of the hibernating hamsters (torpor) rather than in the hippocampus. Furthermore, we demonstrate that the proliferative capacity is recovered after 3-4days of torpor when arousal is triggered under natural conditions (i.e., not artificially provoked). In addition, we show that tau3R, a tau isoform with three microtubule-binding domains, is a suitable marker to study neurogenesis both in the SVZ and subgranular zone (SGZ) of the Syrian hamster brain. PMID:27436535

  19. Nitric oxide negatively regulates mammalian adult neurogenesis

    NASA Astrophysics Data System (ADS)

    Packer, Michael A.; Stasiv, Yuri; Benraiss, Abdellatif; Chmielnicki, Eva; Grinberg, Alexander; Westphal, Heiner; Goldman, Steven A.; Enikolopov, Grigori

    2003-08-01

    Neural progenitor cells are widespread throughout the adult central nervous system but only give rise to neurons in specific loci. Negative regulators of neurogenesis have therefore been postulated, but none have yet been identified as subserving a significant role in the adult brain. Here we report that nitric oxide (NO) acts as an important negative regulator of cell proliferation in the adult mammalian brain. We used two independent approaches to examine the function of NO in adult neurogenesis. In a pharmacological approach, we suppressed NO production in the rat brain by intraventricular infusion of an NO synthase inhibitor. In a genetic approach, we generated a null mutant neuronal NO synthase knockout mouse line by targeting the exon encoding active center of the enzyme. In both models, the number of new cells generated in neurogenic areas of the adult brain, the olfactory subependyma and the dentate gyrus, was strongly augmented, which indicates that division of neural stem cells in the adult brain is controlled by NO and suggests a strategy for enhancing neurogenesis in the adult central nervous system.

  20. Glucocorticoids and lithium in adult hippocampal neurogenesis.

    PubMed

    Boku, Shuken; Nakagawa, Shin; Koyama, Tsukasa

    2010-01-01

    Adult hippocampal neurogenesis is decreased in rodent models for stress-related disorders partly through an elevated level of glucocorticoids (GCs). On the other hand, lithium (Li), a mood stabilizer and an inhibitor of GSK-3beta, increases adult hippocampal neurogenesis. However, it remains unclear whether GCs-induced decrease can be recovered by Li or not. Recently we established the culture system of adult rat dentate gyrus-derived neural precursor cell (ADP) and examined GCs and Li actions on ADP proliferation. GCs decreased ADP proliferation and Li recovered it. Both cyclin Dl expression and nuclear beta-catenin are also reciprocally regulated by GCs and Li. In addition, GCs activated GSK-3beta. Therefore, GSK-3beta/beta-catenin pathway may be important in the reciprocal actions of GCs and Li on ADP proliferation. In this manuscript, we review the past literature and our study and summarize what is currently known about the effects of GCs and Li on adult hippocampal neurogenesis.

  1. Detrimental role of prolonged sleep deprivation on adult neurogenesis

    PubMed Central

    Fernandes, Carina; Rocha, Nuno Barbosa F.; Rocha, Susana; Herrera-Solís, Andrea; Salas-Pacheco, José; García-García, Fabio; Murillo-Rodríguez, Eric; Yuan, Ti-Fei; Machado, Sergio; Arias-Carrión, Oscar

    2015-01-01

    Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID:25926773

  2. Detrimental role of prolonged sleep deprivation on adult neurogenesis.

    PubMed

    Fernandes, Carina; Rocha, Nuno Barbosa F; Rocha, Susana; Herrera-Solís, Andrea; Salas-Pacheco, José; García-García, Fabio; Murillo-Rodríguez, Eric; Yuan, Ti-Fei; Machado, Sergio; Arias-Carrión, Oscar

    2015-01-01

    Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis. PMID:25926773

  3. Adult Neurogenesis and the Olfactory System

    PubMed Central

    Whitman, Mary C.; Greer, Charles A.

    2009-01-01

    Though initially described in the early 1960s, it is only within the past decade that the concept of continuing adult neurogenesis has gained widespread acceptance. Neuroblasts from the subventricular zone (SVZ) migrate along the rostral migratory stream (RMS) into the olfactory bulb, where they differentiate into interneurons. Neuroblasts from the subgranular zone (SGZ) of the hippocampal formation show relatively little migratory behavior, and differentiate into dentate gyrus granule cells. In sharp contrast to embryonic and perinatal development, these newly differentiated neurons must integrate into a fully functional circuit, without disrupting ongoing performance. Here, after a brief historical overview and introduction to olfactory circuitry, we review recent advances in the biology of neural stem cells, mechanisms of migration in the RMS and olfactory bulb, differentiation and survival of new neurons, and finally mechanisms of synaptic integration. Our primary focus is on the olfactory system, but we also contrast the events occurring there with those in the hippocampal formation. Although both SVZ and SGZ neurogenesis are involved in some types of learning, their full functional significance remains unclear. Since both systems offer models of integration of new neuroblasts, there is immense interest in using neural stem cells to replace neurons lost in injury or disease. Though many questions remain unanswered, new insights appear daily about adult neurogenesis, regulatory mechanisms, and the fates of the progeny. We discuss here some of the central features of these advances, as well as speculate on future research directions. PMID:19615423

  4. Modulation of neurogenesis by targeting epigenetic enzymes using small molecules: an overview.

    PubMed

    Swaminathan, Amrutha; Kumar, Manoj; Halder Sinha, Sarmistha; Schneider-Anthony, Anne; Boutillier, Anne-Laurence; Kundu, Tapas K

    2014-12-17

    Neurogenesis consists of a plethora of complex cellular processes including neural stem cell (NSC) proliferation, migration, maturation or differentiation to neurons, and finally integration into the pre-existing neural circuits in the brain, which are temporally regulated and coordinated sequentially. Mammalian neurogenesis begins during embryonic development and continues in postnatal brain (adult neurogenesis). It is now evident that adult neurogenesis is driven by extracellular and intracellular signaling pathways, where epigenetic modifications like reversible histone acetylation, methylation, as well as DNA methylation play a vital role. Epigenetic regulation of gene expression during neural development is governed mainly by histone acetyltransferases (HATs), histone methyltransferase (HMTs), DNA methyltransferases (DNMTs), and also the enzymes for reversal, like histone deacetylases (HDACs), and many of these have also been shown to be involved in the regulation of adult neurogenesis. The contribution of these epigenetic marks to neurogenesis is increasingly being recognized, through knockout studies and small molecule modulator based studies. These small molecules are directly involved in regeneration and repair of neurons, and not only have applications from a therapeutic point of view, but also provide a tool to study the process of neurogenesis itself. In the present Review, we will focus on small molecules that act predominantly on epigenetic enzymes to enhance neurogenesis and neuroprotection and discuss the mechanism and recent advancements in their synthesis, targeting, and biology.

  5. Cell cycle-linked MeCP2 phosphorylation modulates adult neurogenesis involving the Notch signaling pathway

    PubMed Central

    Li, Hongda; Zhong, Xiaofen; Chau, Kevin Fongching; Santistevan, Nicholas J.; Guo, Weixiang; Kong, Guangyao; Li, Xuekun; Kadakia, Mitul; Masliah, Jamie; Chi, Jingyi; Jin, Peng; Zhang, Jing; Zhao, Xinyu; Chang, Qiang

    2014-01-01

    Neuronal activity regulates the phosphorylation states at multiple sites on MeCP2 in postmitotic neurons. The precise control of the phosphorylation status of MeCP2 in neurons is critical for the normal development and function of the mammalian brain. However, it is unknown whether phosphorylation at any of the previously identified sites on MeCP2 can be induced by signals other than neuronal activity in other cell types, and what functions MeCP2 phosphorylation may have in those contexts. Here we show that, in neural progenitor cells isolated from the adult mouse hippocampus, cell cycle-linked phosphorylation at serine 421 on MeCP2 is directly regulated by aurora kinase B, and modulates the balance between proliferation and neural differentiation through the Notch signaling pathway. Our findings suggest MeCP2 S421 phosphorylation may function as a general epigenetic switch accessible by different extracellular stimuli through different signaling pathways for regulating diverse biological functions in different cell types. PMID:25420914

  6. Functional neurogenesis in the adult hippocampus

    NASA Astrophysics Data System (ADS)

    van Praag, Henriette; Schinder, Alejandro F.; Christie, Brian R.; Toni, Nicolas; Palmer, Theo D.; Gage, Fred H.

    2002-02-01

    There is extensive evidence indicating that new neurons are generated in the dentate gyrus of the adult mammalian hippocampus, a region of the brain that is important for learning and memory. However, it is not known whether these new neurons become functional, as the methods used to study adult neurogenesis are limited to fixed tissue. We use here a retroviral vector expressing green fluorescent protein that only labels dividing cells, and that can be visualized in live hippocampal slices. We report that newly generated cells in the adult mouse hippocampus have neuronal morphology and can display passive membrane properties, action potentials and functional synaptic inputs similar to those found in mature dentate granule cells. Our findings demonstrate that newly generated cells mature into functional neurons in the adult mammalian brain.

  7. Allergy Enhances Neurogenesis and Modulates Microglial Activation in the Hippocampus

    PubMed Central

    Klein, Barbara; Mrowetz, Heike; Thalhamer, Josef; Scheiblhofer, Sandra; Weiss, Richard; Aigner, Ludwig

    2016-01-01

    Allergies and their characteristic TH2-polarized inflammatory reactions affect a substantial part of the population. Since there is increasing evidence that the immune system modulates plasticity and function of the central nervous system (CNS), we investigated the effects of allergic lung inflammation on the hippocampus—a region of cellular plasticity in the adult brain. The focus of the present study was on microglia, the resident immune cells of the CNS, and on hippocampal neurogenesis, i.e., the generation of new neurons. C57BL/6 mice were sensitized with a clinically relevant allergen derived from timothy grass pollen (Phl p 5). As expected, allergic sensitization induced high serum levels of allergen-specific immunoglobulins (IgG1 and IgE) and of TH2 cytokines (IL-5 and IL-13). Surprisingly, fewer Iba1+ microglia were found in the granular layer (GL) and subgranular zone (SGZ) of the hippocampal dentate gyrus and also the number of Iba1+MHCII+ cells was lower, indicating a reduced microglial surveillance and activation in the hippocampus of allergic mice. Neurogenesis was analyzed by labeling of proliferating cells with bromodeoxyuridine (BrdU) and determining their fate 4 weeks later, and by quantitative analysis of young immature neurons, i.e., cells expressing doublecortin (DCX). The number of DCX+ cells was clearly increased in the allergy animals. Moreover, there were more BrdU+ cells present in the hippocampus of allergic mice, and these newly born cells had differentiated into neurons as indicated by a higher number of BrdU+NeuN+ cells. In summary, allergy led to a reduced microglia presence and activity and to an elevated level of neurogenesis in the hippocampus. This effect was apparently specific to the hippocampus, as we did not observe these alterations in the subventricular zone (SVZ)/olfactory bulb (OB) system, also a region of high cellular plasticity and adult neurogenesis. PMID:27445696

  8. Homeostatic regulation of adult hippocampal neurogenesis in aging rats: long-term effects of early exercise

    PubMed Central

    Merkley, Christina M.; Jian, Charles; Mosa, Adam; Tan, Yao-Fang; Wojtowicz, J. Martin

    2014-01-01

    Adult neurogenesis is highly responsive to environmental and physiological factors. The majority of studies to date have examined short-term consequences of enhancing or blocking neurogenesis but long-term changes remain less well understood. Current evidence for age-related declines in neurogenesis warrant further investigation into these long-term changes. In this report we address the hypothesis that early life experience, such as a period of voluntary running in juvenile rats, can alter properties of adult neurogenesis for the remainder of the animal's life. The results indicate that the number of proliferating and differentiating neuronal precursors is not altered in runners beyond the initial weeks post-running, suggesting homeostatic regulation of these processes. However, the rate of neuronal maturation and survival during a 4 week period after cell division was enhanced up to 11 months of age (the end of the study period). This study is the first to show that a transient period of physical activity at a young age promotes changes in neurogenesis that persist over the long-term, which is important for our understanding of the modulation of neurogenesis by exercise with age. Functional integration of adult-born neurons within the hippocampus that resist homeostatic regulation with aging, rather than the absolute number of adult-born neurons, may be an essential feature of adult neurogenesis that promotes the maintenance of neural plasticity in old age. PMID:25071426

  9. 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

    2014-10-01

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may 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.

  10. Role of adult hippocampal neurogenesis in stress resilience.

    PubMed

    Levone, Brunno R; Cryan, John F; O'Leary, Olivia F

    2015-01-01

    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

  11. VEGF is necessary for exercise-induced adult hippocampal neurogenesis.

    PubMed

    Fabel, Klaus; Fabel, Konstanze; Tam, Betty; Kaufer, Daniela; Baiker, Armin; Simmons, Natalie; Kuo, Calvin J; Palmer, Theo D

    2003-11-01

    Declining learning and memory function is associated with the attenuation of adult hippocampal neurogenesis. As in humans, chronic stress or depression in animals is accompanied by hippocampal dysfunction, and neurogenesis is correspondingly down regulated, in part, by the activity of the hypothalamic-pituitary-adrenal axis as well as glutamatergic and serotonergic networks. Antidepressants can reverse this effect over time but one of the most clinically effective moderators of stress or depression and robust stimulators of neurogenesis is simple voluntary physical exercise such as running. Curiously, running also elevates circulating stress hormone levels yet neurogenesis is doubled in running animals. In evaluating the signalling that running provides to the central nervous system in mice, we have found that peripheral vascular endothelial growth factor (VEGF) is necessary for the effects of running on adult hippocampal neurogenesis. Peripheral blockade of VEGF abolished running-induced neurogenesis but had no detectable effect on baseline neurogenesis in non-running animals. These data suggest that VEGF is an important element of a 'somatic regulator' of adult neurogenesis and that these somatic signalling networks can function independently of the central regulatory networks that are typically considered in the context of hippocampal neurogenesis.

  12. Prion diseases and adult neurogenesis: how do prions counteract the brain's endogenous repair machinery?

    PubMed

    Relaño-Ginés, Aroa; Lehmann, Sylvain; Crozet, Carole

    2014-01-01

    Scientific advances in stem cell biology and adult neurogenesis have raised the hope that neurodegenerative disorders could benefit from stem cell-based therapy. Adult neurogenesis might be part of the physiological regenerative process, however it might become impaired by the disease's mechanism and therefore contribute to neurodegeneration. In prion disorders this endogenous repair system has rarely been studied. Whether adult neurogenesis plays a role or not in brain repair or in the propagation of prion pathology remains unclear. We have recently investigated the status of adult neural stem cells isolated from prion-infected mice. We were able to show that neural stem cells accumulate and replicate prions thus resulting in an alteration of their neuronal destiny. We also reproduced these results in adult neural stem cells, which were infected in vitro. The fact that endogenous adult neurogenesis could be altered by the accumulation of misfolded prion protein represents another great challenge. Inhibiting prion propagation in these cells would thus help the endogenous neurogenesis to compensate for the injured neuronal system. Moreover, understanding the endogenous modulation of the neurogenesis system would help develop effective neural stem cell-based therapies.

  13. Inflammation is detrimental for neurogenesis in adult brain

    NASA Astrophysics Data System (ADS)

    Ekdahl, Christine T.; Claasen, Jan-Hendrik; Bonde, Sara; Kokaia, Zaal; Lindvall, Olle

    2003-11-01

    New hippocampal neurons are continuously generated in the adult brain. Here, we demonstrate that lipopolysaccharide-induced inflammation, which gives rise to microglia activation in the area where the new neurons are born, strongly impairs basal hippocampal neurogenesis in rats. The increased neurogenesis triggered by a brain insult is also attenuated if it is associated with microglia activation caused by tissue damage or lipopolysaccharide infusion. The impaired neurogenesis in inflammation is restored by systemic administration of minocycline, which inhibits microglia activation. Our data raise the possibility that suppression of hippocampal neurogenesis by activated microglia contributes to cognitive dysfunction in aging, dementia, epilepsy, and other conditions leading to brain inflammation.

  14. Regulation and Function of Adult Neurogenesis. From Genes to Cognition

    DOE PAGES

    Aimone, J. B.; Li, Y.; Lee, S. W.; Clemenson, G. D.; Deng, W.; Gage, F. H.

    2014-10-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages ofmore » maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.« less

  15. Regulation and Function of Adult Neurogenesis: From Genes to Cognition

    PubMed Central

    Aimone, James B.; Li, Yan; Lee, Star W.; Clemenson, Gregory D.; Deng, Wei; Gage, Fred H.

    2014-01-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders. PMID:25287858

  16. Regulation and Function of Adult Neurogenesis. From Genes to Cognition

    SciTech Connect

    Aimone, J. B.; Li, Y.; Lee, S. W.; Clemenson, G. D.; Deng, W.; Gage, F. H.

    2014-10-01

    Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. Our review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. Furthermore, the increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.

  17. A Transgenic Rat for Specifically Inhibiting Adult Neurogenesis123

    PubMed Central

    Grigereit, Laura; Pickel, James

    2016-01-01

    Abstract The growth of research on adult neurogenesis and the development of new models and tools have greatly advanced our understanding of the function of newborn neurons in recent years. However, there are still significant limitations in the ability to identify the functions of adult neurogenesis in available models. Here we report a transgenic rat (TK rat) that expresses herpes simplex virus thymidine kinase in GFAP+ cells. Upon treating TK rats with the antiviral drug valganciclovir, granule cell neurogenesis can be completely inhibited in adulthood, in both the hippocampus and olfactory bulb. Interestingly, neurogenesis in the glomerular and external plexiform layers of the olfactory bulb was only partially inhibited, suggesting that some adult-born neurons in these regions derive from a distinct precursor population that does not express GFAP. Within the hippocampus, blockade of neurogenesis was rapid and nearly complete within 1 week of starting treatment. Preliminary behavioral analyses indicate that general anxiety levels and patterns of exploration are generally unaffected in neurogenesis-deficient rats. However, neurogenesis-deficient TK rats showed reduced sucrose preference, suggesting deficits in reward-related behaviors. We expect that TK rats will facilitate structural, physiological, and behavioral studies that complement those possible in existing models, broadly enhancing understanding of the function of adult neurogenesis. PMID:27257630

  18. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis

    PubMed Central

    Lehmann, Michael L.; Brachman, Rebecca A.; Martinowich, Keri; Schloesser, Robert J.; Herkenham, Miles

    2013-01-01

    Both social defeat stress and environmental enrichment stimulate adrenal glucocorticoid secretion, but they have opposing effects on hippocampal neurogenesis and mood. Hypothalamic-pituitary-adrenal (HPA) axis dysregulation and decreased neurogenesis are consequences of social defeat. These outcomes are correlated with depressive states, but a causal role in the etiology of depression remains elusive. The antidepressant actions of environmental enrichment are neurogenesis-dependent, but the contribution of enrichment-elevated glucocorticoids is unexplored. Importantly, for both social defeat and environmental enrichment, how glucocorticoids interact with neurogenesis to alter mood is unknown. Here we investigate causal roles of glucocorticoids and neurogenesis in induction of depressive-like behavior and its amelioration by environmental enrichment in mice. By blocking neurogenesis and surgically clamping adrenal hormone secretions, we showed that neurogenesis—via HPA axis interactions —is directly involved in precipitating the depressive phenotype following social defeat. Mice adrenalectomized prior to social defeat showed enhanced behavioral resiliency and increased survival of adult-born hippocampal neurons compared to sham-operated defeated mice. However, mice lacking hippocampal neurogenesis did not show protective effects of adrenalectomy. Moreover, glucocorticoids secreted during environmental enrichment promoted neurogenesis and were required for restoration of normal behavior after social defeat. The data demonstrate that glucocorticoid-dependent declines in neurogenesis drive changes in mood following social defeat and that glucocorticoids secreted during enrichment promote neurogenesis and restore normal behavior after defeat. These data provide new evidence for direct involvement of neurogenesis in the etiology of depression, suggesting that treatments promoting neurogenesis can enhance stress resilience. PMID:23407954

  19. The interplay between reproductive social stimuli and adult olfactory bulb neurogenesis.

    PubMed

    Peretto, Paolo; Schellino, Roberta; De Marchis, Silvia; Fasolo, Aldo

    2014-01-01

    Adult neurogenesis is a striking form of structural plasticity that adapts the brain to the changing world. Accordingly, new neuron production is involved in cognitive functions, such as memory, learning, and pattern separation. Recent data in rodents indicate a close link between adult neurogenesis and reproductive social behavior. This provides a key to unravel the functional meaning of adult neurogenesis in biological relevant contexts and, in parallel, opens new perspectives to explore the way the brain is processing social stimuli. In this paper we will summarize some of the major achievements on cues and mechanisms modulating adult neurogenesis during social behaviors related to reproduction and possible role/s played by olfactory newborn neurons in this context. We will point out that newborn interneurons in the accessory olfactory bulb (AOB) represent a privileged cellular target for social stimuli that elicit reproductive behaviors and that such cues modulate adult neurogenesis at two different levels increasing both proliferation of neuronal progenitors in the germinative regions and integration of newborn neurons into functional circuits. This dual mechanism provides fresh neurons that can be involved in critical activities for the individual fitness, that is, the processing of social stimuli driving the parental behavior and partner recognition.

  20. Adult Human Neurogenesis: From Microscopy to Magnetic Resonance Imaging

    PubMed Central

    Sierra, Amanda; Encinas, Juan M.; Maletic-Savatic, Mirjana

    2011-01-01

    Neural stem cells reside in well-defined areas of the adult human brain and are capable of generating new neurons throughout the life span. In rodents, it is well established that the new born neurons are involved in olfaction as well as in certain forms of memory and learning. In humans, the functional relevance of adult human neurogenesis is being investigated, in particular its implication in the etiopathology of a variety of brain disorders. Adult neurogenesis in the human brain was discovered by utilizing methodologies directly imported from the rodent research, such as immunohistological detection of proliferation and cell-type specific biomarkers in postmortem or biopsy tissue. However, in the vast majority of cases, these methods do not support longitudinal studies; thus, the capacity of the putative stem cells to form new neurons under different disease conditions cannot be tested. More recently, new technologies have been specifically developed for the detection and quantification of neural stem cells in the living human brain. These technologies rely on the use of magnetic resonance imaging, available in hospitals worldwide. Although they require further validation in rodents and primates, these new methods hold the potential to test the contribution of adult human neurogenesis to brain function in both health and disease. This review reports on the current knowledge on adult human neurogenesis. We first review the different methods available to assess human neurogenesis, both ex vivo and in vivo and then appraise the changes of adult neurogenesis in human diseases. PMID:21519376

  1. Regeneration of Zebrafish CNS: Adult Neurogenesis

    PubMed Central

    Ghosh, Sukla; Hui, Subhra Prakash

    2016-01-01

    Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming. PMID:27382491

  2. Regeneration of Zebrafish CNS: Adult Neurogenesis.

    PubMed

    Ghosh, Sukla; Hui, Subhra Prakash

    2016-01-01

    Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming. PMID:27382491

  3. Regeneration of Zebrafish CNS: Adult Neurogenesis.

    PubMed

    Ghosh, Sukla; Hui, Subhra Prakash

    2016-01-01

    Regeneration in the animal kingdom is one of the most fascinating problems that have allowed scientists to address many issues of fundamental importance in basic biology. However, we came to know that the regenerative capability may vary across different species. Among vertebrates, fish and amphibians are capable of regenerating a variety of complex organs through epimorphosis. Zebrafish is an excellent animal model, which can repair several organs like damaged retina, severed spinal cord, injured brain and heart, and amputated fins. The focus of the present paper is on spinal cord regeneration in adult zebrafish. We intend to discuss our current understanding of the cellular and molecular mechanism(s) that allows formation of proliferating progenitors and controls neurogenesis, which involve changes in epigenetic and transcription programs. Unlike mammals, zebrafish retains radial glia, a nonneuronal cell type in their adult central nervous system. Injury induced proliferation involves radial glia which proliferate, transcribe embryonic genes, and can give rise to new neurons. Recent technological development of exquisite molecular tools in zebrafish, such as cell ablation, lineage analysis, and novel and substantial microarray, together with advancement in stem cell biology, allowed us to investigate how progenitor cells contribute to the generation of appropriate structures and various underlying mechanisms like reprogramming.

  4. 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

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

    PubMed

    Oosthuizen, M K; Amrein, I

    2016-06-01

    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. PMID:26979050

  6. 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.

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

    PubMed

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

    2011-08-03

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

  8. Could adult hippocampal neurogenesis be relevant for human behavior?

    PubMed Central

    Snyder, Jason S.; Cameron, Heather A.

    2011-01-01

    Although the function of adult neurogenesis is still unclear, tools for directly studying the behavioral role of new hippocampal neurons now exist in rodents. Since similar studies are impossible to do in humans, it is important to assess whether the role of new neurons in rodents is likely to be similar to that in humans. One feature of adult neurogenesis that varies tremendously across species is the number of neurons that are generated, so a key question is whether there are enough neurons generated in humans to impact function. In this review we examine neuroanatomy and circuit function in the hippocampus to ask how many granule neurons are needed to impact hippocampal function and then discuss what is known about numbers of new neurons produced in adult rats and humans. We conclude that relatively small numbers of neurons could affect hippocampal circuits and that the magnitude of adult neurogenesis in adult rats and humans is probably larger than generally believed. PMID:21736900

  9. NF-κB mediated regulation of adult hippocampal neurogenesis: relevance to mood disorders and antidepressant activity.

    PubMed

    Bortolotto, Valeria; Cuccurazzu, Bruna; Canonico, Pier Luigi; Grilli, Mariagrazia

    2014-01-01

    Adult hippocampal neurogenesis is a peculiar form of process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF- κ B family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF- κ B signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed. PMID:24678511

  10. Regulatory triangle of neurodegeneration, adult neurogenesis and microRNAs.

    PubMed

    Singh, Tanisha; Jauhari, Abhishek; Pandey, Ankita; Singh, Parul; Pant, Aditya B; Parmar, Devendra; Yadav, Sanjay

    2014-02-01

    MicroRNAs (miRNAs) have emerged as a new class of RNA molecules which are short in length, less in number but play bigger role in regulation of cellular events. miRNAs keep cellular homeostasis in tight control by fine tuning expression of protein coding genes at post-transcriptional level. Neurogenesis and neurodegeneration are two complex processes which are regulated by dynamic expression of regulatory proteins like transcription factors and signaling proteins. Evidences are accumulating that expression of miRNAs play major role in fate determination of neuronal cells undergoing neurogenesis or neurodegeneration. Neurodegeneration either induced by genetic factors or environmental chemicals results in development of neurodegenerative disorders like Parkinson's or Alzheimer's. With increasing acceptance of adult neurogenesis, it seems possible that inducing neurogenesis in adult brain can help in fighting with neurodegenerative disorders. Regulatory RNA molecules, like miRNAs are presenting them as potential therapeutic targets for inducing neurogenesis and controlling neurodegeneration. In the current review, we are exploring the link between neurodegeneration and adult neurogenesis regulation by focusing on miRNAs.

  11. The adaptive significance of adult neurogenesis: an integrative approach

    PubMed Central

    Konefal, Sarah; Elliot, Mick; Crespi, Bernard

    2013-01-01

    Adult neurogenesis in mammals is predominantly restricted to two brain regions, the dentate gyrus (DG) of the hippocampus and the olfactory bulb (OB), suggesting that these two brain regions uniquely share functions that mediate its adaptive significance. Benefits of adult neurogenesis across these two regions appear to converge on increased neuronal and structural plasticity that subserves coding of novel, complex, and fine-grained information, usually with contextual components that include spatial positioning. By contrast, costs of adult neurogenesis appear to center on potential for dysregulation resulting in higher risk of brain cancer or psychological dysfunctions, but such costs have yet to be quantified directly. The three main hypotheses for the proximate functions and adaptive significance of adult neurogenesis, pattern separation, memory consolidation, and olfactory spatial, are not mutually exclusive and can be reconciled into a simple general model amenable to targeted experimental and comparative tests. Comparative analysis of brain region sizes across two major social-ecological groups of primates, gregarious (mainly diurnal haplorhines, visually-oriented, and in large social groups) and solitary (mainly noctural, territorial, and highly reliant on olfaction, as in most rodents) suggest that solitary species, but not gregarious species, show positive associations of population densities and home range sizes with sizes of both the hippocampus and OB, implicating their functions in social-territorial systems mediated by olfactory cues. Integrated analyses of the adaptive significance of adult neurogenesis will benefit from experimental studies motivated and structured by ecologically and socially relevant selective contexts. PMID:23882188

  12. Adult neurogenesis in the olfactory system and neurodegenerative disease.

    PubMed

    Gallarda, B W; Lledo, P-M

    2012-12-01

    The olfactory system is unique in many respects-two of which include the process of adult neurogenesis which continually supplies it with newborn neurons, and the fact that neurodegenerative diseases are often accompanied by a loss of smell. A link between these two phenomena has been hypothesized, but recent evidence for the lack of robust adult neurogenesis in the human olfactory system calls into question this hypothesis. Nevertheless, model organisms continue to play a critical role in the exploration of neurodegenerative disease. In part one of this review we discuss the most promising recent technological advancements for studying adult neurogenesis in the murine olfactory system. Part two continues by looking at emerging evidence related to adult neurogenesis in neurodegenerative disease studied in model organisms and the differences between animal and human olfactory system adult neurogenesis. Hopefully, the careful application of advanced research methods to the study of neurodegenerative disease in model organisms, while taking into account the recently reported differences between the human and model organism olfactory system, will lead to a better understanding of the reasons for the susceptibility of olfaction to disease.

  13. Organotypic Cultures as a Model to Study Adult Neurogenesis in CNS Disorders

    PubMed Central

    Cavaliere, Fabio; Benito-Muñoz, Monica; Matute, Carlos

    2016-01-01

    Neural regeneration resides in certain specific regions of adult CNS. Adult neurogenesis occurs throughout life, especially from the subgranular zone of hippocampus and the subventricular zone, and can be modulated in physiological and pathological conditions. Numerous techniques and animal models have been developed to demonstrate and observe neural regeneration but, in order to study the molecular and cellular mechanisms and to characterize multiple types of cell populations involved in the activation of neurogenesis and gliogenesis, investigators have to turn to in vitro models. Organotypic cultures best recapitulate the 3D organization of the CNS and can be explored taking advantage of many techniques. Here, we review the use of organotypic cultures as a reliable and well defined method to study the mechanisms of neurogenesis under normal and pathological conditions. As an example, we will focus on the possibilities these cultures offer to study the pathophysiology of diseases like Alzheimer disease, Parkinson's disease, and cerebral ischemia. PMID:27127518

  14. 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.

  15. The Contradictory Effects of Neuronal Hyperexcitation on Adult Hippocampal Neurogenesis

    PubMed Central

    Pineda, José R.; Encinas, Juan M.

    2016-01-01

    Adult hippocampal neurogenesis is a highly plastic process that responds swiftly to neuronal activity. Adult hippocampal neurogenesis can be regulated at the level of neural stem cell recruitment and activation, progenitor proliferation, as well as newborn cell survival and differentiation. An “excitation-neurogenesis” rule was proposed after the demonstration of the capability of cultured neural stem and progenitor cells to intrinsically sense neuronal excitatory activity. In vivo, this property has remained elusive although recently the direct response of neural stem cells to GABA in the hippocampus via GABAA receptors has evidenced a mechanism for a direct talk between neurons and neural stem cells. As it is pro-neurogenic, the effect of excitatory neuronal activity has been generally considered beneficial. But what happens in situations of neuronal hyperactivity in which neurogenesis can be dramatically boosted? In animal models, electroconvulsive shock markedly increases neurogenesis. On the contrary, in epilepsy rodent models, seizures induce the generation of misplaced neurons with abnormal morphological and electrophysiological properties, namely aberrant neurogenesis. We will herein discuss what is known about the mechanisms of influence of neurons on neural stem cells, as well as the severe effects of neuronal hyperexcitation on hippocampal neurogenesis. PMID:26973452

  16. Selective estrogen receptor modulators (SERMs) enhance neurogenesis and spine density following focal cerebral ischemia.

    PubMed

    Khan, Mohammad M; Wakade, Chandramohan; de Sevilla, Liesl; Brann, Darrell W

    2015-02-01

    Selective estrogen receptor modulators (SERMs) have been reported to enhance synaptic plasticity and improve cognitive performance in adult rats. SERMs have also been shown to induce neuroprotection against cerebral ischemia and other CNS insults. In this study, we sought to determine whether acute regulation of neurogenesis and spine remodeling could be a novel mechanism associated with neuroprotection induced by SERMs following cerebral ischemia. Toward this end, ovariectomized adult female rats were either implanted with pellets of 17β-estradiol (estrogen) or tamoxifen, or injected with raloxifene. After one week, cerebral ischemia was induced by the transient middle-cerebral artery occlusion (MCAO) method. Bromodeoxyuridine (BrdU) was injected to label dividing cells in brain. We analyzed neurogenesis and spine density at day-1 and day-5 post MCAO. In agreement with earlier findings, we observed a robust induction of neurogenesis in the ipsilateral subventricular zone (SVZ) of both the intact as well as ovariectomized female rats following MCAO. Interestingly, neurogenesis in the ipsilateral SVZ following ischemia was significantly higher in estrogen and raloxifene-treated animals compared to placebo-treated rats. In contrast, this enhancing effect on neurogenesis was not observed in tamoxifen-treated rats. Finally, both SERMs, as well as estrogen significantly reversed the spine density loss observed in the ischemic cortex at day-5 post ischemia. Taken, together these results reveal a profound structural remodeling potential of SERMs in the brain following cerebral ischemia. This article is part of a Special Issue entitled "Sex steroids and brain disorders".

  17. Discovery of nigral dopaminergic neurogenesis in adult mice

    PubMed Central

    Morrison, Brad E.

    2016-01-01

    Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra. As a result, intensive efforts have focused upon mechanisms that facilitate the death of mature dopaminergic neurons. Unfortunately, these efforts have been unsuccessful in providing an effective treatment to address neurodegeneration in this disease. Therefore, alternative theories of pathogenesis are being explored. Adult neurogenesis of dopaminergic neurons is an attractive concept that would provide a possible mechanism of neurodegeneration as well as offer an endogenous means to replenish affected neurons. To determine whether dopaminergic neurons experience neurogenesis in adult mice we developed a novel cell lineage tracing model that permitted detection of neurogenesis without many of the issues associated with popular techniques. Remarkably, we discovered that dopaminergic neurons are replenished in adult mice by Nestin+/Sox2- progenitor cells. What's more, the rate of neurogenesis is similar to the rate of dopaminergic neuron loss reported using a chronic, systemic inflammatory response mouse model. This observation may indicate that neuron loss in Parkinson's disease results from inhibition of neurogenesis. PMID:27482200

  18. [Regulation of neurogenesis: factors affecting of new neurons formation in adult mammals brain].

    PubMed

    Respondek, Michalina; Buszman, Ewa

    2015-12-31

    Neurogenesis is a complex and multi-step process of generating completely functional neurons. This process in adult brain is based on pluripotentional neuronal stem cells (NSC), which are able to proliferation and differentiation into mature neurons or glial cells. NSC are located in subgranular zone inside hippocampus and in subventricular zone. The new neurons formation depends on many endo- and exogenous factors which modulate each step of neurogenesis. This article describes the most important regulators of adult neurogenesis, mainly: neurotrophins, growth factors, hormones, neurotransmitters and microenvironment of NSC. Some drugs, especially antipsychotics, antidepressants and normothymics may affect the neurogenic properties of adult brain. Moreover pathological processes such as neuroinflammation, stroke or epilepsy are able to induce proliferation of NSC. The proneurogenic effects of psychotropic drugs and pathological processes are associated with their ability to increase some hormones and neurotrophins level, as well as with rising the expression of antiapoptotic Bcl-2 protein and metalloproteinase MMP-2. Additionaly, some drugs, for example haloperidol, are able to block prolactin and dopaminergic neuroblasts receptors. Down-regulation of adult neurogenesis is associated with alcohol abuse and high stress level. Negative effect of many drugs, such as cytostatics, COX-2 inhibitors and opioides was also observed. The proneurogenic effect of described factors suggest their broad therapeutic potential and gives a new perspective on an effective and modern treatment of many neuropsychiatric disorders. This effect can also help to clarify the pathogenesis of disorders associated with proliferation and degeneration of adult brain cells.

  19. Transcription-Factor-Dependent Control of Adult Hippocampal Neurogenesis.

    PubMed

    Beckervordersandforth, Ruth; Zhang, Chun-Li; Lie, Dieter Chichung

    2015-10-01

    Adult-generated dentate granule neurons have emerged as major contributors to hippocampal plasticity. New neurons are generated from neural stem cells through a complex sequence of proliferation, differentiation, and maturation steps. Development of the new neuron is dependent on the precise temporal activity of transcription factors, which coordinate the expression of stage-specific genetic programs. Here, we review current knowledge in transcription factor-mediated regulation of mammalian neural stem cells and neurogenesis and will discuss potential mechanisms of how transcription factor networks, on one hand, allow for precise execution of the developmental sequence and, on the other hand, allow for adaptation of the rate and timing of adult neurogenesis in response to complex stimuli. Understanding transcription factor-mediated control of neuronal development will provide new insights into the mechanisms underlying neurogenesis-dependent plasticity in health and disease.

  20. Sleep and adult neurogenesis: implications for cognition and mood.

    PubMed

    Mueller, Anka D; Meerlo, Peter; McGinty, Dennis; Mistlberger, Ralph E

    2015-01-01

    The hippocampal dentate gyrus plays a critical role in learning and memory throughout life, in part by the integration of adult-born neurons into existing circuits. Neurogenesis in the adult hippocampus is regulated by numerous environmental, physiological, and behavioral factors known to affect learning and memory. Sleep is also important for learning and memory. Here we critically examine evidence from correlation, deprivation, and stimulation studies that sleep may be among those factors that regulate hippocampal neurogenesis. There is mixed evidence for correlations between sleep variables and rates of hippocampal cell proliferation across the day, the year, and the lifespan. There is modest evidence that periods of increased sleep are associated with increased cell proliferation or survival. There is strong evidence that disruptions of sleep exceeding 24 h, by total deprivation, selective REM sleep deprivation, and chronic restriction or fragmentation, significantly inhibit cell proliferation and in some cases neurogenesis. The mechanisms by which sleep disruption inhibits neurogenesis are not fully understood. Although sleep disruption procedures are typically at least mildly stressful, elevated adrenal corticosterone secretion is not necessary for this effect. However, procedures that prevent both elevated corticosterone and interleukin 1β signaling have been found to block the effect of sleep deprivation on cell proliferation. This result suggests that sleep loss impairs hippocampal neurogenesis by the presence of wake-dependent factors, rather than by the absence of sleep-specific processes. This would weigh against a hypothesis that regulation of neurogenesis is a function of sleep. Nonetheless, impaired neurogenesis may underlie some of the memory and mood effects associated with acute and chronic sleep disruptions.

  1. CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS.

    EPA Science Inventory

    CHRONIC DEVELOPMENTAL LEAD EXPOSURE REDUCES NEUROGENESIS IN ADULT HIPPOCAMPUS. ME Gilbert1, ME Kelly2, S. Salant3, T Shafer1, J Goodman3 1Neurotoxicology Div, US EPA, RTP, NC, 27711, 2Children's Hospital, Philadelphia, PA, 19104, 3Helen Hayes Hospital, Haverstraw, NY, 10993.
    ...

  2. Neuronal fate determinants of adult olfactory bulb neurogenesis.

    PubMed

    Hack, Michael A; Saghatelyan, Armen; de Chevigny, Antoine; Pfeifer, Alexander; Ashery-Padan, Ruth; Lledo, Pierre-Marie; Götz, Magdalena

    2005-07-01

    Adult neurogenesis in mammals is restricted to two small regions, including the olfactory bulb, where GABAergic and dopaminergic interneurons are newly generated throughout the entire lifespan. However, the mechanisms directing them towards a specific neuronal phenotype are not yet understood. Here, we demonstrate the dual role of the transcription factor Pax6 in generating neuronal progenitors and also in directing them towards a dopaminergic periglomerular phenotype in adult mice. We present further evidence that dopaminergic periglomerular neurons originate in a distinct niche, the rostral migratory stream, and are fewer derived from precursors in the zone lining the ventricle. This regionalization of the adult precursor cells is further supported by the restricted expression of the transcription factor Olig2, which specifies transit-amplifying precursor fate and opposes the neurogenic role of Pax6. Together, these data explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis.

  3. Adult neurogenesis and the memories of drug addiction.

    PubMed

    Canales, Juan J

    2007-08-01

    Evidence accumulated in the last decade indicating that psychoactive substances negatively influence neurogenesis in the adult hippocampus has provided new insights into the neurobiology of drug addiction. Using a variety of experimental approaches and treatments, drugs such as psychomotor stimulants, opioids, alcohol and psychedelic compounds have been shown to alter one or several aspects of adult neurogenesis, including the rate of progenitor proliferation, the survival of newly generated cells, and the maturation and acquisition of cellular phenotype. This evidence, though critical from a neurotoxicological standpoint, cannot be linked unambiguously to the process of drug dependence at this stage of research. Drug addiction is a complex recurrent process involving the acquisition and maintenance of drug taking, followed by detoxification, abstinence and eventual relapse to drug seeking. The specific contribution of adult hippocampal neurogenesis to each of these processes is yet to be determined. This notwithstanding, the suggested role of the hippocampus in the storage and retrieval of declarative and contextual memories on the one hand, and in the regulation of mood and affect on the other, provides a fertile ground for further exploring the mutual relationships between postnatal hippocampal neurogenesis and addictive behaviours.

  4. Hypothalamic subependymal niche: a novel site of the adult neurogenesis.

    PubMed

    Rojczyk-Gołębiewska, Ewa; Pałasz, Artur; Wiaderkiewicz, Ryszard

    2014-07-01

    The discovery of undifferentiated, actively proliferating neural stem cells (NSCs) in the mature brain opened a brand new chapter in the contemporary neuroscience. Adult neurogenesis appears to occur in specific brain regions (including hypothalamus) throughout vertebrates' life, being considered an important player in the processes of memory, learning, and neural plasticity. In the adult mammalian brain, NSCs are located mainly in the subgranular zone (SGZ) of the hippocampal dentate gyrus and in the subventricular zone (SVZ) of the lateral ventricle ependymal wall. Besides these classical regions, hypothalamic neurogenesis occurring mainly along and beneath the third ventricle wall seems to be especially well documented. Neurogenic zones in SGZ, SVZ, and in the hypothalamus share some particular common features like similar cellular cytoarchitecture, vascularization pattern, and extracellular matrix properties. Hypothalamic neurogenic niche is formed mainly by four special types of radial glia-like tanycytes. They are characterized by distinct expression of some neural progenitor and stem cell markers. Moreover, there are numerous suggestions that newborn hypothalamic neurons have a significant ability to integrate into the local neural pathways and to play important physiological roles, especially in the energy balance regulation. Newly formed neurons in the hypothalamus can synthesize and release food intake regulating neuropeptides and they are sensitive to the leptin. On the other hand, high-fat diet positively influences hypothalamic neurogenesis in rodents. The nature of this intriguing new site of adult neurogenesis is still so far poorly studied and requires further investigations.

  5. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

    PubMed Central

    Liu, He; Song, Ni

    2016-01-01

    Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and brain tumors. PMID:27375363

  6. Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases.

    PubMed

    Liu, He; Song, Ni

    2016-01-01

    Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors. PMID:27375363

  7. Cell proliferation and neurogenesis in adult mouse brain.

    PubMed

    Bordiuk, Olivia L; Smith, Karen; Morin, Peter J; Semënov, Mikhail V

    2014-01-01

    Neurogenesis, the formation of new neurons, can be observed in the adult brain of many mammalian species, including humans. Despite significant progress in our understanding of adult neurogenesis, we are still missing data about the extent and location of production of neural precursors in the adult mammalian brain. We used 5-ethynyl-2'-deoxyuridine (EdU) to map the location of proliferating cells throughout the entire adult mouse brain and found that neurogenesis occurs at two locations in the mouse brain. The larger one we define as the main proliferative zone (MPZ), and the smaller one corresponds to the subgranular zone of the hippocampus. The MPZ can be divided into three parts. The caudate migratory stream (CMS) occupies the middle part of the MPZ. The cable of proliferating cells emanating from the most anterior part of the CMS toward the olfactory bulbs forms the rostral migratory stream. The thin layer of proliferating cells extending posteriorly from the CMS forms the midlayer. We have not found any additional aggregations of proliferating cells in the adult mouse brain that could suggest the existence of other major neurogenic zones in the adult mouse brain.

  8. Cell proliferation and neurogenesis in adult mouse brain.

    PubMed

    Bordiuk, Olivia L; Smith, Karen; Morin, Peter J; Semënov, Mikhail V

    2014-01-01

    Neurogenesis, the formation of new neurons, can be observed in the adult brain of many mammalian species, including humans. Despite significant progress in our understanding of adult neurogenesis, we are still missing data about the extent and location of production of neural precursors in the adult mammalian brain. We used 5-ethynyl-2'-deoxyuridine (EdU) to map the location of proliferating cells throughout the entire adult mouse brain and found that neurogenesis occurs at two locations in the mouse brain. The larger one we define as the main proliferative zone (MPZ), and the smaller one corresponds to the subgranular zone of the hippocampus. The MPZ can be divided into three parts. The caudate migratory stream (CMS) occupies the middle part of the MPZ. The cable of proliferating cells emanating from the most anterior part of the CMS toward the olfactory bulbs forms the rostral migratory stream. The thin layer of proliferating cells extending posteriorly from the CMS forms the midlayer. We have not found any additional aggregations of proliferating cells in the adult mouse brain that could suggest the existence of other major neurogenic zones in the adult mouse brain. PMID:25375658

  9. Adult Hippocampal Neurogenesis, Fear Generalization, and Stress.

    PubMed

    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.

  10. Neurotoxic effects of AZT on developing and adult neurogenesis

    PubMed Central

    Demir, Meryem; Laywell, Eric D.

    2015-01-01

    Azidothymidine (AZT) is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions. We employed in vitro and in vivo models of mouse neurogenesis in order to assess the effects of AZT on developing and adult neurogenesis. Using in vitro assays we show that AZT reduces the population expansion potential of neural stem/progenitor cells by inducing senescence. Additionally, in a model of in vitro neurogenesis AZT severely attenuates neuroblast production. These effects are mirrored in vivo by clinically-relevant animal models. We show that in utero AZT exposure perturbs both population expansion and neurogenesis among neural stem/progenitor cells. Additionally, a short-term AZT regimen in adult mice suppresses subependymal zone neurogenesis. These data reveal novel negative effects of AZT on neural stem cell biology. Given that the sequelae of HIV infection often include neurologic deficits—subsumed under AIDS Dementia Complex (Brew, 1999)—it is important to determine to what extent AZT negatively affects neurological function in ways that contribute to, or exacerbate, ADC in order to avoid attributing iatrogenic drug effects to the underlying disease process, and thereby skewing the risk/benefit analysis of AZT therapy. PMID:25852464

  11. Neurotoxic effects of AZT on developing and adult neurogenesis.

    PubMed

    Demir, Meryem; Laywell, Eric D

    2015-01-01

    Azidothymidine (AZT) is a synthetic, chain-terminating nucleoside analog used to treat HIV-1 infection. While AZT is not actively transported across the blood brain barrier, it does accumulate at high levels in cerebrospinal fluid, and subsequently diffuses into the overlying parenchyma. Due to the close anatomical proximity of the neurogenic niches to the ventricular system, we hypothesize that diffusion from CSF exposes neural stem/progenitor cells and their progeny to biologically relevant levels of AZT sufficient to perturb normal cell functions. We employed in vitro and in vivo models of mouse neurogenesis in order to assess the effects of AZT on developing and adult neurogenesis. Using in vitro assays we show that AZT reduces the population expansion potential of neural stem/progenitor cells by inducing senescence. Additionally, in a model of in vitro neurogenesis AZT severely attenuates neuroblast production. These effects are mirrored in vivo by clinically-relevant animal models. We show that in utero AZT exposure perturbs both population expansion and neurogenesis among neural stem/progenitor cells. Additionally, a short-term AZT regimen in adult mice suppresses subependymal zone neurogenesis. These data reveal novel negative effects of AZT on neural stem cell biology. Given that the sequelae of HIV infection often include neurologic deficits-subsumed under AIDS Dementia Complex (Brew, 1999)-it is important to determine to what extent AZT negatively affects neurological function in ways that contribute to, or exacerbate, ADC in order to avoid attributing iatrogenic drug effects to the underlying disease process, and thereby skewing the risk/benefit analysis of AZT therapy. PMID:25852464

  12. Astrocytes regulate adult hippocampal neurogenesis through ephrin-B signaling

    PubMed Central

    Ashton, Randolph S.; Conway, Anthony; Pangarkar, Chinmay; Bergen, Jamie; Lim, Kwang-Il; Shah, Priya; Bissell, Mina; Schaffer, David V.

    2012-01-01

    Neurogenesis in the adult hippocampus involves activation of quiescent neural stem cells (NSCs) to yield transiently amplifying NSCs and progenitors, and ultimately neurons that affect learning and memory. This process is tightly controlled by microenvironmental cues, though few endogenous factors are known to regulate neuronal differentiation. While astrocytes have been implicated, their role in juxtacrine (i.e. cell-cell contact-dependent) signaling within NSC niches has not been investigated. We show that ephrin-B2 presented from rodent hippocampal astrocytes regulates neurogenesis in vivo. Furthermore, clonal analysis in NSC fate-mapping studies reveals a novel role for ephrin-B2 in instructing neuronal differentiation. Additionally, ephrin-B2 signaling, transduced by EphB4 receptors on NSCs, activates β-catenin in vitro and in vivo independent of Wnt signaling and upregulates proneural transcription factors. Ephrin-B2+ astrocytes thus promote neuronal differentiation of adult NSCs through juxtacrine signaling, findings that advance our understanding of adult neurogenesis and may have future regenerative medicine implications. PMID:22983209

  13. The Mammalian Adult Neurogenesis Gene Ontology (MANGO) Provides a Structural Framework for Published Information on Genes Regulating Adult Hippocampal Neurogenesis

    PubMed Central

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

    2012-01-01

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

  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. Role of neuronal ras activity in adult hippocampal neurogenesis and cognition.

    PubMed

    Manns, Martina; Leske, Oliver; Gottfried, Sebastian; Bichler, Zoë; Lafenêtre, Pauline; Wahle, Petra; Heumann, Rolf

    2011-01-01

    Hippocampal neurogenesis in the adult mammalian brain is modulated by various signals like growth factors, hormones, neuropeptides, and neurotransmitters. All of these factors can (but not necessarily do) converge on the activation of the G protein Ras. We used a transgenic mouse model (synRas mice) expressing constitutively activated G12V-Harvey Ras selectively in differentiated neurons to investigate the possible effects onto neurogenesis. H-Ras activation in neurons attenuates hippocampal precursor cell generation at an early stage of the proliferative cascade before neuronal lineage determination occurs. Therefore it is unlikely that the transgenically activated H-Ras in neurons mediates this effect by a direct, intracellular signaling mechanism. Voluntary exercise restores neurogenesis up to wild type level presumably mediated by brain-derived neurotrophic factor. Reduced neurogenesis is linked to impairments in spatial short-term memory and object recognition, the latter can be rescued by voluntary exercise, as well. These data support the view that new cells significantly increase complexity that can be processed by the hippocampal network when experience requires high demands to associate stimuli over time and/or space.

