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

Hippocampal neurogenesis continues into adulthood in mammalian vertebrates, and in experimental rodent models it is powerfully stimulated by exposure to a voluntary running wheel. In this study, we demonstrate that exposure to a running wheel environment, in the absence of running, is sufficient to regulate specific aspects of hippocampal neurogenesis. Adult mice were provided with standard housing, housing enriched with a running wheel or housing enriched with a locked wheel (i.e., an environment comparable to that of running animals, without the possibility of engaging in running). We found that mice in the running wheel and locked wheel groups exhibited equivalent increases in proliferation within the neurogenic niche of the dentate gyrus; this included comparable increases in the proliferation of radial glia‐like stem cells and the number of proliferating neuroblasts. However, only running animals displayed increased numbers of postmitotic neuroblasts and mature neurons. These results demonstrate that the running wheel environment itself is sufficient for promoting proliferation of early lineage hippocampal precursors, while running per se enables newly generated neuroblasts to survive and mature into functional hippocampal neurons. Thus, both running‐independent and running‐dependent stimuli are integral to running wheel‐induced hippocampal neurogenesis. © 2010 Wiley Periodicals, Inc.     

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

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.     

Modulation of adult hippocampal neurogenesis during myelin-directed autoimmune neuroinflammation

In chronic autoimmune diseases of the central nervous system (CNS) such as multiple sclerosis (MS) clinical signs of cognitive dysfunction have been associated with structural changes in the hippocampus. Moreover, experimental studies indicate that inflammatory responses within the CNS modulate the homeostasis of newborn cells in the adult dentate gyrus (DG). However, it remained open whether such changes happen regardless of the primary immunological target or whether a CNS antigen-directed T lymphocyte-mediated autoimmune response may exert a specific impact. We therefore induced experimental autoimmune encephalomyelitis (EAE), a common model of MS serving as a paradigm for a CNS-specific immune response, by immunizing C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG) p35-55. In EAE animals, we found enhanced de novo generation and survival of doublecortin (DCX)-positive immature neurons when compared with controls immunized with CNS-irrelevant antigen (ovalbumine). However, despite activation of neurogenesis, we observed a reduced capacity of these cells to generate mature neurons. Moreover, the high number of newly born cells retained the expression of the glial marker GFAP. These effects were associated with downregulation of pro-neurogenic factors Neurogenin1 and Neurogenin2 and dysregulation of Notch, β-catenin, Sonic Hedgehog (Shh) signaling as suggested by altered gene expression of effector molecules. Thus, a CNS antigen-specific immune response leads to an aberrant differentiation of neural precursors associated with dysbalance of signaling pathways relevant for adult hippocampal neurogenesis. These results may further extend our understanding of disturbed regeneration in the course of chronic inflammatory CNS diseases such as MS.     

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

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.     

Methods to study adult hippocampal neurogenesis in humans and across the phylogeny

The hippocampus hosts the continuous addition of new neurons throughout life—a phenomenon named adult hippocampal neurogenesis (AHN). Here we revisit the occurrence of AHN in more than 110 mammalian species, including humans, and discuss the further validation of these data by single-cell RNAseq and other alternative techniques. In this regard, our recent studies have addressed the long-standing controversy in the field, namely whether cells positive for AHN markers are present in the adult human dentate gyrus (DG). Here we review how we developed a tightly controlled methodology, based on the use of high-quality brain samples (characterized by short postmortem delays and ≤24 h of fixation in freshly prepared 4% paraformaldehyde), to address human AHN. We review that the detection of AHN markers in samples fixed for 24 h required mild antigen retrieval and chemical elimination of autofluorescence. However, these steps were not necessary for samples subjected to shorter fixation periods. Moreover, the detection of labile epitopes (such as Nestin) in the human hippocampus required the use of mild detergents. The application of this strictly controlled methodology allowed reconstruction of the entire AHN process, thus revealing the presence of neural stem cells, proliferative progenitors, neuroblasts, and immature neurons at distinct stages of differentiation in the human DG. The data reviewed here demonstrate that methodology is of utmost importance when studying AHN by means of distinct techniques across the phylogenetic scale. In this regard, we summarize the major findings made by our group that emphasize that overlooking fundamental technical principles might have consequences for any given research field.     