  16. Functional Interrogation of Adult Hypothalamic Neurogenesis with Focal Radiological Inhibition

    PubMed Central

    Lee, Daniel A.; Salvatierra, Juan; Velarde, Esteban; Wong, John; Ford, Eric C.; Blackshaw, Seth

    2013-01-01

    The functional characterization of adult-born neurons remains a significant challenge. Approaches to inhibit adult neurogenesis via invasive viral delivery or transgenic animals have potential confounds that make interpretation of results from these studies difficult. New radiological tools are emerging, however, that allow one to noninvasively investigate the function of select groups of adult-born neurons through accurate and precise anatomical targeting in small animals. Focal ionizing radiation inhibits the birth and differentiation of new neurons, and allows targeting of specific neural progenitor regions. In order to illuminate the potential functional role that adult hypothalamic neurogenesis plays in the regulation of physiological processes, we developed a noninvasive focal irradiation technique to selectively inhibit the birth of adult-born neurons in the hypothalamic median eminence. We describe a method for Computer tomography-guided focal irradiation (CFIR) delivery to enable precise and accurate anatomical targeting in small animals. CFIR uses three-dimensional volumetric image guidance for localization and targeting of the radiation dose, minimizes radiation exposure to nontargeted brain regions, and allows for conformal dose distribution with sharp beam boundaries. This protocol allows one to ask questions regarding the function of adult-born neurons, but also opens areas to questions in areas of radiobiology, tumor biology, and immunology. These radiological tools will facilitate the translation of discoveries at the bench to the bedside. PMID:24300415

  17. Fingolimod induces neurogenesis in adult mouse hippocampus and improves contextual fear memory.

    PubMed

    Efstathopoulos, P; Kourgiantaki, A; Karali, K; Sidiropoulou, K; Margioris, A N; Gravanis, A; Charalampopoulos, I

    2015-11-24

    Fingolimod (FTY720) was the first per os administered disease-modifying agent approved for the treatment of relapsing-remitting multiple sclerosis. It is thought that fingolimod modulates the immune response by activating sphingosine-1 phosphate receptor type 1 (S1P1) on lymphocytes following its in vivo phosphorylation. In addition to its immune-related effects, there is evidence that fingolimod exerts several other effects in the central nervous system, including regulation of the proliferation, survival and differentiation of various cell types and their precursors. In the present study, we have investigated the effect of fingolimod on the production of new neurons in the adult mouse hippocampus and the association of this effect with the ability for pattern separation, an established adult neurogenesis-dependent memory function. Immunofluorescence analysis after chronic administration of a physiologic dose of fingolimod (0.3 mg kg(-1)) revealed a significant increase in both the proliferation and the survival of neural progenitors in the area of dentate gyrus of hippocampus, compared with control animals. These effects were replicated in vitro, in cultures of murine hippocampal neural stem/precursor cells that express S1P1 receptor, suggesting cell-autonomous actions. The effects of fingolimod on neurogenesis were correlated to enhanced ability for context discrimination after fear conditioning. Since impairment of adult hippocampal neurogenesis and memory is a common feature of many neuropsychiatric conditions, fingolimod treatment may be beneficial in therapeutic armamentarium of these disorders.

  18. Adult neurogenesis restores dopaminergic neuronal loss in the olfactory bulb.

    PubMed

    Lazarini, Françoise; Gabellec, Marie-Madeleine; Moigneu, Carine; de Chaumont, Fabrice; Olivo-Marin, Jean-Christophe; Lledo, Pierre-Marie

    2014-10-22

    Subventricular zone (SVZ) neurogenesis continuously provides new GABA- and dopamine (DA)-containing interneurons for the olfactory bulb (OB) in most adult mammals. DAergic interneurons are located in the glomerular layer (GL) where they participate in the processing of sensory inputs. To examine whether adult neurogenesis might contribute to regeneration after circuit injury in mice, we induce DAergic neuronal loss by injecting 6-hydroxydopamine (6-OHDA) in the dorsal GL or in the right substantia nigra pars compacta. We found that a 6-OHDA treatment of the OB produces olfactory deficits and local inflammation and partially decreases the number of neurons expressing the enzyme tyrosine hydroxylase (TH) near the injected site. Blockade of inflammation by minocycline treatment immediately after the 6-OHDA administration rescued neither TH(+) interneuron number nor the olfactory deficits, suggesting that the olfactory impairments are most likely linked to TH(+) cell death and not to microglial activation. TH(+) interneuron number was restored 1 month later. This rescue resulted at least in part from enhanced recruitment of immature neurons targeting the lesioned GL area. Seven days after 6-OHDA lesion in the OB, we found that the integration of lentivirus-labeled adult-born neurons was biased: newly formed neurons were preferentially incorporated into glomerular circuits of the lesioned area. Behavioral rehabilitation occurs 2 months after lesion. This study establishes a new model into which loss of DAergic cells could be compensated by recruiting newly formed neurons. We propose that adult neurogenesis not only replenishes the population of DAergic bulbar neurons but that it also restores olfactory sensory processing. PMID:25339754

  19. From network structure to network reorganization: implications for adult neurogenesis

    NASA Astrophysics Data System (ADS)

    Schneider-Mizell, Casey M.; Parent, Jack M.; Ben-Jacob, Eshel; Zochowski, Michal R.; Sander, Leonard M.

    2010-12-01

    Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells.

  20. Dopamine receptor activation promotes adult neurogenesis in an acute Parkinson model

    PubMed Central

    Winner, Beate; Desplats, Paula; Hagl, Christian; Klucken, Jochen; Aigner, Robert; Ploetz, Sonja; Laemke, Jörn; Karl, Alexandra; Aigner, Ludwig; Masliah, Eliezer; Buerger, Erich; Winkler, Jürgen

    2016-01-01

    Cell proliferation of neural progenitors in the subventricular zone (SVZ) of Parkinson disease (PD) patients and animal models is decreased. It was previously demonstrated that the neurotransmitter dopamine modulates cell proliferation in the embryonic brain. The aim of the present study was to analyze whether oral treatment with the dopamine receptor agonist pramipexole (PPX) modulates adult neurogenesis in the SVZ/ olfactory bulb system in a dopaminergic lesion model. 6-Hydroxydopamine (6-OHDA) lesioned adult rats received either PPX (1,0 mg/kg) or PBS orally twice daily and bromodeoxyuridine (BrdU, a cell proliferation marker) for 10 days and were perfused immediately after treatment or 4 weeks after PPX withdrawal. Stereological analysis revealed a significant augmentation in SVZ proliferation by PPX. Consecutively, enhanced neuronal differentiation and more new neurons were present in the olfactory bulb 4 weeks after PPX withdrawal. In addition, dopaminergic neurogenesis was increased in the olfactory bulb after PPX treatment. Motor activity as assessed by using an open field paradigm was permanently increased even after long term PPX withdrawal. In addition, we demonstrate that D2 and D3 receptors are present on adult rat SVZ derived neural progenitors in vitro, and PPX specifically increased mRNA levels of epidermal growth factor receptor (EGF-R) and paired box gene 6 (Pax6). Oral PPX treatment selectively increases adult neurogenesis in the SVZ-olfactory bulb system by increasing proliferation and cell survival of newly generated neurons. Analyzing the neurogenic fate decisions mediated by D2/D3 signaling pathways may lead to new avenues to induce neural repair in the adult brain. PMID:19619535

  1. Adult neurogenesis in the mammalian hippocampus: Why the dentate gyrus?

    PubMed Central

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

    2013-01-01

    In the adult mammalian brain, newly generated neurons are continuously incorporated into two networks: interneurons born in the subventricular zone migrate to the olfactory bulb, whereas the dentate gyrus (DG) of the hippocampus integrates locally born principal neurons. That the rest of the mammalian brain loses significant neurogenic capacity after the perinatal period suggests that unique aspects of the structure and function of DG and olfactory bulb circuits allow them to benefit from the adult generation of neurons. In this review, we consider the distinctive features of the DG that may account for it being able to profit from this singular form of neural plasticity. Approaches to the problem of neurogenesis are grouped as “bottom-up,” where the phenotype of adult-born granule cells is contrasted to that of mature developmentally born granule cells, and “top-down,” where the impact of altering the amount of neurogenesis on behavior is examined. We end by considering the primary implications of these two approaches and future directions. PMID:24255101

  2. Acute deep brain stimulation in the thalamic reticular nucleus protects against acute stress and modulates initial events of adult hippocampal neurogenesis.

    PubMed

    Magdaleno-Madrigal, Víctor Manuel; Pantoja-Jiménez, Christopher Rodrigo; Bazaldúa, Adrián; Fernández-Mas, Rodrigo; Almazán-Alvarado, Salvador; Bolaños-Alejos, Fernanda; Ortíz-López, Leonardo; Ramírez-Rodriguez, Gerardo Bernabé

    2016-11-01

    Deep brain stimulation (DBS) is used as an alternative therapeutic procedure for pharmacoresistant psychiatric disorders. Recently the thalamic reticular nucleus (TRN) gained attention due to the description of a novel pathway from the amygdala to this nucleus suggesting that may be differentially disrupted in mood disorders. The limbic system is implicated in the regulation of these disorders that are accompanied by neuroplastic changes. The hippocampus is highly plastic and shows the generation of new neurons, process affected by stress but positively regulated by antidepressant drugs. We explored the impact of applying acute DBS to the TRN (DBS-TRN) in male Wistar rats exposed to acute stress caused by the forced-swim Porsolt's test (FST) and on initial events of hippocampal neurogenesis. After the first session of forced-swim, rats were randomly subdivided in a DBS-TRN and a Sham group. Stimulated rats received 10min of DBS, thus the depressant-like behavior reflected as immobility was evaluated in the second session of forced-swim. Locomotricity was evaluated in the open field test. Cell proliferation and doublecortin-associated cells were quantified in the hippocampus of other cohorts of rats. No effects of electrode implantation were found in locomotricity. Acute DBS-TRN reduced immobility in comparison to the Sham group (p<0.001). DBS-TRN increased cell proliferation (Ki67 or BrdU-positive cells; p=0.02, p=0.02) and the number of doublecortin-cells compared to the Sham group (p<0.02). Similar effects were found in rats previously exposed to the first session of forced-swim. Our data could suggest that TRN brain region may be a promising target for DBS to treat intractable depression.

  3. Acute deep brain stimulation in the thalamic reticular nucleus protects against acute stress and modulates initial events of adult hippocampal neurogenesis.

    PubMed

    Magdaleno-Madrigal, Víctor Manuel; Pantoja-Jiménez, Christopher Rodrigo; Bazaldúa, Adrián; Fernández-Mas, Rodrigo; Almazán-Alvarado, Salvador; Bolaños-Alejos, Fernanda; Ortíz-López, Leonardo; Ramírez-Rodriguez, Gerardo Bernabé

    2016-11-01

    Deep brain stimulation (DBS) is used as an alternative therapeutic procedure for pharmacoresistant psychiatric disorders. Recently the thalamic reticular nucleus (TRN) gained attention due to the description of a novel pathway from the amygdala to this nucleus suggesting that may be differentially disrupted in mood disorders. The limbic system is implicated in the regulation of these disorders that are accompanied by neuroplastic changes. The hippocampus is highly plastic and shows the generation of new neurons, process affected by stress but positively regulated by antidepressant drugs. We explored the impact of applying acute DBS to the TRN (DBS-TRN) in male Wistar rats exposed to acute stress caused by the forced-swim Porsolt's test (FST) and on initial events of hippocampal neurogenesis. After the first session of forced-swim, rats were randomly subdivided in a DBS-TRN and a Sham group. Stimulated rats received 10min of DBS, thus the depressant-like behavior reflected as immobility was evaluated in the second session of forced-swim. Locomotricity was evaluated in the open field test. Cell proliferation and doublecortin-associated cells were quantified in the hippocampus of other cohorts of rats. No effects of electrode implantation were found in locomotricity. Acute DBS-TRN reduced immobility in comparison to the Sham group (p<0.001). DBS-TRN increased cell proliferation (Ki67 or BrdU-positive cells; p=0.02, p=0.02) and the number of doublecortin-cells compared to the Sham group (p<0.02). Similar effects were found in rats previously exposed to the first session of forced-swim. Our data could suggest that TRN brain region may be a promising target for DBS to treat intractable depression. PMID:27435420

  4. Adult hippocampal neurogenesis and its role in cognition

    PubMed Central

    Oomen, Charlotte A.; Bekinschtein, Pedro; Kent, Brianne A.; Saksida, Lisa M.; Bussey, Timothy J.

    2015-01-01

    Adult hippocampal neurogenesis (AHN) has intrigued neuroscientists for decades. Several lines of evidence show that adult-born neurons in the hippocampus are functionally integrated and contribute to cognitive function, in particular learning and memory processes. Biological properties of immature hippocampal neurons indicate that these cells are more easily excitable compared to mature neurons, and demonstrate enhanced structural plasticity. The structure in which adult-born hippocampal neurons are situated -the dentate gyrus- is thought to contribute to hippocampus function by disambiguating similar input patterns, a process referred to as pattern separation. Several ideas about AHN function have been put forward; currently there is good evidence in favour of a role for AHN in pattern separation. This function of AHN may be understood within a ‘representational-hierarchical’ view of brain organisation. PMID:26308746

  5. 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.

  6. 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. PMID:25870909

  7. Memory-enhancing effects of Cuscuta japonica Choisy via enhancement of adult hippocampal neurogenesis in mice.

    PubMed

    Moon, Minho; Jeong, Hyun Uk; Choi, Jin Gyu; Jeon, Seong Gak; Song, Eun Ji; Hong, Seon-Pyo; Oh, Myung Sook

    2016-09-15

    It is generally accepted that functional and structural changes within the hippocampus are involved in learning and memory and that adult neurogenesis in this region may modulate cognition. The extract of Cuscuta japonica Choisy (CJ) is a well-known traditional Chinese herbal medicine that has been used since ancient times as a rejuvenation remedy. The systemic effects of this herb are widely known and can be applied for the treatment of a number of physiological diseases, but there is a lack of evidence describing its effects on brain function. Thus, the present study investigated whether CJ would enhance memory function and/or increase hippocampal neurogenesis using mice orally administered with CJ water extract or vehicle for 21days. Performance on the novel object recognition and passive avoidance tests revealed that treatment with CJ dose-dependently improved the cognitive function of mice. Additionally, CJ increased the Ki-67-positive proliferating cells and the number of doublecortin-stained neuroblasts in the dentate gyrus (DG) of the hippocampus, and double labeling with 5-bromo-2-deoxyuridine and neuronal specific nuclear protein showed that CJ increased the number of mature neurons in the DG. Finally, CJ resulted in the upregulated expression of neurogenic differentiation factor, which is essential for the maturation and differentiation of granule cells in the hippocampus. Taken together, the present findings indicate that CJ stimulated neuronal cell proliferation, differentiation, and maturation, which are all processes associated with neurogenesis. Additionally, these findings suggest that CJ may improve learning and memory via the enhancement of adult hippocampal neurogenesis.

  8. 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.

  9. 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.

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

    PubMed Central

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

    2010-01-01

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

  11. Liquid diets reduce cell proliferation but not neurogenesis in the adult rat hippocampus.

    PubMed

    Patten, A R; Moller, D J; Graham, J; Gil-Mohapel, J; Christie, B R

    2013-12-19

    Neurogenesis continues to occur in restricted regions of the brain throughout adulthood and can be modulated by dietary factors. Liquid or "soft" diets are commonly used for the administration of drugs in experimental models of disease, making it critical to determine whether dietary composition itself can affect neurogenesis. In this study Sprague-Dawley rats were fed either a liquid or a solid diet of identical composition from weaning until young adulthood. No differences in neuronal differentiation and survival of newly born cells were observed between rats that were fed a liquid diet and those that received a solid diet. However, a significant reduction in hippocampal cell proliferation was observed in the liquid diet-fed group, as assessed by the expression of two endogenous proliferation markers, Ki67 and proliferating cell nuclear antigen (PCNA). The method of feeding did not alter the basal function of the hypothalamic-pituitary-adrenal (HPA) axis in these animals, as no changes in circulating levels of corticosterone (CORT) were detected between liquid and solid diet-fed groups. There was also a significant reduction in cellular proliferation in the hypothalamus of liquid diet-fed rats, a brain region known to be involved in feeding-related behaviors. These findings indicate that liquid diets themselves can directly impact rates of cellular proliferation, but this does not seem to impact levels of overall neurogenesis in the adult brain.

  12. Characterization of the role of adult neurogenesis in touch-screen discrimination learning.

    PubMed

    Swan, Alicia A; Clutton, Jonathan Edward; Chary, Priyanka Kesavan; Cook, Sarah G; Liu, Grace G; Drew, Michael R

    2014-12-01

    Recent theories posit that adult neurogenesis supports dentate gyrus pattern separation and hence is necessary for some types of discrimination learning. Using an inducible transgenic mouse model, we investigated the contribution of adult-born neurons to spatial and nonspatial touch-screen discriminations of varying levels of difficulty. Arresting neurogenesis caused a modest but statistically significant impairment in a position discrimination task. However, the effect was present only on trials after a learned discrimination was reversed, suggesting that neurogenesis supports cognitive flexibility rather than spatial discrimination per se. The deficit was present 4-10 weeks after the arrest of neurogenesis but not immediately after, consistent with previous evidence that the behavioral effects of arresting neurogenesis arise because of the depletion of adult-born neurons at least 1 month old. The arrest of neurogenesis failed to affect a nonspatial brightness discrimination task that was equal in difficulty to the spatial task. The data suggest that adult neurogenesis is not strictly necessary for spatial or perceptual discrimination learning and instead implicate adult neurogenesis in factors related to reversal learning, such as cognitive flexibility or proactive interference.

  13. 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.

  14. 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. PMID:25833129

  15. Site-specific regulation of adult neurogenesis by dietary fatty acid content, vitamin E and flight exercise in European starlings.

    PubMed

    Hall, Zachary J; Bauchinger, Ulf; Gerson, Alexander R; Price, Edwin R; Langlois, Lillie A; Boyles, Michelle; Pierce, Barbara; McWilliams, Scott R; Sherry, David F; Macdougall-Shackleton, Scott A

    2014-03-01

    Exercise is known to have a strong effect on neuroproliferation in mammals ranging from rodents to humans. Recent studies have also shown that fatty acids and other dietary supplements can cause an upregulation of neurogenesis. It is not known, however, how exercise and diet interact in their effects on adult neurogenesis. We examined neuronal recruitment in multiple telencephalic sites in adult male European starlings (Sturnus vulgaris) exposed to a factorial combination of flight exercise, dietary fatty acids and antioxidants. Experimental birds were flown in a wind tunnel following a training regime that mimicked the bird's natural flight behaviour. In addition to flight exercise, we manipulated the composition of dietary fatty acids and the level of enrichment with vitamin E, an antioxidant reported to enhance neuronal recruitment. We found that all three factors - flight exercise, fatty acid composition and vitamin E enrichment - regulate neuronal recruitment in a site-specific manner. We also found a robust interaction between flight training and vitamin E enrichment at multiple sites of neuronal recruitment. Specifically, flight training was found to enhance neuronal recruitment across the telencephalon, but only in birds fed a diet with a low level of vitamin E. Conversely, dietary enrichment with vitamin E upregulated neuronal recruitment, but only in birds not flown in the wind tunnel. These findings indicate conserved modulation of adult neurogenesis by exercise and diet across vertebrate taxa and indicate possible therapeutic interventions in disorders characterized by reduced adult neurogenesis.

  16. An old test for new neurons: refining the Morris water maze to study the functional relevance of adult hippocampal neurogenesis

    PubMed Central

    Garthe, Alexander; Kempermann, Gerd

    2013-01-01

    The Morris water maze represents the de-facto standard for testing hippocampal function in laboratory rodents. In the field of adult hippocampal neurogenesis, however, using this paradigm to assess the functional relevance of the new neurons yielded surprisingly inconsistent results. While some authors found aspects of water maze performance to be linked to adult neurogenesis, others obtained different results or could not demonstrate any effect of manipulating adult neurogenesis. In this review we discuss evidence that the large diversity of protocols and setups used is an important aspect in interpreting the differences in the results that have been obtained. Even simple parameters such as pool size, number, and configuration of visual landmarks, or number of trials can become highly relevant for getting the new neurons involved at all. Sets of parameters are often chosen with implicit or explicit concepts in mind and these might lead to different views on the function of adult-generated neurons. We propose that the classical parameters usually used to measure spatial learning performance in the water maze might not be particularly well-suited to sensitively and specifically detect the supposedly highly specific functional changes elicited by the experimental modulation of adult hippocampal neurogenesis. As adult neurogenesis is supposed to affect specific aspects of information processing only in the hippocampus, any claim for a functional relevance of the new neurons has to be based on hippocampus-specific parameters. We also placed a special emphasis on the fact that the dentate gyrus (DG) facilitates the differentiation between contexts as opposed to just differentiating places. In conclusion, while the Morris water maze has proven to be one of the most effective testing paradigms to assess hippocampus-dependent spatial learning, new and more specific questions ask for new parameters. Therefore, the full potential of the water maze task remains to be tapped

  17. Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis

    PubMed Central

    Mandyam, Chitra D.; Wee, Sunmee; Crawford, Elena F.; Eisch, Amelia J.; Richardson, Heather N.; Koob, George F.

    2008-01-01

    Background Chronic abuse of methamphetamine produces deficits in hippocampal function, perhaps by altering hippocampal neurogenesis and plasticity. We examined how intravenous methamphetamine self-administration modulates active division, proliferation of late progenitors, differentiation, maturation, survival, and mature phenotype of hippocampal subgranular zone (SGZ) progenitors. Methods Adult male Wistar rats were given access to methamphetamine 1 h twice weekly (intermittent short), 1 h daily (short), or 6 h daily (long). Rats received one intraperitoneal injection of bromodeoxyuridine (BrdU) to label progenitors in the synthesis (S) phase, and 28-day-old surviving BrdU-immunoreactive (IR) cells were quantified. Ki-67, doublecortin (DCX), and activated caspase-3 (AC-3) were used to visualize and quantify proliferating, differentiating, maturing, and apoptotic cells. Terminal corticosterone was measured to determine changes in adrenal steroids. Results Intermittent access to methamphetamine increased Ki-67 and DCX-IR cells, but opposing effects on late progenitors and postmitotic neurons resulted in no overall change in neurogenesis. Daily access to methamphetamine decreased all studied aspects of neurogenesis and reduced hippocampal granule neurons and volume, changes that likely are mediated by decreased proliferative and neurogenic capacity of the SGZ. Furthermore, methamphetamine self-administration relative to the amount of methamphetamine intake produced a biphasic effect on hippocampal apoptosis and reduced corticosterone levels. Conclusions Intermittent (occasional access) and daily (limited and extended access) self-administration of methamphetamine impact different aspects of neurogenesis, the former producing initial pro-proliferative effects and the latter producing downregulating effects. These findings suggest that altered hippocampal integrity by even modest doses of methamphetamine could account for pronounced pathology linked to methamphetamine

  18. Differential effects of stress and glucocorticoids on adult neurogenesis.

    PubMed

    Schoenfeld, Timothy J; Gould, Elizabeth

    2013-01-01

    Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms.

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

    PubMed

    Kitamura, Takashi; Inokuchi, Kaoru

    2014-01-01

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

  20. Absent or low rate of adult neurogenesis in the hippocampus of bats (Chiroptera).

    PubMed

    Amrein, Irmgard; Dechmann, Dina K N; Winter, York; Lipp, Hans-Peter

    2007-01-01

    Bats are the only flying mammals and have well developed navigation abilities for 3D-space. Even bats with comparatively small home ranges cover much larger territories than rodents, and long-distance migration by some species is unique among small mammals. Adult proliferation of neurons, i.e., adult neurogenesis, in the dentate gyrus of rodents is thought to play an important role in spatial memory and learning, as indicated by lesion studies and recordings of neurons active during spatial behavior. Assuming a role of adult neurogenesis in hippocampal function, one might expect high levels of adult neurogenesis in bats, particularly among fruit- and nectar-eating bats in need of excellent spatial working memory. The dentate gyrus of 12 tropical bat species was examined immunohistochemically, using multiple antibodies against proteins specific for proliferating cells (Ki-67, MCM2), and migrating and differentiating neurons (Doublecortin, NeuroD). Our data show a complete lack of hippocampal neurogenesis in nine of the species (Glossophaga soricina, Carollia perspicillata, Phyllostomus discolor, Nycteris macrotis, Nycteris thebaica, Hipposideros cyclops, Neoromicia rendalli, Pipistrellus guineensis, and Scotophilus leucogaster), while it was present at low levels in three species (Chaerephon pumila, Mops condylurus and Hipposideros caffer). Although not all antigens were recognized in all species, proliferation activity in the subventricular zone and rostral migratory stream was found in all species, confirming the appropriateness of our methods for detecting neurogenesis. The small variation of adult hippocampal neurogenesis within our sample of bats showed no indication of a correlation with phylogenetic relationship, foraging strategy, type of hunting habitat or diet. Our data indicate that the widely accepted notion of adult neurogenesis supporting spatial abilities needs to be considered carefully. Given their astonishing longevity, certain bat species may be

  1. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination.

    PubMed

    Malik, Astha; Kondratov, Roman V; Jamasbi, Roudabeh J; Geusz, Michael E

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  2. Developmental and adult GAP-43 deficiency in mice dynamically alters hippocampal neurogenesis and mossy fiber volume.

    PubMed

    Latchney, Sarah E; Masiulis, Irene; Zaccaria, Kimberly J; Lagace, Diane C; Powell, Craig M; McCasland, James S; Eisch, Amelia J

    2014-01-01

    Growth-associated protein-43 (GAP-43) is a presynaptic protein that plays key roles in axonal growth and guidance and in modulating synapse formation. Previous work has demonstrated that mice lacking one allele of this gene (GAP-43+/- mice) exhibit hippocampal structural abnormalities, impaired spatial learning and stress-induced behavioral withdrawal and anxiety, behaviors that are dependent on proper hippocampal circuitry and function. Given the correlation between hippocampal function, synaptic connectivity and neurogenesis, we tested if behaviorally naïve GAP-43+/- mice had alterations in either neurogenesis or synaptic connectivity in the hippocampus during early postnatal development and young adulthood, and following behavior testing in older adults. To test our hypothesis, we examined hippocampal cell proliferation (Ki67), number of immature neuroblasts (doublecortin, DCX) and mossy fiber volume (synaptoporin) in behaviorally naïve postnatal day 9 (P9) and P26, and behaviorally experienced 5- to 7-month-old GAP-43+/- and +/+ littermate mice. P9 GAP-43+/- mice had fewer Ki67+ and DCX+ cells compared to +/+ mice, particularly in the posterior dentate gyrus, and smaller mossy fiber volume in the same region. In young adulthood, however, male GAP-43+/- mice had more Ki67+ and DCX+ cells and greater mossy fiber volume in the posterior dentate gyrus relative to male +/+ mice. These increases were not seen in females. In 5- to 7-month-old GAP-43+/- mice (whose behaviors were the focus of our prior publication), there was no global change in the number of proliferating or immature neurons relative to +/+ mice. However, more detailed analysis revealed fewer proliferative DCX+ cells in the anterior dentate gyrus of male GAP-43+/- mice compared to male +/+ mice. This reduction was not observed in females. These results suggest that young GAP-43+/- mice have decreased hippocampal neurogenesis and synaptic connectivity, but slightly older mice have greater hippocampal

  3. Circadian Clock Genes Are Essential for Normal Adult Neurogenesis, Differentiation, and Fate Determination

    PubMed Central

    Kondratov, Roman V.; Jamasbi, Roudabeh J.

    2015-01-01

    Adult neurogenesis creates new neurons and glia from stem cells in the human brain throughout life. It is best understood in the dentate gyrus (DG) of the hippocampus and the subventricular zone (SVZ). Circadian rhythms have been identified in the hippocampus, but the role of any endogenous circadian oscillator cells in hippocampal neurogenesis and their importance in learning or memory remains unclear. Any study of stem cell regulation by intrinsic circadian timing within the DG is complicated by modulation from circadian clocks elsewhere in the brain. To examine circadian oscillators in greater isolation, neurosphere cultures were prepared from the DG of two knockout mouse lines that lack a functional circadian clock and from mPer1::luc mice to identify circadian oscillations in gene expression. Circadian mPer1 gene activity rhythms were recorded in neurospheres maintained in a culture medium that induces neurogenesis but not in one that maintains the stem cell state. Although the differentiating neural stem progenitor cells of spheres were rhythmic, evidence of any mature neurons was extremely sparse. The circadian timing signal originated in undifferentiated cells within the neurosphere. This conclusion was supported by immunocytochemistry for mPER1 protein that was localized to the inner, more stem cell-like neurosphere core. To test for effects of the circadian clock on neurogenesis, media conditions were altered to induce neurospheres from BMAL1 knockout mice to differentiate. These cultures displayed unusually high differentiation into glia rather than neurons according to GFAP and NeuN expression, respectively, and very few BetaIII tubulin-positive, immature neurons were observed. The knockout neurospheres also displayed areas visibly devoid of cells and had overall higher cell death. Neurospheres from arrhythmic mice lacking two other core clock genes, Cry1 and Cry2, showed significantly reduced growth and increased astrocyte proliferation during

  4. The effects of running and of inhibiting adult neurogenesis on learning and memory in rats.

    PubMed

    Wojtowicz, J Martin; Askew, Michele L; Winocur, Gordon

    2008-03-01

    The presence of ongoing adult neurogenesis within the highly plastic hippocampal circuitry poses questions as to the relevance of new neurons to learning and memory. Correlational and causal evidence suggests that some, but not all, hippocampal tasks involve the new neurons. The evidence with regard to spatial learning in the water maze, one of the most commonly used hippocampal tasks, is contradictory. In this study we examined the effects of irradiation-induced reduction in neurogenesis on spatial learning and another standard hippocampal task, contextual fear conditioning, in rats that experienced normal cage conditions or voluntary running. The results indicate that reduced neurogenesis had little effect on spatial learning but severely impaired contextual fear conditioning. It was suggested that compensatory mechanisms within the hippocampus may have contributed selectively to sparing of spatial function. Performance on the fear conditioning task was weakly related to enhanced neurogenesis or running. The results improve our understanding of the functional role of adult neurogenesis in behaving animals.

  5. No effect of running and laboratory housing on adult hippocampal neurogenesis in wild caught long-tailed wood mouse

    PubMed Central

    Hauser, Thomas; Klaus, Fabienne; Lipp, Hans-Peter; Amrein, Irmgard

    2009-01-01

    Background Studies of adult hippocampal neurogenesis (AHN) in laboratory rodents have raised hopes for therapeutic interventions in neurodegenerative diseases and mood disorders, as AHN can be modulated by physical exercise, stress and environmental changes in these animals. Since it is not known whether cell proliferation and neurogenesis in wild living mice can be experimentally changed, this study investigates the responsiveness of AHN to voluntary running and to environmental change in wild caught long-tailed wood mice (Apodemus sylvaticus). Results Statistical analyses show that running had no impact on cell proliferation (p = 0.44), neurogenesis (p = 0.94) or survival of newly born neurons (p = 0.58). Likewise, housing in the laboratory has no effect on AHN. In addition, interindividual differences in the level of neurogenesis are not related to interindividual differences of running wheel performance (rs = -0.09, p = 0.79). There is a correlation between the number of proliferating cells and the number of cells of neuronal lineage (rs = 0.63, p < 0.001) and the number of pyknotic cells (rs = 0.5, p = 0.009), respectively. Conclusion Plasticity of adult neurogenesis is an established feature in strains of house mice and brown rats. Here, we demonstrate that voluntary running and environmental changes which are effective in house mice and brown rats cannot influence AHN in long-tailed wood mice. This indicates that in wild long-tailed wood mice different regulatory mechanisms act on cell proliferation and neurogenesis. If this difference reflects a species-specific adaptation or a broader adaptive strategy to a natural vs. domestic environment is unknown. PMID:19419549

  6. Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule

    PubMed Central

    Petrik, David; Jiang, Yindi; Birnbaum, Shari G.; Powell, Craig M.; Kim, Mi-Sung; Hsieh, Jenny; Eisch, Amelia J.

    2012-01-01

    Adult neurogenesis occurs throughout life in the mammalian hippocampus and is essential for memory and mood control. There is significant interest in identifying ways to promote neurogenesis and ensure maintenance of these hippocampal functions. Previous work with a synthetic small molecule, isoxazole 9 (Isx-9), highlighted its neuronal-differentiating properties in vitro. However, the ability of Isx-9 to drive neurogenesis in vivo or improve hippocampal function was unknown. Here we show that Isx-9 promotes neurogenesis in vivo, enhancing the proliferation and differentiation of hippocampal subgranular zone (SGZ) neuroblasts, and the dendritic arborization of adult-generated dentate gyrus neurons. Isx-9 also improves hippocampal function, enhancing memory in the Morris water maze. Notably, Isx-9 enhances neurogenesis and memory without detectable increases in cellular or animal activity or vascularization. Molecular exploration of Isx-9-induced regulation of neurogenesis (via FACS and microarray of SGZ stem and progenitor cells) suggested the involvement of the myocyte-enhancer family of proteins (Mef2). Indeed, transgenic-mediated inducible knockout of all brain-enriched Mef2 isoforms (Mef2a/c/d) specifically from neural stem cells and their progeny confirmed Mef2's requirement for Isx-9-induced increase in hippocampal neurogenesis. Thus, Isx-9 enhances hippocampal neurogenesis and memory in vivo, and its effects are reliant on Mef2, revealing a novel cell-intrinsic molecular pathway regulating adult neurogenesis.—Petrik, D., Jiang, Y., Birnbaum, S. G., Powell, C. M., Kim, M.-S., Hsieh, J., Eisch, A. J. Functional and mechanistic exploration of an adult neurogenesis-promoting small molecule. PMID:22542682

  7. 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

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

    PubMed

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

    2016-01-01

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

  9. Comparative neuroscience of stimulant-induced memory dysfunction: role for neurogenesis in the adult hippocampus.

    PubMed

    Canales, Juan J

    2010-09-01

    The discovery that the addictive drugs impair neurogenesis in the adult hippocampus has prompted the elaboration of new biological hypotheses to explain addiction and drug-induced cognitive dysfunction. Considerable evidence now implicates the process of adult neurogenesis in at least some critical components of hippocampal-dependent memory function. In experimental models, psychomotor stimulant drugs produce alterations in the rate of birth, survival, maturation and functional integration of adult-born hippocampal neurons. Thus some of the deleterious consequences of drug abuse on memory could result from the neurotoxic actions of drugs on adult hippocampal neurogenesis. In this review, we will first summarize preclinical and clinical literature on the disruptive effects of drugs such as cocaine and ecstasy in the areas of learning, memory and attention. We will also summarize data that document the widespread effects of stimulant drugs on progenitor activity and precursor incorporation in the adult dentate gyrus. Finally, we will examine evidence that supports the involvement of hippocampal neurogenesis in specific aspects of learning and memory function and we will consider critically the hypothesis that some of the negative consequences of drug abuse on cognition might be ascribed to deficits in adult hippocampal neurogenesis. Evidence suggests that stimulant abuse impacts negatively on at least four areas of memory/cognitive function that may be influenced by adult hippocampal neurogenesis: contextual memory, spatial memory, working memory and cognitive flexibility.

  10. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects.

    PubMed

    Jiang, Wen; Zhang, Yun; Xiao, Lan; Van Cleemput, Jamie; Ji, Shao-Ping; Bai, Guang; Zhang, Xia

    2005-11-01

    The hippocampal dentate gyrus in the adult mammalian brain contains neural stem/progenitor cells (NS/PCs) capable of generating new neurons, i.e., neurogenesis. Most drugs of abuse examined to date decrease adult hippocampal neurogenesis, but the effects of cannabis (marijuana or cannabinoids) on hippocampal neurogenesis remain unknown. This study aimed at investigating the potential regulatory capacity of the potent synthetic cannabinoid HU210 on hippocampal neurogenesis and its possible correlation with behavioral change. We show that both embryonic and adult rat hippocampal NS/PCs are immunoreactive for CB1 cannabinoid receptors, indicating that cannabinoids could act on CB1 receptors to regulate neurogenesis. This hypothesis is supported by further findings that HU210 promotes proliferation, but not differentiation, of cultured embryonic hippocampal NS/PCs likely via a sequential activation of CB1 receptors, G(i/o) proteins, and ERK signaling. Chronic, but not acute, HU210 treatment promoted neurogenesis in the hippocampal dentate gyrus of adult rats and exerted anxiolytic- and antidepressant-like effects. X-irradiation of the hippocampus blocked both the neurogenic and behavioral effects of chronic HU210 treatment, suggesting that chronic HU210 treatment produces anxiolytic- and antidepressant-like effects likely via promotion of hippocampal neurogenesis.

  11. Glycogen Synthase Kinase 3 Inhibition Promotes Adult Hippocampal Neurogenesis in Vitro and in Vivo

    PubMed Central

    2012-01-01

    Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine. PMID:23173075

  12. Glycogen synthase kinase 3 inhibition promotes adult hippocampal neurogenesis in vitro and in vivo.

    PubMed

    Morales-Garcia, Jose A; Luna-Medina, Rosario; Alonso-Gil, Sandra; Sanz-Sancristobal, Marina; Palomo, Valle; Gil, Carmen; Santos, Angel; Martinez, Ana; Perez-Castillo, Ana

    2012-11-21

    Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase originally identified as a regulator of glycogen metabolism but it also plays a pivotal role in numerous cellular functions, including differentiation, cell cycle regulation, and proliferation. The dentate gyrus of the hippocampus, together with the subventricular zone of the lateral ventricles, is one of the regions in which neurogenesis takes place in the adult brain. Here, using a chemical genetic approach that involves the use of several diverse inhibitors of GSK-3 as pharmacological tools, we show that inhibition of GSK-3 induces proliferation, migration, and differentiation of neural stem cells toward a neuronal phenotype in in vitro studies. Also, we demonstrate that inhibition of GSK-3 with the small molecule NP03112, called tideglusib, induces neurogenesis in the dentate gyrus of the hippocampus of adult rats. Taken together, our results suggest that GSK-3 should be considered as a new target molecule for modulating the production and integration of new neurons in the hippocampus as a treatment for neurodegenerative diseases or brain injury and, consequently, its inhibitors may represent new potential therapeutic drugs in neuroregenerative medicine.

  13. Reduction of adult hippocampal neurogenesis confers vulnerability in an animal model of cocaine addiction

    PubMed Central

    Noonan, Michele A.; Bulin, Sarah; Fuller, Dwain C.; Eisch, Amelia J.

    2010-01-01

    Drugs of abuse dynamically regulate adult neurogenesis, which appears important for some types of learning and memory. Interestingly, a major site of adult neurogenesis - the hippocampus - is important in the formation of drug-context associations and in the mediation of drug-taking and drug-seeking behaviors in animal models of addiction. Correlative evidence suggests an inverse relationship between hippocampal neurogenesis and drug-taking or drug-seeking behaviors, but the lack of a causative link has made the relationship between adult-generated neurons and addiction unclear. We used rat i.v. cocaine self-administration in rodents, a clinicall-relevant animal model of addiction, to test the hypothesis that suppression of adult hippocampal neurogenesis enhances vulnerability to addiction and relapse. Suppression of adult hippocampal neurogenesis via cranial irradiation before drug-taking significantly increased cocaine self-administration on both fixed-ratio and progressive-ratio schedules, as well as induced a vertical shift in the dose-response curve. This was not a general enhancement of learning, motivation or locomotion, as sucrose self-administration and locomotor activity were unchanged in irradiated rats. Suppression of adult hippocampal neurogenesis after drug-taking significantly enhanced resistance to extinction of drug-seeking behavior. These studies identify reduced adult hippocampal neurogenesis as a novel risk factor for addiction-related behaviors in an animal model of cocaine addiction. Further, they suggest that therapeutics to specifically increase or stabilize adult hippocampal neurogenesis could aid in preventing initial addiction as well as future relapse. PMID:20053911

  14. Converging action of alcohol consumption and cannabinoid receptor activation on adult hippocampal neurogenesis.

    PubMed

    Alén, Francisco; Mouret, Aurélie; Viveros, Maria-Paz; Llorente, Ricardo; Lepousez, Gabriel; Lledo, Pierre-Marie; López-Moreno, José Antonio

    2010-03-01

    Alcoholism is characterized by successive periods of abstinence and relapse, resulting from long-lasting changes in various circuits of the central nervous system. Accumulating evidence points to the endocannabinoid system as one of the most relevant biochemical systems mediating alcohol addiction. The endocannabinoid system regulates adult neurogenesis, a form of long-lasting adult plasticity that occurs in a few areas of the brain, including the dentate gyrus. Because exposure to psychotropic drugs regulates adult neurogenesis, it is possible that neurogenesis might be implicated in the pathophysiology, and hence treatment, of neurobiological illnesses related to drugs of abuse. Here, we investigated the sensitivity of adult hippocampal neurogenesis to alcohol and the cannabinoid receptor agonist WIN 55,212-2 (WIN). Specifically, we analysed the potential link between alcohol relapse, cannabinoid receptor activation, and adult neurogenesis. Adult rats were exposed to subchronic alcohol binge intoxication and received the cannabinoid receptor agonist WIN. Another group of rats were subjected to an alcohol operant self-administration task. Half of these latter animals had continuous access to alcohol, while the other half were subjected to alcohol deprivation, with or without WIN administration. WIN treatment, when administered during alcohol deprivation, resulted in the greatest increase in alcohol consumption during relapse. Together, forced alcohol binge intoxication and WIN administration dramatically reduced hippocampal neurogenesis. Furthermore, adult neurogenesis inversely correlated with voluntary consumption of alcohol. These findings suggest that adult hippocampal neurogenesis is a key factor involved in drug abuse and that it may provide a new strategy for the treatment of alcohol addiction and dependence.

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

    PubMed

    O'Leary, Olivia F; Cryan, John F

    2014-12-01

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

  16. TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus.

    PubMed

    Matsuda, Taito; Murao, Naoya; Katano, Yuki; Juliandi, Berry; Kohyama, Jun; Akira, Shizuo; Kawai, Taro; Nakashima, Kinichi

    2015-01-01

    Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neurogenesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-α, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity. PMID:25751136

  17. Gene-environment interaction in programming hippocampal plasticity: focus on adult neurogenesis

    PubMed Central

    Koehl, Muriel

    2015-01-01

    Interactions between genes and environment are a critical feature of development and both contribute to shape individuality. They are at the core of vulnerability resiliency for mental illnesses. During the early postnatal period, several brain structures involved in cognitive and emotional processing, such as the hippocampus, still develop and it is likely that interferences with this neuronal development, which is genetically determined, might lead to long-lasting structural and functional consequences and increase the risk of developing psychopathology. One particular target is adult neurogenesis, which is involved in the regulation of cognitive and emotional processes. Insights into the dynamic interplay between genes and environmental factors in setting up individual rates of neurogenesis have come from laboratory studies exploring experience-dependent changes in adult neurogenesis as a function of individual’s genetic makeup. These studies have implications for our understanding of the mechanisms regulating adult neurogenesis, which could constitute a link between environmental challenges and psychopathology. PMID:26300723

  18. TLR9 signalling in microglia attenuates seizure-induced aberrant neurogenesis in the adult hippocampus.

    PubMed

    Matsuda, Taito; Murao, Naoya; Katano, Yuki; Juliandi, Berry; Kohyama, Jun; Akira, Shizuo; Kawai, Taro; Nakashima, Kinichi

    2015-03-09

    Pathological conditions such as epilepsy cause misregulation of adult neural stem/progenitor populations in the adult hippocampus in mice, and the resulting abnormal neurogenesis leads to impairment in learning and memory. However, how animals cope with abnormal neurogenesis remains unknown. Here we show that microglia in the mouse hippocampus attenuate convulsive seizure-mediated aberrant neurogenesis through the activation of Toll-like receptor 9 (TLR9), an innate immune sensor known to recognize microbial DNA and trigger inflammatory responses. We found that microglia sense self-DNA from degenerating neurons following seizure, and secrete tumour necrosis factor-α, resulting in attenuation of aberrant neurogenesis. Furthermore, TLR9 deficiency exacerbated seizure-induced cognitive decline and recurrent seizure severity. Our findings thus suggest the existence of bidirectional communication between the innate immune and nervous systems for the maintenance of adult brain integrity.

  19. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

    PubMed

    Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

    2014-07-01

    Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis.

  20. An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus.

    PubMed

    Pereira, Ana C; Huddleston, Dan E; Brickman, Adam M; Sosunov, Alexander A; Hen, Rene; McKhann, Guy M; Sloan, Richard; Gage, Fred H; Brown, Truman R; Small, Scott A

    2007-03-27

    With continued debate over the functional significance of adult neurogenesis, identifying an in vivo correlate of neurogenesis has become an important goal. Here we rely on the coupling between neurogenesis and angiogenesis and test whether MRI measurements of cerebral blood volume (CBV) provide an imaging correlate of neurogenesis. First, we used an MRI approach to generate CBV maps over time in the hippocampal formation of exercising mice. Among all hippocampal subregions, exercise was found to have a primary effect on dentate gyrus CBV, the only subregion that supports adult neurogenesis. Moreover, exercise-induced increases in dentate gyrus CBV were found to correlate with postmortem measurements of neurogenesis. Second, using similar MRI technologies, we generated CBV maps over time in the hippocampal formation of exercising humans. As in mice, exercise was found to have a primary effect on dentate gyrus CBV, and the CBV changes were found to selectively correlate with cardiopulmonary and cognitive function. Taken together, these findings show that dentate gyrus CBV provides an imaging correlate of exercise-induced neurogenesis and that exercise differentially targets the dentate gyrus, a hippocampal subregion important for memory and implicated in cognitive aging.

  1. Targeting Nicotinamide Phosphoribosyltransferase as a Potential Therapeutic Strategy to Restore Adult Neurogenesis.

    PubMed

    Wang, Shu-Na; Xu, Tian-Ying; Li, Wen-Lin; Miao, Chao-Yu

    2016-06-01

    Adult neurogenesis is the process of generating new neurons throughout life in the olfactory bulb and hippocampus of most mammalian species, which is closely related to aging and disease. Nicotinamide phosphoribosyltransferase (NAMPT), also an adipokine known as visfatin, is the rate-limiting enzyme for mammalian nicotinamide adenine dinucleotide (NAD) salvage synthesis by generating nicotinamide mononucleotide (NMN) from nicotinamide. Recent findings from our laboratory and other laboratories have provided much evidence that NAMPT might serve as a therapeutic target to restore adult neurogenesis. NAMPT-mediated NAD biosynthesis in neural stem/progenitor cells is important for their proliferation, self-renewal, and formation of oligodendrocytes in vivo and in vitro. Therapeutic interventions by the administration of NMN, NAD, or recombinant NAMPT are effective for restoring adult neurogenesis in several neurological diseases. We summarize adult neurogenesis in aging, ischemic stroke, traumatic brain injury, and neurodegenerative disease and review the advances of targeting NAMPT in restoring neurogenesis. Specifically, we provide emphasis on the P7C3 family, a class of proneurogenic compounds that are potential NAMPT activators, which might shed light on future drug development in neurogenesis restoration. PMID:27018006

  2. Hippocampal adult neurogenesis: Its regulation and potential role in spatial learning and memory.

    PubMed

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

    2016-08-01

    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

  3. 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

  4. Control of adult neurogenesis by programmed cell death in the mammalian brain.

    PubMed

    Ryu, Jae Ryun; Hong, Caroline Jeeyeon; Kim, Joo Yeon; Kim, Eun-Kyoung; Sun, Woong; Yu, Seong-Woon

    2016-04-21

    The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

  5. Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

    PubMed

    Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

    2014-09-01

    The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression.

  6. Pheromones from males of different familiarity exert divergent effects on adult neurogenesis in the female accessory olfactory bulb.

    PubMed

    Wu, Jyun-Han; Han, Yueh-Ting; Yu, Jenn-Yah; Wang, Tsu-Wei

    2013-08-01

    Pheromones from urine of unfamiliar conspecific male animals can reinitiate a female's estrus cycle to cause pregnancy block through the vomeronasal organ (VNO)-accessory olfactory bulb (AOB)-hypothalamic pathway. This phenomenon is called the Bruce effect. Pheromones from the mate of the female, however, do not trigger re-entrance of the estrus cycle because an olfactory memory toward its mate is formed. The activity of the VNO-AOB-hypothalamic pathway is negatively modulated by GABAergic granule cells in the AOB. Since these cells are constantly replenished by neural stem cells in the subventricular zone (SVZ) of the lateral ventricle throughout adulthood and adult neurogenesis is required for mate recognition and fertility, we tested the hypothesis that pheromones from familiar and unfamiliar males may have different effects on adult AOB neurogenesis in female mice. When female mice were exposed to bedding used by a male or lived with one, cell proliferation and neuroblast production in the SVZ were increased. Furthermore, survival of newly generated cells in the AOB was enhanced. This survival effect was transient and mediated by norepinephrine. Interestingly, male bedding-induced newborn cell survival in the AOB but not cell proliferation in the SVZ was attenuated when females were subjected to bedding from an unfamiliar male. Our results indicate that male pheromones from familiar and unfamiliar males exert different effects on neurogenesis in the adult female AOB. Given that adult neurogenesis is required for reproductive behaviors, these divergent pheromonal effects may provide a mechanism for the Bruce effect. © 2013 Wiley Periodicals, Inc. Develop Neurobiol 73: 632-645, 2013.

  7. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice

    PubMed Central

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  8. Prenatal lipopolysaccharide exposure increases depression-like behaviors and reduces hippocampal neurogenesis in adult rats.

    PubMed

    Lin, Yu-Lung; Wang, Sabrina

    2014-02-01

    Major depression is one of the most prevalent mental disorders in the population. In addition to genetic influences, disturbances in fetal nervous system development might be a contributing factor. Maternal infection during pregnancy may affect fetal brain development and consequently lead to neurological and mental disorders. Previously, we used low-dose lipopolysaccharide (LPS) exposure on embryonic day 10.5 to mimic mild maternal infection in rats and found that dopaminergic and serotonergic neurons were reduced in the offspring. The offspring also showed more anxiety-like behavior and an enhanced stress response. In the present study we used forced swim test and chronic mild stress challenge to assess depression-like behaviors in the affected offspring and examined their adult hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) concentration. Our results showed that prenatally LPS-exposed rats (LPS rats) displayed more depression-like behaviors and had reduced adult neurogenesis and BDNF. The behavioral abnormalities and reduction in adult neurogenesis could be reversed by chronic fluoxetine (FLX) treatment. This study demonstrates that during the critical time of embryonic development LPS exposure can produce long-term behavioral changes and reduction in adult neurogenesis. The findings of enhanced depression-like behaviors, reduced adult neurogenesis, and their responsiveness to chronic antidepressant treatment suggest that prenatal LPS exposure could serve as an animal model of depression.

  9. Functional role of adult hippocampal neurogenesis as a therapeutic strategy for mental disorders.

    PubMed

    Jun, Heechul; Mohammed Qasim Hussaini, Syed; Rigby, Michael J; Jang, Mi-Hyeon

    2012-01-01

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

  10. Energy Metabolism, Adult Neurogenesis and their Possible Roles in Alzheimer's Disease: A Brief Overview.

    PubMed

    Sun, Ping; Hua, Qian; Schmitt, Angelika G

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent human neurodegenerative disease. Disturbances of brain glucose uptake, glucose tolerance, glucose utilization and of the insulin/insulin receptor signaling cascade are thought to be key features of the pathophysiology of AD. Changes in energy homeostasis in the brain and in the periphery dramatically influence the proliferation of adult neural stem cells and neurogenesis in the hippocampus. Recent findings suggest that adult neurogenesis is altered in the hippocampus of AD patients and in various animal models of AD. Several factors associated with the pathogenesis of AD are also known to be involved in the regulation of adult neurogenesis. Understanding the mechanisms underlying these changes at different stages of AD could provide insights into its pathogenesis, contribute to identifying biomarkers of early AD, and supply fundamental knowledge that will allow novel therapeutic approaches to treating AD by intervening in adult neurogenesis. In this review we provide an overview of the connections between energy metabolism, adult neurogenesis and AD.

  11. Running increases neurogenesis without retinoic acid receptor activation in the adult mouse dentate gyrus.

    PubMed

    Aberg, Elin; Perlmann, Thomas; Olson, Lars; Brené, Stefan

    2008-01-01

    Both vitamin A deficiency and high doses of retinoids can result in learning and memory impairments, depression as well as decreases in cell proliferation, neurogenesis and cell survival. Physical activity enhances hippocampal neurogenesis and can also exert an antidepressant effect. Here we elucidate a putative link between running, retinoid signaling, and neurogenesis in hippocampus. Adult transgenic reporter mice designed to detect ligand-activated retinoic acid receptors (RAR) or retinoid X receptors (RXR) were used to localize the distribution of activated RAR or RXR at the single-cell level in the brain. Two months of voluntary wheel-running induced an increase in hippocampal neurogenesis as indicated by an almost two-fold increase in doublecortin-immunoreactive cells. Running activity was correlated with neurogenesis. Under basal conditions a distinct pattern of RAR-activated cells was detected in the granule cell layer of the dentate gyrus (DG), thalamus, and cerebral cortex layers 3-4 and to a lesser extent in hippocampal pyramidal cell layers CA1-CA3. Running did not change the number of RAR-activated cells in the DG. There was no correlation between running and RAR activation or between RAR activation and neurogenesis in the DG of hippocampus. Only a few scattered activated retinoid X receptors were found in the DG under basal conditions and after wheel-running, but RXR was detected in other areas such as in the hilus region of hippocampus and in layer VI of cortex cerebri. RAR agonists affect mood in humans and reduce neurogenesis, learning and memory in animal models. In our study, long-term running increased neurogenesis but did not alter RAR ligand activation in the DG in individually housed mice. Thus, our data suggest that the effects of exercise on neurogenesis and other plasticity changes in the hippocampal formation are mediated by mechanisms that do not involve retinoid receptor activation.

  12. Photoperiodic regulation of hippocampal neurogenesis in adult male white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Aubrecht, Taryn G; Weil, Zachary M; Leuner, Benedetta; Nelson, Randy J

    2014-08-01

    Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis, as males, in addition to having reduced hippocampal volume in short days (SD) with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog bromodeoxyuridine at multiple time points across 10 weeks of SD exposure. Compared with counterparts held in long day (LD) lengths, across the first 8 weeks of SD exposure hippocampal neurogenesis was reduced. However, at 10 weeks in SD lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in LD lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes and adaptive responses to changing day lengths affects brain structure, function and behavior at multiple levels. PMID:24893623

  13. Photoperiodic regulation of hippocampal neurogenesis in adult male white-footed mice (Peromyscus leucopus).

    PubMed

    Walton, James C; Aubrecht, Taryn G; Weil, Zachary M; Leuner, Benedetta; Nelson, Randy J

    2014-08-01

    Photoperiodic organisms monitor environmental day length to engage in seasonally appropriate adaptions in physiology and behavior. Among these adaptations are changes in brain volume and neurogenesis, which have been well described in multiple species of birds, yet few studies have described such changes in the brains of adult mammals. White-footed mice (Peromyscus leucopus) are an excellent species in which to investigate the effects of day length on adult hippocampal neurogenesis, as males, in addition to having reduced hippocampal volume in short days (SD) with concomitant impairments in hippocampus-mediated behaviors, have photoperiod-dependent changes in olfactory bulb neurogenesis. We performed the current experiment to assess the effects of photoperiod on hippocampal neurogenesis longitudinally, using the thymidine analog bromodeoxyuridine at multiple time points across 10 weeks of SD exposure. Compared with counterparts held in long day (LD) lengths, across the first 8 weeks of SD exposure hippocampal neurogenesis was reduced. However, at 10 weeks in SD lengths neurogenic levels in the hippocampus were elevated above those levels in mice held in LD lengths. The current findings are consistent with the natural photoperiodic cycle of hippocampal function in male white-footed mice, and may help to inform research on photoperiodic plasticity in neurogenesis and provide insight into how the complex interplay among the environment, genes and adaptive responses to changing day lengths affects brain structure, function and behavior at multiple levels.

  14. 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

    2015-08-01

    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.

  15. 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

  16. BIRDS AS A MODEL TO STUDY ADULT NEUROGENESIS: BRIDGING EVOLUTIONARY, COMPARATIVE AND NEUROETHOLOGICAL APPROCHES

    PubMed Central

    BARNEA, ANAT; PRAVOSUDOV, VLADIMIR

    2011-01-01

    During the last few decades evidence has demonstrated that adult neurogenesis is a well-preserved feature throughout the animal kingdom. In birds, ongoing neuronal addition occurs rather broadly, to a number of brain regions. This review describes adult avian neurogenesis and neuronal recruitment, discusses factors that regulate these processes, and touches upon the question of their genetic control. Several attributes make birds an extremely advantageous model to study neurogenesis. First, song learning exhibits seasonal variation that is associated with seasonal variation in neuronal turnover in some song control brain nuclei, which seems to be regulated via adult neurogenesis. Second, food-caching birds naturally use memory-dependent behavior in learning locations of thousands of food caches scattered over their home ranges. In comparison with other birds, food-caching species have relatively enlarged hippocampi with more neurons and intense neurogenesis, which appears to be related to spatial learning. Finally, migratory behavior and naturally occurring social systems in birds also provide opportunities to investigate neurogenesis. Such diversity of naturally-occurring memory-based behaviors, combined with the fact that birds can be studied both in the wild and in the laboratory, make them ideal for investigation of neural processes underlying learning. This can be done by using various approaches, from evolutionary and comparative to neuroethological and molecular. Finally, we connect the avian arena to a broader view by providing a brief comparative and evolutionary overview of adult neurogenesis and by discussing the possible functional role of the new neurons. We conclude by indicating future directions and possible medical applications. PMID:21929623

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

    PubMed

    Jin, Junghee; Kim, Seung-Nam; Liu, Xuqing; Zhang, Haijun; Zhang, Chao; Seo, Ji-Seon; Kim, Yong; Sun, Tao

    2016-08-01

    Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here, we show that altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact on neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors decreases neurogenesis in the dentate gyrus, while its overexpression increases neurogenesis. miR-17-92 affects neurogenesis by regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects induced by corticosterone in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors through regulation of neurogenesis and anxiety- and depression-like behaviors. PMID:27477270

  18. Molecular Biomarkers for Embryonic and Adult Neural Stem Cell and Neurogenesis

    PubMed Central

    Zhang, Juan; Jiao, Jianwei

    2015-01-01

    The procedure of neurogenesis has made numerous achievements in the past decades, during which various molecular biomarkers have been emerging and have been broadly utilized for the investigation of embryonic and adult neural stem cell (NSC). Nevertheless, there is not a consistent and systematic illustration to depict the functional characteristics of the specific markers expressed in distinct cell types during the different stages of neurogenesis. Here we gathered and generalized a series of NSC biomarkers emerging during the procedures of embryonic and adult neural stem cell, which may be used to identify the subpopulation cells with distinguishing characters in different timeframes of neurogenesis. The identifications of cell patterns will provide applications to the detailed investigations of diverse developmental cell stages and the extents of cell differentiation, which will facilitate the tracing of cell time-course and fate determination of specific cell types and promote the further and literal discoveries of embryonic and adult neurogenesis. Meanwhile, via the utilization of comprehensive applications under the aiding of the systematic knowledge framework, researchers may broaden their insights into the derivation and establishment of novel technologies to analyze the more detailed process of embryogenesis and adult neurogenesis. PMID:26421301

  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. Adult Hippocampal Neurogenesis: Regulation, Functional Implications, And Contribution to Disease Pathology

    PubMed Central

    Balu, Darrick T.; Lucki, Irwin

    2009-01-01

    It is now well established that the mammalian brain has the capacity to produce new neurons into adulthood. One such region that provides the proper milieu to sustain progenitor cells and is permissive to neuronal fate determination is located in the dentate gyrus of the hippocampus. This review will discuss in detail the complex process of adult hippocampal neurogenesis, including proliferation, differentiation, survival, and incorporation into neuronal networks. The regulation of this phenomenon by a number of factors is described, including neurotransmitter systems, growth factors, paracrine signaling molecules, neuropeptides, transcription factors, endogenous psychotropic systems, sex hormones, stress, and others. This review also addresses the functional significance of adult born hippocampal granule cells with regard to hippocampal circuitry dynamics and behavior. Furthermore, the relevance of perturbations in adult hippocampal neurogenesis to the pathophysiology of various disease states, including depression, schizophrenia, epilepsy, and diabetes are examined. Finally, this review discusses the potential of using hippocampal neurogenesis as a therapeutic target for these disorders. PMID:18786562

  1. Sleep deprivation inhibits adult neurogenesis in the hippocampus by elevating glucocorticoids.

    PubMed

    Mirescu, Christian; Peters, Jennifer D; Noiman, Liron; Gould, Elizabeth

    2006-12-12

    Prolonged sleep deprivation is stressful and has been associated with adverse consequences for health and cognitive performance. Here, we show that sleep deprivation inhibits adult neurogenesis at a time when circulating levels of corticosterone are elevated. Moreover, clamping levels of this hormone prevents the sleep deprivation-induced reduction of cell proliferation. The recovery of normal levels of adult neurogenesis after chronic sleep deprivation occurs over a 2-wk period and involves a temporary increase in new neuron formation. This compensatory increase is dissociated from glucocorticoid levels as well as from the restoration of normal sleep patterns. Collectively, these findings suggest that, although sleep deprivation inhibits adult neurogenesis by acting as a stressor, its compensatory aftereffects involve glucocorticoid-independent factors.

  2. Additive effects of physical exercise and environmental enrichment on adult hippocampal neurogenesis in mice.

    PubMed

    Fabel, Klaus; Wolf, Susanne A; Ehninger, Dan; Babu, Harish; Leal-Galicia, Perla; Kempermann, Gerd

    2009-01-01

    Voluntary physical exercise (wheel running, RUN) and environmental enrichment both stimulate adult hippocampal neurogenesis but do so by different mechanisms. RUN induces precursor cell proliferation, whereas ENR exerts a survival-promoting effect on newborn cells. In addition, continued RUN prevented the physiologically occurring age-related decline in precursor cell in the dentate gyrus but did not lead to a corresponding increase in net neurogenesis. We hypothesized that in the absence of appropriate cognitive stimuli the potential for neurogenesis could not be realized but that an increased potential by proliferating precursor cells due to RUN could actually lead to more adult neurogenesis if an appropriate survival-promoting stimulus follows the exercise. We thus asked whether a sequential combination of RUN and ENR (RUNENR) would show additive effects that are distinct from the application of either paradigm alone. We found that the effects of 10 days of RUN followed by 35 days of ENR were additive in that the combined stimulation yielded an approximately 30% greater increase in new neurons than either stimulus alone, which also increased neurogenesis. Surprisingly, this result indicates that although overall the amount of proliferating cells in the dentate gyrus is poorly predictive of net adult neurogenesis, an increased neurogenic potential nevertheless provides the basis for a greater efficiency of the same survival-promoting stimulus. We thus propose that physical activity can "prime" the neurogenic region of the dentate gyrus for increased neurogenesis in the case the animal is exposed to an additional cognitive stimulus, here represented by the enrichment paradigm.

  3. Oxytocin stimulates adult neurogenesis even under conditions of stress and elevated glucocorticoids.

    PubMed

    Leuner, Benedetta; Caponiti, Julia M; Gould, Elizabeth

    2012-04-01

    Oxytocin has been linked to social behavior, including social recognition, pair bonding and parenting, but its potential role in promoting neuronal growth has not been investigated. We show here that oxytocin, but not vasopressin, stimulates both cell proliferation and adult neurogenesis in the hippocampus of rats. Oxytocin is also capable of stimulating adult neurogenesis in rats subjected to glucocorticoid administration or cold water swim stress. These findings suggest that oxytocin stimulates neuronal growth and may protect against the suppressive effects of stress hormones on hippocampal plasticity.

  4. Regulation of stroke-induced neurogenesis in adult brain--recent scientific progress.

    PubMed

    Kokaia, Zaal; Thored, Pär; Arvidsson, Andreas; Lindvall, Olle

    2006-07-01

    Stroke induced by middle cerebral artery occlusion in adult rodents induces the formation of new neurons in the damaged striatum, a region that normally does not show neurogenesis. Here we describe recent findings on the regulation of neurogenesis after stroke, in particular regarding the duration of the neurogenic response and the influence of age, as well as the molecular mechanisms influencing migration and survival of the new neurons. We also discuss some crucial issues that need to be addressed in the further exploration of this potential self-repair mechanism after damage to the adult brain. PMID:16766702

  5. Deficient plasticity in the hippocampus and the spiral of addiction: focus on adult neurogenesis.

    PubMed

    Canales, Juan J

    2013-01-01

    Addiction is a complex neuropsychiatric disorder which causes disruption at multiple levels, including cognitive, emotional, and behavioral domains. Traditional biological theories of addiction have focused on the mesolimbic dopamine pathway and the nucleus accumbens as anatomical substrates mediating addictive-like behaviors. More recently, we have begun to recognize the engagement and dynamic influence of a much broader circuitry which encompasses the frontal cortex, the amygdala, and the hippocampus. In particular, neurogenesis in the adult hippocampus has become a major focus of attention due to its ability to influence memory, motivation, and affect, all of which are disrupted in addiction. First, I summarize toxicological data that reveal strongly suppressive effects of drug exposure on adult hippocampal neurogenesis. Then, I discuss the impact of deficient neurogenesis on learning and memory function, stress responsiveness and affective behavior, as they relate to addiction. Finally, I examine recent behavioral observations that implicate neurogenesis in the adult hippocampus in the emergence and maintenance of addictive behavior. The evidence reviewed here suggests that deficient neurogenesis is associated with several components of the downward spiraling loop that characterizes addiction, including elevated sensitivity to drug-induced reward and reinforcement, enhanced neurohormonal responsiveness, emergence of a negative affective state, memory impairment, and inflexible behavior. PMID:22976276

  6. Deficient plasticity in the hippocampus and the spiral of addiction: focus on adult neurogenesis.

    PubMed

    Canales, Juan J

    2013-01-01

    Addiction is a complex neuropsychiatric disorder which causes disruption at multiple levels, including cognitive, emotional, and behavioral domains. Traditional biological theories of addiction have focused on the mesolimbic dopamine pathway and the nucleus accumbens as anatomical substrates mediating addictive-like behaviors. More recently, we have begun to recognize the engagement and dynamic influence of a much broader circuitry which encompasses the frontal cortex, the amygdala, and the hippocampus. In particular, neurogenesis in the adult hippocampus has become a major focus of attention due to its ability to influence memory, motivation, and affect, all of which are disrupted in addiction. First, I summarize toxicological data that reveal strongly suppressive effects of drug exposure on adult hippocampal neurogenesis. Then, I discuss the impact of deficient neurogenesis on learning and memory function, stress responsiveness and affective behavior, as they relate to addiction. Finally, I examine recent behavioral observations that implicate neurogenesis in the adult hippocampus in the emergence and maintenance of addictive behavior. The evidence reviewed here suggests that deficient neurogenesis is associated with several components of the downward spiraling loop that characterizes addiction, including elevated sensitivity to drug-induced reward and reinforcement, enhanced neurohormonal responsiveness, emergence of a negative affective state, memory impairment, and inflexible behavior.

  7. Environmental enrichment requires adult neurogenesis to facilitate the recovery from psychosocial stress

    PubMed Central

    Schloesser, R J; Lehmann, M; Martinowich, K; Manji, H K; Herkenham, M

    2010-01-01

    The subgranular zone of the adult hippocampal dentate gyrus contains a pool of neural stem cells that continuously divide and differentiate into functional granule cells. It has been shown that production of new hippocampal neurons is necessary for amelioration of stress-induced behavioral changes by antidepressants in animal models of depression. The survival of newly born hippocampal neurons is decreased by chronic psychosocial stress and increased by exposure to enriched environments. These observations suggest the existence of a link between hippocampal neurogenesis, stress-induced behavioral changes, and the beneficial effects of enriched environment. To show causality, we subjected transgenic mice with conditionally suppressed neurogenesis to psychosocial stress followed by environmental enrichment. First, we showed that repeated social defeat coupled with chronic exposure to an aggressor produces robust and quantifiable indices of submissive and depressive-like behaviors; second, subsequent exposure to an enriched environment led to extinction of the submissive phenotype, while animals exposed to an impoverished environment retained the submissive phenotype; and third, enrichment was not effective in reversing the submissive and depressive-like behaviors in transgenic mice lacking neurogenesis. Our data show two main findings. First, living in an enriched environment is highly effective in extinguishing submissive behavioral traits developed during chronic social stress, and second, these effects are critically dependent on adult neurogenesis, indicating that beneficial behavioral adaptations are dependent on intact adult neurogenesis. PMID:20308988

  8. Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate?

    PubMed

    Ryan, Sinéad M; Nolan, Yvonne M

    2016-02-01

    Adult hippocampal neurogenesis is believed to be integral for certain forms of learning and memory. Dysregulation of hippocampal neurogenesis has been shown to be an important mechanism underlying the cognitive impairment associated with normal aging, as well as the cognitive deficits evident in preclinical models of Alzheimer's disease and other neurodegenerative diseases. Neuroinflammation is a significant pathological feature of these conditions; it contributes to the observed cognitive decline, and recent evidence demonstrates that it also negatively affects hippocampal neurogenesis. Conversely, during the past twenty years, it has been robustly shown that exercise is a potent inducer of hippocampal neurogenesis, and it is believed that the positive beneficial effect of exercise on cognitive function is likely due to its pro-neurogenic effects. However, the interplay between exercise- and neuroinflammatory-induced changes in hippocampal neurogenesis and associated cognitive function has only recently begun to receive attention. Here we review the current literature on exercise-induced effects on hippocampal neurogenesis, cognitive function and neuroinflammation, and consider exercise as a potential pro-neurogenic and anti-inflammatory intervention for cognition.

  9. Adult hippocampal neurogenesis is functionally important for stress-induced social avoidance

    PubMed Central

    Lagace, Diane C.; Donovan, Michael H.; DeCarolis, Nathan A.; Farnbauch, Laure A.; Malhotra, Shveta; Berton, Olivier; Nestler, Eric J.; Krishnan, Vaishnav; Eisch, Amelia J.

    2010-01-01

    The long-term response to chronic stress is variable, with some individuals developing maladaptive functioning, although other “resilient” individuals do not. Stress reduces neurogenesis in the dentate gyrus subgranular zone (SGZ), but it is unknown if stress-induced changes in neurogenesis contribute to individual vulnerability. Using a chronic social defeat stress model, we explored whether the susceptibility to stress-induced social avoidance was related to changes in SGZ proliferation and neurogenesis. Immediately after social defeat, stress-exposed mice (irrespective of whether they displayed social avoidance) had fewer proliferating SGZ cells labeled with the S-phase marker BrdU. The decrease was transient, because BrdU cell numbers were normalized 24 h later. The survival of BrdU cells labeled before defeat stress was also not altered. However, 4 weeks later, mice that displayed social avoidance had more surviving dentate gyrus neurons. Thus, dentate gyrus neurogenesis is increased after social defeat stress selectively in mice that display persistent social avoidance. Supporting a functional role for adult-generated dentate gyrus neurons, ablation of neurogenesis via cranial ray irradiation robustly inhibited social avoidance. These data show that the time window after cessation of stress is a critical period for the establishment of persistent cellular and behavioral responses to stress and that a compensatory enhancement in neurogenesis is related to the long-term individual differences in maladaptive responses to stress. PMID:20176946

  10. 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.

  11. Human tau expression reduces adult neurogenesis in a mouse model of tauopathy.

    PubMed

    Komuro, Yutaro; Xu, Guixiang; Bhaskar, Kiran; Lamb, Bruce T

    2015-06-01

    Accumulation of hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) is a central feature of a class of neurodegenerative diseases termed tauopathies. Notably, there is increasing evidence that tauopathies, including Alzheimer's disease, are also characterized by a reduction in neurogenesis, the birth of adult neurons. However, the exact relationship between hyperphosphorylation and aggregation of MAPT and neurogenic deficits remains unclear, including whether this is an early- or late-stage disease marker. In the present study, we used the genomic-based hTau mouse model of tauopathy to examine the temporal and spatial regulation of adult neurogenesis during the course of the disease. Surprisingly, hTau mice exhibited reductions in adult neurogenesis in 2 different brain regions by as early as 2 months of age, before the development of robust MAPT pathology in this model. This reduction was found to be due to reduced proliferation and not because of enhanced apoptosis in the hippocampus. At these same time points, hTau mice also exhibited altered MAPT phosphorylation with neurogenic precursors. To examine whether the effects of MAPT on neurogenesis were cell autonomous, neurospheres prepared from hTau animals were examined in vitro, revealing a growth deficit when compared with non-transgenic neurosphere cultures. Taken together, these studies provide evidence that altered adult neurogenesis is a robust and early marker of altered, cell-autonomous function of MAPT in the hTau mouse mode of tauopathy and that altered adult neurogenesis should be examined as a potential marker and therapeutic target for human tauopathies.

  12. Inducible activation of ERK5 MAP kinase enhances adult neurogenesis in the olfactory bulb and improves olfactory function.

    PubMed

    Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M; Xu, Lihong; Storm, Daniel R; Xia, Zhengui

    2015-05-20

    Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury.

  13. Inducible Activation of ERK5 MAP Kinase Enhances Adult Neurogenesis in the Olfactory Bulb and Improves Olfactory Function

    PubMed Central

    Wang, Wenbin; Lu, Song; Li, Tan; Pan, Yung-Wei; Zou, Junhui; Abel, Glen M.; Xu, Lihong; Storm, Daniel R.

    2015-01-01

    Recent discoveries have suggested that adult neurogenesis in the subventricular zone (SVZ) and olfactory bulb (OB) may be required for at least some forms of olfactory behavior in mice. However, it is unclear whether conditional and selective enhancement of adult neurogenesis by genetic approaches is sufficient to improve olfactory function under physiological conditions or after injury. Furthermore, specific signaling mechanisms regulating adult neurogenesis in the SVZ/OB are not fully defined. We previously reported that ERK5, a MAP kinase selectively expressed in the neurogenic regions of the adult brain, plays a critical role in adult neurogenesis in the SVZ/OB. Using a site-specific knock-in mouse model, we report here that inducible and targeted activation of the endogenous ERK5 in adult neural stem/progenitor cells enhances adult neurogenesis in the OB by increasing cell survival and neuronal differentiation. This conditional ERK5 activation also improves short-term olfactory memory and odor-cued associative olfactory learning under normal physiological conditions. Furthermore, these mice show enhanced recovery of olfactory function and have more adult-born neurons after a zinc sulfate-induced lesion of the main olfactory epithelium. We conclude that ERK5 MAP kinase is an important endogenous signaling pathway regulating adult neurogenesis in the SVZ/OB, and that conditional activation of endogenous ERK5 is sufficient to enhance adult neurogenesis in the OB thereby improving olfactory function both under normal conditions and after injury. PMID:25995470

  14. Mature neurons modulate neurogenesis through chemical signals acting on neural stem cells.

    PubMed

    Pardal, Ricardo; López Barneo, José

    2016-06-01

    The discovery of neural stem cells has revealed a much higher structural and functional plasticity in the adult nervous system than previously anticipated. Progenitor cells are able to give rise to new neurons and glial cells when needed, thanks to their surveillance of the environment from the germinal niches. Multiple different factors define neural stem cell niches, including cellular and non-cellular components. Innervation of neurogenic centers is crucial, as it allows the functional connection between stem cell behavior and surrounding neuronal activity. Although the association between organismal behavior and neurogenesis is well documented, much less is known about the cellular and molecular mechanisms by which neurons control stem cell activity. In this review we discuss the existing data on this type of regulation from the three best characterized germinal niches in the adult nervous system: the subventricular zone, the hippocampal subgranular zone, and the carotid body. In all cases, neuronal activity modulates stem cell behavior either by neurotransmitter spillover or by synaptic-like contacts. Currently, the molecular mechanisms underlying mature neuron-stem cell interaction are being clarified. Functional consequences and potential clinical relevance of these phenomena are also discussed.

  15. Time-of-Day-Dependent Enhancement of Adult Neurogenesis in the Hippocampus

    PubMed Central

    Fukada, Yoshitaka

    2008-01-01

    Background Adult neurogenesis occurs in specific regions of the mammalian brain such as the dentate gyrus of the hippocampus. In the neurogenic region, neural progenitor cells continuously divide and give birth to new neurons. Although biological properties of neurons and glia in the hippocampus have been demonstrated to fluctuate depending on specific times of the day, it is unclear if neural progenitors and neurogenesis in the adult brain are temporally controlled within the day. Methodology/Principal Findings Here we demonstrate that in the dentate gyrus of the adult mouse hippocampus, the number of M-phase cells shows a day/night variation throughout the day, with a significant increase during the nighttime. The M-phase cell number is constant throughout the day in the subventricular zone of the forebrain, another site of adult neurogenesis, indicating the daily rhythm of progenitor mitosis is region-specific. Importantly, the nighttime enhancement of hippocampal progenitor mitosis is accompanied by a nighttime increase of newborn neurons. Conclusions/Significance These results indicate that neurogenesis in the adult hippocampus occurs in a time-of-day-dependent fashion, which may dictate daily modifications of dentate gyrus physiology. PMID:19048107

  16. Apigenin and related compounds stimulate adult neurogenesis. Mars, Inc., the Salk Institute for Biological Studies: WO2008147483.

    PubMed

    Taupin, Philippe

    2009-04-01

    The application is in the field of adult neurogenesis and its therapeutic potential. It aims to characterize the activity of apigenin and related compounds on adult neurogenesis in vivo and in vitro. Apigenin and related compounds are derivatives used in food products. They were administered intraperitoneally and orally in adult rodents and assessed for their activity in promoting the generation of neuronal cells and learning and memory performance. They were also tested on adult rat hippocampal-derived neural progenitor and stem cells to assess their neurogenic property. Apigenin and related compounds stimulate adult neurogenesis in vivo and in vitro, by promoting neuronal differentiation. Apigenin promotes learning and memory performance in the Morris water task. The application claims the use of apigenin and related compounds for stimulating adult neurogenesis and for the treatment of neurological diseases, disorders and injuries, by stimulating the generation of neuronal cells in the adult brain.

  17. Aberrant Neural Stem Cell Proliferation and Increased Adult Neurogenesis in Mice Lacking Chromatin Protein HMGB2

    PubMed Central

    Reddy, Avanish S.; Maletic-Savatic, Mirjana; Aguirre, Adan; Tsirka, Stella E.

    2013-01-01

    Neural stem and progenitor cells (NSCs/NPCs) are distinct groups of cells found in the mammalian central nervous system (CNS). Previously we determined that members of the High Mobility Group (HMG) B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2−/− mice exhibit SVZ hyperproliferation, increased numbers of SVZ NSCs, and a trend towards aberrant increases in newly born neurons in the olfactory bulb (OB) granule cell layer. Increases in the levels of the transcription factor p21 and the Neural cell adhesion molecule (NCAM), along with down-regulation of the transcription/pluripotency factor Oct4 in the Hmgb2−/− SVZ point to a possible pathway for this increased proliferation/differentiation. Our findings suggest that HMGB2 functions as a modulator of neurogenesis in young adult mice through regulation of NSC proliferation, and identify a potential target via which CNS repair could be amplified following trauma or disease-based neuronal degeneration. PMID:24391977

  18. 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

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

    PubMed

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

    2016-01-01

    Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus-a region crucial for learning and memory. PMID:27143977

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

    PubMed Central

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

    2016-01-01

    Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus—a region crucial for learning and memory. PMID:27143977

  1. ALK5-dependent TGF-β signaling is a major determinant of late stage adult neurogenesis

    PubMed Central

    He, Yingbo; Zhang, Hui; Yung, Andrea; Villeda, Saul A; Jaeger, Philipp A; Olayiwola, Oluwatobi; Fainberg, Nina; Wyss-Coray, Tony

    2014-01-01

    The transforming growth factor-β (TGF-β) signaling pathway serves critical functions in central nervous system (CNS) development, but apart from its proposed neuroprotective actions, its physiological role in the adult brain is unclear. We observed a prominent activation of TGF-β signaling in the adult dentate gyrus and expression of downstream Smad proteins in this neurogenic zone. Consistent with a function of TGF-β signaling in adult neurogenesis, genetic deletion of the TGF-β receptor ALK5 reduced the number, migration, and dendritic arborization of newborn neurons. Conversely, constitutive activation of neuronal ALK5 in forebrain caused a striking increase in these aspects of neurogenesis and was associated with higher expression of c-fos in newborn neurons and with stronger memory function. Our findings describe a new and unexpected role for ALK5-dependent TGF-β signaling as a regulator of the late stages of adult hippocampal neurogenesis which may have implications for changes in neurogenesis during aging and disease. PMID:24859199

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

    PubMed

    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.

  3. All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

    PubMed

    Vivar, Carmen; Potter, Michelle C; van Praag, Henriette

    2013-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

  4. All About Running: Synaptic Plasticity, Growth Factors and Adult Hippocampal Neurogenesis

    PubMed Central

    Vivar, Carmen; Potter, Michelle C.; van Praag, Henriette

    2015-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF). PMID:22847651

  5. Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats

    PubMed Central

    Speisman, Rachel. B.; Kumar, Ashok; Rani, Asha; Foster, Thomas C.; Ormerod, Brandi K.

    2012-01-01

    We tested whether daily exercise modulates immune and neuroimmune cytokines, hippocampus-dependent behavior and hippocampal neurogenesis in aging male F344 rats (18 mo upon arrival). Twelve weeks after conditioned running or control group assignment (n = 6 per group), the rats were trained and tested in a rapid water maze followed by an inhibitory avoidance task. The rats were BrdU-injected beginning 12 days after behavioral testing and killed 3 weeks later to quantify cytokines and neurogenesis. Daily exercise increased neurogenesis and improved immediate and 24 h water maze discrimination index (DI) scores and 24 h inhibitory avoidance retention latencies. Daily exercise decreased cortical VEGF, hippocampal IL-1β and serum MCP-1, GRO-KC and leptin levels but increased hippocampal GRO-KC and IL-18 concentrations. Serum leptin concentration correlated negatively with new neuron number and both DI scores while hippocampal IL-1β concentration correlated negatively with memory scores in both tasks. Cortical VEGF, serum GRO-KC and serum MCP-1 levels correlated negatively with immediate DI score and we found a novel positive correlation between hippocampal IL-18 and GRO-KC levels and new neuron number. Pathway analyses revealed distinct serum, hippocampal and cortical compartment cytokine relationships. Our results suggest that daily exercise potentially improves cognition in aging rats by modulating hippocampal neurogenesis and immune and neuroimmune cytokine signaling. PMID:23078985

  6. Ephrins as negative regulators of adult neurogenesis in diverse regions of the central nervous system

    PubMed Central

    Jiao, Jian-wei; Feldheim, David A.; Chen, Dong Feng

    2008-01-01

    In the central nervous system (CNS) of adult mammals, neurogenesis occurs in only two restricted areas, the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Isolation of multipotent progenitor cells from other CNS regions suggests that their neurogenic potential is dictated by local environmental cues. Here, we report that astrocytes in areas outside of the SGZ and SVZ of adult mice express high levels of ephrin-A2 and -A3, which present an inhibitory niche, negatively regulating neural progenitor cell growth. Adult mice lacking both ephrin-A2 and -A3 display active ongoing neurogenesis throughout the CNS. These findings suggest that neural cell replacement therapies for neurodegeneration or injury in the adult CNS may be achieved by manipulating ephrin signaling pathways. PMID:18562299

  7. Adult neurogenesis, neural stem cells and Alzheimer's disease: developments, limitations, problems and promises.

    PubMed

    Taupin, Philippe

    2009-12-01

    Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease, leading to severe incapacity and death. It is the most common form of dementia among older people. AD is characterized in the brain by amyloid plaques, neurofibrillary tangles, neuronal degeneration, aneuploidy and enhanced neurogenesis and by cognitive, behavioral and physical impairments. Inherited mutations in several genes and genetic, acquired and environmental risk factors have been reported as causes for developing the disease, for which there is currently no cure. Current treatments for AD involve drugs and occupational therapies, and future developments involve early diagnosis and stem cell therapy. In this manuscript, we will review and discuss the recent developments, limitations, problems and promises on AD, particularly related to aneuploidy, adult neurogenesis, neural stem cells (NSCs) and cellular therapy. Though adult neurogenesis may be beneficial for regeneration of the nervous system, it may underly the pathogenesis of AD. Cellular therapy is a promising strategy for AD. Limitations in protocols to establish homogeneous populations of neural progenitor and stem cells and niches for neurogenesis need to be resolved and unlocked, for the full potential of adult NSCs to be realized for therapy.

  8. Anxiety- rather than depression-like behavior is associated with adult neurogenesis in a female mouse model of higher trait anxiety- and comorbid depression-like behavior.

    PubMed

    Sah, A; Schmuckermair, C; Sartori, S B; Gaburro, S; Kandasamy, M; Irschick, R; Klimaschewski, L; Landgraf, R; Aigner, L; Singewald, N

    2012-01-01

    Adult neurogenesis has been implicated in affective disorders and the action of antidepressants (ADs) although the functional significance of this association is still unclear. The use of animal models closely mimicking human comorbid affective and anxiety disorders seen in the majority of patients should provide relevant novel information. Here, we used a unique genetic mouse model displaying higher trait anxiety (HAB) and comorbid depression-like behavior. We demonstrate that HABs have a lower rate of hippocampal neurogenesis and impaired functional integration of newly born neurons as compared with their normal anxiety/depression-like behavior (NAB) controls. In HABs, chronic treatment with the AD fluoxetine alleviated their higher depression-like behavior and protected them from relapse for 3 but not 7 weeks after discontinuation of the treatment without affecting neurogenesis. Similar to what has been observed in depressed patients, fluoxetine treatment induced anxiogenic-like effects during the early treatment phase in NABs along with a reduction in neurogenesis. On the other hand, treatment with AD drugs with a particularly strong anxiolytic component, namely the neurokinin-1-receptor-antagonist L-822 429 or tianeptine, increased the reduced rate of neurogenesis in HABs up to NAB levels. In addition, challenge-induced hypoactivation of dentate gyrus (DG) neurons in HABs was normalized by all three drugs. Overall, these data suggest that AD-like effects in a psychopathological mouse model are commonly associated with modulation of DG hypoactivity but not neurogenesis, suggesting normalization of hippocampal hypoactivity as a neurobiological marker indicating successful remission. Finally, rather than to higher depression-related behavior, neurogenesis seems to be linked to pathological anxiety. PMID:23047242

  9. 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.

  10. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

    PubMed

    Chiu, W-H; Depboylu, C; Hermanns, G; Maurer, L; Windolph, A; Oertel, W H; Ries, V; Höglinger, G U

    2015-08-01

    Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively.

  11. Long-term treatment with L-DOPA or pramipexole affects adult neurogenesis and corresponding non-motor behavior in a mouse model of Parkinson's disease.

    PubMed

    Chiu, W-H; Depboylu, C; Hermanns, G; Maurer, L; Windolph, A; Oertel, W H; Ries, V; Höglinger, G U

    2015-08-01

    Non-motor symptoms such as hyposmia and depression are often observed in Parkinson's disease (PD) and can precede the onset of motor symptoms for years. The underlying pathological alterations in the brain are not fully understood so far. Dysregulation of adult neurogenesis in the dentate gyrus of the hippocampus and the olfactory bulb has been recently suggested to be implicated in non-motor symptoms of PD. However, there is so far no direct evidence to support the relationship of non-motor symptoms and the modulation of adult neurogenesis following dopamine depletion and/or dopamine replacement. In this study, we investigated the long-term effects of l-DOPA and pramipexole, a dopamine agonist, in a mouse model of bilateral intranigral 6-OHDA lesion, in order to assess the impact of adult neurogenesis on non-motor behavior. We found that l-DOPA and pramipexole can normalize decreased neurogenesis in the hippocampal dentate gyrus and the periglomerular layer of the olfactory bulb caused by a 6-OHDA lesion. Interestingly, pramipexole showed an antidepressant and anxiolytic effect in the forced swim test and social interaction test. However, there was no significant change in learning and memory function after dopamine depletion and dopamine replacement, respectively. PMID:25839898

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

    PubMed Central

    Garthe, Alexander; Roeder, Ingo

    2016-01-01

    ABSTRACT 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. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:26311488

  13. Genetic activation of ERK5 MAP kinase enhances adult neurogenesis and extends hippocampus-dependent long-term memory.

    PubMed

    Wang, Wenbin; Pan, Yung-Wei; Zou, Junhui; Li, Tan; Abel, Glen M; Palmiter, Richard D; Storm, Daniel R; Xia, Zhengui

    2014-02-01

    Recent studies have shown that inhibition of adult neurogenesis impairs the formation of hippocampus-dependent memory. However, it is not known whether increasing adult neurogenesis affects the persistence of hippocampus-dependent long-term memory. Furthermore, signaling mechanisms that regulate adult neurogenesis are not fully defined. We recently reported that the conditional and targeted knock-out of ERK5 MAP kinase in adult neurogenic regions of the mouse brain attenuates adult neurogenesis in the hippocampus and disrupts several forms of hippocampus-dependent memory. Here, we developed a gain-of-function knock-in mouse model to specifically activate endogenous ERK5 in the neurogenic regions of the adult brain. We report that the selective and targeted activation of ERK5 increases adult neurogenesis in the dentate gyrus by enhancing cell survival, neuronal differentiation, and dendritic complexity. Conditional ERK5 activation also improves the performance of challenging forms of spatial learning and memory and extends hippocampus-dependent long-term memory. We conclude that enhancing signal transduction of a single signaling pathway within adult neural stem/progenitor cells is sufficient to increase adult neurogenesis and improve the persistence of hippocampus-dependent memory. Furthermore, activation of ERK5 may provide a novel therapeutic target to improve long-term memory.

  14. Adult neurogenesis and cellular brain repair with neural progenitors, precursors and stem cells

    PubMed Central

    Shivraj Sohur, U; Emsley, Jason G; Mitchell, Bartley D; Macklis, Jeffrey D

    2006-01-01

    Recent work in neuroscience has shown that the adult central nervous system (CNS) contains neural progenitors, precursors and stem cells that are capable of generating new neurons, astrocytes and oligodendrocytes. While challenging the previous dogma that no new neurons are born in the adult mammalian CNS, these findings bring with them the future possibilities for development of novel neural repair strategies. The purpose of this review is to present the current knowledge about constitutively occurring adult mammalian neurogenesis, highlight the critical differences between ‘neurogenic’ and ‘non-neurogenic’ regions in the adult brain, and describe the cardinal features of two well-described neurogenic regions—the subventricular zone/olfactory bulb system and the dentate gyrus of the hippocampus. We also provide an overview of presently used models for studying neural precursors in vitro, mention some precursor transplantation models and emphasize that, in this rapidly growing field of neuroscience, one must be cautious with respect to a variety of methodological considerations for studying neural precursor cells both in vitro and in vivo. The possibility of repairing neural circuitry by manipulating neurogenesis is an intriguing one, and, therefore, we also review recent efforts to understand the conditions under which neurogenesis can be induced in non-neurogenic regions of the adult CNS. This work aims towards molecular and cellular manipulation of endogenous neural precursors in situ, without transplantation. We conclude this review with a discussion of what might be the function of newly generated neurons in the adult brain, and provide a summary of present thinking about the consequences of disturbed adult neurogenesis and the reaction of neurogenic regions to disease. PMID:16939970

  15. 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.

  16. Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference.

    PubMed

    Faillace, M P; Zwiller, J; Bernabeu, R O

    2015-08-01

    Adult neurogenesis occurs in mammals within the dentate gyrus, a hippocampal subarea. It is known to be induced by antidepressant treatment and reduced in response to nicotine administration. We checked here whether the antidepressant fluoxetine would inverse the decrease in hippocampal neurogenesis caused by nicotine. It is shown that repeated, but not a single injection of rats with fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. We measured the expression of several biochemical parameters known to be associated with neurogenesis in the dentate gyrus. Both drugs increased the expression of p75 neurotrophin receptor, which promotes proliferation and early maturation of dentate gyrus cells. Using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Expression of nicotine-induced CPP was accompanied by an increase of phospho-CREB (cyclic AMP-responsive element-binding protein) and HDAC2 (histone deacetylase 2) expression in the nucleus accumbens. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. Since fluoxetine was able to disrupt the association between nicotine and the environment, this antidepressant may be tested as a treatment for nicotine addiction using cue exposure therapy.

  17. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.

    PubMed

    van Praag, H; Kempermann, G; Gage, F H

    1999-03-01

    Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents. Environmental enrichment, however, typically consists of many components, such as expanded learning opportunities, increased social interaction, more physical activity and larger housing. We attempted to separate components by assigning adult mice to various conditions: water-maze learning (learner), swim-time-yoked control (swimmer), voluntary wheel running (runner), and enriched (enriched) and standard housing (control) groups. Neither maze training nor yoked swimming had any effect on bromodeoxyuridine (BrdU)-positive cell number. However, running doubled the number of surviving newborn cells, in amounts similar to enrichment conditions. Our findings demonstrate that voluntary exercise is sufficient for enhanced neurogenesis in the adult mouse dentate gyrus.

  18. Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis.

    PubMed

    Shin, Jaehoon; Berg, Daniel A; Zhu, Yunhua; Shin, Joseph Y; Song, Juan; Bonaguidi, Michael A; Enikolopov, Grigori; Nauen, David W; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2015-09-01

    Somatic stem cells contribute to tissue ontogenesis, homeostasis, and regeneration through sequential processes. Systematic molecular analysis of stem cell behavior is challenging because classic approaches cannot resolve cellular heterogeneity or capture developmental dynamics. Here we provide a comprehensive resource of single-cell transcriptomes of adult hippocampal quiescent neural stem cells (qNSCs) and their immediate progeny. We further developed Waterfall, a bioinformatic pipeline, to statistically quantify singe-cell gene expression along a de novo reconstructed continuous developmental trajectory. Our study reveals molecular signatures of adult qNSCs, characterized by active niche signaling integration and low protein translation capacity. Our analyses further delineate molecular cascades underlying qNSC activation and neurogenesis initiation, exemplified by decreased extrinsic signaling capacity, primed translational machinery, and regulatory switches in transcription factors, metabolism, and energy sources. Our study reveals the molecular continuum underlying adult neurogenesis and illustrates how Waterfall can be used for single-cell omics analyses of various continuous biological processes.

  19. Novel function of Tau in regulating the effects of external stimuli on adult hippocampal neurogenesis.

    PubMed

    Pallas-Bazarra, Noemí; Jurado-Arjona, Jerónimo; Navarrete, Marta; Esteban, Jose A; Hernández, Félix; Ávila, Jesús; Llorens-Martín, María

    2016-07-01

    Tau is a microtubule-associated neuronal protein found mainly in axons. However, its presence in dendrites and dendritic spines is particularly relevant due to its involvement in synaptic plasticity and neurodegeneration. Here, we show that Tau plays a novel in vivo role in the morphological and synaptic maturation of newborn hippocampal granule neurons under basal conditions. Furthermore, we reveal that Tau is involved in the selective cell death of immature granule neurons caused by acute stress. Also, Tau deficiency protects newborn neurons from the stress-induced dendritic atrophy and loss of postsynaptic densities (PSDs). Strikingly, we also demonstrate that Tau regulates the increase in newborn neuron survival triggered by environmental enrichment (EE). Moreover, newborn granule neurons from Tau(-/-) mice did not show any stimulatory effect of EE on dendritic development or on PSD generation. Thus, our data demonstrate that Tau(-/-) mice show impairments in the maturation of newborn granule neurons under basal conditions and that they are insensitive to the modulation of adult hippocampal neurogenesis exerted by both stimulatory and detrimental stimuli.

  20. Untangling the Influences of Voluntary Running, Environmental Complexity, Social Housing and Stress on Adult Hippocampal Neurogenesis

    PubMed Central

    Grégoire, Catherine-Alexandra; Bonenfant, David; Le Nguyen, Adalie; Aumont, Anne; Fernandes, Karl J. L.

    2014-01-01

    Environmental enrichment (EE) exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel “Alternating EE” paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1) voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2) a complex environment (comprised of both social interactions and rotated inanimate objects) had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions) and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects); and (3) neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this “Alternating EE” paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity. PMID:24465980

  1. Curcumin stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus.

    PubMed

    Kim, So Jung; Son, Tae Gen; Park, Hee Ra; Park, Mikyung; Kim, Min-Sun; Kim, Hyung Sik; Chung, Hae Young; Mattson, Mark P; Lee, Jaewon

    2008-05-23

    Curcumin is a natural phenolic component of yellow curry spice, which is used in some cultures for the treatment of diseases associated with oxidative stress and inflammation. Curcumin has been reported to be capable of preventing the death of neurons in animal models of neurodegenerative disorders, but its possible effects on developmental and adult neuroplasticity are unknown. In the present study, we investigated the effects of curcumin on mouse multi-potent neural progenitor cells (NPC) and adult hippocampal neurogenesis. Curcumin exerted biphasic effects on cultured NPC; low concentrations stimulated cell proliferation, whereas high concentrations were cytotoxic. Curcumin activated extracellular signal-regulated kinases (ERKs) and p38 kinases, cellular signal transduction pathways known to be involved in the regulation of neuronal plasticity and stress responses. Inhibitors of ERKs and p38 kinases effectively blocked the mitogenic effect of curcumin in NPC. Administration of curcumin to adult mice resulted in a significant increase in the number of newly generated cells in the dentate gyrus of hippocampus, indicating that curcumin enhances adult hippocampal neurogenesis. Our findings suggest that curcumin can stimulate developmental and adult hippocampal neurogenesis, and a biological activity that may enhance neural plasticity and repair.

  2. Adult neurogenesis: examples from the decapod crustaceans and comparisons with mammals.

    PubMed

    Sandeman, David C; Bazin, Francois; Beltz, Barbara S

    2011-05-01

    Defining evolutionary origins is a means of understanding an organism's position within the integrated web of living beings, and not only to trace characteristics back in time, but also to project forward in an attempt to reveal relationships with more recently evolved forms. Both the vertebrates and arthropods possess condensed nervous systems, but this is dorsal in the vertebrates and ventral in the arthropods. Also, whereas the nervous system in the vertebrates develops from a neural tube in the embryo, that of the arthropods comes from an ectodermal plate. Despite these apparently fundamental differences, it is now generally accepted that life-long neurogenesis, the generation of functionally integrated neurons from progenitor cells, is a common feature of the adult brains of a variety of organisms, ranging from insects and crustaceans to birds and mammals. Among decapod crustaceans, there is evidence for adult neurogenesis in basal species of the Dendrobranchiata, as well as in more recent terrestrial, marine and fresh-water species. The widespread nature of this phenomenon in decapod species may relate to the importance of the adult-born neurons, although their functional contribution is not yet known. The many similarities between the systems generating neurons in the adult brains of decapod crustaceans and mammals, reviewed in this paper, suggest that adult neurogenesis is governed by common ancestral mechanisms that have been retained in a phylogenetically broad group of species.

  3. S-Nitrosylation—Mediated Redox Transcriptional Switch Modulates Neurogenesis and Neuronal Cell Death

    PubMed Central

    Okamoto, Shu-ichi; Nakamura, Tomohiro; Cieplak, Piotr; Chan, Shing Fai; Kalashnikova, Evgenia; Liao, Lujian; Saleem, Sofiyan; Han, Xuemei; Clemente, Arjay; Nutter, Anthony; Sances, Sam; Brechtel, Christopher; Haus, Daniel; Haun, Florian; Sanz-Blasco, Sara; Huang, Xiayu; Li, Hao; Zaremba, Jeffrey D.; Cui, Jiankun; Gu, Zezong; Nikzad, Rana; Harrop, Anne; McKercher, Scott R.; Godzik, Adam; Yates, John R.; Lipton, Stuart A.

    2014-01-01

    SUMMARY Redox-mediated posttranslational modifications represent a molecular switch that controls major mechanisms of cell function. Nitric oxide (NO) can mediate redox reactions via S-nitrosylation, representing transfer of an NO group to a critical protein thiol. NO is known to modulate neurogenesis and neuronal survival in various brain regions in disparate neurodegenerative conditions. However, a unifying molecular mechanism linking these phenomena remains unknown. Here we report that S-nitrosylation of myocyte enhancer factor 2 (MEF2) transcription factors acts as a redox switch to inhibit both neurogenesis and neuronal survival. Structure-based analysis reveals that MEF2 dimerization creates a pocket, facilitating S-nitrosylation at an evolutionally conserved cysteine residue in the DNA binding domain. S-Nitrosylation disrupts MEF2-DNA binding and transcriptional activity, leading to impaired neurogenesis and survival in vitro and in vivo. Our data define a novel molecular switch whereby redox-mediated posttranslational modification controls both neurogenesis and neurodegeneration via a single transcriptional signaling cascade. PMID:25001280

  4. 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.

  5. 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. PMID:24909416

  6. Regulation of adult neurogenesis by stress, sleep disruption, exercise and inflammation: Implications for depression and antidepressant action.