Alpha-tocopherol,an exogenous factor of adult hippocampal neurogenesis regulation

In previous work, we found that adult hippocampal neurogenesis in rat is affected by vitamin E deficiency. Because vitamin E deficiency is a complex condition involving numerous biological systems, it is possible that its effect on postnatal new neuron production could be mediated by unknown changes in different factors that in turn play a role in this process. To clarify if vitamin E plays a direct role in regulating hippocampal neurogenesis, we studied the neurogenesis in adult control rats and in adult rats under supplementation with alpha-tocopherol, the most important compound of vitamin E. The alpha-tocopherol level in control and supplemented rats was monitored. Qualitative and quantitative analysis of cell proliferation and death was carried out and expression of immature neuron markers PSA-NCAM, TUC 4, and DCX was investigated in hippocampus dentate gyrus. alpha-Tocopherol levels increased significantly in both plasma and brain after supplementation. Cell proliferation was inhibited in alpha-tocopherol-supplemented rats, the number of dying cells was reduced, and the number of cells expressing the immature neuron markers was increased. The results obtained confirm and extend the idea that vitamin E is an exogenous factor playing a direct role in regulation of different steps of adult hippocampal neurogenesis. Some hypotheses about the possible mechanisms underlying the complex action of alpha-tocopherol, related to its antioxidant and molecule-specific non-antioxidant properties, are proposed and discussed.     

Adult hippocampal neurogenesis and voluntary running activity: circadian and dose-dependent effects

Running activity increases cell proliferation and neurogenesis in the dentate gyrus of adult mice. The present experiment was designed to investigate whether the effect of activity on adult neurogenesis is dependent on the time of day (circadian phase) and the amount of activity. Mice received restricted access to a running wheel (0, 1, or 3 hr) at one of three times of day: the middle of the light phase (i.e., when mice are normally inactive), dark onset (i.e., when mice begin their nocturnal activity), and the middle of the dark period (i.e., when mice are in the middle of their active period). Cell proliferation and net neurogenesis were assessed after incorporation of the thymidine analog bromodeoxyuridine (BrdU) and immunohistochemical detection of BrdU and neuronal markers. Running activity significantly increased cell proliferation, cell survival, and total number of new neurons only in animals with 3 hr of wheel access during the middle of the dark period. Although activity was positively correlated with increased neurogenesis at all time points, the effects were not statistically significant in animals with wheel access at the beginning of the dark period or during the middle of the light period. These data suggest that the influence of exercise on cell proliferation and neurogenesis is modulated by both circadian phase and the amount of daily exercise, thus providing new insight into the complex relationship between physiological and behavioral factors that can mediate adult neuroplasticity.     

Cell population dynamics in the course of adult hippocampal neurogenesis: Remaining unknowns

Neural stem cells (NSCs) generate new neurons throughout life in the mammalian hippocampus. The distinct developmental steps in the course of adult neurogenesis, including NSC activation, expansion, and neuronal integration, are increasingly well characterized down to the molecular level. However, substantial gaps remain in our knowledge about regulators and mechanisms involved in this biological process. This review highlights three long-standing unknowns. First, we discuss potency and identity of NSCs and the quest for a unifying model of short- and long-term self-renewal dynamics. Next, we examine cell death, specifically focusing on the early demise of newborn cells. Then, we outline the current knowledge on cell integration dynamics, discussing which (if any) neurons are replaced by newly added neurons in the hippocampal circuits. For each of these unknowns, we summarize the trajectory of studies leading to the current state of knowledge. Finally, we offer suggestions on how to fill the remaining gaps by taking advantage of novel technology to reveal currently hidden secrets in the course of adult hippocampal neurogenesis.     