    PubMed

    Lucassen, P J; Meerlo, P; Naylor, A S; van Dam, A M; Dayer, A G; Fuchs, E; Oomen, C A; Czéh, B

    2010-01-01

    Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action.

  7. Adult neurogenesis in the olfactory system shapes odor memory and perception.

    PubMed

    Gheusi, Gilles; Lledo, Pierre-Marie

    2014-01-01

    The olfactory system is a dynamic place. In mammals, not only are sensory neurons located in the sensory organ renewed through adult life, but also its first central relay is reconstructed by continuous neuronal recruitment. Despite these numerous morphological and physiological changes, olfaction is a unique sensory modality endowed with a privileged link to memory. This raises a clear conundrum; how does the olfactory system balance its neuronal turnover with its participation in long-term memory? This review concentrates on the functional aspects of adult neurogenesis, addressing how the integration of late-born neurons participates in olfactory perception and memory. After outlining the properties of adult neurogenesis in the olfactory system, and after describing their regulation by internal and environmental factors, we ask how the process of odorant perception can be influenced by constant neuronal turnover. We then explore the possible functional roles that newborn neurons might have for olfactory memory. Throughout this review, and as we concentrate almost exclusively on mammalian models, we stress the idea that adult neurogenesis is yet another form of plasticity used by the brain to copes with a constantly changing olfactory world.

  8. A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocampus of adult mouse brain.

    PubMed

    Valente, Tony; Hidalgo, Juan; Bolea, Irene; Ramirez, Bartolomé; Anglés, Neus; Reguant, Jordi; Morelló, José Ramón; Gutiérrez, Cristina; Boada, Mercè; Unzeta, Mercedes

    2009-01-01

    At present it is widely accepted that there are at least two neurogenic sites in the adult mammalian brain: the subventricular zone (SVZ) of lateral ventricles and the subgranular zone (SGZ) of the hippocampus dentate gyrus. The adult proliferation rate declines with aging and is altered in several neurodegenerative pathologies including Alzheimer's disease. The aim of this work was to study whether a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) can modulate neurogenesis in adult mice and give insight into putative mechanisms. Results with BrdU and PCNA demonstrated that the LMN fed mice had more newly generated cells in the SVZ and SGZ, and those with DCX (undifferentiated neurons) and tyrosine hydroxylase, calretinin, and calbindin (differentiated neurons) immunostainings and western blots demonstrated a significant effect on neuronal populations, strongly supporting a positive role of the LMN diet on adult neurogenesis. In primary rat neuron cultures, the LMN cream dramatically protected against damage caused by both hydrogen peroxide and Abeta(1-42), demonstrating a potent antioxidant effect that could play a major role in the normal adult neurogenesis and, moreover, the LMN diet could have a significant effect combating the cognitive function decline during both aging and neurodegenerative diseases such as Alzheimer's disease.

  9. Ablating adult neurogenesis in the rat has no effect on spatial processing: evidence from a novel pharmacogenetic model.

    PubMed

    Groves, James O; Leslie, Isla; Huang, Guo-Jen; McHugh, Stephen B; Taylor, Amy; Mott, Richard; Munafò, Marcus; Bannerman, David M; Flint, Jonathan

    2013-01-01

    The function of adult neurogenesis in the rodent brain remains unclear. Ablation of adult born neurons has yielded conflicting results about emotional and cognitive impairments. One hypothesis is that adult neurogenesis in the hippocampus enables spatial pattern separation, allowing animals to distinguish between similar stimuli. We investigated whether spatial pattern separation and other putative hippocampal functions of adult neurogenesis were altered in a novel genetic model of neurogenesis ablation in the rat. In rats engineered to express thymidine kinase (TK) from a promoter of the rat glial fibrillary acidic protein (GFAP), ganciclovir treatment reduced new neurons by 98%. GFAP-TK rats showed no significant difference from controls in spatial pattern separation on the radial maze, spatial learning in the water maze, contextual or cued fear conditioning. Meta-analysis of all published studies found no significant effects for ablation of adult neurogenesis on spatial memory, cue conditioning or ethological measures of anxiety. An effect on contextual freezing was significant at a threshold of 5% (P = 0.04), but not at a threshold corrected for multiple testing. The meta-analysis revealed remarkably high levels of heterogeneity among studies of hippocampal function. The source of this heterogeneity remains unclear and poses a challenge for studies of the function of adult neurogenesis. PMID:24039591

  10. Role of neuroinflammation in adult neurogenesis and Alzheimer disease: therapeutic approaches.

    PubMed

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

    2013-01-01

    Neuroinflammation, a specialized immune response that takes place in the central nervous system, has been linked to neurodegenerative diseases, and specially, it has been considered as a hallmark of Alzheimer disease, the most common cause of dementia in the elderly nowadays. Furthermore, neuroinflammation has been demonstrated to affect important processes in the brain, such as the formation of new neurons, commonly known as adult neurogenesis. For this, many therapeutic approaches have been developed in order to avoid or mitigate the deleterious effects caused by the chronic activation of the immune response. Considering this, in this paper we revise the relationships between neuroinflammation, Alzheimer disease, and adult neurogenesis, as well as the current therapeutic approaches that have been developed in the field.

  11. Dentate gyrus-specific knockdown of adult neurogenesis impairs spatial and object recognition memory in adult rats

    PubMed Central

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

    2009-01-01

    New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior. PMID:19181621

  12. Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice.

    PubMed

    Ben Abdallah, Nada M-B; Filipkowski, Robert K; Pruschy, Martin; Jaholkowski, Piotr; Winkler, Juergen; Kaczmarek, Leszek; Lipp, Hans-Peter

    2013-09-01

    In adult rodents, decreasing hippocampal neurogenesis experimentally using different approaches often impairs performance in hippocampus-dependent processes. Nonetheless, functional relevance of adult neurogenesis is far from being unraveled, and deficits so far described in animal models often lack reproducibility. One hypothesis is that such differences might be the consequence of the extent of the methodological specificity used to alter neurogenesis rather than the extent to which adult neurogenesis is altered. To address this, we focused on cranial irradiation, the most widely used technique to impair hippocampal neurogenesis and consequentially induce hippocampus-dependent behavioral deficits. To investigate the specificity of the technique, we thus exposed 4-5 months old female cyclin D2 knockout mice, a model lacking physiological levels of olfactory and hippocampal neurogenesis, to an X-ray dose of 10 Gy, reported to specifically affect transiently amplifying precursors. After a recovery period of 1.5 months, behavioral tests were performed and probed for locomotor activity, habituation, anxiety, and spatial learning and memory. Spatial learning in the Morris water maze was intact in all experimental groups. Although spatial memory retention assessed 24h following acquisition was also intact in all mice, irradiated wild type and cyclin D2 knockout mice displayed memory deficits one week after acquisition. In addition, we observed significant differences in tests addressing anxiety and locomotor activity dependent on the technique used to alter neurogenesis. Whereas irradiated mice were hyperactive regardless of their genotype, cyclin D2 knockout mice were hypoactive in most of the tests and displayed altered habituation. The present study emphasizes that different approaches aimed at decreasing adult hippocampal neurogenesis may result in distinct behavioral impairments related to locomotion and anxiety. In contrast, spatial long-term memory retention is

  13. 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

  14. In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis.

    PubMed

    Patzke, Nina; Spocter, Muhammad A; Karlsson, Karl Æ; Bertelsen, Mads F; Haagensen, Mark; Chawana, Richard; Streicher, Sonja; Kaswera, Consolate; Gilissen, Emmanuel; Alagaili, Abdulaziz N; Mohammed, Osama B; Reep, Roger L; Bennett, Nigel C; Siegel, Jerry M; Ihunwo, Amadi O; Manger, Paul R

    2015-01-01

    The hippocampus is essential for the formation and retrieval of memories and is a crucial neural structure sub-serving complex cognition. Adult hippocampal neurogenesis, the birth, migration and integration of new neurons, is thought to contribute to hippocampal circuit plasticity to augment function. We evaluated hippocampal volume in relation to brain volume in 375 mammal species and examined 71 mammal species for the presence of adult hippocampal neurogenesis using immunohistochemistry for doublecortin, an endogenous marker of immature neurons that can be used as a proxy marker for the presence of adult neurogenesis. We identified that the hippocampus in cetaceans (whales, dolphins and porpoises) is both absolutely and relatively small for their overall brain size, and found that the mammalian hippocampus scaled as an exponential function in relation to brain volume. In contrast, the amygdala was found to scale as a linear function of brain volume, but again, the relative size of the amygdala in cetaceans was small. The cetacean hippocampus lacks staining for doublecortin in the dentate gyrus and thus shows no clear signs of adult hippocampal neurogenesis. This lack of evidence of adult hippocampal neurogenesis, along with the small hippocampus, questions current assumptions regarding cognitive abilities associated with hippocampal function in the cetaceans. These anatomical features of the cetacean hippocampus may be related to the lack of postnatal sleep, causing a postnatal cessation of hippocampal neurogenesis. PMID:24178679

  15. In contrast to many other mammals, cetaceans have relatively small hippocampi that appear to lack adult neurogenesis.

    PubMed

    Patzke, Nina; Spocter, Muhammad A; Karlsson, Karl Æ; Bertelsen, Mads F; Haagensen, Mark; Chawana, Richard; Streicher, Sonja; Kaswera, Consolate; Gilissen, Emmanuel; Alagaili, Abdulaziz N; Mohammed, Osama B; Reep, Roger L; Bennett, Nigel C; Siegel, Jerry M; Ihunwo, Amadi O; Manger, Paul R

    2015-01-01

    The hippocampus is essential for the formation and retrieval of memories and is a crucial neural structure sub-serving complex cognition. Adult hippocampal neurogenesis, the birth, migration and integration of new neurons, is thought to contribute to hippocampal circuit plasticity to augment function. We evaluated hippocampal volume in relation to brain volume in 375 mammal species and examined 71 mammal species for the presence of adult hippocampal neurogenesis using immunohistochemistry for doublecortin, an endogenous marker of immature neurons that can be used as a proxy marker for the presence of adult neurogenesis. We identified that the hippocampus in cetaceans (whales, dolphins and porpoises) is both absolutely and relatively small for their overall brain size, and found that the mammalian hippocampus scaled as an exponential function in relation to brain volume. In contrast, the amygdala was found to scale as a linear function of brain volume, but again, the relative size of the amygdala in cetaceans was small. The cetacean hippocampus lacks staining for doublecortin in the dentate gyrus and thus shows no clear signs of adult hippocampal neurogenesis. This lack of evidence of adult hippocampal neurogenesis, along with the small hippocampus, questions current assumptions regarding cognitive abilities associated with hippocampal function in the cetaceans. These anatomical features of the cetacean hippocampus may be related to the lack of postnatal sleep, causing a postnatal cessation of hippocampal neurogenesis.

  16. Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders.

    PubMed

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

    2011-05-01

    Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

  17. Differential genomic imprinting regulates paracrine and autocrine roles of IGF2 in mouse adult neurogenesis

    PubMed Central

    Ferrón, S. R.; Radford, E. J.; Domingo-Muelas, A.; Kleine, I.; Ramme, A.; Gray, D.; Sandovici, I.; Constancia, M.; Ward, A.; Menheniott, T. R.; Ferguson-Smith, A. C.

    2015-01-01

    Genomic imprinting is implicated in the control of gene dosage in neurogenic niches. Here we address the importance of Igf2 imprinting for murine adult neurogenesis in the subventricular zone (SVZ) and in the subgranular zone (SGZ) of the hippocampus in vivo. In the SVZ, paracrine IGF2 is a cerebrospinal fluid and endothelial-derived neurogenic factor requiring biallelic expression, with mutants having reduced activation of the stem cell pool and impaired olfactory bulb neurogenesis. In contrast, Igf2 is imprinted in the hippocampus acting as an autocrine factor expressed in neural stem cells (NSCs) solely from the paternal allele. Conditional mutagenesis of Igf2 in blood vessels confirms that endothelial-derived IGF2 contributes to NSC maintenance in SVZ but not in the SGZ, and that this is regulated by the biallelic expression of IGF2 in the vascular compartment. Our findings indicate that a regulatory decision to imprint or not is a functionally important mechanism of transcriptional dosage control in adult neurogenesis. PMID:26369386

  18. 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

  19. Reawakening the sleeping beauty in the adult brain: neurogenesis from parenchymal glia.

    PubMed

    Péron, Sophie; Berninger, Benedikt

    2015-10-01

    Life-long neurogenesis is highly restricted to specialized niches in the adult mammalian brain and therefore the brain's capacity for spontaneous regeneration is extremely limited. However, recent work has demonstrated that under certain circumstances parenchymal astrocytes and NG2 glia can generate neuronal progeny. In the striatum, stroke or excitotoxic lesions can reawaken in astrocytes a latent neurogenic program resulting in the genesis of new neurons. By contrast, in brain areas that fail to mount a neurogenic response following injury, such as the cerebral cortex, forced expression of neurogenic reprogramming factors can lineage convert local glia into induced neurons. Yet, injury-induced and reprogramming-induced neurogenesis exhibit intriguing commonalities, suggesting that they may converge on similar mechanisms.

  20. 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

  1. 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

    2015-09-01

    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.

  2. 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

    2015-09-01

    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. PMID:26231800

  3. Reduced Cerebral Oxygen Content in the DG and SVZ In Situ Promotes Neurogenesis in the Adult Rat Brain In Vivo.

    PubMed

    Zhang, Kuan; Zhou, Yanzhao; Zhao, Tong; Wu, Liying; Huang, Xin; Wu, Kuiwu; Xu, Lun; Li, Dahu; Liu, Shuhong; Zhao, Yongqi; Fan, Ming; Zhu, Lingling

    2015-01-01

    Neurogenesis in the adult brain occurs mainly within two neurogenic structures, the dentate gyrus (DG) of the hippocampus and the sub-ventricular zone (SVZ) of the forebrain. It has been reported that mild hypoxia promoted the proliferation of Neural Stem Cells (NSCs)in vitro. Our previous study further demonstrated that an external hypoxic environment stimulated neurogenesis in the adult rat brain in vivo. However, it remains unknown how external hypoxic environments affect the oxygen content in the brain and result in neurogenesis. Here we use an optical fiber luminescent oxygen sensor to detect the oxygen content in the adult rat brain in situ under normoxia and hypoxia. We found that the distribution of oxygen in cerebral regions is spatiotemporally heterogeneous. The Po2 values in the ventricles (45∼50 Torr) and DG (approximately 10 Torr) were much higher than those of other parts of the brain, such as the cortex and thalamus (approximately 2 Torr). Interestingly, our in vivo studies showed that an external hypoxic environment could change the intrinsic oxygen content in brain tissues, notably reducing oxygen levels in both the DG and SVZ, the major sites of adult neurogenesis. Furthermore, the hypoxic environment also increased the expression of HIF-1α and VEGF, two factors that have been reported to regulate neurogenesis, within the DG and SVZ. Thus, we have demonstrated that reducing the oxygen content of the external environment decreased Po2 levels in the DG and SVZ. This reduced oxygen level in the DG and SVZ might be the main mechanism triggering neurogenesis in the adult brain. More importantly, we speculate that varying oxygen levels may be the physiological basis of the regionally restricted neurogenesis in the adult brain.

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

    ERIC Educational Resources Information Center

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

    2013-01-01

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

  5. Endogenous versus exogenous markers of adult neurogenesis in canaries and other birds: Advantages and Disadvantages

    PubMed Central

    Balthazart, Jacques; Ball, Gregory F.

    2014-01-01

    Although the existence of newborn neurons had originally been suggested, but not broadly accepted, based on studies in adult rodent brains, the presence of an active neurogenesis process in adult homoeothermic vertebrates was first firmly established in songbirds. Adult neurogenesis was initially studied with the tritiated thymidine technique, later replaced by the injection and detection of the marker of DNA replication 5-bromo-2′-deoxyuridine (BrdU). More recently, various endogenous markers were used to identify young neurons or cycling neuronal progenitors. We review here the respective advantages and pitfalls of these different approaches in birds, with specific reference to the microtubule-associated protein, doublecortin (DCX), that has been extensively used to identify young newly born neurons in adult brains. All these techniques of course have limitations. Exogenous markers label cells replicating their DNA only during a brief period and it is difficult to select injection doses that would exhaustively label all these cells without inducing DNA damage that will also result in some form of labeling during repair. On the other hand, specificity of endogenous markers is difficult to establish due to problems related to the specificity of antibodies (these problems can be, but are not always, addressed) and more importantly because it is difficult, if not impossible, to prove that a given marker exhaustively and specifically labels a given cell population. Despite these potential limitations, these endogenous markers and DCX staining in particular clearly represent a useful approach to the detailed study of neurogenesis especially when combined with other techniques such as BrdU. PMID:25131458

  6. TAM receptors affect adult brain neurogenesis by negative regulation of microglial cell activation.

    PubMed

    Ji, Rui; Tian, Shifu; Lu, Helen J; Lu, Qingjun; Zheng, Yan; Wang, Xiaomin; Ding, Jixiang; Li, Qiutang; Lu, Qingxian

    2013-12-15

    TAM tyrosine kinases play multiple functional roles, including regulation of the target genes important in homeostatic regulation of cytokine receptors or TLR-mediated signal transduction pathways. In this study, we show that TAM receptors affect adult hippocampal neurogenesis and loss of TAM receptors impairs hippocampal neurogenesis, largely attributed to exaggerated inflammatory responses by microglia characterized by increased MAPK and NF-κB activation and elevated production of proinflammatory cytokines that are detrimental to neuron stem cell proliferation and neuronal differentiation. Injection of LPS causes even more severe inhibition of BrdU incorporation in the Tyro3(-/-)Axl(-/-)Mertk(-/-) triple-knockout (TKO) brains, consistent with the LPS-elicited enhanced expression of proinflammatory mediators, for example, IL-1β, IL-6, TNF-α, and inducible NO synthase, and this effect is antagonized by coinjection of the anti-inflammatory drug indomethacin in wild-type but not TKO brains. Conditioned medium from TKO microglia cultures inhibits neuron stem cell proliferation and neuronal differentiation. IL-6 knockout in Axl(-/-)Mertk(-/-) double-knockout mice overcomes the inflammatory inhibition of neurogenesis, suggesting that IL-6 is a major downstream neurotoxic mediator under homeostatic regulation by TAM receptors in microglia. Additionally, autonomous trophic function of the TAM receptors on the proliferating neuronal progenitors may also promote progenitor differentiation into immature neurons.

  7. Viral and transgenic reporters and genetic analysis of adult neurogenesis.

    PubMed

    Enikolopov, Grigori; Overstreet-Wadiche, Linda; Ge, Shaoyu

    2015-08-01

    Stem and progenitor cells of the developing and adult brain can be effectively identified and manipulated using reporter genes, introduced into transgenic reporter mouse lines or recombinant viruses. Such reporters rely on an ever-increasing variety of fluorescent proteins and a continuously expanding list of regulatory elements and of mouse lines engineered for cell- or time-specific recombination. An important extension of stem-cell-based genetic strategies is an opportunity to explore the properties of newly generated neurons and their contribution to synaptic plasticity. Here, we review available strategies for marking and quantifying various classes of stem and progenitor cells in the adult brain, genetically tracing their progeny, and studying the properties of stem cells and new neurons. We compare various experimental approaches to labeling and investigating stem cells and their progeny and discuss caveats and limitations inherent to each approach. PMID:26238354

  8. Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms

    PubMed Central

    Pereira Dias, Gisele; Hollywood, Ronan; Bevilaqua, Mário Cesar do Nascimento; da Silveira da Luz, Anna Claudia Domingos; Hindges, Robert; Nardi, Antonio Egidio; Thuret, Sandrine

    2014-01-01

    The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients. PMID:24470543

  9. A possible role for the immune system in adult neurogenesis: new insights from an invertebrate model.

    PubMed

    Harzsch, Steffen; von Bohlen Und Halbach, Oliver

    2016-04-01

    Persistent neurogenesis in the adult brain of both vertebrates and invertebrates was previously considered to be driven by self-renewing neuronal stem cells of ectodermal origin. Recent findings in an invertebrate model challenge this view and instead provide evidence for a recruitment of neuronal precursors from a non-neuronal source. In the brain of adult crayfish, a neurogenic niche was identified that contributes progeny to the adult central olfactory pathway. The niche may function in attracting cells from the hemolymph and transforming them into cells with a neuronal fate. This finding implies that the first-generation neuronal precursors located in the crayfish neurogenic niche are not self-renewing. Evidence is summarized in support of a critical re-evaluation of long-term self-renewal of mammalian neuronal stem cells. Latest findings suggest that a tight link between the immune system and the system driving adult neurogenesis may not only exist in the crayfish but also in mammals. PMID:26739123

  10. Role of the Retinoblastoma protein, Rb, during adult neurogenesis in the olfactory bulb

    PubMed Central

    Naser, Rayan; Vandenbosch, Renaud; Omais, Saad; Hayek, Dayana; Jaafar, Carine; Al Lafi, Sawsan; Saliba, Afaf; Baghdadi, Maarouf; Skaf, Larissa; Ghanem, Noël

    2016-01-01

    Adult neural stem cells (aNSCs) are relatively quiescent populations that give rise to distinct neuronal subtypes throughout life, yet, at a very low rate and restricted differentiation potential. Thus, identifying the molecular mechanisms that control their cellular expansion is critical for regeneration after brain injury. Loss of the Retinoblastoma protein, Rb, leads to several defects in cell cycle as well as neuronal differentiation and migration during brain development. Here, we investigated the role of Rb during adult neurogenesis in the olfactory bulb (OB) by inducing its temporal deletion in aNSCs and progenitors. Loss of Rb was associated with increased proliferation of adult progenitors in the subventricular zone (SVZ) and the rostral migratory stream (RMS) but did not alter self-renewal of aNSCs or neuroblasts subsequent migration and terminal differentiation. Hence, one month after their birth, Rb-null neuroblasts were able to differentiate into distinct subtypes of GABAergic OB interneurons but were gradually lost after 3 months. Similarly, Rb controlled aNSCs/progenitors proliferation in vitro without affecting their differentiation capacity. This enhanced SVZ/OB neurogenesis associated with loss of Rb was only transient and negatively affected by increased apoptosis indicating a critical requirement for Rb in the long-term survival of adult-born OB interneurons. PMID:26847607

  11. Conditional Inhibition of Adult Neurogenesis by Inducible and Targeted Deletion of ERK5 MAP Kinase Is Not Associated with Anxiety/Depression-Like Behaviors1,2

    PubMed Central

    Zou, Junhui; Wang, Wenbin; Pan, Yung-Wei; Abel, Glen M.; Storm, Daniel R.

    2015-01-01

    Abstract Although there is evidence that adult neurogenesis contributes to the therapeutic efficacy of chronic antidepressant treatment for anxiety and depression disorders, the role of adult neurogenesis in the onset of depression-related symptoms is still open to question. To address this issue, we utilized a transgenic mouse strain in which adult neurogenesis was specifically and conditionally impaired by Nestin-CreER-driven, inducible knockout (icKO) of erk5 MAP kinase in Nestin-expressing neural progenitors of the adult mouse brain upon tamoxifen administration. Here, we report that inhibition of adult neurogenesis by this mechanism is not associated with an increase of the baseline anxiety or depression in non-stressed animals, nor does it increase the animal’s susceptibility to depression after chronic unpredictable stress treatment. Our findings indicate that impaired adult neurogenesis does not lead to anxiety or depression. PMID:26464972

  12. Effects of long-term methylphenidate treatment in adolescent and adult rats on hippocampal shape, functional connectivity and adult neurogenesis.

    PubMed

    van der Marel, K; Bouet, V; Meerhoff, G F; Freret, T; Boulouard, M; Dauphin, F; Klomp, A; Lucassen, P J; Homberg, J R; Dijkhuizen, R M; Reneman, L

    2015-11-19

    Methylphenidate (MPH) is a widely prescribed stimulant drug for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents. Its use in this age group raises concerns regarding the potential interference with ongoing neurodevelopmental processes. Particularly the hippocampus is a highly plastic brain region that continues to develop postnatally and is involved in cognition and emotional behavior, functions known to be affected by MPH. In this study, we assessed whether hippocampal structure and function were affected by chronic oral MPH treatment and whether its effects were different in adolescent or adult rats. Using behavioral testing, resting-state functional MRI, post-mortem structural magnetic resonance imaging (MRI), and immunohistochemistry, we assessed MPH's effects on recognition memory, depressive-like behavior, topological features of functional connectivity networks, hippocampal shape and markers for hippocampal neurogenesis and proliferation. Object recognition memory was transiently impaired in adolescent treated rats, while in animals treated during adulthood, increased depressive-like behavior was observed. Neurogenesis was increased in adolescent treated rats, whereas cell proliferation was decreased following adult treatment. Adolescent treated rats showed inward shape deformations adjacent to ventral parahippocampal regions known to be involved in recognition memory, whereas such deformations were not observed in adult treated animals. Irrespective of the age of treatment, MPH affected topological features of ventral hippocampal functional networks. Thus, chronic oral treatment with a therapeutically relevant dose of MPH preferentially affected the ventral part of the hippocampus and induced contrasting effects in adolescent and adult rats. The differences in behavior were paralleled by opposite effects on adult neurogenesis and granule cell proliferation.

  13. 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.

  14. Single-Cell RNA-Seq with Waterfall Reveals Molecular Cascades underlying Adult Neurogenesis.

    PubMed

    Shin, Jaehoon; Berg, Daniel A; Zhu, Yunhua; Shin, Joseph Y; Song, Juan; Bonaguidi, Michael A; Enikolopov, Grigori; Nauen, David W; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2015-09-01

    Somatic stem cells contribute to tissue ontogenesis, homeostasis, and regeneration through sequential processes. Systematic molecular analysis of stem cell behavior is challenging because classic approaches cannot resolve cellular heterogeneity or capture developmental dynamics. Here we provide a comprehensive resource of single-cell transcriptomes of adult hippocampal quiescent neural stem cells (qNSCs) and their immediate progeny. We further developed Waterfall, a bioinformatic pipeline, to statistically quantify singe-cell gene expression along a de novo reconstructed continuous developmental trajectory. Our study reveals molecular signatures of adult qNSCs, characterized by active niche signaling integration and low protein translation capacity. Our analyses further delineate molecular cascades underlying qNSC activation and neurogenesis initiation, exemplified by decreased extrinsic signaling capacity, primed translational machinery, and regulatory switches in transcription factors, metabolism, and energy sources. Our study reveals the molecular continuum underlying adult neurogenesis and illustrates how Waterfall can be used for single-cell omics analyses of various continuous biological processes. PMID:26299571

  15. 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…

  16. Id2 IS REQUIRED FOR SPECIFICATION OF DOPAMINERGIC NEURONS DURING ADULT OLFACTORY NEUROGENESIS

    PubMed Central

    Havrda, Matthew C.; Harris, Brent T.; Mantani, Akio; Ward, Nora M.; Paolella, Brenton R.; Cuzon, Verginia C.; Yeh, Hermes H.; Israel, Mark A.

    2009-01-01

    Understanding the biology of adult neural stem cells has important implications for nervous system development and may contribute to our understanding of neurodegenerative disorders and their treatment. We have characterized the process of olfactory neurogenesis in adult mice lacking Inhibitor of DNA Binding 2 (Id2). We found a diminished olfactory bulb containing reduced numbers of granular and periglomerular neurons with a distinct paucity of dopaminergic periglomerular neurons. While no deficiency of the stem cell compartment was detectable, migrating neuroblasts in Id2−/− mutant mice prematurely undergo astroglial differentiation within a disorganized rostral migratory stream. Further, when evaluated in vitro loss of Id2 results in decreased proliferation of neural progenitors and decreased expression of the Hes1 and Mash1 transcription factors, known mediators of neuronal differentiation. These data support a novel role for sustained Id2 expression in migrating neural progenitors mediating olfactory dopaminergic neuronal differentiation in adult animals. PMID:19109490

  17. 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

  18. 12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

    PubMed Central

    Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J.; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario

    2016-01-01

    Background: Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. Methodology: We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. Results: We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. Conclusions: This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical

  19. Effect of agomelatine on adult hippocampus apoptosis and neurogenesis using the stress model of rats.

    PubMed

    Yucel, Atakan; Yucel, Nermin; Ozkanlar, Seckin; Polat, Elif; Kara, Adem; Ozcan, Halil; Gulec, Mustafa

    2016-04-01

    Agomelatine (AG) is an agonist of melatonin receptors and an antagonist of the 5-HT2C-receptor subtype. The chronobiotic properties of AG are of significant interest due to the disorganization of internal rhythms, which might play a role in the pathophysiology of depression. The present study was designed to assess the effects of the antidepressant-like activity of AG, a new antidepressant drug, on adult neurogenesis and apoptosis using stress-exposed rat brains. Over the period of 1 week, the rats were exposed to light stress twice a day for 1h. After a period of 1 week, the rats were given AG treatment at a dose of either 10mg/kg or 40mg/kg for 15 days. The animals were then scarified, and the obtained tissue sections were stained with immuno-histochemical anti-BrdU, Caspase-3, and Bcl-2 antibodies. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured biochemically using a BDNF Elisa kit. Biochemical BDNF analysis revealed a high concentration of BDNF in the serum of the stress-exposed group, but the concentrations of BDNF were much lower those of the AG-treated groups. Immuno-histochemical analysis revealed that AG treatment decreased the BrdU-positive and Bcl-2-positive cell densities and increased the Caspase-3-positive cell density in the hippocampus of stress-induced rats as compared to those of the stress group. The results of the study demonstrated that AG treatment ameliorated the hippocampal apoptotic cells and increased hippocampal neurogenesis. These results also strengthen the possible relationship between depression and adult neurogenesis, which must be studied further.

  20. Effect of agomelatine on adult hippocampus apoptosis and neurogenesis using the stress model of rats.

    PubMed

    Yucel, Atakan; Yucel, Nermin; Ozkanlar, Seckin; Polat, Elif; Kara, Adem; Ozcan, Halil; Gulec, Mustafa

    2016-04-01

    Agomelatine (AG) is an agonist of melatonin receptors and an antagonist of the 5-HT2C-receptor subtype. The chronobiotic properties of AG are of significant interest due to the disorganization of internal rhythms, which might play a role in the pathophysiology of depression. The present study was designed to assess the effects of the antidepressant-like activity of AG, a new antidepressant drug, on adult neurogenesis and apoptosis using stress-exposed rat brains. Over the period of 1 week, the rats were exposed to light stress twice a day for 1h. After a period of 1 week, the rats were given AG treatment at a dose of either 10mg/kg or 40mg/kg for 15 days. The animals were then scarified, and the obtained tissue sections were stained with immuno-histochemical anti-BrdU, Caspase-3, and Bcl-2 antibodies. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured biochemically using a BDNF Elisa kit. Biochemical BDNF analysis revealed a high concentration of BDNF in the serum of the stress-exposed group, but the concentrations of BDNF were much lower those of the AG-treated groups. Immuno-histochemical analysis revealed that AG treatment decreased the BrdU-positive and Bcl-2-positive cell densities and increased the Caspase-3-positive cell density in the hippocampus of stress-induced rats as compared to those of the stress group. The results of the study demonstrated that AG treatment ameliorated the hippocampal apoptotic cells and increased hippocampal neurogenesis. These results also strengthen the possible relationship between depression and adult neurogenesis, which must be studied further. PMID:26970810

  1. Impact of N-tau on adult hippocampal neurogenesis, anxiety, and memory.

    PubMed

    Pristerà, Andrea; Saraulli, Daniele; Farioli-Vecchioli, Stefano; Strimpakos, Georgios; Costanzi, Marco; di Certo, Maria Grazia; Cannas, Sara; Ciotti, Maria Teresa; Tirone, Felice; Mattei, Elisabetta; Cestari, Vincenzo; Canu, Nadia

    2013-11-01

    Different pathological tau species are involved in memory loss in Alzheimer's disease, the most common cause of dementia among older people. However, little is known about how tau pathology directly affects adult hippocampal neurogenesis, a unique form of structural plasticity implicated in hippocampus-dependent spatial learning and mood-related behavior. To this aim, we generated a transgenic mouse model conditionally expressing a pathological tau fragment (26-230 aa of the longest human tau isoform, or N-tau) in nestin-positive stem/progenitor cells. We found that N-tau reduced the proliferation of progenitor cells in the adult dentate gyrus, reduced cell survival and increased cell death by a caspase-3-independent mechanism, and recruited microglia. Although the number of terminally differentiated neurons was reduced, these showed an increased dendritic arborization and spine density. This resulted in an increase of anxiety-related behavior and an impairment of episodic-like memory, whereas less complex forms of spatial learning remained unaltered. Understanding how pathological tau species directly affect neurogenesis is important for developing potential therapeutic strategies to direct neurogenic instructive cues for hippocampal function repair.

  2. Adult neural stem cell behavior underlying constitutive and restorative neurogenesis in zebrafish.

    PubMed

    Barbosa, Joana S; Ninkovic, Jovica

    2016-01-01

    Adult Neural Stem Cells (aNSCs) generate new neurons that integrate into the pre-existing networks in specific locations of the Vertebrate brain. Moreover, aNSCs contribute with new neurons to brain regeneration in some non-mammalian Vertebrates. The similarities and the differences in the cellular and molecular processes governing neurogenesis in the intact and regenerating brain are still to be assessed. Toward this end, we recently established a protocol for non-invasive imaging of aNSC behavior in their niche in vivo in the adult intact and regenerating zebrafish telencephalon. We observed different modes of aNSC division in the intact brain and a novel mode of neurogenesis by direct conversion, which contributes to stem cell depletion with age. After injury, the generation of neurons is increased both by the activation of additional aNSCs and a shift in the division mode of aNSCs, thereby contributing to the successful neuronal regeneration. The cellular behavior we observed opens new questions regarding long-term aNSC maintenance in homeostasis and in regeneration. In this commentary we discuss our data and new questions arising in the context of aNSC behavior, not only in zebrafish but also in other species, including mammals. PMID:27606336

  3. Effect of postnatal methamphetamine trauma and adolescent methylphenidate treatment on adult hippocampal neurogenesis in gerbils.

    PubMed

    Schaefers, Andrea T; Teuchert-Noodt, Gertraud; Bagorda, Francesco; Brummelte, Susanne

    2009-08-15

    Methylphenidate (e.g. Ritalin) is the most common drug used in the treatment of attention-deficit hyperactivity disorder. However, only a few studies have investigated the neuroanatomical long-term effects of this treatment. Prolonged application of methylphenidate during adolescence causes alterations in dopaminergic fiber or receptor densities in adult rodents. This study was conducted to investigate the effects of adolescent methylphenidate treatment on adult hippocampal neurogenesis in male gerbils (Meriones unguiculatus). Animals were first treated with either a single methamphetamine challenge on postnatal day 14 (to cause a disturbance in the dopaminergic system, to mimic the disturbed dopaminergic system seen in ADHD children) or saline and then received a daily oral application of 5 mg/kg methylphenidate or water from postnatal day 30-60 or were left undisturbed. On postnatal 90 gerbils were injected with bromodeoxyuridine (BrdU, a DNA synthesis marker) and sacrificed seven days later. Results reveal that the pretreatment with methamphetamine causes a decrease in the number of BrdU-positive cells in the dentate gyrus. Methylphenidate treatment however did not cause any differences in the number of labelled cells in any group. This implies that, despite methylphenidate's efficiency in inducing changes in the dopaminergic system and associated areas, it might be less effective in altering neurogenesis in the hippocampus.

  4. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.

    PubMed

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-01-01

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate. PMID:26485032

  5. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain.

    PubMed

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-10-20

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate.

  6. Relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice.

    PubMed

    Kikuchihara, Yoh; Abe, Hajime; Tanaka, Takeshi; Kato, Mizuho; Wang, Liyun; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto

    2015-05-01

    We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) γ-aminobutyric acid (GABA)-ergic interneurons in the hilus of the dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2·xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the dentate hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb.

  7. Crosstalk among Epigenetic Pathways Regulates Neurogenesis.

    PubMed

    Jobe, Emily M; McQuate, Andrea L; Zhao, Xinyu

    2012-01-01

    The process of neurogenesis includes neural stem cell proliferation, fate specification, young neuron migration, neuronal maturation, and functional integration into existing circuits. Although neurogenesis occurs largely during embryonic development, low levels but functionally important neurogenesis persists in restricted regions of the postnatal brain, including the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone of the lateral ventricles. This review will cover both embryonic and adult neurogenesis with an emphasis on the latter. Of the many endogenous mediators of postnatal neurogenesis, epigenetic pathways, such as mediators of DNA methylation, chromatin remodeling systems, and non-coding RNA modulators, appear to play an integral role. Mounting evidence shows that such epigenetic factors form regulatory networks, which govern each step of postnatal neurogenesis. In this review, we explore the emerging roles of epigenetic mechanisms particularly microRNAs, element-1 silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF), polycomb proteins, and methyl-CpG bindings proteins, in regulating the entire process of postnatal and adult neurogenesis. We further summarize recent data regarding how the crosstalk among these different epigenetic proteins forms the critical regulatory network that regulates neuronal development. We finally discuss how crosstalk between these pathways may serve to translate environmental cues into control of the neurogenic process. PMID:22586361

  8. Maintaining appearances-The role of p53 in adult neurogenesis

    SciTech Connect

    Medrano, Silvia; Scrable, Heidi . E-mail: hs2n@virginia.edu

    2005-06-10

    In the adult mammalian brain, neuronal turnover continues to replenish cells in existing neuronal circuits, such as those involved either in odor discrimination or in learning and memory, throughout life. With age, however, the capacity for neurogenesis diminishes and these functions become impaired. Neuronal turnover is a two-step process, which first generates excess neuronal progenitors and then eliminates all but the few that differentiate into fully functional neurons. This process requires a fine balance between cell proliferation and cell death. Altered activity of the tumor suppressor p53 can upset this balance by affecting the rate of cell proliferation, but not the rate of cell death, in neurogenic regions of the adult brain. Genetically engineered mice in which p53 activity is increased demonstrate that premature loss of neurogenic capacity is linked to accelerated organismal aging.

  9. Influence of environmental stimulation on neurogenesis in the adult insect brain.

    PubMed

    Scotto Lomassese, S; Strambi, C; Strambi, A; Charpin, P; Augier, R; Aouane, A; Cayre, M

    2000-11-15

    Mushroom bodies are the main integrative structures of insect brain. They receive sensory information from the eyes, the palps, and the antennae. In the house cricket, Acheta domesticus, a cluster of mushroom body neuroblasts keeps producing new interneurons during an insect's life span. The aim of the present work is to study the impact of environmental stimuli on mushroom body neurogenesis during adulthood. Crickets were reared either in an enriched environment, where they received complex environmental and congeneric stimulations or isolated in small cages and deprived of most visual, auditory, and olfactory stimuli. They then were injected with a S-phase marker, 5-bromo, 2'-deoxyuridine (BrdU) and sacrificed at different periods of their life. Neurogenesis and cell survival were estimated by counting the number of BrdU-labeled cells in the mushroom bodies. Environmentally enriched crickets were found to have an increased number of newborn cells in their mushroom bodies compared with crickets housed in cages with an impoverished environment. This effect of external factors on neurogenesis seems to be limited to the beginning of imaginal life. Furthermore, no cell loss could be detected among the newborn neurons in either environmental situation, suggesting that cell survival was not affected by the quality of the environment. Considering vertebrate studies which showed that enriched environment increases hippocampal cell survival and improves animal performances in spatial learning tests, we suggest that the increased number of interneurons produced in an integrative brain structure after exposure to enriched environment could contribute to adaptive behavioral performances in adult insects.

  10. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.

    PubMed

    Pons-Espinal, Meritxell; Martinez de Lagran, Maria; Dierssen, Mara

    2013-12-01

    Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS.

  11. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.

    PubMed

    Pons-Espinal, Meritxell; Martinez de Lagran, Maria; Dierssen, Mara

    2013-12-01

    Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS. PMID:23969234

  12. The chromatin remodeler CHD7 regulates adult neurogenesis via activation of SoxC transcription factors.

    PubMed

    Feng, Weijun; Khan, Muhammad Amir; Bellvis, Pablo; Zhu, Zhe; Bernhardt, Olga; Herold-Mende, Christel; Liu, Hai-Kun

    2013-07-01

    Chromatin factors that regulate neurogenesis in the central nervous system remain to be explored. Here, we demonstrate that the chromatin remodeler chromodomain-helicase-DNA-binding protein 7 (CHD7), a protein frequently mutated in human CHARGE syndrome, is a master regulator of neurogenesis in mammalian brain. CHD7 is selectively expressed in actively dividing neural stem cells (NSCs) and progenitors. Genetic inactivation of CHD7 in NSCs leads to a reduction of neuronal differentiation and aberrant dendritic development of newborn neurons. Strikingly, physical exercise can rescue the CHD7 mutant phenotype in the adult hippocampal dentate gyrus. We further show that in NSCs, CHD7 stimulates the expression of Sox4 and Sox11 genes via remodeling their promoters to an open chromatin state. Our study demonstrates an essential role of CHD7 in activation of the neuronal differentiation program in NSCs, thus providing insights into epigenetic regulation of stem cell differentiation and molecular mechanism of human CHARGE syndrome. PMID:23827709

  13. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.

    PubMed

    Gregorian, Caroline; Nakashima, Jonathan; Le Belle, Janel; Ohab, John; Kim, Rachel; Liu, Annie; Smith, Kate Barzan; Groszer, Matthias; Garcia, A Denise; Sofroniew, Michael V; Carmichael, S Thomas; Kornblum, Harley I; Liu, Xin; Wu, Hong

    2009-02-11

    Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis. PMID:19211894

  14. Neurogenesis and precursor cell differences in the dorsal and ventral adult canine hippocampus.

    PubMed

    Lowe, Aileen; Dalton, Marshall; Sidhu, Kuldip; Sachdev, Perminder; Reynolds, Brent; Valenzuela, Michael

    2015-04-23

    During evolution a unique anterior-posterior flexure posited the canine dentate gyrus in two distinct dorsal and ventral positions. We therefore sought to explore neurogenesis and neurogenic cell-related difference along the canine hippocampal dorsal-ventral axis. Post mortem histological analysis revealed 49.1% greater doublecortin (DCX)-positive cells and a 158.5% greater percentage of double labeled DCX-positive/neuronal nuclei (NeuN) positive cells in the dorsal subgranular zone compared to the ventral. We then show neural precursor cells isolated from fresh hippocampal tissue are capable of proliferating long term, and after differentiation, express neuronal and glial markers. Dorsal hippocampal isolates produced a 120.0% higher frequency of sphere-forming neural precursor cells compared to ventral hippocampal tissue. Histological DCX and neurosphere assay results were highly correlated. Overall, we provide the first evidence that the dorsal canine hippocampus has a markedly higher rate of adult neurogenesis than the ventral hippocampus, possibly related to a greater frequency of contributory neural precursor cells.

  15. Pten deletion in adult neural stem/progenitor cells enhances constitutive neurogenesis.

    PubMed

    Gregorian, Caroline; Nakashima, Jonathan; Le Belle, Janel; Ohab, John; Kim, Rachel; Liu, Annie; Smith, Kate Barzan; Groszer, Matthias; Garcia, A Denise; Sofroniew, Michael V; Carmichael, S Thomas; Kornblum, Harley I; Liu, Xin; Wu, Hong

    2009-02-11

    Here we show that conditional deletion of Pten in a subpopulation of adult neural stem cells in the subependymal zone (SEZ) leads to persistently enhanced neural stem cell self-renewal without sign of exhaustion. These Pten null SEZ-born neural stem cells and progenies can follow the endogenous migration, differentiation, and integration pathways and contribute to constitutive neurogenesis in the olfactory bulb. As a result, Pten deleted animals have increased olfactory bulb mass and enhanced olfactory function. Pten null cells in the olfactory bulb can establish normal connections with peripheral olfactory epithelium and help olfactory bulb recovery from acute damage. Following a focal stroke, Pten null progenitors give rise to greater numbers of neuroblasts that migrate to peri-infarct cortex. However, in contrast to the olfactory bulb, no significant long-term survival and integration can be observed, indicating that additional factors are necessary for long-term survival of newly born neurons after stroke. These data suggest that manipulating PTEN-controlled signaling pathways may be a useful step in facilitating endogenous neural stem/progenitor expansion for the treatment of disorders or lesions in regions associated with constitutive neurogenesis.

  16. Social isolation impairs adult neurogenesis in the limbic system and alters behaviors in female prairie voles.

    PubMed

    Lieberwirth, Claudia; Liu, Yan; Jia, Xixi; Wang, Zuoxin

    2012-09-01

    Disruptions in the social environment, such as social isolation, are distressing and can induce various behavioral and neural changes in the distressed animal. We conducted a series of experiments to test the hypothesis that long-term social isolation affects brain plasticity and alters behavior in the highly social prairie vole (Microtus ochrogaster). In Experiment 1, adult female prairie voles were injected with a cell division marker, 5-bromo-2'-deoxyuridine (BrdU), and then same-sex pair-housed (control) or single-housed (isolation) for 6 weeks. Social isolation reduced cell proliferation, survival, and neuronal differentiation and altered cell death in the dentate gyrus of the hippocampus and the amygdala. In addition, social isolation reduced cell proliferation in the medial preoptic area and cell survival in the ventromedial hypothalamus. These data suggest that long-term social isolation affects distinct stages of adult neurogenesis in specific limbic brain regions. In Experiment 2, isolated females displayed higher levels of anxiety-like behaviors in both the open field and elevated plus maze tests and higher levels of depression-like behavior in the forced swim test than controls. Further, isolated females showed a higher level of affiliative behavior than controls, but the two groups did not differ in social recognition memory. Together, our data suggest that social isolation not only impairs cell proliferation, survival, and neuronal differentiation in limbic brain areas, but also alters anxiety-like, depression-like, and affiliative behaviors in adult female prairie voles. These data warrant further investigation of a possible link between altered neurogenesis within the limbic system and behavioral changes.

  17. Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis.

    PubMed

    Möhle, Luisa; Mattei, Daniele; Heimesaat, Markus M; Bereswill, Stefan; Fischer, André; Alutis, Marie; French, Timothy; Hambardzumyan, Dolores; Matzinger, Polly; Dunay, Ildiko R; Wolf, Susanne A

    2016-05-31

    Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes.

  18. Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis.

    PubMed

    Möhle, Luisa; Mattei, Daniele; Heimesaat, Markus M; Bereswill, Stefan; Fischer, André; Alutis, Marie; French, Timothy; Hambardzumyan, Dolores; Matzinger, Polly; Dunay, Ildiko R; Wolf, Susanne A

    2016-05-31

    Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes. PMID:27210745

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

    PubMed

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

    2014-03-01

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

  20. Blockade of 2-arachidonoylglycerol hydrolysis produces antidepressant-like effects and enhances adult hippocampal neurogenesis and synaptic plasticity.

    PubMed

    Zhang, Zhen; Wang, Wei; Zhong, Peng; Liu, Sarah J; Long, Jonathan Z; Zhao, Li; Gao, Hai-qing; Cravatt, Benjamin F; Liu, Qing-song

    2015-01-01

    The endocannabinoid ligand 2-arachidonoylglycerol (2-AG) is inactivated primarily by monoacylglycerol lipase (MAGL). We have shown recently that chronic treatments with MAGL inhibitor JZL184 produce antidepressant- and anxiolytic-like effects in a chronic unpredictable stress (CUS) model of depression in mice. However, the underlying mechanisms remain poorly understood. Adult hippocampal neurogenesis has been implicated in animal models of anxiety and depression and behavioral effects of antidepressants. We tested whether CUS and chronic JZL184 treatments affected adult neurogenesis and synaptic plasticity in the dentate gyrus (DG) of mouse hippocampus. We report that CUS induced depressive-like behaviors and decreased the number of bromodeoxyuridine-labeled neural progenitor cells and doublecortin-positive immature neurons in the DG, while chronic JZL184 treatments prevented these behavioral and cellular deficits. We also investigated the effects of CUS and chronic JZL184 on a form long-term potentiation (LTP) in the DG known to be neurogenesis-dependent. CUS impaired LTP induction, whereas chronic JZL184 treatments restored LTP in CUS-exposed mice. These results suggest that enhanced adult neurogenesis and long-term synaptic plasticity in the DG of the hippocampus might contribute to antidepressant- and anxiolytic-like behavioral effects of JZL184.

  1. Analysis of Adult Neurogenesis: Evidence for a Prominent “Non-Neurogenic” DCX-Protein Pool in Rodent Brain

    PubMed Central

    Kremer, Thomas; Jagasia, Ravi; Herrmann, Annika; Matile, Hugues; Borroni, Edilio; Francis, Fiona; Kuhn, Hans Georg; Czech, Christian

    2013-01-01

    Here, we have developed a highly sensitive immunoassay for Dcx to characterize expression in brain and cerebrospinal fluid (CSF) of rodents. We demonstrate that Dcx is widely expressed during development in various brain regions and as well can be detected in cerebrospinal fluid of rats (up to 30 days postnatal). While Dcx protein level decline in adulthood and were detectable in neurogenic regions of the adult rodent brain, similar levels were also detectable in brain regions expected to bear no neurogenesis including the cerebral cortex and CA1/CA3 enriched hippocampus. We monitored DCX protein levels after paradigms to increase or severely decrease adult hippocampal neurogenesis, namely physical activity and cranial radiation, respectively. In both paradigms, Dcx protein- and mRNA-levels clearly reflected changes in neurogenesis in the hippocampus. However, basal Dcx-levels are unaffected in non-neurogenic regions (e.g. CA1/CA3 enriched hippocampus, cortex). These data suggest that there is a substantial “non-neurogenic” pool of Dcx- protein, whose regulation can be uncoupled from adult neurogenesis suggesting caution for the interpretation of such studies. PMID:23690918

  2. Influences of prenatal and postnatal stress on adult hippocampal neurogenesis: the double neurogenic niche hypothesis.

    PubMed

    Ortega-Martínez, Sylvia

    2015-03-15

    Adult hippocampal neurogenesis (AHN) is involved in learning, memory, and stress, and plays a significant role in neurodegenerative and psychiatric disorders. As an age-dependent process, AHN is largely influenced by changes that occur during the pre- and postnatal stages of brain development, and constitutes an important field of research. This review examines the current knowledge regarding the regulators of AHN and the influence of prenatal and postnatal stress on later AHN. In addition, a hypothesis is presented suggesting that each kind of stress influences a specific neurogenic pool, developmental or postnatal, that later becomes a precursor with important repercussions for AHN. This hypothesis is referred to as "the double neurogenic niche hypothesis." Discovering what receptors, transcription factors, or genes are specifically activated by different stressors is proposed as an essential line of future research in the field. Such knowledge shall constitute an important starting point toward the goal of modifying AHN in neurodegenerative or psychiatric diseases.

  3. Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment.

    PubMed

    Vivar, Carmen

    2015-01-01

    The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols. PMID:26059358

  4. The Evidence for Increased L1 Activity in the Site of Human Adult Brain Neurogenesis

    PubMed Central

    Kurnosov, Alexey A.; Ustyugova, Svetlana V.; Nazarov, Vadim I.; Minervina, Anastasia A.; Komkov, Alexander Yu.; Shugay, Mikhail; Pogorelyy, Mikhail V.; Khodosevich, Konstantin V.; Mamedov, Ilgar Z.; Lebedev, Yuri B.