Paternal experience suppresses adult neurogenesis without altering hippocampal function in Peromyscus californicus

Paternal care is rare among mammals, occurring in ≈6% of species. California mice (Peromyscus californicus) are unusual; fathers participate extensively in raising their young and display the same components of parental care as mothers, with the exception of nursing. Parenting is a complex experience, having stressful and enriching aspects. The hippocampus is sensitive to experience and responds to both stress and environmental enrichment with changes in structure and function. In rats, where females care exclusively for offspring, parenting is associated with suppressed hippocampal adult neurogenesis. Since this effect has been causally linked to lactation, it is unlikely that fathers would show a similar change. To investigate this issue, we examined adult neurogenesis in the hippocampus of California mouse fathers compared to males without pups and observed reduced adult neurogenesis. Similar effects were found in California mouse mothers. Next, we investigated whether behaviors linked to the hippocampus, namely, object recognition and novelty-suppressed feeding, were altered in fathers, and observed no substantial changes. During caregiving, suppressed adult neurogenesis does not appear to be related to changes in behaviors associated with the hippocampus, although it is possible that there are other effects on hippocampal function.     

Environmental enrichment and physical exercise revert behavioral and electrophysiological impairments caused by reduced adult neurogenesis

It is well known that adult neurogenesis occurs in two distinct regions, the subgranular zone of the dentate gyrus and the subventricular zone along the walls of the lateral ventricles. Until now, the contribution of these newly born neurons to behavior and cognition is still uncertain. The current study tested the functional impacts of diminished hippocampal neurogenesis on emotional and cognitive functions in transgenic Gfap‐tk mice. Our results showed that anxiety‐related behavior evaluated both in the elevated plus maze as well as in the open field, social interaction in the sociability test, and spatial working memory in the spontaneous alternation test were not affected. On the other hand, recognition and emotional memory in the object recognition test and contextual fear conditioning, and hippocampal long‐term potentiation were impaired in transgenic mice. Furthermore, we evaluated whether environmental enrichment together with physical exercise could improve or even restore the level of adult neurogenesis, as well as the behavioral functions. Our results clearly demonstrated that environmental enrichment together with physical exercise successfully elevated the overall number of progenitor cells and young neurons in the dentate gyrus of transgenic mice. Furthermore, it led to a significant improvement in object recognition memory and contextual fear conditioning, and reverted impairments in hippocampal long‐term potentiation. Thus, our results confirm the importance of adult neurogenesis for learning and memory processes and for hippocampal circuitry in general. Environmental enrichment and physical exercise beneficially influenced adult neurogenesis after it had been disrupted and most importantly recovered cognitive functions and long‐term potentiation. © 2016 Wiley Periodicals, Inc.     

Ablation of proliferating neural stem cells during early life is sufficient to reduce adult hippocampal neurogenesis

Environmental exposures during early life, but not during adolescence or adulthood, lead to persistent reductions in neurogenesis in the adult hippocampal dentate gyrus (DG). The mechanisms by which early life exposures lead to long‐term deficits in neurogenesis remain unclear. Here, we investigated whether targeted ablation of dividing neural stem cells during early life is sufficient to produce long‐term decreases in DG neurogenesis. Having previously found that the stem cell lineage is resistant to long‐term effects of transient ablation of dividing stem cells during adolescence or adulthood (Kirshenbaum, Lieberman, Briner, Leonardo, & Dranovsky, 2014 ), we used a similar pharmacogenetic approach to target dividing neural stem cells for elimination during early life periods sensitive to environmental insults. We then assessed the Nestin stem cell lineage in adulthood. We found that the adult neural stem cell reservoir was depleted following ablation during the first postnatal week, when stem cells were highly proliferative, but not during the third postnatal week, when stem cells were more quiescent. Remarkably, ablating proliferating stem cells during either the first or third postnatal week led to reduced adult neurogenesis out of proportion to the changes in the stem cell pool, indicating a disruption of the stem cell function or niche following stem cell ablation in early life. These results highlight the first three postnatal weeks as a series of sensitive periods during which elimination of dividing stem cells leads to lasting alterations in adult DG neurogenesis and stem cell function. These findings contribute to our understanding of the relationship between DG development and adult neurogenesis, as well as suggest a possible mechanism by which early life experiences may lead to lasting deficits in adult hippocampal neurogenesis.     