    2015-01-01

    Retroelement activity is a common source of polymorphisms in human genome. The mechanism whereby retroelements contribute to the intraindividual genetic heterogeneity by inserting into the DNA of somatic cells is gaining increasing attention. Brain tissues are suspected to accumulate genetic heterogeneity as a result of the retroelements somatic activity. This study aims to expand our understanding of the role retroelements play in generating somatic mosaicism of neural tissues. Whole-genome Alu and L1 profiling of genomic DNA extracted from the cerebellum, frontal cortex, subventricular zone, dentate gyrus, and the myocardium revealed hundreds of somatic insertions in each of the analyzed tissues. Interestingly, the highest concentration of such insertions was detected in the dentate gyrus—the hotspot of adult neurogenesis. Insertions of retroelements and their activity could produce genetically diverse neuronal subsets, which can be involved in hippocampal-dependent learning and memory. PMID:25689626

  5. p53 Mutation suppresses adult neurogenesis in medaka fish (Oryzias latipes)

    SciTech Connect

    Isoe, Yasuko; Okuyama, Teruhiro; Taniguchi, Yoshihito; Kubo, Takeo; Takeuchi, Hideaki

    2012-07-13

    Highlights: Black-Right-Pointing-Pointer Progenitor migration is accompanied by an increase in their numbers in the adult brain. Black-Right-Pointing-Pointer p53 Mutation suppressed an increase in the number of the migrated progenitors. Black-Right-Pointing-Pointer The decreased progenitor number is not due to enhanced cell death. Black-Right-Pointing-Pointer p53 Mutation did not affect proliferation of stem cells. -- Abstract: Tumor suppressor p53 negatively regulates self-renewal of neural stem cells in the adult murine brain. Here, we report that the p53 null mutation in medaka fish (Oryzias latipes) suppressed neurogenesis in the telencephalon, independent of cell death. By using 5-bromo-29-deoxyuridine (BrdU) immunohistochemistry, we identified 18 proliferation zones in the brains of young medaka fish; in situ hybridization showed that p53 was expressed selectively in at least 12 proliferation zones. We also compared the number of BrdU-positive cells present in the whole telencephalon of wild-type (WT) and p53 mutant fish. Immediately after BrdU exposure, the number of BrdU-positive cells did not differ significantly between them. One week after BrdU-exposure, the BrdU-positive cells migrated from the proliferation zone, which was accompanied by an increased number in the WT brain. In contrast, no significant increase was observed in the p53 mutant brain. Terminal deoxynucleotidyl transferase (dUTP) nick end-labeling revealed that there was no significant difference in the number of apoptotic cells in the telencephalon of p53 mutant and WT medaka, suggesting that the decreased number of BrdU-positive cells in the mutant may be due to the suppression of proliferation rather than the enhancement of neural cell death. These results suggest that p53 positively regulates neurogenesis via cell proliferation.

  6. 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

  7. Effect of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis in adult rat hippocampus and spatial learning.

    PubMed

    Ueda, S; Sakakibara, S; Yoshimoto, K

    2005-01-01

    The dentate gyrus of the hippocampal formation produces new neurons throughout adulthood in mammalian species. Several experimental statuses and factors regulating to neurogenesis have been identified in the adult dentate gyrus. For example, exposure to an enriched environment enhances neurogenesis in the dentate gyrus and improves hippocampus-dependent spatial learning. Furthermore, serotonin is known to influence adult neurogenesis, and learning and memory. However, the effects of long-lasting depletion of serotonin over the developing period on neurogenesis have not been investigated. Thus, we examined the influence of long-lasting serotonin depletion on environmental enrichment-induced neurogenesis and spatial memory performance. As reported previously, environmental enrichment significantly increased new neurons in the dentate gyrus. However, there was no improvement of the spatial learning test in adult rats in standard and in environmental enrichment housings. Intracisternal administration of the serotonergic neurotoxin, 5,7-dihydroxytryptamine, on postnatal day 3 apparently reduced serotonin content in the adult hippocampus without regeneration. This experimental depletion of serotonin in the hippocampus of rats housed in an enriched environment had no effect on spatial memory performance, but produced significant decreases in the number of bromodeoxyuridine-labeled new cells in the dentate gyrus. These findings indicate that newly generated cells stimulated by environmental enrichment are not critical for improvements in hippocampus-dependent learning. Furthermore, numbers of bromodeoxyuridine-labeled cells in the dentate gyrus of 5,7-dihydroxytryptamine-injected rats did not differ between 1 day and 4 weeks after bromodeoxyuridine injection. These data suggest that survival of newly generated dentate gyrus cells remains relatively constant under long-lasting serotonin depletion.

  8. Enriched Environment Altered Aberrant Hippocampal Neurogenesis and Improved Long-Term Consequences After Temporal Lobe Epilepsy in Adult Rats.

    PubMed

    Zhang, Xiaoqian; Liu, Tingting; Zhou, Zhike; Mu, Xiaopeng; Song, Chengguang; Xiao, Ting; Zhao, Mei; Zhao, Chuansheng

    2015-06-01

    Abnormal hippocampal neurogenesis is thought to contribute to cognitive impairments in chronic temporal lobe epilepsy (TLE). Stromal cell-derived factor-1 (SDF-1) and its specific receptor CXCR4 play important roles in neurogenesis. We investigated whether enriched environment (EE) might be beneficial for TLE. Adult rats were randomly assigned as control rats, rats subjected to status epilepticus (SE), or post-SE rats treated with EE for 30 days. We used immunofluorescence staining to analyze the hippocampal neurogenesis and Nissl staining to evaluate hippocampal damage. Electroencephalography was used to measure the duration of spontaneous seizures. Cognitive function was evaluated by Morris water maze. Western blot was used to measure the expression of SDF-1 and CXCR4 in the hippocampus. In the present study, we found the TLE model resulted in aberrant neurogenesis such as reduced proliferation, intensified dendritic development of newborn neurons, as well as spontaneous seizures and cognitive impairments. More importantly, EE treatment significantly increased the cell proliferation and survival, extended the apical dendrites, and delayed the attenuation of the expression of SDF-1 and CXCR4, accompanied by decreased long-term seizure activity and improved cognitive impairments in adult rats after TLE. These results provided morphological evidence that EE might be beneficial for treating TLE. PMID:25946980

  9. Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells.

    PubMed

    Butovsky, Oleg; Ziv, Yaniv; Schwartz, Adi; Landa, Gennady; Talpalar, Adolfo E; Pluchino, Stefano; Martino, Gianvito; Schwartz, Michal

    2006-01-01

    Cell renewal in the adult central nervous system (CNS) is limited, and is blocked in inflammatory brain conditions. We show that both neurogenesis and oligodendrogenesis of adult neural progenitor cells in mice are blocked by inflammation-associated (endotoxin-activated) microglia, but induced by microglia activated by cytokines (IL-4 or low level of IFN-gamma) associated with T-helper cells. Blockage was correlated with up-regulation of microglial production of tumor necrosis factor-alpha. The effect induced by IL-4-activated microglia was mediated, at least in part, by insulin-like growth factor-I. The IL-4-activated microglia showed a bias towards oligodendrogenesis whereas the IFN-gamma-activated microglia showed a bias towards neurogenesis. It thus appears that microglial phenotype critically affects their ability to support or impair cell renewal from adult stem cell.

  10. The relationship between behavior acquisition and persistence abilities: Involvement of adult hippocampal neurogenesis.

    PubMed

    Gradari, Simona; Pérez-Domper, Paloma; Butler, Ray G; Martínez-Cué, Carmen; de Polavieja, Gonzalo G; Trejo, José Luis

    2016-07-01

    The influence of the learning process on the persistence of the newly acquired behavior is relevant both for our knowledge of the learning/memory mechanisms and for the educational policy. However, it is unclear whether during an operant conditioning process with a continuous reinforcement paradigm, individual differences in acquisition are also associated to differences in persistence of the acquired behavior. In parallel, adult neurogenesis has been implicated in spatial learning and memory, but the specific role of the immature neurons born in the adult brain is not well known for this process. We have addressed both questions by analyzing the relationship between water maze task acquisition scores, the persistence of the acquired behavior, and the size of the different subpopulations of immature neurons in the adult murine hippocampus. We have found that task acquisition and persistence rates were negatively correlated: the faster the animals find the water maze platform at the end of acquisition stage, the less they persist in searching for it at the learned position in a subsequent non-reinforced trial; accordingly, the correlation in the number of some new neurons' subpopulations and the acquisition rate is negative while with persistence in acquired behavior is positive. These findings reveal an unexpected relationship between the efficiency to learn a task and the persistence of the new behavior after a non-reinforcement paradigm, and suggest that the immature neurons might be involved in different roles in acquisition and persistence/extinction of a learning task. © 2016 Wiley Periodicals, Inc. PMID:26788800

  11. Potential role of radial glia in adult neurogenesis of teleost fish.

    PubMed

    Zupanc, Günther K H; Clint, Sorcha C

    2003-07-01

    Persistence of radial glia within the adult central nervous system is a widespread phenomenon among fish. Based on a series of studies in the teleost species Apteronotus leptorhynchus, we propose that one function of this persistence is the involvement of radial glia in adult neurogenesis, i.e., the generation and further development of new neurons in the adult central nervous system. In particular, evidence has been obtained for the involvement of radial glia in the guidance of migrating young neurons in both the intact and the regenerating brain; for a possible role as precursor cells from which new neurons arise; and for its role as a source of trophic substances promoting the generation, differentiation, and/or survival of new neurons. These functions contribute not only to the potential of the intact brain to generate new neurons continuously, and of the injured brain to replace damaged cells by newly generated ones, but they also provide an essential part of the cellular substrate of behavioral plasticity.

  12. The relationship between behavior acquisition and persistence abilities: Involvement of adult hippocampal neurogenesis.

    PubMed

    Gradari, Simona; Pérez-Domper, Paloma; Butler, Ray G; Martínez-Cué, Carmen; de Polavieja, Gonzalo G; Trejo, José Luis

    2016-07-01

    The influence of the learning process on the persistence of the newly acquired behavior is relevant both for our knowledge of the learning/memory mechanisms and for the educational policy. However, it is unclear whether during an operant conditioning process with a continuous reinforcement paradigm, individual differences in acquisition are also associated to differences in persistence of the acquired behavior. In parallel, adult neurogenesis has been implicated in spatial learning and memory, but the specific role of the immature neurons born in the adult brain is not well known for this process. We have addressed both questions by analyzing the relationship between water maze task acquisition scores, the persistence of the acquired behavior, and the size of the different subpopulations of immature neurons in the adult murine hippocampus. We have found that task acquisition and persistence rates were negatively correlated: the faster the animals find the water maze platform at the end of acquisition stage, the less they persist in searching for it at the learned position in a subsequent non-reinforced trial; accordingly, the correlation in the number of some new neurons' subpopulations and the acquisition rate is negative while with persistence in acquired behavior is positive. These findings reveal an unexpected relationship between the efficiency to learn a task and the persistence of the new behavior after a non-reinforcement paradigm, and suggest that the immature neurons might be involved in different roles in acquisition and persistence/extinction of a learning task. © 2016 Wiley Periodicals, Inc.

  13. Prenatal Activation of Toll-Like Receptor-4 Dampens Adult Hippocampal Neurogenesis in An IL-6 Dependent Manner

    PubMed Central

    Mouihate, Abdeslam

    2016-01-01

    Prenatal immune challenge has been associated with alteration in brain development and plasticity that last into adulthood. We have previously shown that prenatal activation of toll-like receptor 4 by lipopolysaccharide (LPS) induces IL-6-dependent STAT-3 signaling pathway in the fetal brain. Whether this IL-6-dependent activation of fetal brain results in long lasting impact in brain plasticity is still unknown. Furthermore, it has been shown that prenatal LPS heightens the hypothalamic–pituitary–adrenal (HPA) response in adulthood. In the present study we tested whether LPS administration during pregnancy affects neurogenesis in adult male offspring. Because corticosterone, the end-product of HPA axis activity in rats, alters neurogenesis we tested whether this enhanced HPA axis responsiveness in adult male offspring played a role in the long lasting impact of LPS on neurogenesis during adulthood. Pregnant rats were given either LPS, or LPS and an IL-6 neutralizing antibody (IL-6Ab). The newly born neurons were monitored in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus of adult male offspring by monitoring doublecortin and T-box brain protein-2 expression: two well-established markers of newly born neurons. Prenatal LPS decreased the number of newly born neurons in the DG, but not in the SVZ of adult offspring. This decreased number of newly born neurons in the DG was absent when IL-6Ab was co-injected with LPS during pregnancy. Furthermore, administration of a corticosterone receptor blocker, RU-486, to adult offspring blunted the prenatal LPS induced decrease in newly born neurons in the DG. These data suggest that maternally triggered IL-6 plays a crucial role in the long lasting impact of LPS on adult neurogenesis. PMID:27445700

  14. Adult neurogenesis in the hedgehog (Erinaceus concolor) and mole (Talpa europaea).

    PubMed

    Bartkowska, K; Turlejski, K; Grabiec, M; Ghazaryan, A; Yavruoyan, E; Djavadian, R L

    2010-01-01

    We investigated adult neurogenesis in two species of mammals belonging to the superorder Laurasiatheria, the southern white-breasted hedgehog (order Erinaceomorpha, species Erinaceus concolor) from Armenia and the European mole (order Soricomorpha, species Talpa europaea) from Poland. Neurogenesis in the brain of these species was examined immunohistochemically, using the endogenous markers doublecortin (DCX) and Ki-67, which are highly conserved among species. We found that in both the hedgehog and mole, like in the majority of earlier investigated mammals, neurogenesis continues in the subventricular zone (SVZ) of the lateral ventricles and in the dentate gyrus (DG). In the DG of both species, DCX-expressing cells and Ki-67-labeled cells were present in the subgranular and granular layers. In the mole, a strong bundle of DCX-labeled processes, presumably axons of granule cells, was observed in the center of the hilus. Proliferating cells (expressing Ki-67) were identified in the SVZ of lateral ventricles of both species, but neuronal precursor cells (expressing DCX) were also observed in the olfactory bulb (OB). In both species, the vast majority of cells expressing DCX in the OB were granule cells with radially orientated dendrites, although some periglomerular cells surrounding the glomeruli were also labeled. In addition, this paper is the first to show DCX-labeled fibers in the anterior commissure of the hedgehog and mole. These fibers must be axons of new neurons making interhemispheric connections between the two OB or piriform (olfactory) cortices. DCX-expressing neurons were observed in the striatum and piriform cortex of both hedgehog and mole. We postulate that in both species a fraction of cells newly generated in the SVZ migrates along the rostral migratory stream to the piriform cortex. This pattern of migration resembles that of the 'second-wave neurons' generated during embryonal development of the neocortex rather than the pattern observed during

  15. Impaired spatial learning and reduced adult hippocampal neurogenesis in histamine H1-receptor knockout mice.

    PubMed

    Ambrée, Oliver; Buschert, Jens; Zhang, Weiqi; Arolt, Volker; Dere, Ekrem; Zlomuzica, Armin

    2014-08-01

    The histamine H1-receptor (H1R) is expressed in wide parts of the brain including the hippocampus, which is involved in spatial learning and memory. Previous studies in H1R knockout (H1R-KO) mice revealed deficits in a variety of learning and memory tasks. It was also proposed that H1R activation is crucial for neuronal differentiation of neural progenitors. Therefore, the aim of this study was to investigate negatively reinforced spatial learning in the water-maze and to assess survival and neuronal differentiation of newborn cells in the adult hippocampus of H1R-KO mice. H1R-KO and wild-type (WT) mice were subjected to the following sequence of tests: (a) cued version, (b) place learning, (c) spatial probe, (d) long-term retention and (e) reversal learning. Furthermore hippocampal neurogenesis in terms of survival and differentiation was assessed in H1R-KO and WT mice. H1R-KO mice showed normal cued learning, but impaired place and reversal learning as well as impaired long-term retention performance. In addition, a marked reduction of newborn neurons in the hippocampus but no changes in differentiation of neural progenitors into neuronal and glial lineage was found in H1R-KO mice. Our data suggest that H1R deficiency in mice is associated with pronounced deficits in hippocampus-dependent spatial learning and memory. Furthermore, we herein provide first evidence that H1R deficiency in the mouse leads to a reduced neurogenesis. However, the exact mechanisms for the reduced number of cells in H1R-KO mice remain elusive and might be due to a reduced survival of newborn hippocampal neurons and/or a reduction in cell proliferation.

  16. 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.

  17. Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze.

    PubMed

    Merritt, Jennifer R; Rhodes, Justin S

    2015-03-01

    Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2- to 5-fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6 J, 129S1/SvImJ, B6129SF1/J, DBA/2 J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2 J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running.

  18. Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze

    PubMed Central

    Merritt, Jennifer; Rhodes, Justin S.

    2014-01-01

    Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2 to 5 fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6J, 129S1/SvImJ, B6129SF1/J, DBA/2J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running. PMID:25435316

  19. Brain-Derived Neurotrophic Factor Signaling Does Not Stimulate Subventricular Zone Neurogenesis in Adult Mice and Rats

    PubMed Central

    Galvão, Rui P.; Garcia-Verdugo, José Manuel; Alvarez-Buylla, Arturo

    2009-01-01

    In rodents, the adult subventricular zone (SVZ) generates neuroblasts which migrate to the olfactory bulb (OB) and differentiate into interneurons. Recent work suggests that the neurotrophin Brain-Derived Neurotrophic Factor (BDNF) can enhance adult SVZ neurogenesis, but the mechanism by which it acts is unknown. Here, we analyzed the role of BDNF and its receptor TrkB in adult SVZ neurogenesis. We found that TrkB is the most prominent neurotrophin receptor in the mouse SVZ, but only the truncated, kinase-negative isoform (TrkB-TR) was detected. TrkB-TR is expressed in SVZ astrocytes and ependymal cells, but not in neuroblasts. TrkB mutants have reduced SVZ proliferation and survival and fewer new OB neurons. To test if this effect is cell-autonomous, we grafted SVZ cells from TrkB knockout mice (TrkB-KO) into the SVZ of wild-type mice (WT). Grafted progenitors generated neuroblasts that migrated to the OB in the absence of TrkB. The survival and differentiation of granular interneurons and Calbindin+ periglomerular interneurons seemed unaffected by the loss of TrkB, while dopaminergic periglomerular neurons were reduced. Intra-ventricular infusion of BDNF yielded different results depending on the animal species, having no effect on neuron production from mouse SVZ, while decreasing it in rats. Interestingly, mice and rats also differ in their expression of the neurotrophin receptor, p75. Our results indicate that TrkB is not essential for adult SVZ neurogenesis and do not support the current view that delivering BDNF to the SVZ can enhance adult neurogenesis. PMID:19074010

  20. Anatomical gradients of adult neurogenesis and activity: young neurons in the ventral dentate gyrus are activated by water maze training

    PubMed Central

    Snyder, Jason S.; Radik, Ruvim; Wojtowicz, J. Martin; Cameron, Heather A.

    2009-01-01

    Hippocampal function varies in a subregion-specific fashion: spatial processing is thought to rely on the dorsal hippocampus, while anxiety-related behavior relies more on the ventral hippocampus. During development, neurogenesis in the dentate gyrus proceeds along ventral to dorsal as well as suprapyramidal to infrapyramidal gradients, but it is unclear whether regional differences in neurogenesis are maintained in adulthood. Moreover, it is unknown whether young neurons in the adult exhibit subregion-specific patterns of activation. We therefore examined the magnitude of neurogenesis and the activation of young and mature granule cells in dentate gyrus subregions in adult rats that learned a spatial water maze task, swam with no platform, or were left untouched. We found that both adult neurogenesis and granule cell activation, as defined by c-fos expression in the granule cell population as a whole, were higher in the dorsal than the ventral dentate gyrus. In contrast, c-fos expression in adult-born granule cells, identified by PSA-NCAM or location in the subgranular zone, occurred at a higher rate in the opposite subregion, the ventral dentate gyrus. Interestingly, c-fos expression in the entire granule cell population was equivalent in water maze-trained rats and swim control rats, but was increased in the young granule cells only in the learning condition. These results provide new evidence that hippocampally-relevant experience activates young and mature neurons in different dentate gyrus subregions and with different experiential specificity, and suggest that adult-born neurons may play a specific role in anxiety-related behavior or other non-spatial aspects of hippocampal function. PMID:19004012

  1. Sex and strategy use matters for pattern separation, adult neurogenesis, and immediate early gene expression in the hippocampus.

    PubMed

    Yagi, Shunya; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

    2016-01-01

    Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation, and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis, and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague-Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the eight-arm radial arm maze. Twenty-seven days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore, male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly, neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity.

  2. 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.

  3. 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. PMID:27118134

  4. 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.

  5. Study of adult neurogenesis in the Gallotia galloti lizard during different seasons.

    PubMed

    Delgado-Gonzalez, F J; Gonzalez-Granero, S; Trujillo-Trujillo, C M; García-Verdugo, J M; Damas-Hernandez, M C

    2011-05-16

    In a previous study we found a seasonal distribution of cell proliferation (the first stage of adult neurogenesis) in the telencephalic ventricular walls of the adult Gallotia galloti lizard. The aim of the present work was to determine the influence of seasonality on the subsequent migration of the resulting immature neurons. We used wild animals injected with bromodeoxyuridine and kept in captivity within 30 days. To confirm the neuronal identity of these cells, we used double immunohistochemical 5-bromo-2'-deoxyuridine (BrdU) and doublecortin (DCX, an early neuronal marker) labeling, as well as autoradiography after the administration of methyl-[³H]thymidine ([³H]T). We found that: (1) the rate of cell division and/or migration from the ventricular walls varied with the season, especially in regions related with olfaction. (2) Immature neuron-like cells appeared to migrate in an apparently radial and tangential way towards different parts of the telencephalic parenchyma. (3) We did not observe ultrastructurally mature neurons until at least 90 days later, a period considerably greater than that reported for other species of vertebrates in similar studies.

  6. 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

  7. Exercise can rescue recognition memory impairment in a model with reduced adult hippocampal neurogenesis.

    PubMed

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

    2010-01-01

    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.

  8. Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits.

    PubMed

    Garthe, A; Huang, Z; Kaczmarek, L; Filipkowski, R K; Kempermann, G

    2014-04-01

    Studies using the Morris water maze to assess hippocampal function in animals, in which adult hippocampal neurogenesis had been suppressed, have yielded seemingly contradictory results. Cyclin D2 knockout (Ccnd2(-/-)) mice, for example, have constitutively suppressed adult hippocampal neurogenesis but had no overt phenotype in the water maze. In other paradigms, however, ablation of adult neurogenesis was associated with specific deficits in the water maze. Therefore, we hypothesized that the neurogenesis-related phenotype might also become detectable in Ccnd2(-/-) mice, if we used the exact setup and protocol that in our previous study had revealed deficits in mice with suppressed adult neurogenesis. Ccnd2(-/-) mice indeed learned the task and developed a normal preference for the goal quadrant, but were significantly less precise for the exact goal position and were slower in acquiring efficient and spatially more precise search strategies. Upon goal reversal (when the hidden platform was moved to a new position) Ccnd2(-/-) mice showed increased perseverance at the former platform location, implying that they were less flexible in updating the previously learned information. Both with respect to adult neurogenesis and behavioral performance, Ccnd2(+/-) mice ranged between wild types and knockouts. Importantly, hippocampus-dependent learning was not generally impaired by the mutation, but specifically functional aspects relying on precise and flexible encoding were affected. Whether ablation of adult neurogenesis causes a specific behavioral phenotype thus also depends on the actual task demands. The test parameters appear to be important variables influencing whether a task can pick up a contribution of adult neurogenesis to test performance.

  9. Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis

    PubMed Central

    Chen, Zhiguo; Palmer, Theo D.

    2013-01-01

    Tumor necrosis factor alpha (TNFα) is a potent inhibitor of neurogenesis in vitro but here we show that TNFα signaling has both positive and negative effects on neurogenesis in vivo and is required to moderate the negative impact of cranial irradiation on hippocampal neurogenesis. In vitro, basal levels of TNFα signaling through TNFR2 are required for normal neural progenitor cell proliferation while basal signaling through TNFR1 impairs neural progenitor proliferation. TNFR1 also mediates further reductions in proliferation and elevated cell death following exposure to recombinant TNFα. In vivo, TNFR1−/− and TNFα−/− animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNFα is also implicated in defects in neurogenesis that follow radiation injury but we find that loss of TNFR1 has no protective effects on neurogenesis and loss of TNFα or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNFα mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1. PMID:23402793

  10. Elevated adult neurogenesis in brain subventricular zone following in vivo manganese exposure: roles of copper and DMT1.

    PubMed

    Fu, Sherleen; O'Neal, Stefanie; Hong, Lan; Jiang, Wendy; Zheng, Wei

    2015-02-01

    The brain subventricular zone (SVZ) is a source of neural precursor cells; these cells travel along the rostral migratory stream (RMS) to destination areas in the process of adult neurogenesis. Recent x-ray fluorescence (XRF) studies reveal an extensive accumulation of copper (Cu) in the SVZ. Earlier human and animal studies also suggest an altered Cu homeostasis after manganese (Mn) exposure. This study was designed to test the hypothesis that Mn exposure by acting on the divalent metal transporter-1 (DMT1) altered Cu levels in SVZ and RMS, thereby affecting adult neurogenesis. Adult rats received intraperitoneal (i.p.) injections of 6 mg Mn/kg as MnCl2 once daily for 4 weeks with concomitant injections of bromodeoxyuridine (BrdU) for 5 days in the last week. In control rats, Cu levels were significantly higher in the SVZ than other brain regions examined. Mn exposure significantly reduced Cu concentrations in the SVZ (P < 0.01). Immunohistochemical data showed that in vivo Mn exposure significantly increased numbers of BrdU(+) cells, which were accompanied with increased GFAP(+) astrocytic stem cells and DCX(+) neuroblasts in SVZ and RMS. Quantitative RT-PCR and Western blot confirmed the increased expression of DMT1 in SVZ following in vivo Mn exposure, which contributed to Mn accumulation in the neurogenesis pathway. Taken together, these results indicate a clear disruptive effect of Mn on adult neurogenesis; the effect appears due partly to Mn induction of DMT1 and its interference with cellular Cu regulation in SVZ and RMS. The future research directions based on these observations are also discussed. PMID:25575534

  11. Elevated Adult Neurogenesis in Brain Subventricular Zone Following In vivo Manganese Exposure: Roles of Copper and DMT1

    PubMed Central

    Fu, Sherleen; O'Neal, Stefanie; Hong, Lan; Jiang, Wendy; Zheng, Wei

    2015-01-01

    The brain subventricular zone (SVZ) is a source of neural precursor cells; these cells travel along the rostral migratory stream (RMS) to destination areas in the process of adult neurogenesis. Recent x-ray fluorescence (XRF) studies reveal an extensive accumulation of copper (Cu) in the SVZ. Earlier human and animal studies also suggest an altered Cu homeostasis after manganese (Mn) exposure. This study was designed to test the hypothesis that Mn exposure by acting on the divalent metal transporter-1 (DMT1) altered Cu levels in SVZ and RMS, thereby affecting adult neurogenesis. Adult rats received intraperitoneal (i.p.) injections of 6 mg Mn/kg as MnCl2 once daily for 4 weeks with concomitant injections of bromodeoxyuridine (BrdU) for 5 days in the last week. In control rats, Cu levels were significantly higher in the SVZ than other brain regions examined. Mn exposure significantly reduced Cu concentrations in the SVZ (P < 0.01). Immunohistochemical data showed that in vivo Mn exposure significantly increased numbers of BrdU(+) cells, which were accompanied with increased GFAP(+) astrocytic stem cells and DCX(+) neuroblasts in SVZ and RMS. Quantitative RT-PCR and Western blot confirmed the increased expression of DMT1 in SVZ following in vivo Mn exposure, which contributed to Mn accumulation in the neurogenesis pathway. Taken together, these results indicate a clear disruptive effect of Mn on adult neurogenesis; the effect appears due partly to Mn induction of DMT1 and its interference with cellular Cu regulation in SVZ and RMS. The future research directions based on these observations are also discussed. PMID:25575534

  12. Suppression of c-Kit signaling induces adult neurogenesis in the mouse intestine after myenteric plexus ablation with benzalkonium chloride.

    PubMed

    Tamada, Hiromi; Kiyama, Hiroshi

    2016-01-01

    Adult neurogenesis rarely occurs in the enteric nervous system (ENS). In this study, we demonstrated that, after intestinal myenteric plexus (MP) ablation with benzalkonium chloride (BAC), adult neurogenesis in the ENS was significantly induced in c-kit loss-of-function mutant mice (W/W(v)). Almost all neurons and fibers in the MP disappeared after BAC treatment. However, 1 week after ablation, substantial penetration of nerve fibers from the non-damaged area was observed in the MP, longitudinal muscle and subserosal layers in both wildtype and W/W(v) mice. Two weeks after BAC treatment, in addition to the penetrating fibers, a substantial number of ectopic neurons appeared in the subserosal and longitudinal muscle layers of W/W(v) mice, whereas only a few ectopic neurons appeared in wildtype mice. Such ectopic neurons expressed either excitatory or inhibitory intrinsic motor neuron markers and formed ganglion-like structures, including glial cells, synaptic vesicles and basal lamina. Furthermore, oral administration of imatinib, an inhibitor of c-Kit and an anticancer agent for gastrointestinal stromal tumors, markedly induced appearance of ectopic neurons after BAC treatment, even in wildtype mice. These results suggest that adult neurogenesis in the ENS is negatively regulated by c-Kit signaling in vivo. PMID:27572504

  13. Suppression of c-Kit signaling induces adult neurogenesis in the mouse intestine after myenteric plexus ablation with benzalkonium chloride

    PubMed Central

    Tamada, Hiromi; Kiyama, Hiroshi

    2016-01-01

    Adult neurogenesis rarely occurs in the enteric nervous system (ENS). In this study, we demonstrated that, after intestinal myenteric plexus (MP) ablation with benzalkonium chloride (BAC), adult neurogenesis in the ENS was significantly induced in c-kit loss-of-function mutant mice (W/Wv). Almost all neurons and fibers in the MP disappeared after BAC treatment. However, 1 week after ablation, substantial penetration of nerve fibers from the non-damaged area was observed in the MP, longitudinal muscle and subserosal layers in both wildtype and W/Wv mice. Two weeks after BAC treatment, in addition to the penetrating fibers, a substantial number of ectopic neurons appeared in the subserosal and longitudinal muscle layers of W/Wv mice, whereas only a few ectopic neurons appeared in wildtype mice. Such ectopic neurons expressed either excitatory or inhibitory intrinsic motor neuron markers and formed ganglion-like structures, including glial cells, synaptic vesicles and basal lamina. Furthermore, oral administration of imatinib, an inhibitor of c-Kit and an anticancer agent for gastrointestinal stromal tumors, markedly induced appearance of ectopic neurons after BAC treatment, even in wildtype mice. These results suggest that adult neurogenesis in the ENS is negatively regulated by c-Kit signaling in vivo. PMID:27572504

  14. IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

    PubMed Central

    Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

    2016-01-01

    The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

  15. 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.

  16. Tool Use Specific Adult Neurogenesis and Synaptogenesis in Rodent (Octodon degus) Hippocampus

    PubMed Central

    Kumazawa-Manita, Noriko; Hama, Hiroshi; Miyawaki, Atsushi; Iriki, Atsushi

    2013-01-01

    We previously demonstrated that degus (Octodon degus), which are a species of small caviomorph rodents, could be trained to use a T-shaped rake as a hand tool to expand accessible spaces. To elucidate the neurobiological underpinnings of this higher brain function, we compared this tool use learning task with a simple spatial (radial maze) memory task and investigated the changes that were induced in the hippocampal neural circuits known to subserve spatial perception and learning. With the exposure to an enriched environment in home cage, adult neurogenesis in the dentate gyrus of the hippocampus was augmented by tool use learning, but not radial maze learning, when compared to control conditions. Furthermore, the proportion of new synapses formed in the CA3 region of the hippocampus, the target area for projections of mossy fiber axons emanating from newborn neurons, was specifically increased by tool use learning. Thus, active tool use behavior by rodents, learned through multiple training sessions, requires the hippocampus to generate more novel neurons and synapses than spatial information processing in radial maze learning. PMID:23516527

  17. Major unsolved points in adult neurogenesis: doors open on a translational future?

    PubMed Central

    Peretto, Paolo; Bonfanti, Luca

    2014-01-01

    In spite of many data gathered during the last two decades on adult neurogenesis (AN) it is evident that such knowledge is not sufficient for granting translational outcomes in brain repair, especially if the ultimate goal is to promote cell replacement. Alternative strategies aimed at fostering AN physiological functions (restorative approaches) are still undefined. By asking the question whether AN research field has to be considered as a dead end in the context of brain repair, here we review some unresolved issues: multifaceted evolutionary constraints in mammals, stem/progenitor cell type/availability and tissue permissivity, impact on other brain functions, interplay with other forms of plasticity, and relevance in humans. We suggest that full understanding of AN biology is an essential step for its possible exploitation in brain repair, and that further fundamental, multidisciplinary research is required to reach translational outcomes. Scientist's attitude and their communication skills are also important. To avoid overestimation of AN reparative potential in a translational perspective, more distant goals of cell replacement should be kept clearly distinct from restorative approaches involving AN functional plasticity. PMID:24966812

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

    PubMed Central

    Marques, Alessandra Aparecida; Bevilaqua, Mário Cesar do Nascimento; da Fonseca, Alberto Morais Pinto; Nardi, Antonio Egidio; Thuret, Sandrine; Dias, Gisele Pereira

    2016-01-01

    Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences between male and female rodents with regard to anxiety-related behavior and physiology, with a special focus on AHN. The differences between male and female physiologies are greatly influenced by hormonal differences. Gonadal hormones and their fluctuations during the estrous cycle have often been identified as agents responsible for sexual dimorphism in behavior and AHN. During sexual maturity, hormone levels fluctuate cyclically in females more than in males, increasing the stress response and the susceptibility to anxiety. It is therefore of great importance that future research investigates anxiety and other neurophysiological aspects in the female model, so that results can be more accurately applicable to the female population. PMID:26885403

  19. The Neurogenic Factor NeuroD1 Is Expressed in Post-Mitotic Cells during Juvenile and Adult Xenopus Neurogenesis and Not in Progenitor or Radial Glial Cells

    PubMed Central

    D'Amico, Laure Anne; Boujard, Daniel; Coumailleau, Pascal

    2013-01-01

    In contrast to mammals that have limited proliferation and neurogenesis capacities, the Xenopus frog exhibit a great potential regarding proliferation and production of new cells in the adult brain. This ability makes Xenopus a useful model for understanding the molecular programs required for adult neurogenesis. Transcriptional factors that control adult neurogenesis in vertebrate species undergoing widespread neurogenesis are unknown. NeuroD1 is a member of the family of proneural genes, which function during embryonic neurogenesis as a potent neuronal differentiation factor. Here, we study in detail the expression of NeuroD1 gene in the juvenile and adult Xenopus brains by in situ hybridization combined with immunodetections for proliferation markers (PCNA, BrdU) or in situ hybridizations for cell type markers (Vimentin, Sox2). We found NeuroD1 gene activity in many brain regions, including olfactory bulbs, pallial regions of cerebral hemispheres, preoptic area, habenula, hypothalamus, cerebellum and medulla oblongata. We also demonstrated by double staining NeuroD1/BrdU experiments, after long post-BrdU administration survival times, that NeuroD1 gene activity was turned on in new born neurons during post-metamorphic neurogenesis. Importantly, we provided evidence that NeuroD1-expressing cells at this brain developmental stage were post-mitotic (PCNA-) cells and not radial glial (Vimentin+) or progenitors (Sox2+) cells. PMID:23799108

  20. Opposite-sex attraction in male mice requires testosterone-dependent regulation of adult olfactory bulb neurogenesis

    PubMed Central

    Schellino, Roberta; Trova, Sara; Cimino, Irene; Farinetti, Alice; Jongbloets, Bart C.; Pasterkamp, R. Jeroen; Panzica, Giancarlo; Giacobini, Paolo; De Marchis, Silvia; Peretto, Paolo

    2016-01-01

    Opposite-sex attraction in most mammals depends on the fine-tuned integration of pheromonal stimuli with gonadal hormones in the brain circuits underlying sexual behaviour. Neural activity in these circuits is regulated by sensory processing in the accessory olfactory bulb (AOB), the first central station of the vomeronasal system. Recent evidence indicates adult neurogenesis in the AOB is involved in sex behaviour; however, the mechanisms underlying this function are unknown. By using Semaphorin 7A knockout (Sema7A ko) mice, which show a reduced number of gonadotropin-releasing-hormone neurons, small testicles and subfertility, and wild-type males castrated during adulthood, we demonstrate that the level of circulating testosterone regulates the sex-specific control of AOB neurogenesis and the vomeronasal system activation, which influences opposite-sex cue preference/attraction in mice. Overall, these data highlight adult neurogenesis as a hub for the integration of pheromonal and hormonal cues that control sex-specific responses in brain circuits. PMID:27782186

  1. Environmental changes in oxygen tension reveal ROS-dependent neurogenesis and regeneration in the adult newt brain

    PubMed Central

    Hameed, L Shahul; Berg, Daniel A; Belnoue, Laure; Jensen, Lasse D; Cao, Yihai; Simon, András

    2015-01-01

    Organisms need to adapt to the ecological constraints in their habitat. How specific processes reflect such adaptations are difficult to model experimentally. We tested whether environmental shifts in oxygen tension lead to events in the adult newt brain that share features with processes occurring during neuronal regeneration under normoxia. By experimental simulation of varying oxygen concentrations, we show that hypoxia followed by re-oxygenation lead to neuronal death and hallmarks of an injury response, including activation of neural stem cells ultimately leading to neurogenesis. Neural stem cells accumulate reactive oxygen species (ROS) during re-oxygenation and inhibition of ROS biosynthesis counteracts their proliferation as well as neurogenesis. Importantly, regeneration of dopamine neurons under normoxia also depends on ROS-production. These data demonstrate a role for ROS-production in neurogenesis in newts and suggest that this role may have been recruited to the capacity to replace lost neurons in the brain of an adult vertebrate. DOI: http://dx.doi.org/10.7554/eLife.08422.001 PMID:26485032

  2. Network Modeling of Adult Neurogenesis: Shifting Rates of Neuronal Turnover Optimally Gears Network Learning according to Novelty Gradient

    PubMed Central

    Chambers, R. Andrew; Conroy, Susan K.

    2010-01-01

    Apoptotic and neurogenic events in the adult hippocampus are hypothesized to play a role in cognitive responses to new contexts. Corticosteroid-mediated stress responses and other neural processes invoked by substantially novel contextual changes may regulate these processes. Using elementary three-layer neural networks that learn by incremental synaptic plasticity, we explored whether the cognitive effects of differential regimens of neuronal turnover depend on the environmental context in terms of the degree of novelty in the new information to be learned. In “adult” networks that had achieved mature synaptic connectivity upon prior learning of the Roman alphabet, imposition of apoptosis/neurogenesis before learning increasingly novel information (alternate Roman < Russian < Hebrew) reveals optimality of informatic cost benefits when rates of turnover are geared in proportion to the degree of novelty. These findings predict that flexible control of rates of apoptosis–neurogenesis within plastic, mature neural systems optimizes learning attributes under varying degrees of contextual change, and that failures in this regulation may define a role for adult hippocampal neurogenesis in novelty- and stress-responsive psychiatric disorders. PMID:17214558

  3. Adult neurogenesis and its anatomical context in the hippocampus of three mole-rat species

    PubMed Central

    Amrein, Irmgard; Becker, Anton S.; Engler, Stefanie; Huang, Shih-hui; Müller, Julian; Slomianka, Lutz; Oosthuizen, Maria K.

    2014-01-01

    African mole-rats (family Bathyergidae) are small to medium sized, long-lived, and strictly subterranean rodents that became valuable animal models as a result of their longevity and diversity in social organization. The formation and integration of new hippocampal neurons in adult mammals (adult hippocampal neurogenesis, AHN) correlates negatively with age and positively with habitat complexity. Here we present quantitative data on AHN in wild-derived mole-rats of 1 year and older, and briefly describe its anatomical context including markers of neuronal function (calbindin and parvalbumin). Solitary Cape mole-rats (Georychus capensis), social highveld mole-rats (Cryptomys hottentotus pretoriae), and eusocial naked mole-rats (Heterocephalus glaber) were assessed. Compared to other rodents, the hippocampal formation in mole-rats is small, but shows a distinct cytoarchitecture in the dentate gyrus and CA1. Distributions of the calcium-binding proteins differ from those seen in rodents; e.g., calbindin in CA3 of naked mole-rats distributes similar to the pattern seen in early primate development, and calbindin staining extends into the stratum lacunosum-moleculare of Cape mole-rats. Proliferating cells and young neurons are found in low numbers in the hippocampus of all three mole-rat species. Resident granule cell numbers are low as well. Proliferating cells expressed as a percentage of resident granule cells are in the range of other rodents, while the percentage of young neurons is lower than that observed in surface dwelling rodents. Between mole-rat species, we observed no difference in the percentage of proliferating cells. The percentages of young neurons are high in social highveld and naked mole-rats, and low in solitary Cape mole-rats. The findings support that proliferation is regulated independently of average life expectancy and habitat. Instead, neuronal differentiation reflects species-specific demands, which appear lower in subterranean rodents. PMID

  4. Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome.

    PubMed

    Mardirossian, Sandrine; Rampon, Claire; Salvert, Denise; Fort, Patrice; Sarda, Nicole

    2009-12-01

    Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, seizures and sleep disturbances. It results from lack of the functional maternal allele of UBE3A gene. Ube3a maternal-deficient mice (Ube3a m-/p+), animal models for AS, are impaired in hippocampal-dependent learning tasks as compared with control (Ube3a m+/p+) mice. We first examined the basal expression of immediate early genes which expression is required for synaptic plasticity and memory formation. We found that basal expression of c-fos and Arc genes is reduced in the DG of Ube3a maternal deficient mice compared to their non-transgenic littermates. We then examined whether adult hippocampal neurogenesis, which likely serves as a mechanism toward brain plasticity, is altered in these transgenic mice. Neurogenesis occurs throughout life in mammalian dentate gyrus (DG) and recent findings suggest that newborn granule cells are involved in some forms of learning and memory. Whether maternal Ube3a deletion is detrimental on hippocampal neurogenesis is unclear. Herein, we show, using the mitotic marker Ki67, the birthdating marker 5-bromo-2'-dexoyuridine (BrdU) and the marker doublecortin (DCX) to respectively label cell proliferation, cell survival or young neuron production, that the Ube3a maternal deletion does not affect the proliferation nor the survival of newborn cells in the hippocampus. In contrast, using the postmitotic neuronal marker (NeuN), we show that Ube3a maternal deletion is associated with a lower fraction of BrdU+/NeuN+ newborn neurons among the population of surviving new cells in the hippocampus. Collectively, these findings suggest that some aspects of adult neurogenesis and plasticity are affected by Ube3a deletion and may contribute to the hippocampal dysfunction observed in AS mice.

  5. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels

    PubMed Central

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-il; Moon, Minho

    2016-01-01

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189

  6. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels.

    PubMed

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-Il; Moon, Minho

    2016-08-31

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189

  7. Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone

    PubMed Central

    López-Juárez, Alejandro; Howard, Jennifer; Ullom, Kristy; Howard, Lindsey; Grande, Andrew; Pardo, Andrea; Waclaw, Ronald; Sun, Yu-Yo; Yang, Dianer; Kuan, Chia-Yi; Campbell, Kenneth; Nakafuku, Masato

    2013-01-01

    Neural stem cells (NSCs) reside in widespread regions along the lateral ventricle and generate diverse olfactory bulb (OB) interneuron subtypes in the adult mouse brain. Molecular mechanisms underlying their regional diversity, however, are not well understood. Here we show that the homeodomain transcription factor Gsx2 plays a crucial role in the region-specific control of adult NSCs in both persistent and injury-induced neurogenesis. In the intact brain, Gsx2 is expressed in a regionally restricted subset of NSCs and promotes the activation and lineage progression of stem cells, thereby controlling the production of selective OB neuron subtypes. Moreover, Gsx2 is ectopically induced in damaged brains outside its normal expression domains and is required for injury-induced neurogenesis in the subventricular zone (SVZ). These results demonstrate that mobilization of adult NSCs is controlled in a region-specific manner and that distinct mechanisms operate in continuous and injury-induced neurogenesis in the adult brain. PMID:23723414

  8. Gsx2 controls region-specific activation of neural stem cells and injury-induced neurogenesis in the adult subventricular zone.

    PubMed

    López-Juárez, Alejandro; Howard, Jennifer; Ullom, Kristy; Howard, Lindsey; Grande, Andrew; Pardo, Andrea; Waclaw, Ronald; Sun, Yu-Yo; Yang, Dianer; Kuan, Chia-Yi; Campbell, Kenneth; Nakafuku, Masato

    2013-06-01

    Neural stem cells (NSCs) reside in widespread regions along the lateral ventricle and generate diverse olfactory bulb (OB) interneuron subtypes in the adult mouse brain. Molecular mechanisms underlying their regional diversity, however, are not well understood. Here we show that the homeodomain transcription factor Gsx2 plays a crucial role in the region-specific control of adult NSCs in both persistent and injury-induced neurogenesis. In the intact brain, Gsx2 is expressed in a regionally restricted subset of NSCs and promotes the activation and lineage progression of stem cells, thereby controlling the production of selective OB neuron subtypes. Moreover, Gsx2 is ectopically induced in damaged brains outside its normal expression domains and is required for injury-induced neurogenesis in the subventricular zone (SVZ). These results demonstrate that mobilization of adult NSCs is controlled in a region-specific manner and that distinct mechanisms operate in continuous and injury-induced neurogenesis in the adult brain.

  9. Chronic inhibition of nitric oxide synthesis enhances both subventricular zone neurogenesis and olfactory learning in adult mice.

    PubMed

    Romero-Grimaldi, Carmen; Gheusi, Gilles; Lledo, Pierre-Marie; Estrada, Carmen

    2006-11-01

    The ability to generate new neurons during the course of adult life is preserved in the subventricular zone of the lateral ventricles and the dentate gyrus of the hippocampus in the mammalian brain. These two regions constitute specifically regulated neurogenic niches, and provide newborn neurons involved in olfactory and spatial learning, respectively. Nitric oxide (NO) is a negative regulator of neurogenesis in the subventricular zone, whereas its role in the dentate gyrus remains controversial. Using systemic administration of NO synthase (NOS) inhibitors to chronically inhibit NO production, we increased neural precursor proliferation in the subventricular zone as well as neurogenesis in the olfactory bulb, without modifying the number of mitotic cells or the granular cell layer thickness in the dentate gyrus. The same treatment specifically improved olfactory learning performance, whereas spatial learning and memory was unchanged, thus demonstrating that olfactory memory is closely associated with the level of ongoing neurogenesis in the subventricular zone-olfactory bulb. The anatomical specificity of the NOS inhibitor actions was not due to differences in the availability of NO, as demonstrated by immunohistochemical detection of neuronal NOS and S-nitrosylated proteins in both regions. Remarkably, the distinct NO sensitivity might result from a differential expression of epidermal growth factor receptor in precursor cells in both regions, as the proliferative effect of NOS inhibitors in the subventricular zone was restricted to the cells that expressed this receptor.

  10. Long-Term Effects of Intracerebroventricular Streptozotocin Treatment on Adult Neurogenesis in the Rat Hippocampus.

    PubMed

    Sun, Ping; Knezovic, Ana; Parlak, Milena; Cuber, Jacqueline; Karabeg, Margherita M; Deckert, Jürgen; Riederer, Peter; Hua, Qian; Salkovic-Petrisic, Melita; Schmitt, Angelika G

    2015-01-01

    Altered adult hippocampal neurogenesis (AN) plays a role in the etiopathology of Alzheimer's disease (AD), a disorder characterized by a progressive loss of memory and spatial orientation impairment. Diabetes is shown to be one risk factor for the development of the sporadic form of AD (sAD), which affects >95% of AD patients. Streptozotocin intracerebroventricularily (STZ icv) treated rats, which develop an insulin-resistant brain state and learning and memory deficits preceding amyloid beta and tau pathology, may act as an appropriate animal model for sAD. The goal of our quantitative immunohistochemistry study was to compare short-term (1 month) and long-term (3 months) effects of STZ icv treatment on different AN stages. Applying MCM2 antibodies we quantified cell (e.g. stem cell) proliferation, by the use of NeuroD and DCX antibodies we analyzed immature neurons. BrdU incorporation with approximately 27 days of survival before sacrifice allowed us to quantify and identify surviving newborn cells. Performing co-localization studies with antibodies detecting BrdU and cell-type specific markers we could confirm that STZ treatment does not affect the differentiation fate of newly generated cells. Whereas STZ icv treatment does not seem to considerably influence cell proliferation over a shortterm period (1 month), in the long-term (3 months) it significantly decreased generation of immature and mature neurons. This reduction seen after 3 months was specific for the septal hippocampus, discussed to be important for spatial learning. Moreover, AN changes display the same timeline as the development of amyloid beta pathology in this animal model of sAD.

  11. Melatonin attenuates methamphetamine-induced inhibition of neurogenesis in the adult mouse hippocampus: An in vivo study.

    PubMed

    Singhakumar, Rachen; Boontem, Parichart; Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Mukda, Sujira; Chetsawang, Banthit; Govitrapong, Piyarat

    2015-10-01

    Methamphetamine (METH), a highly addictive psychostimulant drug, is known to exert neurotoxic effects to the dopaminergic neural system. Long-term METH administration impairs brain functions such as cognition, learning and memory. Newly born neurons in the dentate gyrus of the hippocampus play an important role in spatial learning and memory. Previous in vitro studies have shown that METH inhibits cell proliferation and neurogenesis in the hippocampus. On the other hand, melatonin, a major indole secreted by the pineal gland, enhances neurogenesis in both the subventricular zone and dentate gyrus. In this study, adult C57BL/6 mice were used to study the beneficial effects of melatonin on METH-induced alterations in neurogenesis and post-synaptic proteins related to learning and memory functions in the hippocampus. The results showed that METH caused a decrease in neuronal phenotypes as determined by the expressions of nestin, doublecortin (DCX) and beta-III tubulin while causing an increase in glial fibrillary acidic protein (GFAP) expression. Moreover, METH inhibited mitogen-activated protein kinase (MAPK) signaling activity and altered expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A and NR2B as well as calcium/calmodulin-dependent protein kinase II (CaMKII). These effects could be attenuated by melatonin pretreatment. In conclusion, melatonin prevented the METH-induced reduction in neurogenesis, increase in astrogliogenesis and alteration of NMDA receptor subunit expression. These findings may indicate the beneficial effects of melatonin on the impairment of learning and memory caused by METH.

  12. The circadian molecular clock regulates adult hippocampal neurogenesis by controlling the timing of cell-cycle entry and exit.

    PubMed

    Bouchard-Cannon, Pascale; Mendoza-Viveros, Lucia; Yuen, Andrew; Kærn, Mads; Cheng, Hai-Ying M

    2013-11-27

    The subgranular zone (SGZ) of the adult hippocampus contains a pool of quiescent neural progenitor cells (QNPs) that are capable of entering the cell cycle and producing newborn neurons. The mechanisms that control the timing and extent of adult neurogenesis are not well understood. Here, we show that QNPs of the adult SGZ express molecular-clock components and proliferate in a rhythmic fashion. The clock proteins PERIOD2 and BMAL1 are critical for proper control of neurogenesis. The absence of PERIOD2 abolishes the gating of cell-cycle entrance of QNPs, whereas genetic ablation of bmal1 results in constitutively high levels of proliferation and delayed cell-cycle exit. We use mathematical model simulations to show that these observations may arise from clock-driven expression of a cell-cycle inhibitor that targets the cyclin D/Cdk4-6 complex. Our findings may have broad implications for the circadian clock in timing cell-cycle events of other stem cell populations throughout the body.

  13. Neuropeptides and hippocampal neurogenesis.

    PubMed

    Zaben, M J; Gray, W P

    2013-12-01

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

  14. Deficits in Adult Neurogenesis, Contextual Fear Conditioning, and Spatial Learning in a Gfap Mutant Mouse Model of Alexander Disease

    PubMed Central

    Paylor, Richard; Messing, Albee

    2013-01-01

    Glial fibrillary acidic protein (GFAP) is the major intermediate filament of mature astrocytes in the mammalian CNS. Dominant gain of function mutations in GFAP lead to the fatal neurodegenerative disorder, Alexander disease (AxD), which is characterized by cytoplasmic protein aggregates known as Rosenthal fibers along with variable degrees of leukodystrophy and intellectual disability. The mechanisms by which mutant GFAP leads to these pleiotropic effects are unknown. In addition to astrocytes, GFAP is also expressed in other cell types, particularly neural stem cells that form the reservoir supporting adult neurogenesis in the hippocampal dentate gyrus and subventricular zone of the lateral ventricles. Here, we show that mouse models of AxD exhibit significant pathology in GFAP-positive radial glia-like cells in the dentate gyrus, and suffer from deficits in adult neurogenesis. In addition, they display impairments in contextual learning and spatial memory. This is the first demonstration of cognitive phenotypes in a model of primary astrocyte disease. PMID:24259590

  15. BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis

    PubMed Central

    Kuipers, Sjoukje D.; Trentani, Andrea; Tiron, Adrian; Mao, Xiaosong; Kuhl, Dietmar; Bramham, Clive R.

    2016-01-01

    Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus. PMID:26888068

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

    PubMed Central

    Plümpe, Tobias; Ehninger, Dan; Steiner, Barbara; Klempin, Friederike; Jessberger, Sebastian; Brandt, Moritz; Römer, Benedikt; Rodriguez, Gerardo Ramirez; Kronenberg, Golo; Kempermann, Gerd

    2006-01-01

    Background In the course of adult hippocampal neurogenesis most regulation takes place during the phase of doublecortin (DCX) expression, either as pro-proliferative effect on precursor cells or as survival-promoting effect on postmitotic cells. We here obtained quantitative data about the proliferative population and the dynamics of postmitotic dendrite development during the period of DCX expression. The question was, whether any indication could be obtained that the initiation of dendrite development is timely bound to the exit from the cell cycle. Alternatively, the temporal course of morphological maturation might be subject to additional regulatory events. Results We found that (1) 20% of the DCX population were precursor cells in cell cycle, whereas more than 70% were postmitotic, (2) the time span until newborn cells had reached the most mature stage associated with DCX expression varied between 3 days and several weeks, (3) positive or negative regulation of precursor cell proliferation did not alter the pattern and dynamics of dendrite development. Dendrite maturation was largely independent of close contacts to astrocytes. Conclusion These data imply that dendrite maturation of immature neurons is initiated at varying times after cell cycle exit, is variable in duration, and is controlled independently of the regulation of precursor cell proliferation. We conclude that in addition to the major regulatory events in cell proliferation and selective survival, additional micro-regulatory events influence the course of adult hippocampal neurogenesis. PMID:17105671

  17. Transcranial Direct Current Stimulation Modulates Neurogenesis and Microglia Activation in the Mouse Brain

    PubMed Central

    Pikhovych, Anton; Stolberg, Nina Paloma; Jessica Flitsch, Lea; Walter, Helene Luise; Graf, Rudolf; Fink, Gereon Rudolf; Schroeter, Michael

    2016-01-01

    Transcranial direct current stimulation (tDCS) has been suggested as an adjuvant tool to promote recovery of function after stroke, but the mechanisms of its action to date remain poorly understood. Moreover, studies aimed at unraveling those mechanisms have essentially been limited to the rat, where tDCS activates resident microglia as well as endogenous neural stem cells. Here we studied the effects of tDCS on microglia activation and neurogenesis in the mouse brain. Male wild-type mice were subjected to multisession tDCS of either anodal or cathodal polarity; sham-stimulated mice served as control. Activated microglia in the cerebral cortex and neuroblasts generated in the subventricular zone as the major neural stem cell niche were assessed immunohistochemically. Multisession tDCS at a sublesional charge density led to a polarity-dependent downregulation of the constitutive expression of Iba1 by microglia in the mouse cortex. In contrast, both anodal and, to an even greater extent, cathodal tDCS induced neurogenesis from the subventricular zone. Data suggest that tDCS elicits its action through multifacetted mechanisms, including immunomodulation and neurogenesis, and thus support the idea of using tDCS to induce regeneration and to promote recovery of function. Furthermore, data suggest that the effects of tDCS may be animal- and polarity-specific. PMID:27403166

  18. Hypocellularity in the Murine Model for Down Syndrome Ts65Dn Is Not Affected by Adult Neurogenesis

    PubMed Central

    López-Hidalgo, Rosa; Ballestín, Raul; Vega, Jessica; Blasco-Ibáñez, José M.; Crespo, Carlos; Gilabert-Juan, Javier; Nácher, Juan; Varea, Emilio

    2016-01-01

    Down syndrome (DS) is caused by the presence of an extra copy of the chromosome 21 and it is the most common aneuploidy producing intellectual disability. Neural mechanisms underlying this alteration may include defects in the formation of neuronal networks, information processing and brain plasticity. The murine model for DS, Ts65Dn, presents reduced adult neurogenesis. This reduction has been suggested to underlie the hypocellularity of the hippocampus as well as the deficit in olfactory learning in the Ts65Dn mice. Similar alterations have also been observed in individuals with DS. To determine whether the impairment in adult neurogenesis is, in fact, responsible for the hypocellularity in the hippocampus and physiology of the olfactory bulb, we have analyzed cell proliferation and neuronal maturation in the two major adult neurogenic niches in the Ts656Dn mice: the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ). Additionally, we carried out a study to determine the survival rate and phenotypic fate of newly generated cells in both regions, injecting 5′BrdU and sacrificing the mice 21 days later, and analyzing the number and phenotype of the remaining 5′BrdU-positive cells. We observed a reduction in the number of proliferating (Ki67 positive) cells and immature (doublecortin positive) neurons in the subgranular and SVZ of Ts65Dn mice, but we did not observe changes in the number of surviving cells or in their phenotype. These data correlated with a lower number of apoptotic cells (cleaved caspase 3 positive) in Ts65Dn. We conclude that although adult Ts65Dn mice have a lower number of proliferating cells, it is compensated by a lower level of cell death. This higher survival rate in Ts65Dn produces a final number of mature cells similar to controls. Therefore, the reduction of adult neurogenesis cannot be held responsible for the neuronal hypocellularity in the hippocampus or for the olfactory learning deficit of Ts65Dn mice

  19. Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease

    PubMed Central

    Rodríguez, José J.; Jones, Victoria C.; Tabuchi, Masashi; Allan, Stuart M.; Knight, Elysse M.; LaFerla, Frank M.; Oddo, Salvatore; Verkhratsky, Alexei

    2008-01-01

    It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (β-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of β-amyloid plaques and an increase in the number of β-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest

  20. Shopping. An Adult Competency Education Learning Module.

    ERIC Educational Resources Information Center

    Wallace, Virginia

    This instructional unit on shopping is one of six Adult Competency Education Learning Modules designed for use in a program of competency-based instruction for students with reading levels of 4.0-7.5. It is self-contained and designed for immediate classroom use. Each module is a complete instructional package, including Adult Performance Level…

  1. Career Education for Adults: Consumer Economics Module.

    ERIC Educational Resources Information Center

    Auburn Univ., AL. Dept. of Vocational and Adult Education.

    An outgrowth of State-sponsored institutes conducted by Auburn University, Alabama, to produce career education teaching modules for adults, the consumer economics module is one of five field-tested curriculum guides adopted from findings of the nationally oriented Adult Performance Level Study conducted at the University of Texas. The primary…

  2. Short-term calorie restriction enhances adult hippocampal neurogenesis and remote fear memory in a Ghsr-dependent manner

    PubMed Central

    Hornsby, Amanda K.E.; Redhead, Yushi T.; Rees, Daniel J.; Ratcliff, Michael S.G.; Reichenbach, Alex; Wells, Timothy; Francis, Lewis; Amstalden, Katia; Andrews, Zane B.; Davies, Jeffrey S.

    2016-01-01

    The beneficial effects of calorie restriction (CR) have been described at both organismal and cellular levels in multiple organs. However, our understanding of the causal mediators of such hormesis is poorly understood, particularly in the context of higher brain function. Here, we show that the receptor for the orexigenic hormone acyl-ghrelin, the growth hormone secretagogue receptor (Ghsr), is enriched in the neurogenic niche of the hippocampal dentate gyrus (DG). Acute elevation of acyl-ghrelin levels by injection or by overnight CR, increased DG levels of the neurogenic transcription factor, Egr-1. Two weeks of CR increased the subsequent number of mature newborn neurons in the DG of adult wild-type but not Ghsr−/− mice. CR wild-type mice also showed improved remote contextual fear memory. Our findings suggest that Ghsr mediates the beneficial effects of CR on enhancing adult hippocampal neurogenesis and memory. PMID:26460782

  3. Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse

    PubMed Central

    García-Fuster, M. Julia; Perez, Javier A.; Clinton, Sarah M.; Watson, Stanley J; Akil, Huda

    2014-01-01

    Hippocampal plasticity (e.g., neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and BrdU for older cells born prior to sensitization. Results show that: (1) bHRs exhibited greater psychomotor response to cocaine than bLRs. (2) Acute cocaine did not alter cell proliferation in bLR/bHR rats. (3) Chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence. (4) Neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype. (5) Cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine. (6) Cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR versus bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization. PMID:20104651

  4. Interactions with the young down-regulate adult olfactory neurogenesis and enhance the maturation of olfactory neuroblasts in sheep mothers

    PubMed Central

    Brus, Maïna; Meurisse, Maryse; Keller, Matthieu; Lévy, Frédéric

    2014-01-01

    New neurons are continuously added in the dentate gyrus (DG) and the olfactory bulb of mammalian brain. While numerous environmental factors controlling survival of newborn neurons have been extensively studied, regulation by social interactions is less documented. We addressed this question by investigating the influence of parturition and interactions with the young on neurogenesis in sheep mothers. Using Bromodeoxyuridine, a marker of cell division, in combination with markers of neuronal maturation, the percentage of neuroblasts and new mature neurons in the olfactory bulb and the DG was compared between groups of parturient ewes which could interact or not with their lamb, and virgins. In addition, a morphological analysis was performed by measuring the dendritic arbor of neuroblasts in both structures. We showed that the postpartum period was associated with a decrease in olfactory and hippocampal adult neurogenesis. In the olfactory bulb, the suppressive effect on neuroblasts was dependent on interactions with the young whereas in the DG the decrease in new mature neurons was associated with parturition. In addition, dendritic length and number of nodes of neuroblasts were significantly enhanced by interactions with the lamb in the olfactory bulb but not in the DG. Because interactions with the young involved learning of the olfactory signature of the lamb, we hypothesize that this learning is associated with a down-regulation in olfactory neurogenesis and an enhancement of olfactory neuroblast maturation. Our assumption is that fewer new neurons decrease cell competition in the olfactory bulb and enhance maturation of those new neurons selected to participate in the learning of the young odor. PMID:24600367

  5. Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice.

    PubMed

    Nishijima, Takeshi; Llorens-Martín, María; Tejeda, Gonzalo Sanchez; Inoue, Koshiro; Yamamura, Yuhei; Soya, Hideaki; Trejo, José Luis; Torres-Alemán, Ignacio

    2013-05-15

    While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4 weeks old) were assigned to one of the following groups, and housed until 21 weeks old; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), housed in a running wheel cage; and (3) exercise-no exercise (Ex-noEx), housed in a running wheel cage for 8 weeks and subsequently in a standard cage. Behavioral evaluations suggested that Ex-noEx mice were more anxious compared to noEx control mice, but no differences were found in depression-like behavior. The number of BrdU-labeled surviving cells in the dentate gyrus was significantly higher in Ex but not in Ex-noEx compared with noEx, indicating that the facilitative effects of exercise on cell survival are reversible. Surprisingly, the ratio of differentiation of BrdU-positive cells to doublecortin-positive immature neurons was significantly lower in Ex-noEx compared to the other groups, suggesting that the cessation of wheel running impairs an important component of hippocampal neurogenesis in mice. These results indicate that hippocampal adaptation to physical inactivity is not simply a return to the conditions present in sedentary mice. As the impaired neurogenesis is predicted to increase a vulnerability to stress-induced mood disorders, the reduction of physical activity may contribute to a greater risk of these disorders.

  6. Differential expression of id genes and their potential regulator znf238 in zebrafish adult neural progenitor cells and neurons suggests distinct functions in adult neurogenesis.

    PubMed

    Diotel, Nicolas; Beil, Tanja; Strähle, Uwe; Rastegar, Sepand

    2015-01-01

    Teleost fish display a remarkable ability to generate new neurons and to repair brain lesions during adulthood. They are, therefore, a very popular model to investigate the molecular mechanisms of constitutive and induced neurogenesis in adult vertebrates. In this study, we investigated the expression patterns of inhibitor of DNA binding (id) genes and of their potential transcriptional repressor, znf238, in the whole brain of adult zebrafish. We show that while id1 is exclusively expressed in ventricular cells in the whole brain, id2a, id3 and id4 genes are expressed in broader areas. Interestingly, znf238 was also detected in these regions, its expression overlapping with id2a, id3 and id4 expression. Further detailed characterization of the id-expressing cells demonstrated that (a) id1 is expressed in type 1 and type 2 neural progenitors as previously published, (b) id2a in type 1, 2 and 3 neural progenitors, (c) id3 in type 3 neural progenitors and (d) id4 in postmitotic neurons. Our data provide a detailed map of id and znf238 expression in the brain of adult zebrafish, supplying a framework for studies of id genes function during adult neurogenesis and brain regeneration in the zebrafish.

  7. The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells.

    PubMed

    Gao, Zhengliang; Ure, Kerstin; Ding, Peiguo; Nashaat, Mostafa; Yuan, Laura; Ma, Jing; Hammer, Robert E; Hsieh, Jenny

    2011-06-29

    Transcriptional regulation is a critical mechanism in the birth, specification, and differentiation of granule neurons in the adult hippocampus. One of the first negative-acting transcriptional regulators implicated in vertebrate development is repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF)--thought to regulate hundreds of neuron-specific genes--yet its function in the adult brain remains elusive. Here we report that REST/NRSF is required to maintain the adult neural stem cell (NSC) pool and orchestrate stage-specific differentiation. REST/NRSF recruits CoREST and mSin3A corepressors to stem cell chromatin for the regulation of pro-neuronal target genes to prevent precocious neuronal differentiation in cultured adult NSCs. Moreover, mice lacking REST/NRSF specifically in NSCs display a transient increase in adult neurogenesis that leads to a loss in the neurogenic capacity of NSCs and eventually diminished granule neurons. Our work identifies REST/NRSF as a master negative regulator of adult NSC differentiation and offers a potential molecular target for neuroregenerative approaches. PMID:21715642

  8. 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

  9. Microglial CX3CR1 promotes adult neurogenesis by inhibiting Sirt 1/p65 signaling independent of CX3CL1.

    PubMed

    Sellner, Sabine; Paricio-Montesinos, Ricardo; Spieß, Alena; Masuch, Annette; Erny, Daniel; Harsan, Laura A; Elverfeldt, Dominik V; Schwabenland, Marius; Biber, Knut; Staszewski, Ori; Lira, Sergio; Jung, Steffen; Prinz, Marco; Blank, Thomas

    2016-01-01

    Homo and heterozygote cx3cr1 mutant mice, which harbor a green fluorescent protein (EGFP) in their cx3cr1 loci, represent a widely used animal model to study microglia and peripheral myeloid cells. Here we report that microglia in the dentate gyrus (DG) of cx3cr1 (-/-) mice displayed elevated microglial sirtuin 1 (SIRT1) expression levels and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) p65 activation, despite unaltered morphology when compared to cx3cr1 (+/-) or cx3cr1 (+/+) controls. This phenotype was restricted to the DG and accompanied by reduced adult neurogenesis in cx3cr1 (-/-) mice. Remarkably, adult neurogenesis was not affected by the lack of the CX3CR1-ligand, fractalkine (CX3CL1). Mechanistically, pharmacological activation of SIRT1 improved adult neurogenesis in the DG together with an enhanced performance of cx3cr1 (-/-) mice in a hippocampus-dependent learning and memory task. The reverse condition was induced when SIRT1 was inhibited in cx3cr1 (-/-) mice, causing reduced adult neurogenesis and lowered hippocampal cognitive abilities. In conclusion, our data indicate that deletion of CX3CR1 from microglia under resting conditions modifies brain areas with elevated cellular turnover independent of CX3CL1. PMID:27639555

  10. Severe instead of mild hyperglycemia inhibits neurogenesis in the subventricular zone of adult rats after transient focal cerebral ischemia.

    PubMed

    Tan, S; Zhi, P K; Luo, Z K; Shi, J

    2015-09-10

    Accumulated evidence suggests that enhanced neurogenesis stimulated by ischemic injury contributes to stroke outcome. However, it is unclear whether hyperglycemia, which is frequently tested positive in patients with acute ischemic stroke, influences stroke-induced neurogenesis. The aim of the present study is to examine the effect of hyperglycemia on stroke-induced neurogenesis in a rat model of transient focal cerebral ischemia. For this purpose, adult male Sprague-Dawley rats (220-250 g) were subjected to 90 min of middle cerebral artery occlusion (MCAO). Glucose was administered during ischemia to produce target blood levels ranging from 4.83 ± 0.94 mM (normoglycemia) to 20.76 ± 1.56 mM. To label proliferating cells in ischemic ipsilateral subventricular zone (SVZ) of lateral ventricles, 5'-bromo-2'-deoxyuridine (BrdU) was injected 24h after MCAO. Brains were harvested 2h post-BrdU to evaluate the effects of hyperglycemia on infarct volume and SVZ cell proliferation. Rats that were severely hyperglycemic (19.26 ± 1.48 mM to 20.76 ± 1.56 mM) during ischemia had 24.26% increase in infarct volume (P<0.05) and more serious neurological function deficits (P<0.05). The severe hyperglycemic rats also showed dramatically decreased proliferation of neural stem/progenitor cells (NSPCs) (P<0.05) and down-regulation of the phosphorylation of cyclic-AMP response element-binding protein (pCREB) (P<0.05)and brain-derived neurotrophic factor (BDNF) (P<0.05) in ipsilateral SVZ. But the above-mentioned detrimental effects were not observed in rats that were rendered with mild hyperglycemia (9.43 ± 1.39-10.13 ± 1.24 mM). Our findings indicate that severe instead of mild hyperglycemia exacerbates ischemic injury and inhibits stroke-induced SVZ neurogenesis by a mechanism involving suppression of CREB and BDNF signaling.

  11. Inhibition of the histone demethylase Kdm5b promotes neurogenesis and derepresses Reln (reelin) in neural stem cells from the adult subventricular zone of mice.

    PubMed

    Zhou, Qiong; Obana, Edwin A; Radomski, Kryslaine L; Sukumar, Gauthaman; Wynder, Christopher; Dalgard, Clifton L; Doughty, Martin L

    2016-02-15

    The role of epigenetic regulators in the control of adult neurogenesis is largely undefined. We show that the histone demethylase enzyme Kdm5b (Jarid1b) negatively regulates neurogenesis from adult subventricular zone (SVZ) neural stem cells (NSCs) in culture. shRNA-mediated depletion of Kdm5b in proliferating adult NSCs decreased proliferation rates and reduced neurosphere formation in culture. When transferred to differentiation culture conditions, Kdm5b-depleted adult NSCs migrated from neurospheres with increased velocity. Whole-genome expression screening revealed widespread transcriptional changes with Kdm5b depletion, notably the up-regulation of reelin (Reln), the inhibition of steroid biosynthetic pathway component genes and the activation of genes with intracellular transport functions in cultured adult NSCs. Kdm5b depletion increased extracellular reelin concentration in the culture medium and increased phosphorylation of the downstream reelin signaling target Disabled-1 (Dab1). Sequestration of extracellular reelin with CR-50 reelin-blocking antibodies suppressed the increase in migratory velocity of Kdm5b-depleted adult NSCs. Chromatin immunoprecipitation revealed that Kdm5b is present at the proximal promoter of Reln, and H3K4me3 methylation was increased at this locus with Kdm5b depletion in differentiating adult NSCs. Combined the data suggest Kdm5b negatively regulates neurogenesis and represses Reln in neural stem cells from the adult SVZ.

  12. Enhanced habit-based learning and decreased neurogenesis in the adult hippocampus in a murine model of chronic social stress.

    PubMed

    Ferragud, A; Haro, A; Sylvain, A; Velázquez-Sánchez, C; Hernández-Rabaza, V; Canales, J J

    2010-06-26

    Stress can induce preferential engagement of habit learning mediated by the basal ganglia, relative to learning that involves complex spatial associations contributed by the hippocampal formation. We explored in mice the influence that chronic episodes of social stress exert on the selection of cognitive/spatial vs. habit-based learning strategies. Male mice were exposed to repeated episodes of social confrontation and were categorized as dominant, subordinate or undetermined according to quantitative ethologically relevant parameters of aggression. Mice were then trained in a conditional discrimination task in the T-maze in the presence of allocentric cues until five correct choices were made. The T-maze was then turned 180 degrees and mice were categorized as "cue-learners" or "place-learners" on the basis of their first response in the probe test. Mice showed a graded preference for place vs. cue learning strategies depending on their social categorization (control>undetermined>dominant>subordinate), which ranged from 55% in controls to only 10% in subordinate mice. The response of subordinate mice differed significantly from controls. Hippocampal neurogenesis was studied in the different groups of mice. In keeping with the tendency to engage habit learning, 2,5-bromodeoxyuridine (BrdU) incorporation in the DG was reduced in mice that experienced agonistic encounters, and so was the expression of doublecortin, a marker for immature neurons. These observations suggest that chronic social stress impairs neurogenesis in the adult hippocampus, weakens spatial learning and strengthens habit-like responses.

  13. Only watching others making their experiences is insufficient to enhance adult neurogenesis and water maze performance in mice

    PubMed Central

    Iggena, Deetje; Klein, Charlotte; Garthe, Alexander; Winter, York; Kempermann, Gerd; Steiner, Barbara

    2015-01-01

    In the context of television consumption and its opportunity costs the question arises how far experiencing mere representations of the outer world would have the same neural and cognitive consequences than actively interacting with that environment. Here we demonstrate that physical interaction and direct exposition are essential for the beneficial effects of environmental enrichment. In our experiment, the mice living in a simple standard cage placed in the centre of a large enriched environment only indirectly experiencing the stimulus-rich surroundings (IND) did not display increased adult hippocampal neurogenesis. In contrast, the mice living in and directly experiencing the surrounding enriched environment (DIR) and mice living in a similar enriched cage containing an uninhabited inner cage (ENR) showed enhanced neurogenesis compared to mice in control conditions (CTR). Similarly, the beneficial effects of environmental enrichment on learning performance in the Morris Water maze depended on the direct interaction of the individual with the enrichment. In contrast, indirectly experiencing a stimulus-rich environment failed to improve memory functions indicating that direct interaction and activity within the stimulus-rich environment are necessary to induce structural and functional changes in the hippocampus. PMID:26369255

  14. Postnatal day 7 ethanol treatment causes persistent reductions in adult mouse brain volume and cortical neurons with sex specific effects on neurogenesis.

    PubMed

    Coleman, Leon G; Oguz, Ipek; Lee, Joohwi; Styner, Martin; Crews, Fulton T

    2012-09-01

    Ethanol treatment on postnatal day seven (P7) causes robust brain cell death and is a model of late gestational alcohol exposure (Ikonomidou et al., 2000). To investigate the long-term effects of P7 ethanol treatment on adult brain, mice received either two doses of saline or ethanol on P7 (2.5 g/kg, s.c., 2 h apart) and were assessed as adults (P82) for brain volume (using postmortem MRI) and cellular architecture (using immunohistochemistry). Adult mice that received P7 ethanol had reduced MRI total brain volume (4%) with multiple brain regions being reduced in both males and females. Immunohistochemistry indicated reduced frontal cortical parvalbumin immunoreactive (PV + IR) interneurons (18-33%) and reduced Cux1+IR layer II pyramidal neurons (15%) in both sexes. Interestingly, markers of adult hippocampal neurogenesis differed between sexes, with only ethanol treated males showing increased doublecortin and Ki67 expression (52 and 57% respectively) in the dentate gyrus, consistent with increased neurogenesis compared to controls. These findings suggest that P7 ethanol treatment causes persistent reductions in adult brain volume and frontal cortical neurons in both males and females. Increased adult neurogenesis in males, but not females, is consistent with differential adaptive responses to P7 ethanol toxicity between the sexes. One day of ethanol exposure, e.g. P7, causes persistent adult brain dysmorphology.

  15. A Distinct Population of Microglia Supports Adult Neurogenesis in the Subventricular Zone

    PubMed Central

    Ribeiro Xavier, Anna L.; Kress, Benjamin T.; Goldman, Steven A.; Lacerda de Menezes, João R.

    2015-01-01

    Microglia are involved in synaptic pruning both in development and in the mature CNS. In this study, we investigated whether microglia might further contribute to circuit plasticity by modulating neuronal recruitment from the neurogenic subventricular zone (SVZ) of the adult mouse striatum. We found that microglia residing in the SVZ and adjacent rostral migratory stream (RMS) comprise a morphologically and antigenically distinct phenotype of immune effectors. Whereas exhibiting characteristics of alternatively activated microglia, the SVZ/RMS microglia were clearly distinguished by their low expression of purinoceptors and lack of ATP-elicitable chemotaxis. Furthermore, the in vivo depletion of these microglia hampered the survival and migration of newly generated neuroblasts through the RMS to the olfactory bulb. SVZ and RMS microglia thus appear to comprise a functionally distinct class that is selectively adapted to the support and direction of neuronal integration into the olfactory circuitry. Therefore, this unique microglial subpopulation may serve as a novel target with which to modulate cellular addition from endogenous neural stem and progenitor cells of the adult brain. SIGNIFICANCE STATEMENT Microglial cells are a specialized population of macrophages in the CNS, playing key roles as immune mediators. As integral components in the CNS, the microglia stand out for using the same mechanisms, phagocytosis and cytochemokine release, to promote homeostasis, synaptic pruning, and neural circuitry sculpture. Here, we addressed microglial functions in the subventricular zone (SVZ), the major postnatal neurogenic niche. Our results depict microglia as a conspicuous component of SVZ and its anterior extension, the rostral migratory stream, a pathway used by neuroblasts during their transit toward olfactory bulb layers. In addition to other unique populations residing in the SVZ niche, microglia display distinct morphofunctional properties that boost neuronal

  16. Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice.

    PubMed

    Yun, Sanghee; Donovan, Michael H; Ross, Michele N; Richardson, Devon R; Reister, Robin; Farnbauch, Laure A; Fischer, Stephanie J; Riethmacher, Dieter; Gershenfeld, Howard K; Lagace, Diane C; Eisch, Amelia J

    2016-01-01

    Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient-rather than permanent-inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12-30 days post-TAM displayed indices of a stress-induced anxiety phenotype-longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype-longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety and a

  17. Stress-Induced Anxiety- and Depressive-Like Phenotype Associated with Transient Reduction in Neurogenesis in Adult Nestin-CreERT2/Diphtheria Toxin Fragment A Transgenic Mice

    PubMed Central

    Yun, Sanghee; Donovan, Michael H.; Ross, Michele N.; Richardson, Devon R.; Reister, Robin; Farnbauch, Laure A.; Fischer, Stephanie J.; Riethmacher, Dieter; Gershenfeld, Howard K.; Lagace, Diane C.; Eisch, Amelia J.

    2016-01-01

    Depression and anxiety involve hippocampal dysfunction, but the specific relationship between these mood disorders and adult hippocampal dentate gyrus neurogenesis remains unclear. In both humans with MDD and rodent models of depression, administration of antidepressants increases DG progenitor and granule cell number, yet rodents with induced ablation of DG neurogenesis typically do not demonstrate depressive- or anxiety-like behaviors. The conflicting data may be explained by the varied duration and degree to which adult neurogenesis is reduced in different rodent neurogenesis ablation models. In order to test this hypothesis we examined how a transient–rather than permanent–inducible reduction in neurogenesis would alter depressive- and anxiety-like behaviors. Transgenic Nestin-CreERT2/floxed diphtheria toxin fragment A (DTA) mice (Cre+DTA+) and littermates (Cre+DTA-; control) were given tamoxifen (TAM) to induce recombination and decrease nestin-expressing stem cells and their progeny. The decreased neurogenesis was transient: 12 days post-TAM Cre+DTA+ mice had fewer DG proliferating Ki67+ cells and fewer DCX+ neuroblasts/immature neurons relative to control, but 30 days post-TAM Cre+DTA+ mice had the same DCX+ cell number as control. This ability of DG neurogenesis to recover after partial ablation also correlated with changes in behavior. Relative to control, Cre+DTA+ mice tested between 12–30 days post-TAM displayed indices of a stress-induced anxiety phenotype–longer latency to consume highly palatable food in the unfamiliar cage in the novelty-induced hypophagia test, and a depression phenotype–longer time of immobility in the tail suspension test, but Cre+DTA+ mice tested after 30 days post-TAM did not. These findings suggest a functional association between adult neurogenesis and stress induced anxiety- and depressive-like behaviors, where induced reduction in DCX+ cells at the time of behavioral testing is coupled with stress-induced anxiety

  18. p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis.

    PubMed

    Talos, F; Abraham, A; Vaseva, A V; Holembowski, L; Tsirka, S E; Scheel, A; Bode, D; Dobbelstein, M; Brück, W; Moll, U M

    2010-12-01

    The p53 family member p73 is essential for brain development, but its precise role and scope remain unclear. Global p73 deficiency determines an overt and highly penetrant brain phenotype marked by cortical hypoplasia with ensuing hydrocephalus and hippocampal dysgenesis. The ΔNp73 isoform is known to function as a prosurvival factor of mature postmitotic neurons. In this study, we define a novel essential role of p73 in the regulation of the neural stem cell compartment. In both embryonic and adult neurogenesis, p73 has a critical role in maintaining an adequate neurogenic pool by promoting self-renewal and proliferation and inhibiting premature senescence of neural stem and early progenitor cells. Thus, products of the p73 gene locus are essential maintenance factors in the central nervous system, whose broad action stretches across the entire differentiation arch from stem cells to mature postmitotic neurons.

  19. Regulation of Injury-Induced Neurogenesis by Nitric Oxide

    PubMed Central

    Carreira, Bruno P.; Carvalho, Caetana M.; Araújo, Inês M.

    2012-01-01

    The finding that neural stem cells (NSCs) are able to divide, migrate, and differentiate into several cellular types in the adult brain raised a new hope for restorative neurology. Nitric oxide (NO), a pleiotropic signaling molecule in the central nervous system (CNS), has been described to be able to modulate neurogenesis, acting as a pro- or antineurogenic agent. Some authors suggest that NO is a physiological inhibitor of neurogenesis, while others described NO to favor neurogenesis, particularly under inflammatory conditions. Thus, targeting the NO system may be a powerful strategy to control the formation of new neurons. However, the exact mechanisms by which NO regulates neural proliferation and differentiation are not yet completely clarified. In this paper we will discuss the potential interest of the modulation of the NO system for the treatment of neurodegenerative diseases or other pathological conditions that may affect the CNS. PMID:22997523

  20. The Adult Ventricular-Subventricular Zone (V-SVZ) and Olfactory Bulb (OB) Neurogenesis.

    PubMed

    Lim, Daniel A; Alvarez-Buylla, Arturo

    2016-05-02

    A large population of neural stem/precursor cells (NSCs) persists in the ventricular-subventricular zone (V-SVZ) located in the walls of the lateral brain ventricles. V-SVZ NSCs produce large numbers of neuroblasts that migrate a long distance into the olfactory bulb (OB) where they differentiate into local circuit interneurons. Here, we review a broad range of discoveries that have emerged from studies of postnatal V-SVZ neurogenesis: the identification of NSCs as a subpopulation of astroglial cells, the neurogenic lineage, new mechanisms of neuronal migration, and molecular regulators of precursor cell proliferation and migration. It has also become evident that V-SVZ NSCs are regionally heterogeneous, with NSCs located in different regions of the ventricle wall generating distinct OB interneuron subtypes. Insights into the developmental origins and molecular mechanisms that underlie the regional specification of V-SVZ NSCs have also begun to emerge. Other recent studies have revealed new cell-intrinsic molecular mechanisms that enable lifelong neurogenesis in the V-SVZ. Finally, we discuss intriguing differences between the rodent V-SVZ and the corresponding human brain region. The rapidly expanding cellular and molecular knowledge of V-SVZ NSC biology provides key insights into postnatal neural development, the origin of brain tumors, and may inform the development regenerative therapies from cultured and endogenous human neural precursors.

  1. Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

    PubMed

    Workman, Joanna L; Raineki, Charlis; Weinberg, Joanne; Galea, Liisa A M

    2015-07-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis. PMID:25900594

  2. Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

    PubMed

    Workman, Joanna L; Raineki, Charlis; Weinberg, Joanne; Galea, Liisa A M

    2015-07-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis.

  3. Short-Term Environmental Enrichment Enhances Adult Neurogenesis, Vascular Network and Dendritic Complexity in the Hippocampus of Type 1 Diabetic Mice

    PubMed Central

    Beauquis, Juan; Roig, Paulina; De Nicola, Alejandro F.; Saravia, Flavia

    2010-01-01

    Background Several brain disturbances have been described in association to type 1 diabetes in humans. In animal models, hippocampal pathological changes were reported together with cognitive deficits. The exposure to a variety of environmental stimuli during a certain period of time is able to prevent brain alterations and to improve learning and memory in conditions like stress, aging and neurodegenerative processes. Methodology/Principal Findings We explored the modulation of hippocampal alterations in streptozotocin-induced type 1 diabetic mice by environmental enrichment. In diabetic mice housed in standard conditions we found a reduction of adult neurogenesis in the dentate gyrus, decreased dendritic complexity in CA1 neurons and a smaller vascular fractional area in the dentate gyrus, compared with control animals in the same housing condition. A short exposure -10 days- to an enriched environment was able to enhance proliferation, survival and dendritic arborization of newborn neurons, to recover dendritic tree length and spine density of pyramidal CA1 neurons and to increase the vascular network of the dentate gyrus in diabetic animals. Conclusions/Significance The environmental complexity seems to constitute a strong stimulator competent to rescue the diabetic brain from neurodegenerative progression. PMID:21085588

  4. Prenatal exposure to alcohol and 3,4-methylenedioxymethamphetamine (ecstasy) alters adult hippocampal neurogenesis and causes enduring memory deficits.

    PubMed

    Canales, Juan J; Ferrer-Donato, Agueda

    2014-01-01

    Recreational drug use among pregnant women is a source of concern due to potential harmful effects of drug exposure on prenatal and infant development. The simultaneous abuse of ecstasy [3,4-methylenedioxymethamphetamine (MDMA)] and alcohol is prevalent among young adults, including young expectant mothers. Here, we used a rat model to study the potential risks associated with exposure to alcohol and MDMA during pregnancy. Pregnant rats received alcohol, MDMA, or both alcohol and MDMA by gavage at E13 through E15 twice daily. Female offspring treated prenatally with the combination of alcohol and MDMA, but not those exposed to either drug separately, showed at 3 months of age decreased exploratory activity and impaired working memory function. Prenatal treatment with the combination of alcohol and MDMA decreased proliferation of neuronal precursors in the adult dentate gyrus of the hippocampus, as measured by 5-bromo-2-deoxyuridine labelling, and adult neurogenesis, assessed by quantifying doublecortin expression. These results provide the first evidence that the simultaneous abuse of alcohol and ecstasy during pregnancy, even for short periods of time, may cause significant abnormalities in neurocognitive development.

  5. Role of hypothalamic neurogenesis in feeding regulation.

    PubMed

    Sousa-Ferreira, Lígia; de Almeida, Luís Pereira; Cavadas, Cláudia

    2014-02-01

    The recently described generation of new neurons in the adult hypothalamus, the center for energy regulation, suggests that hypothalamic neurogenesis is a crucial part of the mechanisms that regulate food intake. Accordingly, neurogenesis in both the adult and embryonic hypothalamus is affected by nutritional cues and metabolic disorders such as obesity, with consequent effects on energy-balance. This review critically discusses recent findings on the contribution of adult hypothalamic neurogenesis to feeding regulation, the impact of energy-balance disorders on adult hypothalamic neurogenesis, and the influence of embryonic hypothalamic neurogenesis upon feeding regulation in the adult. Understanding how hypothalamic neurogenesis contributes to food intake control will change the paradigm on how we perceive energy-balance regulation.

  6. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2.

    PubMed

    Chugh, Deepti; Ali, Idrish; Bakochi, Anahita; Bahonjic, Elma; Etholm, Lars; Ekdahl, Christine T

    2015-01-01

    Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread. PMID:26177381

  7. Unlocking epigenetic codes in neurogenesis

    PubMed Central

    Yao, Bing; Jin, Peng

    2014-01-01

    During embryonic and adult neurogenesis, neuronal stem cells follow a highly conserved path of differentiation to give rise to functional neurons at various developmental stages. Epigenetic regulation—including DNA modifications, histone modifications, and noncoding regulatory RNAs, such as microRNA (miRNA) and long noncoding RNA (lncRNA)—plays a pivotal role in embryonic and adult neurogenesis. Here we review the latest in our understanding of the epigenetic regulation in neurogenesis, with a particular focus on newly identified cytosine modifications and their dynamics, along with our perspective for future studies. PMID:24939932

  8. Ion Transporter NKCC1, Modulator of Neurogenesis in Murine Olfactory Neurons*

    PubMed Central

    Haering, Claudia; Kanageswaran, Ninthujah; Bouvain, Pascal; Scholz, Paul; Altmüller, Janine; Becker, Christian; Gisselmann, Günter; Wäring-Bischof, Janine; Hatt, Hanns

    2015-01-01

    Olfaction is one of the most crucial senses for vertebrates regarding foraging and social behavior. Therefore, it is of particular interest to investigate the sense of smell, its function on a molecular level, the signaling proteins involved in the process and the mechanism of required ion transport. In recent years, the precise role of the ion transporter NKCC1 in olfactory sensory neuron (OSN) chloride accumulation has been a controversial subject. NKCC1 is expressed in OSNs and is involved in chloride accumulation of dissociated neurons, but it had not been shown to play a role in mouse odorant sensation. Here, we present electro-olfactogram recordings (EOG) demonstrating that NKCC1-deficient mice exhibit significant defects in perception of a complex odorant mixture (Henkel100) in both air-phase and submerged approaches. Using next generation sequencing (NGS) and RT-PCR experiments of NKCC1-deficient and wild type mouse transcriptomes, we confirmed the absence of a highly expressed ion transporter that could compensate for NKCC1. Additional histological investigations demonstrated a reduced number of cells in the olfactory epithelium (OE), resulting in a thinner neuronal layer. Therefore, we conclude that NKCC1 is an important transporter involved in chloride ion accumulation in the olfactory epithelium, but it is also involved in OSN neurogenesis. PMID:25713142

  9. 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

  10. The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety.

    PubMed

    Dias, Gisele Pereira; Cavegn, Nicole; Nix, Alina; do Nascimento Bevilaqua, Mário Cesar; Stangl, Doris; Zainuddin, Muhammad Syahrul Anwar; Nardi, Antonio Egidio; Gardino, Patricia Franca; Thuret, Sandrine

    2012-01-01

    Although it has been long believed that new neurons were only generated during development, there is now growing evidence indicating that at least two regions in the brain are capable of continuously generating functional neurons: the subventricular zone and the dentate gyrus of the hippocampus. Adult hippocampal neurogenesis (AHN) is a widely observed phenomenon verified in different adult mammalian species including humans. Factors such as environmental enrichment, voluntary exercise, and diet have been linked to increased levels of AHN. Conversely, aging, stress, anxiety and depression have been suggested to hinder it. However, the mechanisms underlying these effects are still unclear and yet to be determined. In this paper, we discuss some recent findings addressing the effects of different dietary polyphenols on hippocampal cell proliferation and differentiation, models of anxiety, and depression as well as some proposed molecular mechanisms underlying those effects with particular focus on those related to AHN. As a whole, dietary polyphenols seem to exert positive effects on anxiety and depression, possibly in part via regulation of AHN. Studies on the effects of dietary polyphenols on behaviour and AHN may play an important role in the approach to use diet as part of the therapeutic interventions for mental-health-related conditions.

  11. Mice lacking the PSD-95-interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning.

    PubMed

    Park, Hanwool; Yang, Jinhee; Kim, Ryunhee; Li, Yan; Lee, Yeunkum; Lee, Chungwoo; Park, Jongil; Lee, Dongmin; Kim, Hyun; Kim, Eunjoon

    2015-11-10

    Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson's disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin(-/-)) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. Behaviorally, Dorfin(-/-) mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin(-/-) brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory.

  12. Voluntary running prevents progressive memory decline and increases adult hippocampal neurogenesis and growth factor expression after whole-brain irradiation.

    PubMed

    Wong-Goodrich, Sarah J E; Pfau, Madeline L; Flores, Catherine T; Fraser, Jennifer A; Williams, Christina L; Jones, Lee W

    2010-11-15

    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 4 months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting 1 month after sham or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdUrd) immunolabeling and enzyme-linked immunosorbent assay indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdUrd+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor-1, and occurred despite irradiation-induced elevations in hippocampal proinflammatory 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.

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

    PubMed

    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

  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. Adult neurogenesis in the central olfactory pathway in the absence of receptor neuron turnover in Libinia emarginata

    PubMed Central

    Sullivan, Jeremy M.; Beltz, Barbara S.

    2009-01-01

    Life-long neurogenesis is a characteristic feature of the olfactory pathways of a phylogenetically diverse array of animals. In both vertebrates and invertebrates, the life-long addition of olfactory interneurons in the brain occurs in parallel with the continuous proliferation of olfactory receptor neurons in the olfactory organ. It has been proposed that these two processes are related functionally, with new olfactory interneurons being added to accommodate the new olfactory receptor neurons added in the periphery. While this has not been tested directly because the two processes are not readily separable, this question can be addressed in the olfactory pathway of the crab, Libinia emarginata. Unlike most decapod crustaceans, which moult and grow throughout life, L. emarginata has a terminal, maturational moult after which animals become anecdysic (stop moulting). Because the addition of new receptor neurons in crustaceans is associated with moulting, a comparison of neurogenesis in immature and mature L. emarginata provides an opportunity to examine the interdependence of central and peripheral neurogenesis in the olfactory pathway. This study demonstrates that the continuous addition of olfactory receptor neurons in L. emarginata ceases at the terminal moult but that proliferation and differentiation of olfactory interneurons in the brain continues in mature animals. Contrary to the general assumption, therefore, continuous neurogenesis in the central olfactory pathway of this species does not occur as part of a process involving the coregulation of central and peripheral neurogenesis. These findings suggest that peripheral neurogenesis is not a requirement for continuous neurogenesis in the central olfactory pathway. PMID:16307582

  16. Interactive effect of excitotoxic injury and dietary restriction on neurogenesis and neurotrophic factors in adult male rat brain.

    PubMed

    Kumar, Sushil; Parkash, Jyoti; Kataria, Hardeep; Kaur, Gurcharan

    2009-12-01

    Dietary restriction (DR) is known to have potential health benefits including enhanced resistance of neurons to excitotoxic, oxidative and metabolic insults, cancer, stress, diabetes, reduced morbidity, and increased life span. In the present study, we examined the effect of DR (alternate day feeding regimen) on neurogenesis, expression of immature neuronal marker polysialic acid neural cell adhesion molecule (PSA-NCAM) and neurotrophic factors from different brain regions such as subventricular zone (SVZ), subgranular zone (SGZ) of hippocampus, median eminence arcuate (ME-ARC) region of hypothalamus, and piriform cortex (PIR) of adult male rats and further challenged ad libitum fed (AL) and DR rats with pilocarpine to induce excitotoxic injury. The quantitative analysis of bromodeoxyuridine (BrdU) labeling revealed a significant increase in the proliferation rate of neuronal progenitor cells from discrete brain regions in DR rats with and without pilocarpine induced seizures as compared to AL rats. DR significantly enhanced the expression of PSA-NCAM and neurotrophic factors, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). There was a marked reduction in neuronal cell death in SVZ and PIR cortex after pilocarpine administration in DR rats. These results add to the accumulating evidence that DR may be an effective intervention to enhance the resistance of brain to excitotoxic injury.

  17. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation

    PubMed Central

    Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Soto-Rodríguez, Sofía; González-Perez, Oscar

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD. PMID:27579149

  18. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation.

    PubMed

    López-Armas, Gabriela; Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Jave-Suarez, Luis Felipe; Soto-Rodríguez, Sofía; Rusanova, Iryna; Acuña-Castroviejo, Dario; González-Perez, Oscar; González-Castañeda, Rocío Elizabeth

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD.

  19. Prophylactic Role of Oral Melatonin Administration on Neurogenesis in Adult Balb/C Mice during REM Sleep Deprivation.

    PubMed

    López-Armas, Gabriela; Flores-Soto, Mario Eduardo; Chaparro-Huerta, Verónica; Jave-Suarez, Luis Felipe; Soto-Rodríguez, Sofía; Rusanova, Iryna; Acuña-Castroviejo, Dario; González-Perez, Oscar; González-Castañeda, Rocío Elizabeth

    2016-01-01

    Purpose. The aim of this study was to assess the effect of melatonin in the proliferation of neural progenitors, melatonin concentration, and antiapoptotic proteins in the hippocampus of adult mice exposed to 96 h REM sleep deprivation (REMSD) prophylactic administration of melatonin for 14 days. Material and Methods. Five groups of Balb/C mice were used: (1) control, (2) REMSD, (3) melatonin (10 mg/kg) plus REMSD, (4) melatonin and intraperitoneal luzindole (once a day at 5 mg/kg) plus REMSD, and (5) luzindole plus REMSD. To measure melatonin content in hippocampal tissue we used HPLC. Bcl-2 and Bcl-xL proteins were measured by Western Blot and neurogenesis was determined by injecting 5-bromo-2-deoxyuridine (BrdU) and BrdU/nestin expressing cells in the subgranular zone of the dentate gyrus were quantified by epifluorescence. Results. The melatonin-treated REMSD group showed an increased neural precursor in 44% with respect to the REMSD group and in 28% when contrasted with the control group (P < 0.021). The melatonin-treated REMSD group also showed the highest expression of Bcl-2 and Bcl-xL as compared to the rest of the groups. Conclusion. The exogenous administration of melatonin restores the tissue levels of sleep-deprived group and appears to be an efficient neuroprotective agent against the deleterious effects of REMSD. PMID:27579149

  20. Gonadectomy increases neurogenesis in the male adolescent rhesus macaque hippocampus.

    PubMed

    Allen, K M; Fung, S J; Rothmond, D A; Noble, P L; Weickert, C Shannon

    2014-02-01

    New neurons are continuously produced in the subgranular zone of the adult hippocampus and can modulate hippocampal plasticity across life. Adolescence is characterized by dramatic changes in sex hormone levels, and social and emotional behaviors. It is also an age for increased risk of psychiatric disorders, including schizophrenia, which may involve altered hippocampal neurogenesis. The extent to which testosterone and other testicular hormones modulate hippocampal neurogenesis and adolescent behavioral development is unclear. This study aimed to determine if removal of testicular hormones during adolescence alters neurogenesis in the male rhesus macaque hippocampus. We used stereology to examine levels of cell proliferation, cell survival and neuronal differentiation in late adolescent male rhesus macaques (4.6-yrs old) that had previously been gonadectomized or sham operated prior to puberty (2.4-yrs old). While the absence of adolescent testicular hormones had no effect on cell proliferation, cell survival was increased by 65% and indices of immature neuronal differentiation were increased by 56% in gonadectomized monkeys compared to intact monkeys. We show for the first time that presence of circulating testicular hormones, including testosterone, may decrease neuronal survival in the primate hippocampus during adolescence. Our findings are in contrast to existing studies in adults where testosterone tends to be a pro-survival factor and demonstrate that testicular hormones may reduce hippocampal neurogenesis during the age typical of schizophrenia onset.

  1. Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle.

    PubMed

    Thuret, Raphaël; Auger, Hélène; Papalopulu, Nancy

    2015-11-30

    Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU) incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level.

  2. Analysis of neural progenitors from embryogenesis to juvenile adult in Xenopus laevis reveals biphasic neurogenesis and continuous lengthening of the cell cycle

    PubMed Central

    Thuret, Raphaël; Auger, Hélène; Papalopulu, Nancy

    2015-01-01

    ABSTRACT Xenopus laevis is a prominent model system for studying neural development, but our understanding of the long-term temporal dynamics of neurogenesis remains incomplete. Here, we present the first continuous description of neurogenesis in X. laevis, covering the entire period of development from the specification of neural ectoderm during gastrulation to juvenile frog. We have used molecular markers to identify progenitors and neurons, short-term bromodeoxyuridine (BrdU) incorporation to map the generation of newborn neurons and dual pulse S-phase labelling to characterise changes in their cell cycle length. Our study revealed the persistence of Sox3-positive progenitor cells from the earliest stages of neural development through to the juvenile adult. Two periods of intense neuronal generation were observed, confirming the existence of primary and secondary waves of neurogenesis, punctuated by a period of quiescence before metamorphosis and culminating in another period of quiescence in the young adult. Analysis of multiple parameters indicates that neural progenitors alternate between global phases of differentiation and amplification and that, regardless of their behaviour, their cell cycle lengthens monotonically during development, at least at the population level. PMID:26621828

  3. Glycidol induces axonopathy by adult-stage exposure and aberration of hippocampal neurogenesis affecting late-stage differentiation by developmental exposure in rats.