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

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.     

Differential effects of adolescent and adult‐initiated exercise on cognition and hippocampal neurogenesis

Adolescence is a critical period for postnatal brain maturation and thus a time when environmental influences may affect cognitive processes in later life. Exercise during adulthood has been shown to increase hippocampal neurogenesis and enhance cognition. However, the impact of exercise initiated in adolescence on the brain and behavior in adulthood is not fully understood. The aim of this study was to compare the impact of voluntary exercise that is initiated during adolescence or early adulthood on cognitive performance in hippocampal‐dependent and ‐independent processes using both object‐based and touchscreen operant paradigms. Adult (8 week) and adolescent (4 week) male Sprague–Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for 4 weeks prior to behavioral testing and for the duration of the experiment. Results from touchscreen‐based tasks showed that reversal learning was enhanced by both adult and adolescent‐initiated exercise, while only exercise that began in adolescence induced a subtle but transient increase in performance on a location discrimination task. Spontaneous alternation in the Y‐maze was impaired following adolescent onset exercise, while object memory was unaffected by either adult or adolescent‐initiated exercise. Adolescent‐initiated exercise increased the number of hippocampal DCX cells, an indicator of neurogenesis. It also promoted the complexity of neurites on DCX cells, a key process for synaptic integration, to a greater degree than adult‐initiated exercise. Together the data here show that exercise during the adolescent period compared to adulthood differentially affects cognitive processes and the development of new hippocampal neurons in later life.     

Prolonged voluntary wheel‐running stimulates neural precursors in the hippocampus and forebrain of adult CD1 mice

Voluntary wheel‐running induces a rapid increase in proliferation and neurogenesis by neural precursors present in the adult rodent hippocampus. In contrast, the responses of hippocampal and other central nervous system neural precursors following longer periods of voluntary physical activity are unclear and are an issue of potential relevance to physical rehabilitation programs. We investigated the effects of a prolonged, 6‐week voluntary wheel‐running paradigm on neural precursors of the CD1 mouse hippocampus and forebrain. Examination of the hippocampus following 6 weeks of running revealed two to three times as many newly born neurons and 60% more proliferating cells when compared with standard‐housed control mice. Among running mice, the number of newly born neurons correlated with the total running distance. To establish the effects of wheel‐running on hippocampal precursors dividing during later stages of the prolonged running regime, BrdU was administered after 3 weeks of running and the BrdU‐retaining cells were analyzed 18 days later. Quantifications revealed that the effects of wheel‐running were maintained in late‐stage proliferating cells, as running mice had two to three times as many BrdU‐retaining cells within the hippocampal dentate gyrus, and these yielded greater proportions of both mature neurons and proliferative cells. The effects of prolonged wheel‐running were also detected beyond the hippocampus. Unlike short‐term wheel‐running, prolonged wheel‐running was associated with higher numbers of proliferating cells within the ventral forebrain subventricular region, a site of age‐associated decreases in neural precursor proliferation and neurogenesis. Collectively, these findings indicate that (i) prolonged voluntary wheel‐running maintains an increased level of hippocampal neurogenesis whose magnitude is linked to total running performance, and (ii) that it influences multiple neural precursor populations of the adult mouse brain. © 2009 Wiley‐Liss, Inc.     

Impairment of hippocampal neurogenesis in streptozotocin-treated diabetic rats

Objectives –  Adult neurogenesis in dentate gyrus (DG) is an evolutionarily preserved trait in most mammals examined thus far. Neuronal proliferation and subsequent integration of new neurons into the hippocampal circuit are regulated processes that can have profound effects on an animal's behaviour. A streptozotocin model of type I diabetes, characterized by low insulin and high plasma glucose levels, affects not only body's overall metabolism but also brain activity.
Materials and methods –  Neurogenesis was measured within the DG of the hippocampus using immunohistochemical markers Ki67, Doublecortin, Calbindin (CaBP) and bromodeoxyuridine (BrdU).
Results –  Cell proliferation, measured with the endogenous marker Ki67, was reduced by 45%, and cell survival, measured with BrdU, was reduced by 64% of the control. Combined effects on proliferation and survival produced dramatically lower neuronal production. Among the surviving cells only 33% matured normally as judged by the co-labelling of BrdU and CaBP.
Conclusion –  Such a reduction lowered the number of surviving cells with neuronal phenotype by over 80% of the control values and this is expected to cause a significant functional impairment of learning and memory in diabetic animals. These results may shed light on causes of diabetic neuropathology and provide an explanation for the memory deficiencies seen in some diabetic patients.     