    PubMed

    Akane, Hirotoshi; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Ohishi, Takumi; Mitsumori, Kunitoshi; Shibutani, Makoto

    2013-07-01

    To investigate the neurotoxicity profile of glycidol and its effect on developmental hippocampal neurogenesis, pregnant Sprague Dawley rats were given drinking water containing 0, 100, 300, or 1000 ppm glycidol from gestational day 6 until weaning on day 21 after delivery. At 1000 ppm, dams showed progressively worsening gait abnormalities, and histopathological examination showed generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells, and axonal degeneration in the sciatic nerves. Decreased dihydropyrimidinase-like 3(+) immature granule cells in the subgranular zone (SGZ) and increased immature reelin(+) or calbindin-2(+) γ-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein (NeuN)(+) mature neurons were found in the dentate hilus of the offspring of the 1000 ppm group on weaning. Hilar changes remained until postnatal day 77, with the increases in reelin(+) and NeuN(+) cells being present at ≥ 300 ppm, although the SGZ change disappeared. Thus, glycidol caused axon injury in the central and peripheral nervous systems of adult rats, suggesting that glycidol targets the newly generating nerve terminals of immature granule cells, resulting in the suppression of late-stage hippocampal neurogenesis. The sustained hilar changes may be a sign of continued aberrations in neurogenesis and migration. The no-observed-adverse-effect level was determined to be 300 ppm (48.8mg/kg body weight/day) for dams and 100 ppm (18.5mg/kg body weight/day) for offspring. The sustained developmental exposure effect on offspring neurogenesis was more sensitive than the adult axonal injury.

  4. Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

    PubMed Central

    Bruel-Jungerman, Elodie; Veyrac, Alexandra; Dufour, Franck; Horwood, Jennifer; Laroche, Serge; Davis, Sabrina

    2009-01-01

    Background Physical exercise has been shown to increase adult neurogenesis in the dentate gyrus and enhances synaptic plasticity. The antiapoptotic kinase, Akt has also been shown to be phosphorylated following voluntary exercise; however, it remains unknown whether the PI3K-Akt signaling pathway is involved in exercise-induced neurogenesis and the associated facilitation of synaptic plasticity in the dentate gyrus. Methodology/Principal Findings To gain insight into the potential role of this signaling pathway in exercise-induced neurogenesis and LTP in the dentate gyrus rats were infused with the PI3K inhibitor, LY294002 or vehicle control solution (icv) via osmotic minipumps and exercised in a running wheel for 10 days. Newborn cells in the dentate gyrus were date-labelled with BrdU on the last 3 days of exercise. Then, they were either returned to the home cage for 2 weeks to assess exercise-induced LTP and neurogenesis in the dentate gyrus, or were killed on the last day of exercise to assess proliferation and activation of the PI3K-Akt cascade using western blotting. Conclusions/Significance Exercise increases cell proliferation and promotes survival of adult-born neurons in the dentate gyrus. Immediately after exercise, we found that Akt and three downstream targets, BAD, GSK3β and FOXO1 were activated. LY294002 blocked exercise-induced phosphorylation of Akt and downstream target proteins. This had no effect on exercise-induced cell proliferation, but it abolished most of the beneficial effect of exercise on the survival of newly generated dentate gyrus neurons and prevented exercise-induced increase in dentate gyrus LTP. These results suggest that activation of the PI3 kinase-Akt signaling pathway plays a significant role via an antiapoptotic function in promoting survival of newly formed granule cells generated during exercise and the associated increase in synaptic plasticity in the dentate gyrus. PMID:19936256

  5. Acute and fractionated exposure to high-LET (56)Fe HZE-particle radiation both result in similar long-term deficits in adult hippocampal neurogenesis.

    PubMed

    Rivera, Phillip D; Shih, Hung-Ying; Leblanc, Junie A; Cole, Mara G; Amaral, Wellington Z; Mukherjee, Shibani; Zhang, Shichuan; Lucero, Melanie J; Decarolis, Nathan A; Chen, Benjamin P C; Eisch, Amelia J

    2013-12-01

    Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreER(T2)/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy (56)Fe-particle exposure or five fractionated 20 cGy (56)Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of (56)Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed. PMID:24320054

  6. Acute and Fractionated Exposure to High-LET 56Fe HZE-Particle Radiation Both Result in Similar Long-Term Deficits in Adult Hippocampal Neurogenesis

    PubMed Central

    Rivera, Phillip D.; Shih, Hung-Ying; LeBlanc, Junie A.; Cole, Mara G.; Amaral, Wellington Z.; Mukherjee, Shibani; Zhang, Shichuan; Lucero, Melanie J.; DeCarolis, Nathan A.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-01-01

    Astronauts on multi-year interplanetary missions will be exposed to a low, chronic dose of high-energy, high-charge particles. Studies in rodents show acute, nonfractionated exposure to these particles causes brain changes such as fewer adult-generated hippocampal neurons and stem cells that may be detrimental to cognition and mood regulation and thus compromise mission success. However, the influence of a low, chronic dose of these particles on neurogenesis and stem cells is unknown. To examine the influence of galactic cosmic radiation on neurogenesis, adult-generated stem and progenitor cells in Nestin-CreERT2/R26R-YFP transgenic mice were inducibly labeled to allow fate tracking. Mice were then sham exposed or given one acute 100 cGy 56Fe-particle exposure or five fractionated 20 cGy 56Fe-particle exposures. Adult-generated hippocampal neurons and stem cells were quantified 24 h or 3 months later. Both acute and fractionated exposure decreased the amount of proliferating cells and immature neurons relative to sham exposure. Unexpectedly, neither acute nor fractionated exposure decreased the number of adult neural stem cells relative to sham expsoure. Our findings show that single and fractionated exposures of 56Fe-particle irradiation are similarly detrimental to adult-generated neurons. Implications for future missions and ground-based studies in space radiation are discussed. PMID:24320054

  7. Decreased brain zinc availability reduces hippocampal neurogenesis in mice and rats.

    PubMed

    Suh, Sang Won; Won, Seok Joon; Hamby, Aaron M; Yoo, Byung Hoon; Fan, Yang; Sheline, Christian T; Tamano, Haruna; Takeda, Atsushi; Liu, Jialing

    2009-09-01

    In the adult brain, neurogenesis occurs in the subgranular zone of the dentate gyrus (DG), where high levels of vesicular zinc are localized in the presynaptic terminals. To determine whether zinc has a role in modulating hippocampal neurogenesis under normal or pathologic conditions, we manipulated the level of vesicular zinc experimentally. To reduce hippocampal vesicular zinc, rats were either fed a zinc-deficient diet or treated with a zinc chelator, clioquinol (CQ). The number of progenitor cells and immature neurons was decreased significantly in the DG after 6 weeks of dietary zinc deprivation. Conversely, the number of progenitor cells and immature neurons was restored after a 2-week reversal to a normal zinc-containing diet. Similarly, a 1-week treatment with the zinc chelator, CQ, reduced the number of progenitor cells. The results of our previous study showed that hypoglycemia increased hippocampal neurogenesis. This study shows that zinc chelation reduced hypoglycemia-induced progenitor cell proliferation and neurogenesis. Finally, the role of vesicular zinc on neurogenesis was further assessed in zinc transporter 3 (ZnT3) gene deleted mice. Zinc transporter 3 knockout (KO) mice had significantly fewer proliferating progenitor cells and immature neurons after hypoglycemia. Our data provide converging evidence in support of the essential role zinc has in modulating hippocampal neurogenesis.

  8. A new chapter in the field of memory: adult hippocampal neurogenesis.

    PubMed

    Koehl, Muriel; Abrous, Djoher N

    2011-03-01

    Understanding the cellular mechanisms underlying learning and memory is a major challenge in neurobiology. Structural and functional changes occurring in the hippocampus such as synaptic remodeling and long-term potentiation are key signatures of long-term memory processes. The discovery of a de novo hippocampal production of neurons in the adult brain has been a breakthrough in the field of plasticity and memory, introducing a new actor that could sustain memory processes. Here we will review our current knowledge on the role of these adult new neurons in memory. In particular we will provide evidence showing that they are required for learning and memory and that an alteration in their production rate or maturation leads to memory impairments. Through a thorough survey of the literature, we will also acknowledge that there are many controversies regarding the specific role played by newborn neurons. The emerging picture is that they are involved in the establishment of spatiotemporal relationships among multiple environmental cues for the flexible use of the acquired information. Indeed, newborn neurons have been found to be required for separating events based on their spatial and temporal characteristics, a process that preserves the uniqueness of a memory representation. Thus, adult-born neurons are required for allocentric space representation, for long-term memory retention and for flexible inferential memory expression. Finally, we will conclude by highlighting directions for future research, emphasizing that the exact participation of newborn neurons in memory processes will not be approached without considering the hippocampal network in general.

  9. P2X7 receptor inhibition increases CNTF in the subventricular zone, but not neurogenesis or neuroprotection after stroke in adult mice.

    PubMed

    Kang, Seong Su; Keasey, Matthew Phillip; Hagg, Theo

    2013-10-01

    Increasing endogenous ciliary neurotrophic factor (CNTF) expression with a pharmacological agent might be beneficial after stroke as CNTF both promotes neurogenesis and, separately, is neuroprotective. P2X7 purinergic receptor inhibition is neuroprotective in rats and increases CNTF release in rat CMT1A Schwann cells. We, first, investigated the role of P2X7 in regulating CNTF and neurogenesis in adult mouse subventricular zone (SVZ). CNTF expression was increased by daily intravenous injections of the P2X7 antagonist Brilliant Blue G (BBG) in naïve C57BL/6 or Balb/c mice over 3 days. Despite the ∼40-60 % increase or decrease in CNTF with BBG or the agonist BzATP, respectively, the number of proliferated BrdU+SVZ nuclei did not change. BBG failed to increase FGF2, which is involved in CNTF-regulated neurogenesis, but induced IL-6, LIF, and EGF, which are known to reduce SVZ proliferation. Injections of IL-6 next to the SVZ induced CNTF and FGF2, but not proliferation, suggesting that IL-6 counteracts their neurogenesis-inducing effects. Following ischemic injury of the striatum by middle cerebral artery occlusion (MCAO), a 3-day BBG treatment increased CNTF in the medial penumbra containing the SVZ. BBG also induced CNTF and LIF, which are known to be protective following stroke, in the whole striatum after MCAO, but not GDNF or BDNF. However, BBG treatment did not reduce the lesion area or apoptosis in the penumbra. Even so, this study shows that P2X7 can be targeted with systemic drug treatments to differentially regulate neurotrophic factors in the brain following stroke.

  10. Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis

    PubMed Central

    Wu, Xiaoting; Fleming, Angeleen; Ricketts, Thomas; Pavel, Mariana; Virgin, Herbert; Menzies, Fiona M.; Rubinsztein, David C.

    2016-01-01

    Autophagy is a conserved, intracellular, lysosomal degradation pathway. While mechanistic aspects of this pathway are increasingly well defined, it remains unclear how autophagy modulation impacts normal physiology. It is, however, becoming clear that autophagy may play a key role in regulating developmental pathways. Here we describe for the first time how autophagy impacts stem cell differentiation by degrading Notch1. We define a novel route whereby this plasma membrane-resident receptor is degraded by autophagy, via uptake into ATG16L1-positive autophagosome-precursor vesicles. We extend our findings using a physiologically relevant mouse model with a hypomorphic mutation in Atg16L1, a crucial autophagy gene, which shows developmental retention of early-stage cells in various tissues where the differentiation of stem cells is retarded and thus reveal how modest changes in autophagy can impact stem cell fate. This may have relevance for diverse disease conditions, like Alzheimer's Disease or Crohn's Disease, associated with altered autophagy. PMID:26837467

  11. Autophagy regulates Notch degradation and modulates stem cell development and neurogenesis.

    PubMed

    Wu, Xiaoting; Fleming, Angeleen; Ricketts, Thomas; Pavel, Mariana; Virgin, Herbert; Menzies, Fiona M; Rubinsztein, David C

    2016-01-01

    Autophagy is a conserved, intracellular, lysosomal degradation pathway. While mechanistic aspects of this pathway are increasingly well defined, it remains unclear how autophagy modulation impacts normal physiology. It is, however, becoming clear that autophagy may play a key role in regulating developmental pathways. Here we describe for the first time how autophagy impacts stem cell differentiation by degrading Notch1. We define a novel route whereby this plasma membrane-resident receptor is degraded by autophagy, via uptake into ATG16L1-positive autophagosome-precursor vesicles. We extend our findings using a physiologically relevant mouse model with a hypomorphic mutation in Atg16L1, a crucial autophagy gene, which shows developmental retention of early-stage cells in various tissues where the differentiation of stem cells is retarded and thus reveal how modest changes in autophagy can impact stem cell fate. This may have relevance for diverse disease conditions, like Alzheimer's Disease or Crohn's Disease, associated with altered autophagy. PMID:26837467

  12. Is forebrain neurogenesis a potential repair mechanism after stroke?

    PubMed

    Inta, Dragos; Gass, Peter

    2015-07-01

    The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ generates predominantly calretinin (CR)-expressing GABAergic interneurons, which cannot replace the broad spectrum of neuronal subtypes damaged by stroke. Therefore, SVZ neurogenesis may represent a repair mechanism only after genetic manipulation redirecting its differentiation.

  13. Is forebrain neurogenesis a potential repair mechanism after stroke?

    PubMed Central

    Inta, Dragos; Gass, Peter

    2015-01-01

    The use of adult subventricular zone (SVZ) neurogenesis as brain repair strategy after stroke represents a hot topic in neurologic research. Recent radiocarbon-14 dating has revealed a lack of poststroke neurogenesis in the adult human neocortex; however, adult neurogenesis has been shown to occur, even under physiologic conditions, in the human striatum. Here, these results are contrasted with experimental poststroke neurogenesis in the murine brain. Both in humans and in rodents, the SVZ generates predominantly calretinin (CR)-expressing GABAergic interneurons, which cannot replace the broad spectrum of neuronal subtypes damaged by stroke. Therefore, SVZ neurogenesis may represent a repair mechanism only after genetic manipulation redirecting its differentiation. PMID:25966955

  14. Adult hippocampal neurogenesis and mRNA expression are altered by perinatal arsenic exposure in mice and restored by brief exposure to enrichment.

    PubMed

    Tyler, Christina R; Allan, Andrea M

    2013-01-01

    Arsenic is a common and pervasive environmental contaminant found in drinking water in varying concentrations depending on region. Exposure to arsenic induces behavioral and cognitive deficits in both human populations and in rodent models. The Environmental Protection Agency (EPA) standard for the allotment of arsenic in drinking water is in the parts-per-billion range, yet our lab has shown that 50 ppb arsenic exposure during development can have far-reaching consequences into adulthood, including deficits in learning and memory, which have been linked to altered adult neurogenesis. Given that the morphological impact of developmental arsenic exposure on the hippocampus is unknown, we sought to evaluate proliferation and differentiation of adult neural progenitor cells in the dentate gyrus after 50 ppb arsenic exposure throughout the perinatal period of development in mice (equivalent to all three trimesters in humans) using a BrdU pulse-chase assay. Proliferation of the neural progenitor population was decreased by 13% in arsenic-exposed mice, but was not significant. However, the number of differentiated cells was significantly decreased by 41% in arsenic-exposed mice compared to controls. Brief, daily exposure to environmental enrichment significantly increased proliferation and differentiation in both control and arsenic-exposed animals. Expression levels of 31% of neurogenesis-related genes including those involved in Alzheimer's disease, apoptosis, axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic exposure and restored after enrichment. Using a concentration previously considered safe by the EPA, perinatal arsenic exposure altered hippocampal morphology and gene expression, but did not inhibit the cellular neurogenic response to enrichment. It is possible that behavioral deficits observed during adulthood in animals exposed to arsenic during development derive from the lack of differentiated neural progenitor cells

  15. Binge ethanol exposure during adolescence leads to a persistent loss of neurogenesis in the dorsal and ventral hippocampus that is associated with impaired adult cognitive functioning

    PubMed Central

    Vetreno, Ryan P.; Crews, Fulton T.

    2015-01-01

    Adolescence is a developmental period that coincides with the maturation of adult cognitive faculties. Binge drinking is common during adolescence and can impact brain maturation. Using a rodent model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 20% EtOH w/v; 2 days on/2 days off from postnatal day [P]25 to P55), we discovered that AIE treatment reduced neurogenesis (i.e., doublecortin-immunoreactive [DCX + IR] cells) in both the dorsal and ventral hippocampal dentate gyrus of late adolescent (P56) male Wistar rats that persisted during abstinence into adulthood (P220). This reduction in neurogenesis was accompanied by a concomitant reduction in proliferating cells (Ki-67) and an increase in cell death (cleaved caspase-3). In the hippocampus, AIE treatment induced a long-term upregulation of neuroimmune genes, including Toll-like receptor 4 (TLR4) and its endogenous agonist high-mobility group box 1 as well as several proinflammatory signaling molecules. Administration of lipopolysaccharide, a gram-negative endotoxin agonist at TLR4, to young adult rats (P70) produced a similar reduction of DCX + IR cells that was observed in AIE-treated animals. Behaviorally, AIE treatment impaired object recognition on the novel object recognition task when assessed from P163 to P165. Interestingly, object recognition memory was positively correlated with DCX + IR in both the dorsal and ventral hippocampal dentate gyrus while latency to enter the center of the apparatus was negatively correlated with DCX + IR in the ventral dentate gyrus. Together, these data reveal that adolescent binge ethanol exposure persistently inhibits neurogenesis throughout the hippocampus, possibly through neuroimmune mechanisms, which might contribute to altered adult cognitive and emotive function. PMID:25729346

  16. Adult Hippocampal Neurogenesis and mRNA Expression are Altered by Perinatal Arsenic Exposure in Mice and Restored by Brief Exposure to Enrichment

    PubMed Central

    Tyler, Christina R.; Allan, Andrea M.

    2013-01-01

    Arsenic is a common and pervasive environmental contaminant found in drinking water in varying concentrations depending on region. Exposure to arsenic induces behavioral and cognitive deficits in both human populations and in rodent models. The Environmental Protection Agency (EPA) standard for the allotment of arsenic in drinking water is in the parts-per-billion range, yet our lab has shown that 50 ppb arsenic exposure during development can have far-reaching consequences into adulthood, including deficits in learning and memory, which have been linked to altered adult neurogenesis. Given that the morphological impact of developmental arsenic exposure on the hippocampus is unknown, we sought to evaluate proliferation and differentiation of adult neural progenitor cells in the dentate gyrus after 50 ppb arsenic exposure throughout the perinatal period of development in mice (equivalent to all three trimesters in humans) using a BrdU pulse-chase assay. Proliferation of the neural progenitor population was decreased by 13% in arsenic-exposed mice, but was not significant. However, the number of differentiated cells was significantly decreased by 41% in arsenic-exposed mice compared to controls. Brief, daily exposure to environmental enrichment significantly increased proliferation and differentiation in both control and arsenic-exposed animals. Expression levels of 31% of neurogenesis-related genes including those involved in Alzheimer’s disease, apoptosis, axonogenesis, growth, Notch signaling, and transcription factors were altered after arsenic exposure and restored after enrichment. Using a concentration previously considered safe by the EPA, perinatal arsenic exposure altered hippocampal morphology and gene expression, but did not inhibit the cellular neurogenic response to enrichment. It is possible that behavioral deficits observed during adulthood in animals exposed to arsenic during development derive from the lack of differentiated neural progenitor

  17. CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors.

    PubMed

    Zhang, Jing; Cai, Cheng-Yun; Wu, Hai-Yin; Zhu, Li-Juan; Luo, Chun-Xia; Zhu, Dong-Ya

    2016-01-01

    Serotonin 1a-receptor (5-HT1aR) has been specifically implicated in the pathogenesis of anxiety. However, the mechanism underlying the role of 5-HT1aR in anxiety remains poorly understood. Here we show in mice that the transcription factor cAMP response element binding protein (CREB) in the hippocampus functions as an effector of 5-HT1aR in modulating anxiety-related behaviors. We generated recombinant lentivirus LV-CREB133-GFP expressing a dominant negative CREB which could not be phosphorylated at Ser133 to specifically reduce CREB activity, and LV-VP16-CREB-GFP expressing a constitutively active fusion protein VP16-CREB which could be phosphorylated by itself to specifically enhance CREB activity. LV-CREB133-GFP neutralized 5-HT1aR agonist-induced up-regulation of synapse density, spine density, dendrite complexity, neurogenesis, and the expression of synapsin and spinophilin, two well-characterized synaptic proteins, and abolished the anxiolytic effect of 5-HT1aR agonist; whereas LV-VP16-CREB-GFP rescued the 5-HT1aR antagonist-induced down-regulation of synapse density, spine density, dendrite complexity, neurogenesis and synapsin and spinophilin expression, and reversed the anxiogenic effect of 5-HT1aR antagonist. The deletion of neurogenesis by irradiation or the diminution of synaptogenesis by knockdown of synapsin expression abolished the anxiolytic effects of both CREB and 5-HT1aR activation. These findings suggest that CREB-mediated hippoacampus structural plasticity is crucial for the role of 5-HT1aR in modulating anxiety-related behaviors. PMID:27404655

  18. CREB-mediated synaptogenesis and neurogenesis is crucial for the role of 5-HT1a receptors in modulating anxiety behaviors

    PubMed Central

    Zhang, Jing; Cai, Cheng-Yun; Wu, Hai-Yin; Zhu, Li-Juan; Luo, Chun-Xia; Zhu, Dong-Ya

    2016-01-01

    Serotonin 1a-receptor (5-HT1aR) has been specifically implicated in the pathogenesis of anxiety. However, the mechanism underlying the role of 5-HT1aR in anxiety remains poorly understood. Here we show in mice that the transcription factor cAMP response element binding protein (CREB) in the hippocampus functions as an effector of 5-HT1aR in modulating anxiety-related behaviors. We generated recombinant lentivirus LV-CREB133-GFP expressing a dominant negative CREB which could not be phosphorylated at Ser133 to specifically reduce CREB activity, and LV-VP16-CREB-GFP expressing a constitutively active fusion protein VP16-CREB which could be phosphorylated by itself to specifically enhance CREB activity. LV-CREB133-GFP neutralized 5-HT1aR agonist-induced up-regulation of synapse density, spine density, dendrite complexity, neurogenesis, and the expression of synapsin and spinophilin, two well-characterized synaptic proteins, and abolished the anxiolytic effect of 5-HT1aR agonist; whereas LV-VP16-CREB-GFP rescued the 5-HT1aR antagonist-induced down-regulation of synapse density, spine density, dendrite complexity, neurogenesis and synapsin and spinophilin expression, and reversed the anxiogenic effect of 5-HT1aR antagonist. The deletion of neurogenesis by irradiation or the diminution of synaptogenesis by knockdown of synapsin expression abolished the anxiolytic effects of both CREB and 5-HT1aR activation. These findings suggest that CREB-mediated hippoacampus structural plasticity is crucial for the role of 5-HT1aR in modulating anxiety-related behaviors. PMID:27404655

  19. Perinatal exposure to methoxychlor enhances adult cognitive responses and hippocampal neurogenesis in mice

    PubMed Central

    Martini, Mariangela; Calandreau, Ludovic; Jouhanneau, Mélanie; Mhaouty-Kodja, Sakina; Keller, Matthieu

    2014-01-01

    During perinatal life, sex steroids, such as estradiol, have marked effects on the development and function of the nervous system. Environmental estrogens or xenoestrogens are man-made chemicals, which animal and human population encounter in the environment and which are able to disrupt the functioning of the endocrine system. Scientific interest in the effects of exposure to xenoestrogens has focused more on fertility and reproductive behaviors, while the effects on cognitive behaviors have received less attention. Therefore, the present study explored whether the organochlorine insecticide Methoxychlor (MXC), with known xenoestrogens properties, administered during the perinatal period (from gestational day 11 to postnatal day 8) to pregnant-lactating females, at an environmentally relevant dose (20 µg/kg (body weight)/day), would also affect learning and memory functions depending on the hippocampus of male and female offspring mice in adulthood. When tested in adulthood, MXC perinatal exposure led to an increase in anxiety-like behavior and in short-term spatial working memory in both sexes. Emotional learning was also assessed using a contextual fear paradigm and MXC treated male and female mice showed an enhanced freezing behavior compared to controls. These results were correlated with an increased survival of adult generated cells in the adult hippocampus. In conclusion, our results show that perinatal exposure to an environmentally relevant dose of MXC has an organizational effect on hippocampus-dependent memory and emotional behaviors. PMID:24982620

  20. Patterns of olfactory bulb neurogenesis in the adult zebrafish are altered following reversible deafferentation.

    PubMed

    Trimpe, Darcy M; Byrd-Jacobs, Christine A

    2016-09-01

    Adult brain plasticity can be investigated using reversible methods that remove afferent innervation but allow return of sensory input. Repeated intranasal irrigation with Triton X-100 in adult zebrafish diminishes innervation to the olfactory bulb, resulting in a number of alterations in bulb structure and function, and cessation of the treatment allows for reinnervation and recovery. Using bromodeoxyuridine, Hu, and caspase-3 immunoreactivity we examined cell proliferation, differentiation, migration, and survival under conditions of acute and chronic deafferentation and reafferentation. Cell proliferation within the olfactory bulb was not influenced by acute or chronic deafferentation or reafferentation, but cell fate (including differentiation, migration, and/or survival of newly formed cells) was affected. We found that chronic deafferentation caused a bilateral increase in the number of newly formed cells that migrated into the bulb, although the amount of cell death of these new cells was significantly increased compared to untreated fish. Reafferentation also increased the number of newly formed cells migrating into both bulbs, suggesting that the deafferentation effect on cell fate was maintained. Reafferentation resulted in a decrease in newly formed cells that became neurons and, although death of newly formed cells was not altered from control levels, survival was reduced in relation to that seen in chronically deafferented fish. The potential effect of age on cell genesis was also examined. While the amount of cell migration into the olfactory bulbs was not affected by fish age, more of the newly formed cells became neurons in older fish. Younger fish displayed more cell death under conditions of chronic deafferentation. In sum, our results show that reversible deafferentation affects several aspects of cell fate, including cell differentiation, migration, and survival, and age of the fish influences the response to deafferentation. PMID:27343831

  1. Thermally reduced graphene is a permissive material for neurons and astrocytes and de novo neurogenesis in the adult olfactory bulb in vivo.

    PubMed

    Defteralı, Çağla; Verdejo, Raquel; Peponi, Laura; Martín, Eduardo D; Martínez-Murillo, Ricardo; López-Manchado, Miguel Ángel; Vicario-Abejón, Carlos

    2016-03-01

    Graphene and graphene-based nanomaterials (GBNs) are being investigated as potential substrates for the growth of neural stem cells (NSCs), neurons and glia in cell culture models. In contrast, reports testing the effects of graphene directly with adult neural cells in vivo are missing. Here we studied the biocompatibility of thermally reduced graphene (TRG) with neurons and glia, as well as with the generation of new neurons in the adult brain in vivo. TRG injected in the brain together with a retroviral vector expressing GFP to label dividing progenitor cells in the core of the adult olfactory bulb (OB) did not alter de novo neurogenesis, neuronal and astrocyte survival nor did it produce a microglial response. These findings indicate that TRG may be a biocompatible material with neuronal and glial cells in vivo and support its use in studies of brain repair and function. PMID:26751821

  2. 56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

    NASA Astrophysics Data System (ADS)

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal R.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-07-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24 h), intermediate (7 d), and/or long time points (2-3 mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  3. (56)Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesis in Vivo.

    PubMed

    DeCarolis, Nathan A; Rivera, Phillip D; Ahn, Francisca; Amaral, Wellington Z; LeBlanc, Junie A; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal; Chen, Benjamin P C; Eisch, Amelia J

    2014-07-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreER(T2)/R26R:YFP mice, respectively). Mice were subjected to (56)Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24h), intermediate (7d), and/or long time points (2-3mo) post-irradiation. (56)Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, (56)Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. (56)Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, (56)Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, (56)Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These

  4. 56Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesis in Vivo

    PubMed Central

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal; Chen, Benjamin P.C.; Eisch, Amelia J.

    2014-01-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24h), intermediate (7d), and/or long time points (2–3mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  5. VGF (TLQP-62)-induced neurogenesis targets early phase neural progenitor cells in the adult hippocampus and requires glutamate and BDNF signaling.

    PubMed

    Thakker-Varia, Smita; Behnke, Joseph; Doobin, David; Dalal, Vidhi; Thakkar, Keya; Khadim, Farah; Wilson, Elizabeth; Palmieri, Alicia; Antila, Hanna; Rantamaki, Tomi; Alder, Janet

    2014-05-01

    The neuropeptide VGF (non-acronymic), which has antidepressant-like effects, enhances adult hippocampal neurogenesis as well as synaptic activity and plasticity in the hippocampus, however the interaction between these processes and the mechanism underlying this regulation remain unclear. In this study, we demonstrate that VGF-derived peptide TLQP-62 specifically enhances the generation of early progenitor cells in nestin-GFP mice. Specifically, TLQP-62 significantly increases the number of Type 2a neural progenitor cells (NPCs) while reducing the number of more differentiated Type 3 cells. The effect of TLQP-62 on proliferation rather than differentiation was confirmed using NPCs in vitro; TLQP-62 but not scrambled peptide PEHN-62 increases proliferation in a cell line as well as in primary progenitors from adult hippocampus. Moreover, TLQP-62 but not scrambled peptide increases Cyclin D mRNA expression. The proliferation of NPCs induced by TLQP-62 requires synaptic activity, in particular through NMDA and metabotropic glutamate receptors. The activation of glutamate receptors by TLQP-62 activation induces phosphorylation of CaMKII through NMDA receptors and protein kinase D through metabotropic glutamate receptor 5 (mGluR5). Furthermore, pharmacological antagonists to CaMKII and PKD inhibit TLQP-62-induced proliferation of NPCs indicating that these signaling molecules downstream of glutamate receptors are essential for the actions of TLQP-62 on neurogenesis. We also show that TLQP-62 gradually activates Brain-Derived Neurotrophic Factor (BDNF)-receptor TrkB in vitro and that Trk signaling is required for TLQP-62-induced proliferation of NPCs. Understanding the precise molecular mechanism of how TLQP-62 influences neurogenesis may reveal mechanisms by which VGF-derived peptides act as antidepressant-like agents.

  6. Long-Term Fate Mapping Using Conditional Lentiviral Vectors Reveals a Continuous Contribution of Radial Glia-Like Cells to Adult Hippocampal Neurogenesis in Mice

    PubMed Central

    Aelvoet, Sarah-Ann; Pascual-Brazo, Jesus; Libbrecht, Sarah; Reumers, Veerle; Gijsbers, Rik; Van den Haute, Chris; Baekelandt, Veerle

    2015-01-01

    Newborn neurons are generated throughout life in two neurogenic regions, the subventricular zone and the hippocampal dentate gyrus. Stimulation of adult neurogenesis is considered as an attractive endogenous repair mechanism to treat different neurological disorders. Although tremendous progress has been made in our understanding of adult hippocampal neurogenesis, important questions remain unanswered, regarding the identity and the behavior of neural stem cells in the dentate gyrus. We previously showed that conditional Cre-Flex lentiviral vectors can be used to label neural stem cells in the subventricular zone and to track the migration of their progeny with non-invasive bioluminescence imaging. Here, we applied these Cre-Flex lentiviral vectors to study neurogenesis in the dentate gyrus with bioluminescence imaging and histological techniques. Stereotactic injection of the Cre-Flex vectors into the dentate gyrus of transgenic Nestin-Cre mice resulted in specific labeling of the nestin-positive neural stem cells. The labeled cell population could be detected with bioluminescence imaging until 9 months post injection, but no significant increase in the number of labeled cells over time was observed with this imaging technique. Nevertheless, the specific labeling of the nestin-positive neural stem cells, combined with histological analysis at different time points, allowed detailed analysis of their neurogenic potential. This long-term fate mapping revealed that a stable pool of labeled nestin-positive neural stem cells continuously contributes to the generation of newborn neurons in the mouse brain until 9 months post injection. In conclusion, the Cre-Flex technology is a valuable tool to address remaining questions regarding neural stem cell identity and behavior in the dentate gyrus. PMID:26600383

  7. Brain Insulin-Like Growth Factor-I Directs the Transition from Stem Cells to Mature Neurons During Postnatal/Adult Hippocampal Neurogenesis.

    PubMed

    Nieto-Estévez, Vanesa; Oueslati-Morales, Carlos O; Li, Lingling; Pickel, James; Morales, Aixa V; Vicario-Abejón, Carlos

    2016-08-01

    The specific actions of insulin-like growth factor-I (IGF-I) and the role of brain-derived IGF-I during hippocampal neurogenesis have not been fully defined. To address the influence of IGF-I on the stages of hippocampal neurogenesis, we studied a postnatal/adult global Igf-I knockout (KO) mice (Igf-I(-/-) ) and a nervous system Igf-I conditional KO (Igf-I(Δ/Δ) ). In both KO mice we found an accumulation of Tbr2(+) -intermediate neuronal progenitors, some of which were displaced in the outer granule cell layer (GCL) and the molecular layer (ML) of the dentate gyrus (DG). Similarly, more ectopic Ki67(+) - cycling cells were detected. Thus, the GCL was disorganized with significant numbers of Prox1(+) -granule neurons outside this layer and altered morphology of radial glial cells (RGCs). Dividing progenitors were also generated in greater numbers in clonal hippocampal stem cell (HPSC) cultures from the KO mice. Indeed, higher levels of Hes5 and Ngn2, transcription factors that maintain the stem and progenitor cell state, were expressed in both HPSCs and the GCL-ML from the Igf-I(Δ/Δ) mice. To determine the impact of Igf-I deletion on neuronal generation in vivo, progenitors in Igf-I(-/-) and Igf-I(+/+) mice were labeled with a GFP-expressing vector. This revealed that in the Igf-I(-/-) mice more GFP(+) -immature neurons were formed and they had less complex dendritic trees. These findings indicate that local IGF-I plays critical roles during postnatal/adult hippocampal neurogenesis, regulating the transition from HPSCs and progenitors to mature granule neurons in a cell stage-dependent manner. Stem Cells 2016;34:2194-2209. PMID:27144663

  8. Experimental ‘Jet Lag’ Inhibits Adult Neurogenesis and Produces Long-Term Cognitive Deficits in Female Hamsters

    PubMed Central

    Gibson, Erin M.; Wang, Connie; Tjho, Stephanie; Khattar, Neera; Kriegsfeld, Lance J.

    2010-01-01

    Background Circadian disruptions through frequent transmeridian travel, rotating shift work, and poor sleep hygiene are associated with an array of physical and mental health maladies, including marked deficits in human cognitive function. Despite anecdotal and correlational reports suggesting a negative impact of circadian disruptions on brain function, this possibility has not been experimentally examined. Methodology/Principal Findings In the present study, we investigated whether experimental ‘jet lag’ (i.e., phase advances of the light∶dark cycle) negatively impacts learning and memory and whether any deficits observed are associated with reductions in hippocampal cell proliferation and neurogenesis. Because insults to circadian timing alter circulating glucocorticoid and sex steroid concentrations, both of which influence neurogenesis and learning/memory, we assessed the contribution of these endocrine factors to any observed alterations. Circadian disruption resulted in pronounced deficits in learning and memory paralleled by marked reductions in hippocampal cell proliferation and neurogenesis. Significantly, deficits in hippocampal-dependent learning and memory were not only seen during the period of the circadian disruption, but also persisted well after the cessation of jet lag, suggesting long-lasting negative consequences on brain function. Conclusions/Significance Together, these findings support the view that circadian disruptions suppress hippocampal neurogenesis via a glucocorticoid-independent mechanism, imposing pronounced and persistent impairments on learning and memory. PMID:21152025

  9. Macrophages modulate adult zebrafish tail fin regeneration.

    PubMed

    Petrie, Timothy A; Strand, Nicholas S; Yang, Chao-Tsung; Tsung-Yang, Chao; Rabinowitz, Jeremy S; Moon, Randall T

    2014-07-01

    Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Although recent evidence suggests that similar cells exist in zebrafish and also migrate to sites of injury in larvae, whether these cells are functionally important for wound healing or regeneration in adult zebrafish is unknown. To begin to address these questions, we first tracked neutrophils (lyzC(+), mpo(+)) and macrophages (mpeg1(+)) in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype. These results provide a cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish. PMID:24961798

  10. Syndecan-4 modulates the proliferation of neural cells and the formation of CaP axons during zebrafish embryonic neurogenesis

    PubMed Central

    Luo, Ning; Li, Hongda; Xiang, Bo; Qiao, Liangjun; He, Jiao; Ji, Yi; Liu, Yuan; Li, Siying; Lu, Ran; Li, Yu; Meng, Wentong; Wu, Yang; Xu, Hong; Mo, Xianming

    2016-01-01

    Syndecan-4 (Syn4), a single-pass transmembrane heparin sulphate proteoglycan (HSPG), plays significant role in the formation of focal adhesions and interacts with many growth factors to regulate cell migration and neural induction. Here, we show the new roles of syndecan-4(syn4) in zebrafish embryonic neurogenesis. Syn4 is broadly and dynamically expressed throughout the early stages of embryonic development. Knockdown of syn4 increases the expression of the marker genes of multiple types of neural cells. The increased expression of the marker genes is resulted from excessive proliferation of the neural cells. In addition, disrupting syn4 expression results in truncated and multiple aberrant branching of caudal primary (CaP) axons. Collectively, these data indicate that Syn4 suppresses the cellular proliferation during neurogenesis and is crucial for the formation of CaP axons during zebrafish embryogenesis. PMID:27143125

  11. Deletion of lysophosphatidic acid receptor LPA1 reduces neurogenesis in the mouse dentate gyrus

    PubMed Central

    Matas-Rico, Elisa; García-Diaz, Beatriz; Llebrez-Zayas, Pedro; López-Barroso, Diana; Santín, Luis; Pedraza, Carmen; Smith-Fernández, Anibal; Fernández-Llebrez, Pedro; Tellez, Teresa; Redondo; Chun, Jerold; De Fonseca, Fernando Rodríguez; Estivill-Torrús, Guillermo

    2013-01-01

    Neurogenesis persists in certain regions of the adult brain including the subgranular zone of the hippocampal dentate gyrus wherein its regulation is essential, particularly in relation to learning, stress and modulation of mood. Lysophosphatidic acid (LPA) is an extracellular signaling phospholipid with important neural regulatory properties mediated by specific G protein-coupled receptors, LPA1-5. LPA1 is highly expressed in the developing neurogenic ventricular zone wherein it is required for normal embryonic neurogenesis, and, by extension may play a role in adult neurogenesis as well. By means of the analyses of a variant of the original LPA1-null mutant mouse, termed the Malaga variant or “maLPA1-null,” which has recently been reported to have defective neurogenesis within the embryonic cerebral cortex, we report here a role for LPA1 in adult hippocampal neurogenesis. Proliferation, differentiation and survival of newly formed neurons are defective in the absence of LPA1 under normal conditions and following exposure to enriched environment and voluntary exercise. Furthermore, analysis of trophic factors in maLPA1-null mice demonstrated alterations in brain-derived neurotrophic factor and insulin growth factor 1 levels after enrichment and exercise. Morphological analyses of doublecortin positive cells revealed the anomalous prevalence of bipolar cells in the subgranular zone, supporting the operation of LPA1 signaling pathways in normal proliferation, maturation and differentiation of neuronal precursors. PMID:18708146

  12. Adult Neurogenesis in the Female Mouse Hypothalamus: Estradiol and High-Fat Diet Alter the Generation of Newborn Neurons Expressing Estrogen Receptor α

    PubMed Central

    Yang, Jane; Nettles, Sabin A.; Byrnes, Elizabeth M.

    2016-01-01

    Estrogens and leptins act in the hypothalamus to maintain reproduction and energy homeostasis. Neurogenesis in the adult mammalian hypothalamus has been implicated in the regulation of energy homeostasis. Recently, high-fat diet (HFD) and estradiol (E2) have been shown to alter cell proliferation and the number of newborn leptin-responsive neurons in the hypothalamus of adult female mice. The current study tested the hypothesis that new cells expressing estrogen receptor α (ERα) are generated in the arcuate nucleus (ARC) and the ventromedial nucleus of the hypothalamus (VMH) of the adult female mouse, hypothalamic regions that are critical in energy homeostasis. Adult mice were ovariectomized and implanted with capsules containing E2 or oil. Within each hormone group, mice were fed an HFD or standard chow for 6 weeks and treated with BrdU to label new cells. Newborn cells that respond to estrogens were identified in the ARC and VMH, of which a subpopulation was leptin sensitive, indicating that the subpopulation consists of neurons. Moreover, there was an interaction between diet and hormone with an effect on the number of these newborn ERα-expressing neurons that respond to leptin. Regardless of hormone treatment, HFD increased the number of ERα-expressing cells in the ARC and VMH. E2 decreased hypothalamic fibroblast growth factor 10 (Fgf10) gene expression in HFD mice, suggesting a role for Fgf10 in E2 effects on neurogenesis. These findings of newly created estrogen-responsive neurons in the adult brain provide a novel mechanism by which estrogens can act in the hypothalamus to regulate energy homeostasis in females. PMID:27679811

  13. Adult Neurogenesis in the Female Mouse Hypothalamus: Estradiol and High-Fat Diet Alter the Generation of Newborn Neurons Expressing Estrogen Receptor α

    PubMed Central

    Yang, Jane; Nettles, Sabin A.; Byrnes, Elizabeth M.

    2016-01-01

    Estrogens and leptins act in the hypothalamus to maintain reproduction and energy homeostasis. Neurogenesis in the adult mammalian hypothalamus has been implicated in the regulation of energy homeostasis. Recently, high-fat diet (HFD) and estradiol (E2) have been shown to alter cell proliferation and the number of newborn leptin-responsive neurons in the hypothalamus of adult female mice. The current study tested the hypothesis that new cells expressing estrogen receptor α (ERα) are generated in the arcuate nucleus (ARC) and the ventromedial nucleus of the hypothalamus (VMH) of the adult female mouse, hypothalamic regions that are critical in energy homeostasis. Adult mice were ovariectomized and implanted with capsules containing E2 or oil. Within each hormone group, mice were fed an HFD or standard chow for 6 weeks and treated with BrdU to label new cells. Newborn cells that respond to estrogens were identified in the ARC and VMH, of which a subpopulation was leptin sensitive, indicating that the subpopulation consists of neurons. Moreover, there was an interaction between diet and hormone with an effect on the number of these newborn ERα-expressing neurons that respond to leptin. Regardless of hormone treatment, HFD increased the number of ERα-expressing cells in the ARC and VMH. E2 decreased hypothalamic fibroblast growth factor 10 (Fgf10) gene expression in HFD mice, suggesting a role for Fgf10 in E2 effects on neurogenesis. These findings of newly created estrogen-responsive neurons in the adult brain provide a novel mechanism by which estrogens can act in the hypothalamus to regulate energy homeostasis in females.

  14. Zinc chelation reduces traumatic brain injury-induced neurogenesis in the subgranular zone of the hippocampal dentate gyrus.

    PubMed

    Choi, Bo Young; Kim, Jin Hee; Kim, Hyun Jung; Lee, Bo Eun; Kim, In Yeol; Sohn, Min; Suh, Sang Won

    2014-10-01

    Numerous studies have demonstrated that traumatic brain injury (TBI) increases hippocampal neurogenesis in the rodent brain. However, the mechanisms underlying increased neurogenesis after TBI remain unknown. Continuous neurogenesis occurs in the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) in the adult brain. The mechanism that maintains active neurogenesis in the hippocampal area is not known. A high level of vesicular zinc is localized in the presynaptic terminals of the SGZ (mossy fiber). The mossy fiber of dentate granular cells contains high levels of chelatable zinc in their terminal vesicles, which can be released into the extracellular space during neuronal activity. Previously, our lab presented findings indicating that a possible correlation may exist between synaptic zinc localization and high rates of neurogenesis in this area after hypoglycemia or epilepsy. Using a weight drop animal model to mimic human TBI, we tested our hypothesis that zinc plays a key role in modulating hippocampal neurogenesis after TBI. Thus, we injected a zinc chelator, clioquinol (CQ, 30mg/kg), into the intraperitoneal space to reduce brain zinc availability twice per day for 1 week. Neuronal death was evaluated with Fluoro Jade-B and NeuN staining to determine whether CQ has neuroprotective effects after TBI. The number of degenerating neurons (FJB (+)) and live neurons (NeuN (+)) was similar in vehicle and in CQ-treated rats at 1 week after TBI. Neurogenesis was evaluated using BrdU, Ki67 and doublecortin (DCX) immunostaining 1 week after TBI. The number of BrdU, Ki67 and DCX positive cell was increased after TBI. However, the number of BrdU, Ki67 and DCX positive cells was significantly decreased by CQ treatment. The present study shows that zinc chelation did not prevent neurodegeneration but did reduce TBI-induced progenitor cell proliferation and neurogenesis. Therefore, this study suggests that zinc has an essential role for modulating hippocampal

  15. n-3 fatty acids: role in neurogenesis and neuroplasticity.

    PubMed

    Crupi, R; Marino, A; Cuzzocrea, S

    2013-01-01

    Omega-3 polyunsaturated fatty acids (PUFA) are essential unsaturated fatty acids with a double bond (C=C) starting after the third carbon atom from the end of the carbon chain. They are important nutrients but, unfortunately, mammals cannot synthesize them, whereby they must be obtained from food sources or from supplements. Amongst nutritionally important polyunsaturated n-3 fatty acids, α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are highly concentrated in the brain and have anti-oxidative stress, anti-inflammatory and antiapoptotic effects. They are involved in many bodily processes and may reportedly lead to neuron protection in neurological diseases. aged or damaged neurons and in Alzheimer's disease. Their effect in cognitive and behavioral functions and in several neurological and psychiatric disorders has been also proven. The dentate gyrus (DG), a sub-region of hippocampus, is implicated in cognition and mood regulation. The hippocampus represents one of the two areas in the mammalian brain in which adult neurogenesis occurs. This process is associated with beneficial effects on cognition, mood and chronic pharmacological treatment. The exposure to n-3 fatty acids enhances adult hippocampal neurogenesis associated with cognitive and behavioral processes, promotes synaptic plasticity by increasing long-term potentiation and modulates synaptic protein expression to stimulate the dendritic arborization and new spines formation. On this basis we review the effect of n-3 fatty acids on adult hippocampal neurogenesis and neuroplasticity. Moreover their possible use as a new therapeutic approach for neurodegenerative diseases is pointed out. PMID:23746276

  16. Effects of neuregulin-1 administration on neurogenesis in the adult mouse hippocampus, and characterization of immature neurons along the septotemporal axis

    PubMed Central

    Mahar, Ian; MacIsaac, Angus; Kim, John Junghan; Qiang, Calvin; Davoli, Maria Antonietta; Turecki, Gustavo; Mechawar, Naguib

    2016-01-01

    Adult hippocampal neurogenesis is associated with learning and affective behavioural regulation. Its diverse functionality is segregated along the septotemporal axis from the dorsal to ventral hippocampus. However, features distinguishing immature neurons in these regions have yet to be characterized. Additionally, although we have shown that administration of the neurotrophic factor neuregulin-1 (NRG1) selectively increases proliferation and overall neurogenesis in the mouse ventral dentate gyrus (DG), likely through ErbB3, NRG1’s effects on intermediate neurogenic stages in immature neurons are unknown. We examined whether NRG1 administration increases DG ErbB3 phosphorylation. We labeled adultborn cells using BrdU, then administered NRG1 to examine in vivo neurogenic effects on immature neurons with respect to cell survival, morphology, and synaptogenesis. We also characterized features of immature neurons along the septotemporal axis. We found that neurogenic effects of NRG1 are temporally and subregionally specific to proliferation in the ventral DG. Particular morphological features differentiate immature neurons in the dorsal and ventral DG, and cytogenesis differed between these regions. Finally, we identified synaptic heterogeneity surrounding the granule cell layer. These results indicate neurogenic involvement of NRG1-induced antidepressant-like behaviour is particularly associated with increased ventral DG cell proliferation, and identify novel distinctions between dorsal and ventral hippocampal neurogenic development. PMID:27469430

  17. [Reparative Neurogenesis in the Brain and Changes in the Optic Nerve of Adult Trout Oncorhynchus mykiss after Mechanical Damage of the Eye].

    PubMed

    Puschina, E V; Varaksin, A A; Obukhov, D K

    2016-01-01

    Reparative proliferation and neurogenesis in the brain integrative centers after mechanical eye injury in an adult trout Oncorhynchus mykiss have been studied. We have found that proliferation and neurogenesis in proliferative brain regions, the cerebellum, and the optic tectum were significantly enhanced after the eye injury. The cerebellum showed a significant increase in the proliferative activity of the cells of the dorsal proliferative zone and parenchymal cells of the molecular and granular layers. One week after the injury, PCNA-positive radial glia cells have been identified in the tectum. We have found for the first time that the eye trauma resulted in the development of local clusters of undifferentiated cells forming so called neurogenic niches in the tectum and cerebellum. The differentiation of neuronal cells detected by labeling cells with antibodies against the protein HuC/D occurred in the proliferative zones of the telencephalon, the optic tectum, cerebellum, and medulla of a trout within 2 days after the injury. We have shown that the HuC/D expression is higher in the proliferative brain regions than in the definitive neurons of a trout. In addition, we have examined cell proliferation, migration, and apoptosis caused by the eye injury in the contra- and ipsilateral optic nerves and adjacent muscle fibers 2 days after the trauma. The qualitative and quantitative assessment of proliferation and apoptosis in the cells of the optic nerve of a trout has been made using antibodies against PCNA and the TUNEL method. PMID:27149746

  18. Genome-wide analysis of the bHLH gene family in planarians identifies factors required for adult neurogenesis and neuronal regeneration.

    PubMed

    Cowles, Martis W; Brown, David D R; Nisperos, Sean V; Stanley, Brianna N; Pearson, Bret J; Zayas, Ricardo M

    2013-12-01

    In contrast to most well-studied model organisms, planarians have a remarkable ability to completely regenerate a functional nervous system from a pluripotent stem cell population. Thus, planarians provide a powerful model to identify genes required for adult neurogenesis in vivo. We analyzed the basic helix-loop-helix (bHLH) family of transcription factors, many of which are crucial for nervous system development and have been implicated in human diseases. However, their potential roles in adult neurogenesis or central nervous system (CNS) function are not well understood. We identified 44 planarian bHLH homologs, determined their patterns of expression in the animal and assessed their functions using RNAi. We found nine bHLHs expressed in stem cells and neurons that are required for CNS regeneration. Our analyses revealed that homologs of coe, hes (hesl-3) and sim label progenitors in intact planarians, and following amputation we observed an enrichment of coe(+) and sim(+) progenitors near the wound site. RNAi knockdown of coe, hesl-3 or sim led to defects in CNS regeneration, including failure of the cephalic ganglia to properly pattern and a loss of expression of distinct neuronal subtype markers. Together, these data indicate that coe, hesl-3 and sim label neural progenitor cells, which serve to generate new neurons in uninjured or regenerating animals. Our study demonstrates that this model will be useful to investigate how stem cells interpret and respond to genetic and environmental cues in the CNS and to examine the role of bHLH transcription factors in adult tissue regeneration.