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus (DG) neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrahippocampal microinjection of kainic acid (KA). Bromodeoxyuridine (BrdU) was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity: lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number (EN) in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.     

Effects of repeated phencyclidine administration on adult hippocampal neurogenesis in the rat

Dysfunctional maturation of neural networks, particularly hippocampus-prefrontal networks, may be of particular interest in determining the pathophysiology of schizophrenia. Phencyclidine (PCP)-induced symptoms in humans appear to offer a more complete model of schizophrenia than do amphetamine-induced symptoms. This study investigated the effects of intermittent i.p. injections of PCP (7.5 mg/kg) on cell proliferation and survival of granule cells in the dentate gyrus of the rat brain using quantitative immunohistochemical techniques for 5-bromo-2'-deoxyuridine (BrdU)-positive cells. After repeated PCP injection for 14 days, mean scores for stereotyped behavior increased with the number of injections, while scores for ataxia and backpedaling as serotonergic behaviors gradually decreased. The number of BrdU-positive cells decreased by 23% in the subgranular zone of the dentate gyrus by 24 h after repeated injections. However, decreased levels of BrdU-positive cells returned to control levels within 1 week. Differentiation of newly formed cells was not influenced. Repeated PCP administration after BrdU injection did not exert any effects on survival of newly generated cells. These findings suggest that transient disturbances of cell proliferation in the dentate gyrus occur under PCP-related behavioral abnormalities. Whether disturbed cell proliferation would thus be closely implicated in the development of behavioral sensitization induced by PCP administration is unclear, but this would possibly result from adaptation to new pharmacological conditions under behavioral sensitization or stressful conditions of PCP-related abnormal behaviors. Further studies are required to elucidate the biological significance of hippocampal neurogenesis in the mechanisms underlying the development of cognitive dysfunctions and the psychosis of schizophrenia.     

Effects of exercise on neurogenesis in the dentate gyrus and ability of learning and memory after hippocampus lesion in adult rats

Objective To explore the effects of exercise on dentate gyrus （DG） neurogenesis and the ability of learning and memory in hippocampus-lesioned adult rats. Methods Hippocampus lesion was produced by intrabippocampal microinjection of kainic acid （KA）. Bromodeoxyuridine （BrdU） was used to label dividing cells. Y maze test was used to evaluate the ability of learning and memory. Exercise was conducted in the form of forced running in a motor-driven running wheel. The speed of wheel revolution was regulated at 3 kinds of intensity： lightly running, moderately running, or heavily running. Results Hippocampus lesion could increase the number of BrdU-labeled DG cells, moderately running after lesion could further enhance the number of BrdU-labeled cells and decrease the error number （EN） in Y maze test, while neither lightly running, nor heavily running had such effects. There was a negative correlation between the number of DG BrdU-labeled cells and the EN in the Y maze test after running. Conclusion Moderate exercise could enhance the DG neurogenesis and ameliorate the ability of learning and memory in hippocampus-lesioned rats.     

Transient elevation of adult hippocampal neurogenesis after dopamine depletion

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

The dynamics of adult neurogenesis in human hippocampus

The phenomenon of adult neurogenesis is now an accepted occurrence in mammals and also in humans.At least two discrete places house stem cells for generation of neurons in adult brain. These are olfactory system and the hippocampus. In animals, newly generated neurons have been directly or indirectly demonstrated to generate a significant amount of new neurons to have a functional role. However, the data in humans on the extent of this process is still scanty and such as difficult to comprehend its functional role in humans. This paper explores the available data on as extent of adult hippocampal neurogenesis in humans and makes comparison to animal data.