  19. 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.

  20. Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2.

    PubMed

    Kirby, Elizabeth D; Muroy, Sandra E; Sun, Wayne G; Covarrubias, David; Leong, Megan J; Barchas, Laurel A; Kaufer, Daniela

    2013-04-16

    Stress is a potent modulator of the mammalian brain. The highly conserved stress hormone response influences many brain regions, particularly the hippocampus, a region important for memory function. The effect of acute stress on the unique population of adult neural stem/progenitor cells (NPCs) that resides in the adult hippocampus is unclear. We found that acute stress increased hippocampal cell proliferation and astrocytic fibroblast growth factor 2 (FGF2) expression. The effect of acute stress occurred independent of basolateral amygdala neural input and was mimicked by treating isolated NPCs with conditioned media from corticosterone-treated primary astrocytes. Neutralization of FGF2 revealed that astrocyte-secreted FGF2 mediated stress-hormone-induced NPC proliferation. 2 weeks, but not 2 days, after acute stress, rats also showed enhanced fear extinction memory coincident with enhanced activation of newborn neurons. Our findings suggest a beneficial role for brief stress on the hippocampus and improve understanding of the adaptive capacity of the brain. DOI:http://dx.doi.org/10.7554/eLife.00362.001.

  1. The effect of amygdala kindling on hippocampal neurogenesis coincides with decreased reelin and DISC1 expression in the adult dentate gyrus.

    PubMed

    Fournier, N M; Andersen, D R; Botterill, J J; Sterner, E Y; Lussier, A L; Caruncho, H J; Kalynchuk, L E

    2010-05-01

    Temporal lobe seizures can induce the proliferation and abnormal migration of newly generated dentate granule cells, but little is known about the molecular mechanisms that govern these pathological events. Reelin and DISC1 (disrupted-in-schizophrenia 1) are proteins that play a regulatory role in the maturation and integration of new neurons in the developing and adult brain. In this study, we examined whether amygdala kindling results in aberrant neurogenesis and altered expression of reelin and DISC1 in the adult dentate gyrus. Using doublecortin immunohistochemistry, we found that short-term kindling (i.e., 30 electrical stimulations) significantly increased the number of immature neurons in the dentate subgranular zone (SGZ), whereas long-term kindling (i.e., 99 electrical stimulations) did not. However, doublecortin-labeled neurons in long-term kindled rats showed greater dendritic complexity than they did in short-term kindled or control rats. We also found that long-term kindling decreased the number of reelin-positive cells and decreased DISC1 expression in the dentate granule cell layer and subgranular zone. Interestingly, kindling-induced changes in reelin and DISC1 expression coincided with the appearance of ectopically located Prox1-labeled granule cells in the hilus. These effects occurred independently of alterations in granule cell layer length, dentate volume, or the number of hilar neurons. Taken together, these findings suggest a novel role for DISC1 in the pathophysiology of temporal lobe epilepsy and further suggest that changes in reelin and DISC1 expression may contribute to aberrant neurogenesis in the kindling model.

  2. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

    PubMed

    Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki; Brulet, Rebecca; Tafacory, Farrah; Zhang, Ling; Good, Levi; Ure, Kerstin; Kernie, Steven G; Birnbaum, Shari G; Scharfman, Helen E; Eisch, Amelia J; Hsieh, Jenny

    2015-03-26

    Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult.

  3. Aberrant hippocampal neurogenesis contributes to epilepsy and associated cognitive decline.

    PubMed

    Cho, Kyung-Ok; Lybrand, Zane R; Ito, Naoki; Brulet, Rebecca; Tafacory, Farrah; Zhang, Ling; Good, Levi; Ure, Kerstin; Kernie, Steven G; Birnbaum, Shari G; Scharfman, Helen E; Eisch, Amelia J; Hsieh, Jenny

    2015-01-01

    Acute seizures after a severe brain insult can often lead to epilepsy and cognitive impairment. Aberrant hippocampal neurogenesis follows the insult but the role of adult-generated neurons in the development of chronic seizures or associated cognitive deficits remains to be determined. Here we show that the ablation of adult neurogenesis before pilocarpine-induced acute seizures in mice leads to a reduction in chronic seizure frequency. We also show that ablation of neurogenesis normalizes epilepsy-associated cognitive deficits. Remarkably, the effect of ablating adult neurogenesis before acute seizures is long lasting as it suppresses chronic seizure frequency for nearly 1 year. These findings establish a key role of neurogenesis in chronic seizure development and associated memory impairment and suggest that targeting aberrant hippocampal neurogenesis may reduce recurrent seizures and restore cognitive function following a pro-epileptic brain insult. PMID:25808087

  4. Role of nitric oxide in subventricular zone neurogenesis.

    PubMed

    Matarredona, Esperanza R; Murillo-Carretero, Maribel; Moreno-López, Bernardo; Estrada, Carmen

    2005-09-01

    A possible role of nitric oxide (NO) in adult neurogenesis has been suggested based on anatomical findings showing that subventricular zone (SVZ) neuroblasts are located close to NO-producing cells, and on the known antiproliferative actions of NO in many cell types. Experiments have been performed in rodents with systemic and intracerebroventricular administrations of the NO synthase (NOS) inhibitor L-NAME. NOS inhibition leads to significant increases in the number of proliferating cells in the SVZ and olfactory bulb (OB). NO exerts its cytostatic action preferentially on the cell population expressing nestin but not betaIII-tubulin, which may correspond to the type C cells described in the SVZ. The negative effect of NO on SVZ cell proliferation has also been confirmed in SVZ primary cultures. An inhibition of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) is described as one of the molecular mechanisms responsible for the antiproliferative effect of NO in SVZ cells. Biochemical data supporting this conclusion has been obtained using the neuroblastoma cell line NB69, which endogenously expresses the EGFR. In these cells, the antimitotic action of NO occurs upon inhibition of the EGFR tyrosine phosphorylation, probably by a direct S-nitrosylation of the receptor. The latest published reports on NO and neurogenesis indicate that NO physiologically participates in the control of adult neurogenesis by modulating the proliferation and fate of the SVZ progenitor cells. These effects might be partially due to a direct inhibition of the EGFR by S-nitrosylation.

  5. The cyclin-dependent kinase inhibitor p27 kip1 regulates radial stem cell quiescence and neurogenesis in the adult hippocampus.

    PubMed

    Andreu, Zoraida; Khan, Muhammad Amir; González-Gómez, Pilar; Negueruela, Santiago; Hortigüela, Rafael; San Emeterio, Juana; Ferrón, Sacri R; Martínez, Gloria; Vidal, Anxo; Fariñas, Isabel; Lie, Dieter Chichung; Mira, Helena

    2015-01-01

    Members of the cyclin-dependent kinase (CDK)-inhibitory protein (CIP)/kinase-inhibitory protein (KIP) family of cyclin-dependent kinase inhibitors regulate proliferation and cell cycle exit of mammalian cells. In the adult brain, the CIP/KIP protein p27(kip1) has been related to the regulation of intermediate progenitor cells located in neurogenic niches. Here, we uncover a novel function of p27(kip1) in the adult hippocampus as a dual regulator of stem cell quiescence and of cell-cycle exit of immature neurons. In vivo, p27(kip1) is detected in radial stem cells expressing SOX2 and in newborn neurons of the dentate gyrus. In vitro, the Cdkn1b gene encoding p27(kip1) is transcriptionally upregulated by quiescence signals such as BMP4. The nuclear accumulation of p27(kip1) protein in adult hippocampal stem cells encompasses the BMP4-induced quiescent state and its overexpression is able to block proliferation. p27(kip1) is also expressed in immature neurons upon differentiation of adult hippocampal stem cell cultures. Loss of p27(kip1) leads to an increase in proliferation and neurogenesis in the adult dentate gyrus, which results from both a decrease in the percentage of radial stem cells that are quiescent and a delay in cell cycle exit of immature neurons. Analysis of animals carrying a disruption in the cyclin-CDK interaction domain of p27(kip1) indicates that the CDK inhibitory function of the protein is necessary to control the activity of radial stem cells. Thus, we report that p27(kip1) acts as a central player of the molecular program that keeps adult hippocampal stem cells out of the cell cycle.

  6. Adipose-derived mesenchymal stem cell transplantation promotes adult neurogenesis in the brains of Alzheimer's disease mice

    PubMed Central

    Yan, Yufang; Ma, Tuo; Gong, Kai; Ao, Qiang; Zhang, Xiufang; Gong, Yandao

    2014-01-01

    In the present study, we transplanted adipose-derived mesenchymal stem cells into the hippocampi of APP/PS1 transgenic Alzheimer's disease model mice. Immunofluorescence staining revealed that the number of newly generated (BrdU+) cells in the subgranular zone of the dentate gyrus in the hippocampus was significantly higher in Alzheimer's disease mice after adipose-derived mesenchymal stem cell transplantation, and there was also a significant increase in the number of BrdU+/DCX+ neuroblasts in these animals. Adipose-derived mesenchymal stem cell transplantation enhanced neurogenic activity in the subventricular zone as well. Furthermore, adipose-derived mesenchymal stem cell transplantation reduced oxidative stress and alleviated cognitive impairment in the mice. Based on these findings, we propose that adipose-derived mesenchymal stem cell transplantation enhances endogenous neurogenesis in both the subgranular and subventricular zones in APP/PS1 transgenic Alzheimer's disease mice, thereby facilitating functional recovery. PMID:25206892

  7. Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure.

    PubMed

    Cacao, Eliedonna; Cucinotta, Francis A

    2016-03-01

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

  8. Modeling Impaired Hippocampal Neurogenesis after Radiation Exposure.

    PubMed

    Cacao, Eliedonna; Cucinotta, Francis A

    2016-03-01

    Radiation impairment of neurogenesis in the hippocampal dentate gyrus is one of several factors associated with cognitive detriments after treatment of brain cancers in children and adults with radiation therapy. Mouse models have been used to study radiation-induced changes in neurogenesis, however the models are limited in the number of doses, dose fractions, age and time after exposure conditions that have been studied. The purpose of this study is to develop a novel predictive mathematical model of radiation-induced changes to neurogenesis using a system of nonlinear ordinary differential equations (ODEs) to represent the time, age and dose-dependent changes to several cell populations participating in neurogenesis as reported in mouse experiments exposed to low-LET radiation. We considered four compartments to model hippocampal neurogenesis and, consequently, the effects of radiation treatment in altering neurogenesis: (1) neural stem cells (NSCs), (2) neuronal progenitor cells or neuroblasts (NB), (3) immature neurons (ImN) and (4) glioblasts (GB). Because neurogenesis is decreasing with increasing mouse age, a description of the age-related dynamics of hippocampal neurogenesis is considered in the model, which is shown to be an important factor in comparisons to experimental data. A key feature of the model is the description of negative feedback regulation on early and late neuronal proliferation after radiation exposure. The model is augmented with parametric descriptions of the dose and time after irradiation dependences of activation of microglial cells and a possible shift of NSC proliferation from neurogenesis to gliogenesis reported at higher doses (∼10 Gy). Predictions for dose-fractionation regimes and for different mouse ages, and prospects for future work are then discussed. PMID:26943452

  9. Hippocampal Neurogenesis and Antidepressive Therapy: Shocking Relations

    PubMed Central

    Rotheneichner, Peter; Lange, Simona; O'Sullivan, Anna; Marschallinger, Julia; Zaunmair, Pia; Geretsegger, Christian; Aigner, Ludwig

    2014-01-01

    Speculations on the involvement of hippocampal neurogenesis, a form of neuronal plasticity, in the aetiology of depression and the mode of action of antidepressive therapies, started to arise more than a decade ago. But still, conclusive evidence that adult neurogenesis contributes to antidepressive effects of pharmacological and physical therapies has not been generated yet. This review revisits recent findings on the close relation between the mode(s) of action of electroconvulsive therapy (ECT), a powerful intervention used as second-line treatment of major depression disorders, and the neurogenic response to ECT. Following application of electroconvulsive shocks, intricate interactions between neurogenesis, angiogenesis, and microglia activation, the hypothalamic-pituitary-adrenal axis and the secretion of neurotrophic factors have been documented. Furthermore, considering the fact that neurogenesis strongly diminishes along aging, we investigated the response to electroconvulsive shocks in young as well as in aged cohorts of mice. PMID:24967107

  10. Single episode of mild murine malaria induces neuroinflammation, alters microglial profile, impairs adult neurogenesis, and causes deficits in social and anxiety-like behavior.

    PubMed

    Guha, Suman K; Tillu, Rucha; Sood, Ankit; Patgaonkar, Mandar; Nanavaty, Ishira N; Sengupta, Arjun; Sharma, Shobhona; Vaidya, Vidita A; Pathak, Sulabha

    2014-11-01

    activation and redistribution, and a definitive, but transient, suppression of adult hippocampal neurogenesis.

  11. Reducing central serotonin in adulthood promotes hippocampal neurogenesis

    PubMed Central

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

    2016-01-01

    Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreERT2 mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis. PMID:26839004

  12. Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network.

    PubMed

    Dabrowski, Ania; Umemori, Hisashi

    2016-01-01

    Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis. PMID:27605441

  13. Impact of the apolipoprotein E polymorphism, age and sex on neurogenesis in mice: pathophysiological relevance for Alzheimer's disease?

    PubMed

    Koutseff, Alexis; Mittelhaeuser, Christophe; Essabri, Karim; Auwerx, Johan; Meziane, Hamid

    2014-01-13

    Apolipoprotein E (ApoE) is found in three different forms in humans (ApoE2, ApoE3 and ApoE4), and ApoE polymorphism is recognized as a major risk factor for Alzheimer's disease (AD). ApoE is involved in lipid and cholesterol transport, cell repair, and amyloid-β deposition and certain studies suggest potential implications in neurogenesis. In this regard, we investigated the possible impact of the three different human ApoE isoforms on neurogenesis. We used ApoE knock-in mice of different ages and sex, and quantified newborn cells in the hippocampus by flow cytometry. Young adult ApoE4 mice (10-12 week-old) from both sexes displayed reduced neurogenesis compared with wild-types and the other genotypes. In addition, young adult ApoE2 female mice showed improved hippocampal progenitor cell proliferation. In older mice (1 year), hippocampal neurogenesis was globally decreased, particularly in females, and the difference between ApoE4 and the other genotypes observed in young animals disappeared for the two sexes, except for aged ApoE3 females. Indeed, a surprising protective effect of the ApoE3 genotype was observed in aged females. Our study highlights the role of ApoE in neurogenesis, and shows for the first time an early inequality between the ApoE genotypes. The reduced neurogenesis observed for the ApoE4 genotype and the improved results obtained in young ApoE2 females support the idea of a difference in the balance between neuronal birth and death modulated by the ApoE polymorphism in young animals. The maintenance of this balance and its modulation can influence pathophysiological mechanisms predisposing to neurodegenerative diseases like AD. PMID:24140109

  14. Scorpion venom heat-resistant peptide (SVHRP) enhances neurogenesis and neurite outgrowth of immature neurons in adult mice by up-regulating brain-derived neurotrophic factor (BDNF).

    PubMed

    Wang, Tao; Wang, Shi-Wei; Zhang, Yue; Wu, Xue-Fei; Peng, Yan; Cao, Zhen; Ge, Bi-Ying; Wang, Xi; Wu, Qiong; Lin, Jin-Tao; Zhang, Wan-Qin; Li, Shao; Zhao, Jie

    2014-01-01

    Scorpion venom heat-resistant peptide (SVHRP) is a component purified from Buthus martensii Karsch scorpion venom. Although scorpions and their venom have been used in Traditional Chinese Medicine (TCM) to treat chronic neurological disorders, the underlying mechanisms of these treatments remain unknown. We applied SVHRP in vitro and in vivo to understand its effects on the neurogenesis and maturation of adult immature neurons and explore associated molecular mechanisms. SVHRP administration increased the number of 5-bromo-2'-dexoxyuridine (BrdU)-positive cells, BrdU-positive/neuron-specific nuclear protein (NeuN)-positive neurons, and polysialylated-neural cell adhesion molecule (PSA-NCAM)-positive immature neurons in the subventricular zone (SVZ) and subgranular zone (SGZ) of hippocampus. Furthermore immature neurons incubated with SVHRP-pretreated astrocyte-conditioned medium exhibited significantly increased neurite length compared with those incubated with normal astrocyte-conditioned medium. This neurotrophic effect was further confirmed in vivo by detecting an increased average single area and whole area of immature neurons in the SGZ, SVZ and olfactory bulb (OB) in the adult mouse brain. In contrast to normal astrocyte-conditioned medium, higher concentrations of brain-derived neurotrophic factor (BDNF) but not nerve growth factor (NGF) or glial cell line-derived neurotrophic factor (GDNF) was detected in the conditioned medium of SVHRP-pretreated astrocytes, and blocking BDNF using anti-BDNF antibodies eliminated these SVHRP-dependent neurotrophic effects. In SVHRP treated mouse brain, more glial fibrillary acidic protein (GFAP)-positive cells were detected. Furthermore, immunohistochemistry revealed increased numbers of GFAP/BDNF double-positive cells, which agrees with the observed changes in the culture system. This paper describes novel effects of scorpion venom-originated peptide on the stem cells and suggests the potential therapeutic values of SVHRP.

  15. Modulation of adult-born neurons in the inflamed hippocampus

    PubMed Central

    Belarbi, Karim; Rosi, Susanna

    2013-01-01

    Throughout life new neurons are continuously added to the hippocampal circuitry involved with spatial learning and memory. These new cells originate from neural precursors in the subgranular zone of the dentate gyrus, migrate into the granule cell layer, and integrate into neural networks encoding spatial and contextual information. This process can be influenced by several environmental and endogenous factors and is modified in different animal models of neurological disorders. Neuroinflammation, as defined by the presence of activated microglia, is a common key factor to the progression of neurological disorders. Analysis of the literature shows that microglial activation impacts not only the production, but also the migration and the recruitment of new neurons. The impact of microglia on adult-born neurons appears much more multifaceted than ever envisioned before, combining both supportive and detrimental effects that are dependent upon the activation phenotype and the factors being released. The development of strategies aimed to change microglia toward states that promote functional neurogenesis could therefore offer novel therapeutic opportunities against neurological disorders associated with cognitive deficits and neuroinflammation. The present review summarizes the current knowledge on how production, distribution, and recruitment of new neurons into behaviorally relevant neural networks are modified in the inflamed hippocampus. PMID:24046730

  16. Neurogenesis in the Hippocampus of Patients with Temporal Lobe Epilepsy.

    PubMed

    Zhong, Qin; Ren, Bo-Xu; Tang, Feng-Ru

    2016-02-01

    The mobilization of endogenous neural stem cells in order to substitute lost neurons in the adult brain may reduce the negative effects of patients with chronic neurodegenerative diseases. However, abnormal neurogenesis may be harmful and could lead to the worsening of patients' symptoms. In the brains of patients and animal models with temporal lobe epilepsy (TLE), increased newly generated neurons in the subgranular zone (SGZ) at early stages after brain insults have been speculated to be involved in epileptogenesis. However, this argument is unsupported by evidence showing that (1) hippocampal neurogenesis is reduced at chronic stages of intractable TLE, (2) decreased neurogenesis is involved in epileptogenesis, and (3) spontaneous recurrent seizures occur before newly generated neurons are integrated into hippocampal neural pathways. Therefore, the hypothesis of increased neurogenesis in epileptogenesis may need to be re-evaluated. In this paper, we systemically reviewed brain neurogenesis and relevant molecules in the regulation of neurogenesis in SGZ. We aimed to update researchers and epileptologists on current progresses on pathophysiological changes of neurogenesis at different stages of TLE in patients and animal models of TLE. The interactions among neurogenesis, epileptogenesis and cognitive impairment, and molecules' mechanism involved in neurogenesis would also be discussed. Future research directions are proposed at the end of this paper.

  17. Neurogenesis of the cholinergic medial septum in female and male C57BL/6J mice.

    PubMed

    Schaevitz, Laura R; Berger-Sweeney, Joanne

    2005-12-01

    Sex differences exist in the structure and function of the cholinergic septo-hippocampal system throughout the lifespan of mammals. How and when these sex differences originate is unclear. Because estrogen modulates sexual differentiation of several brain regions during development and influences neurogenesis in adult mammals, we hypothesized that sexual dimorphism of the cholinergic septo-hippocampal system would extend to its neurogenesis. A birthdating agent 5'-bromo-2'-deoxyuridine (BrdU) was injected into pregnant dams on one of eight gestational days, ranging from embryonic day (E)10 to E17. The offspring were euthanized at 2 months of age, and brains were processed for BrdU and choline acetyltransferase (ChAT) immunoreactivity to label cholinergic neurons that became postmitotic on a given embryonic day and survived to adulthood. Unbiased stereology was used to compare the number of double-labeled neurons in the medial septum (MS) of female and male offspring. Cholinergic neurons in the MS were generated primarily between E11 and E14, similar to other published reports. We found sex differences in the pattern of peak neurogenesis but not in the length of neurogenesis, or in total number of neurons generated in the MS. Additionally, in adult female and male mice, we estimated the total number of cholinergic neurons using unbiased stereology and found no sex differences in the number of cholinergic neurons or in the volume of the MS in adulthood. These results suggest that sex differences noted in the function of the postnatal cholinergic septo-hippocampal system may originate from its neurogenesis.

  18. Anosmin-1 over-expression increases adult neurogenesis in the subventricular zone and neuroblast migration to the olfactory bulb.

    PubMed

    García-González, Diego; Murcia-Belmonte, Verónica; Esteban, Pedro F; Ortega, Felipe; Díaz, David; Sánchez-Vera, Irene; Lebrón-Galán, Rafael; Escobar-Castañondo, Laura; Martínez-Millán, Luis; Weruaga, Eduardo; García-Verdugo, José Manuel; Berninger, Benedikt; de Castro, Fernando

    2016-01-01

    New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over-expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB. PMID:25300351

  19. Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus.

    PubMed

    Inoue, Koshiro; Okamoto, Masahiro; Shibato, Junko; Lee, Min Chul; Matsui, Takashi; Rakwal, Randeep; Soya, Hideaki

    2015-01-01

    Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this

  20. Long-Term Mild, rather than Intense, Exercise Enhances Adult Hippocampal Neurogenesis and Greatly Changes the Transcriptomic Profile of the Hippocampus

    PubMed Central

    Inoue, Koshiro; Okamoto, Masahiro; Shibato, Junko; Lee, Min Chul; Matsui, Takashi; Rakwal, Randeep; Soya, Hideaki

    2015-01-01

    Our six-week treadmill running training (forced exercise) model has revealed that mild exercise (ME) with an intensity below the lactate threshold (LT) is sufficient to enhance spatial memory, while intense exercise (IE) above the LT negates such benefits. To help understand the unrevealed neuronal and signaling/molecular mechanisms of the intensity-dependent cognitive change, in this rat model, we here investigated plasma corticosterone concentration as a marker of stress, adult hippocampal neurogenesis (AHN) as a potential contributor to this ME-induced spatial memory, and comprehensively delineated the hippocampal transcriptomic profile using a whole-genome DNA microarray analysis approach through comparison with IE. Results showed that only IE had the higher corticosterone concentration than control, and that the less intense exercise (ME) is better suited to improve AHN, especially in regards to the survival and maturation of newborn neurons. DNA microarray analysis using a 4 × 44 K Agilent chip revealed that ME regulated more genes than did IE (ME: 604 genes, IE: 415 genes), and only 41 genes were modified with both exercise intensities. The identified molecular components did not comprise well-known factors related to exercise-induced AHN, such as brain-derived neurotrophic factor. Rather, network analysis of the data using Ingenuity Pathway Analysis algorithms revealed that the ME-influenced genes were principally related to lipid metabolism, protein synthesis and inflammatory response, which are recognized as associated with AHN. In contrast, IE-influenced genes linked to excessive inflammatory immune response, which is a negative regulator of hippocampal neuroadaptation, were identified. Collectively, these results in a treadmill running model demonstrate that long-term ME, but not of IE, with minimizing running stress, has beneficial effects on increasing AHN, and provides an ME-specific gene inventory containing some potential regulators of this

  1. The male sex pheromone darcin stimulates hippocampal neurogenesis and cell proliferation in the subventricular zone in female mice

    PubMed Central

    Hoffman, Emma; Pickavance, Lucy; Thippeswamy, Thimmasettappa; Beynon, Robert J.; Hurst, Jane L.

    2015-01-01

    The integration of newly generated neurons persists throughout life in the mammalian olfactory bulb and hippocampus, regions involved in olfactory and spatial learning. Social cues can be potent stimuli for increasing adult neurogenesis; for example, odors from dominant but not subordinate male mice increase neurogenesis in both brain regions of adult females. However, little is known about the role of neurogenesis in social recognition or the assessment of potential mates. Dominant male mice scent-mark territories using urine that contains a number of pheromones including darcin (MUP20), a male-specific major urinary protein that stimulates rapid learned attraction to the spatial location and individual odor signature of the scent owner. Here we investigate whether exposure to darcin stimulates neurogenesis in the female brain. Hippocampal neurons and cellular proliferation in the lateral ventricles that supply neurons to the olfactory bulbs increased in females exposed for 7 days to male urine containing at least 0.5 μg/μl darcin. Darcin was effective whether presented alone or in the context of male urine, but other information in male urine appeared to modulate the proliferative response. When exposed to urine from wild male mice, hippocampal proliferation increased only if urine was from the same individual over 7 days, suggesting that consistency of individual scent signatures is important. While 7 days exposure to male scent initiated the first stages of increased neurogenesis, this caused no immediate increase in female attraction to the scent or in the strength or robustness of spatial learning in short-term conditioned place preference tests. The reliable and consistent stimulation of neurogenesis by a pheromone important in rapid social learning suggests that this may provide an excellent model to explore the relationship between the integration of new neurons and plasticity in spatial and olfactory learning in a socially-relevant context. PMID

  2. Effects of the alpha 2-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death.

    PubMed

    Bauer, S; Moyse, E; Jourdan, F; Colpaert, F; Martel, J C; Marien, M

    2003-01-01

    A dysfunction of noradrenergic mechanisms originating in the locus coeruleus has been hypothesised to be the critical factor underlying the evolution of central neurodegenerative diseases [Colpaert FC (1994) Noradrenergic mechanism Parkinson's disease: a theory. In: Noradrenergic mechanisms in Parkinson's disease (Briley M, Marien M, eds) pp 225-254. Boca Raton, FL, USA: CRC Press Inc.]. alpha(2)-Adrenoceptor antagonists, presumably in part by facilitating central noradrenergic transmission, afford neuroprotection in vivo in models of cerebral ischaemia, excitotoxicity and devascularization-induced neurodegeneration. The present study utilised the rat olfactory bulb as a model system for examining the effects of the selective alpha(2)-adrenoceptor antagonist dexefaroxan upon determinants of neurogenesis (proliferation, survival and death) in the adult brain in vivo. Cell proliferation (5-bromo-2'-deoxyuridine labelling) and cell death associated with DNA fragmentation (terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling assay) were quantified following a 7-day treatment with either vehicle or dexefaroxan (0.63 mg/kg i.p., three times daily), followed by a 3-day washout period. The number of terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling-positive nuclei in the olfactory bulb was lower in dexefaroxan-treated rats, this difference being greatest and significant in the subependymal layer (-52%). In contrast, 5-bromo-2'-deoxyuridine-immunoreactive nuclei were more numerous (+68%) in the bulbs of dexefaroxan-treated rats whilst no differences were detected in the proliferating region of the subventricular zone. Terminal dideoxynucleotidyl transferase-catalysed 2'-deoxyuridine-5'-triphosphate nick end-labelling combination with glial fibrillary acidic protein or neuronal-specific antigen immunohistochemistry revealed that terminal dideoxynucleotidyl transferase

  3. Iptakalim confers an antidepressant effect in a chronic mild stress model of depression through regulating neuro-inflammation and neurogenesis.

    PubMed

    Lu, Ming; Yang, Jing-Zhe; Geng, Fan; Ding, Jian-Hua; Hu, Gang

    2014-09-01

    Depression is a serious mental disorder in the world, but the underlying mechanisms remain unclear and the effective cures are scarce. Iptakalim (Ipt), an ATP-sensitive potassium (K-ATP) channel opener that can cross the blood-brain barrier freely, has been demonstrated to inhibit neuro-inflammation and enhance adult hippocampal neurogenesis. But it is unknown whether Ipt is beneficial to therapy of depression by modulating neurogenesis and neuro-inflammation. This study aimed to determine the potential antidepressant efficacy of Ipt in a chronic mild stress (CMS) mouse model of depression. We showed that treatment with Ipt (10 mg/kg/day, i.p) for 4 wk restored the decrease of sucrose preference and shortened the immobile time in forced swimming tests (FST) and tail suspension tests (TST) in CMS model mice. We further found that Ipt reversed the CMS-induced reduction of the adult hippocampal neurogenesis and improved cerebral insulin signalling in the CMS mice. Furthermore, Ipt negatively regulated nod-like receptor protein 3 (NLRP3) expression and, in turn, inhibited microglia-mediated neuro-inflammation by suppressing the activation of NLRP3-inflammasome/caspase-1/interleukin 1β axis in the hippocampus of CMS mice. Taken together, our findings demonstrate that Ipt plays a potential antidepressant role in CMS model mice through regulating neuro-inflammation and neurogenesis, which will provide potential for Ipt in terms of opening up novel therapeutic avenues for depression.

  4. Mice lacking the PSD-95–interacting E3 ligase, Dorfin/Rnf19a, display reduced adult neurogenesis, enhanced long-term potentiation, and impaired contextual fear conditioning

    PubMed Central

    Park, Hanwool; Yang, Jinhee; Kim, Ryunhee; Li, Yan; Lee, Yeunkum; Lee, Chungwoo; Park, Jongil; Lee, Dongmin; Kim, Hyun; Kim, Eunjoon

    2015-01-01

    Protein ubiquitination has a significant influence on diverse aspects of neuronal development and function. Dorfin, also known as Rnf19a, is a RING finger E3 ubiquitin ligase implicated in amyotrophic lateral sclerosis and Parkinson’s disease, but its in vivo functions have not been explored. We report here that Dorfin is a novel binding partner of the excitatory postsynaptic scaffolding protein PSD-95. Dorfin-mutant (Dorfin−/−) mice show reduced adult neurogenesis and enhanced long-term potentiation in the hippocampal dentate gyrus, but normal long-term potentiation in the CA1 region. Behaviorally, Dorfin−/− mice show impaired contextual fear conditioning, but normal levels of cued fear conditioning, fear extinction, spatial learning and memory, object recognition memory, spatial working memory, and pattern separation. Using a proteomic approach, we also identify a number of proteins whose ubiquitination levels are decreased in the Dorfin−/− brain. These results suggest that Dorfin may regulate adult neurogenesis, synaptic plasticity, and contextual fear memory. PMID:26553645

  5. [The dentate gyrus neurogenesis: a common therapeutic target for Alzheimer disease and senile depression?].

    PubMed

    Tatebayashi, Yoshitaka

    2003-01-01

    Neurogenesis persistently occurs even in the adult dentate gyrus. Since most of the anti-depression therapies increase adult neurogenesis, suppressed neurogenesis has been proposed to be one of the candidate etiologies of depression. Here we show that Cerebrolysin, an anti-dementia drug that improves the activity of daily living of Alzheimer disease (AD) patients, can enhance neurogenesis and spatial learning of adult female rats. Regarding the anatomical importance of the dentate gyrus in AD pathogenesis and the frequent association of depressive symptoms in preclinical phase of AD, our finding suggests a possibility that AD involves suppressed neurogenesis causing the decreased activity of daily living. Pseudodementia might also involve suppressed neurogenesis but differ form AD since the neurodegenerative process in AD may be irreversible.

  6. Older adults, unlike younger adults, do not modulate alpha power to suppress irrelevant information.

    PubMed

    Vaden, Ryan J; Hutcheson, Nathan L; McCollum, Lesley A; Kentros, Jonathan; Visscher, Kristina M

    2012-11-15

    This study examines the neural mechanisms through which younger and older adults ignore irrelevant information, a process that is necessary to effectively encode new memories. Some age-related memory deficits have been linked to a diminished ability to dynamically gate sensory input, resulting in problems inhibiting the processing of distracting stimuli. Whereas oscillatory power in the alpha band (8-12 Hz) over visual cortical areas is thought to dynamically gate sensory input in younger adults, it is not known whether older adults use the same mechanism to gate out sensory input. Here we identified a task in which both older and younger adults could suppress the processing of irrelevant sensory stimuli, allowing us to use electroencephalography (EEG) to explore the neural activity associated with suppression of visual processing. As expected, we found that the younger adults' suppression of visual processing was correlated with robust modulation of alpha oscillatory power. However, older adults did not modulate alpha power to suppress processing of visual information. These results demonstrate that suppression of alpha power is not necessary to inhibit the processing of distracting stimuli in older adults, suggesting the existence of alternative strategies for suppressing irrelevant, potentially distracting information.

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

    ERIC Educational Resources Information Center

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

    2006-01-01

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

  8. Neurogenesis Interferes with the Retrieval of Remote Memories: Forgetting in Neurocomputational Terms

    ERIC Educational Resources Information Center

    Weisz, Victoria I.; Argibay, Pablo F.

    2012-01-01

    In contrast to models and theories that relate adult neurogenesis with the processes of learning and memory, almost no solid hypotheses have been formulated that involve a possible neurocomputational influence of adult neurogenesis on forgetting. Based on data from a previous study that implemented a simple but complete model of the main…

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

    PubMed Central

    Coplan, Jeremy D.; Perera, Tarique D.; Fulton, Sasha L.; Banerji, Mary Ann; Dwork, Andrew J.; Kral, John G.

    2014-01-01

    Glucagon-like peptide-1 (GLP-1) regulates carbohydrate metabolism and promotes neurogenesis. We reported an inverse correlation between adult body mass and neurogenesis in nonhuman primates. Here we examine relationships between physiological levels of the neurotrophic incretin, plasma GLP-1 (pGLP-1), and body mass index (BMI) in adolescence to adult neurogenesis and associations with a diabesity diathesis and infant stress. Morphometry, fasting pGLP-1, insulin resistance, and lipid profiles were measured in early adolescence in 10 stressed and 4 unstressed male bonnet macaques. As adults, dentate gyrus neurogenesis was assessed by doublecortin staining. High pGLP-1, low body weight, and low central adiposity, yet peripheral insulin resistance and high plasma lipids, during adolescence were associated with relatively high adult neurogenesis rates. High pGLP-1 also predicted low body weight with, paradoxically, insulin resistance and high plasma lipids. No rearing effects for neurogenesis rates were observed. We replicated an inverse relationship between BMI and neurogenesis. Adolescent pGLP-1 directly predicted adult neurogenesis. Two divergent processes relevant to human diabesity emerge—high BMI, low pGLP-1, and low neurogenesis and low BMI, high pGLP-1, high neurogenesis, insulin resistance, and lipid elevations. Diabesity markers putatively reflect high nutrient levels necessary for neurogenesis at the expense of peripheral tissues. PMID:25506432

  10. Ornithine-δ-Aminotransferase Inhibits Neurogenesis During Xenopus Embryonic Development

    PubMed Central

    Peng, Ying; Cooper, Sandra K.; Li, Yi; Mei, Jay M.; Qiu, Shuwei; Borchert, Gregory L.; Donald, Steven P.; Kung, Hsiang-fu; Phang, James M.

    2015-01-01

    Purpose. In humans, deficiency of ornithine-δ-aminotransferase (OAT) results in progressive degeneration of the neural retina (gyrate atrophy) with blindness in the fourth decade. In this study, we used the Xenopus embryonic developmental model to study functions of the OAT gene on embryonic development. Methods. We cloned and sequenced full-length OAT cDNA from Xenopus oocytes (X-OAT) and determined X-OAT expression in various developmental stages of Xenopus embryos and in a variety of adult tissues. The phenotype, gene expression of neural developmental markers, and enzymatic activity were detected by gain-of-function and loss-of-function manipulations. Results. We showed that X-OAT is essential for Xenopus embryonic development, and overexpression of X-OAT produces a ventralized phenotype characterized by a small head, lack of axial structure, and defective expression of neural developmental markers. Using X-OAT mutants based on mutations identified in humans, we found that substitution of both Arg 180 and Leu 402 abrogated both X-OAT enzymatic activity and ability to modulate the developmental phenotype. Neurogenesis is inhibited by X-OAT during Xenopus embryonic development. Conclusions. Neurogenesis is inhibited by X-OAT during Xenopus embryonic development, but it is essential for Xenopus embryonic development. The Arg 180 and Leu 402 are crucial for these effects of the OAT molecule in development. PMID:25783604

  11. BDNF isoforms: a round trip ticket between neurogenesis and serotonin?

    PubMed

    Foltran, Rocío Beatriz; Diaz, Silvina Laura

    2016-07-01

    The brain-derived neurotrophic factor, BDNF, was discovered more than 30 years ago and, like other members of the neurotrophin family, this neuropeptide is synthetized as a proneurotrophin, the pro-BDNF, which is further cleaved to yield mature BDNF. The myriad of actions of these two BDNF isoforms in the central nervous system is constantly increasing and requires the development of sophisticated tools and animal models to refine our understanding. This review is focused on BDNF isoforms, their participation in the process of neurogenesis taking place in the hippocampus of adult mammals, and the modulation of their expression by serotonergic agents. Interestingly, around this triumvirate of BDNF, serotonin, and neurogenesis, a series of recent research has emerged with apparently counterintuitive results. This calls for an exhaustive analysis of the data published so far and encourages thorough work in the quest for new hypotheses in the field. BDNF is synthetized as a pre-proneurotrophin. After removal of the pre-region, proBDNF can be cleaved by intracellular or extracellular proteases. Mature BDNF can bind TrkB receptors, promoting their homodimerization and intracellular phosphorylation. Phosphorylated-TrkB can activate three different signaling pathways. Whereas G-protein-coupled receptors can transactivate TrkB receptors, truncated forms can inhibit mBDNF signaling. Pro-BDNF binds p75(NTR) by its mature domain, whereas the pro-region binds co-receptors.

  12. Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo

    PubMed Central

    Brönnimann, Daniel; Dellenbach, Christian; Saveljic, Igor; Rieger, Michael; Rohr, Stephan; Filipovic, Nenad; Djonov, Valentin

    2016-01-01

    Introduction Hemodynamic parameters in zebrafish receive increasing attention because of their important role in cardiovascular processes such as atherosclerosis, hematopoiesis, sprouting and intussusceptive angiogenesis. To study underlying mechanisms, the precise modulation of parameters like blood flow velocity or shear stress is centrally important. Questions related to blood flow have been addressed in the past in either embryonic or ex vivo-zebrafish models but little information is available for adult animals. Here we describe a pharmacological approach to modulate cardiac and hemodynamic parameters in adult zebrafish in vivo. Materials and Methods Adult zebrafish were paralyzed and orally perfused with salt water. The drugs isoprenaline and sodium nitroprusside were directly applied with the perfusate, thus closely resembling the preferred method for drug delivery in zebrafish, namely within the water. Drug effects on the heart and on blood flow in the submental vein were studied using electrocardiograms, in vivo-microscopy and mathematical flow simulations. Results Under control conditions, heart rate, blood flow velocity and shear stress varied less than ± 5%. Maximal chronotropic effects of isoprenaline were achieved at a concentration of 50 μmol/L, where it increased the heart rate by 22.6 ± 1.3% (n = 4; p < 0.0001). Blood flow velocity and shear stress in the submental vein were not significantly increased. Sodium nitroprusside at 1 mmol/L did not alter the heart rate but increased blood flow velocity by 110.46 ± 19.64% (p = 0.01) and shear stress by 117.96 ± 23.65% (n = 9; p = 0.03). Discussion In this study, we demonstrate that cardiac and hemodynamic parameters in adult zebrafish can be efficiently modulated by isoprenaline and sodium nitroprusside. Together with the suitability of the zebrafish for in vivo-microscopy and genetic modifications, the methodology described permits studying biological processes that are dependent on hemodynamic

  13. Chronic exposure to WIN55,212-2 affects more potently spatial learning and memory in adolescents than in adult rats via a negative action on dorsal hippocampal neurogenesis.

    PubMed

    Abboussi, Oualid; Tazi, Abdelouahhab; Paizanis, Eleni; El Ganouni, Soumaya

    2014-05-01

    Several epidemiological studies show an increase in cannabis use among adolescents, especially in Morocco for being one of the major producers in the world. The neurobiological consequences of chronic cannabis use are still poorly understood. In addition, brain plasticity linked to ontogeny portrays adolescence as a period of vulnerability to the deleterious effects of drugs. The aim of this study was to investigate the behavioral neurogenic effects of chronic exposure to the cannabinoid agonist WIN55,212-2 during adolescence, by evaluating the emotional and cognitive performances, and the consequences on neurogenesis along the dorso-ventral axis of the hippocampus in adult rats. WIN55,212 was administered intraperitoneally (i.p.) once daily for 20 days to adolescent (27-30 PND) and adult Wistar rats (54-57 PND) at the dose of 1mg/kg. Following a 20 day washout period, emotional and cognitive functions were assessed by the Morris water maze test and the two-way active avoidance test. Twelve hours after, brains were removed and hippocampal neurogenesis was assessed using the doublecortin (DCX) as a marker for cell proliferation. Our results showed that chronic WIN55,212-2 treatment significantly increased thigmotaxis early in the training process whatever the age of treatment, induced spatial learning and memory deficits in adolescent but not adult rats in the Morris water maze test, while it had no significant effect in the active avoidance test during multitrial training in the shuttle box. In addition, the cognitive deficits assessed in adolescent rats were positively correlated to a decrease in the number of newly generated neurons in dorsal hippocampus. These data suggest that long term exposure to cannabinoids may affect more potently spatial learning and memory in adolescent compared to adult rats via a negative action on hippocampal plasticity.

  14. Chronic hypoxia induces the activation of the Wnt/β-catenin signaling pathway and stimulates hippocampal neurogenesis in wild-type and APPswe-PS1ΔE9 transgenic mice in vivo

    PubMed Central

    Varela-Nallar, Lorena; Rojas-Abalos, Macarena; Abbott, Ana C.; Moya, Esteban A.; Iturriaga, Rodrigo; Inestrosa, Nibaldo C.

    2014-01-01

    Hypoxia modulates proliferation and differentiation of cultured embryonic and adult stem cells, an effect that includes β-catenin, a key component of the canonical Wnt signaling pathway. Here we studied the effect of mild hypoxia on the activity of the Wnt/β-catenin signaling pathway in the hippocampus of adult mice in vivo. The hypoxia-inducible transcription factor-1α (HIF-1α) was analyzed as a molecular control of the physiological hypoxic response. Exposure to chronic hypoxia (10% oxygen for 6–72 h) stimulated the activation of the Wnt/β-catenin signaling pathway. Because the Wnt/β-catenin pathway is a positive modulator of adult neurogenesis, we evaluated whether chronic hypoxia was able to stimulate neurogenesis in the subgranular zone (SGZ) of the hippocampal dentate gyrus. Results indicate that hypoxia increased cell proliferation and neurogenesis in adult wild-type mice as determined by Ki67 staining, Bromodeoxyuridine (BrdU) incorporation and double labeling with doublecortin (DCX). Chronic hypoxia also induced neurogenesis in a double transgenic APPswe-PS1ΔE9 mouse model of Alzheimer’s disease (AD), which shows decreased levels of neurogenesis in the SGZ. Our results show for the first time that exposure to hypoxia in vivo can induce the activation of the Wnt/β-catenin signaling cascade in the hippocampus, suggesting that mild hypoxia may have a therapeutic value in neurodegenerative disorders associated with altered Wnt signaling in the brain and also in pathological conditions in which hippocampal neurogenesis is impaired. PMID:24574965

  15. Epigenetics, hippocampal neurogenesis, and neuropsychiatric disorders: unraveling the genome to understand the mind

    PubMed Central

    Hsieh, Jenny; Eisch, Amelia J.

    2010-01-01

    In mature, differentiated neurons in the central nervous system (CNS), epigenetic mechanisms – including DNA methylation, histone modification, and regulatory noncoding RNAs – play critical roles in encoding experience and environmental stimuli into stable, behaviorally-meaningful changes in gene expression. For example, epigenetic changes in mature hippocampal neurons have been implicated in learning and memory and in a variety of neuropsychiatric disorders, including depression. With all the recent (and warranted) attention given to epigenetic modifications in mature neurons, it is easy to forget that epigenetic mechanisms were initially described for their ability to promote differentiation and drive cell fate in embryonic and early postnatal development, including neurogenesis. Given the discovery of ongoing neurogenesis in the adult brain and the intriguing links among adult hippocampal neurogenesis, hippocampal function, and neuropsychiatric disorders, it is timely to complement the ongoing discussions on the role of epigenetics in mature neurons with a review on what is currently known about the role of epigenetics in adult hippocampal neurogenesis. The process of adult hippocampal neurogenesis is complex, with neural stem cells (NSCs) giving rise to fate-restricted progenitors and eventually mature dentate gyrus granule cells. Notably, neurogenesis occurs within an increasingly well-defined “neurogenic niche”, where mature cellular elements like vasculature, astrocytes, and neurons release signals that can dynamically regulate neurogenesis. Here we review the evidence that key stages and aspects of adult neurogenesis are driven by epigenetic mechanisms. We discuss the intrinsic changes occurring within NSCs and their progeny that are critical for neurogenesis. We also discuss how extrinsic changes occurring in cellular components in the niche can result in altered neurogenesis. Finally we describe the potential relevance of epigenetics for

  16. Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain

    PubMed Central

    Pineda, Jose R; Daynac, Mathieu; Chicheportiche, Alexandra; Cebrian-Silla, Arantxa; Sii Felice, Karine; Garcia-Verdugo, Jose Manuel; Boussin, François D; Mouthon, Marc-André

    2013-01-01

    Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging. PMID:23526803

  17. Effects of Neurotrophic Support and Amyloid-Targeted Combined Therapy on Adult Hippocampal Neurogenesis in a Transgenic Model of Alzheimer's Disease

    PubMed Central

    Brown, Mary E.; Aubert, Isabelle; McLaurin, JoAnne

    2016-01-01

    Although it is recognized that multi-drug therapies may be necessary to combat AD, there is a paucity of preclinical proof of concept studies. We present a combination treatment paradigm, which temporally affects different aspects of Alzheimer’s disease (AD)-like pathology, specifically Aβ-toxicity and neurogenesis. At early stages of AD-like pathology, in TgCRND8 mice, we found that combating Aβ pathology with scyllo-inositol ameliorated deficits in neurogenesis. Older TgCRND8 mice with established amyloid load had decreased progenitor cell proliferation and survival compared to non-transgenic mice, regardless of scyllo-inositol treatment. The prolonged exposure to Aβ-pathology leads to deficits in the neurogenic niche, thus targeting Aβ alone is insufficient to rescue neurogenesis. To support the neurogenic niche, we combined scyllo-inositol treatment with leteprinim potassium (neotrofin), the latter of which stimulates neurotrophin expression. We show that the combination treatment of scyllo-inositol and neotrofin enhances neuronal survival and differentiation. We propose this proof of concept combination therapy of targeting Aβ-pathology and neurotrophin deficits as a potential treatment for AD. PMID:27768761

  18. Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia.

    PubMed

    Mattei, Daniele; Djodari-Irani, Anaïs; Hadar, Ravit; Pelz, Andreas; de Cossío, Lourdes Fernandez; Goetz, Thomas; Matyash, Marina; Kettenmann, Helmut; Winter, Christine; Wolf, Susanne A

    2014-05-01

    Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1β and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.

  19. Borna Disease Virus Phosphoprotein Impairs the Developmental Program Controlling Neurogenesis and Reduces Human GABAergic Neurogenesis

    PubMed Central

    Scordel, Chloé; Szelechowski, Marion; Poulet, Aurélie; Richardson, Jennifer; Benchoua, Alexandra; Gonzalez-Dunia, Daniel; Eloit, Marc; Coulpier, Muriel

    2015-01-01

    It is well established that persistent viral infection may impair cellular function of specialized cells without overt damage. This concept, when applied to neurotropic viruses, may help to understand certain neurologic and neuropsychiatric diseases. Borna disease virus (BDV) is an excellent example of a persistent virus that targets the brain, impairs neural functions without cell lysis, and ultimately results in neurobehavioral disturbances. Recently, we have shown that BDV infects human neural progenitor cells (hNPCs) and impairs neurogenesis, revealing a new mechanism by which BDV may interfere with brain function. Here, we sought to identify the viral proteins and molecular pathways that are involved. Using lentiviral vectors for expression of the bdv-p and bdv-x viral genes, we demonstrate that the phosphoprotein P, but not the X protein, diminishes human neurogenesis and, more particularly, GABAergic neurogenesis. We further reveal a decrease in pro-neuronal factors known to be involved in neuronal differentiation (ApoE, Noggin, TH and Scg10/Stathmin2), demonstrating that cellular dysfunction is associated with impairment of specific components of the molecular program that controls neurogenesis. Our findings thus provide the first evidence that a viral protein impairs GABAergic human neurogenesis, a process that is dysregulated in several neuropsychiatric disorders. They improve our understanding of the mechanisms by which a persistent virus may interfere with brain development and function in the adult. PMID:25923687

  20. Nutrition and the Older Adult. Module A-9. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on nutrition and the older adult is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Five sections present…

  1. Confusion and the Older Adult. Module A-8. Block A. Basic Knowledge of the Aging Process.

    ERIC Educational Resources Information Center

    Harvey, Dexter; Cap, Orest

    This instructional module on confusion and the older adult is one in a block of 10 modules designed to provide the human services worker who works with older adults with basic information regarding the aging process. An introduction provides an overview of the module content. A listing of general objectives follows. Three sections present…

  2. Effects of Microglia on Neurogenesis.

    PubMed

    Sato, Kaoru

    2015-08-01

    This review summarizes and organizes the literature concerning the effects of microglia on neurogenesis, particularly focusing on the subgranular zone (SGZ) of the hippocampus and subventricular zone (SVZ) of the lateral ventricles, in which the neurogenic potential is progressively restricted during the life of the organism. A comparison of microglial roles in neurogenesis in these two regions indicates that microglia regulate neurogenesis in a temporally and spatially specific manner. Microglia may also sense signals from the surrounding environment and have regulatory effects on neurogenesis. We speculate microglia function as a hub for the information obtained from the inner and outer brain regions for regulating neurogenesis.

  3. A novel phosphodiesterase-5 Inhibitor: Yonkenafil