Methylazoxymethanol acetate does not fully block cell genesis in the young and aged dentate gyrus

During adulthood, new neurons are continuously added to the mammalian dentate gyrus (DG). An increasing number of studies have correlated changes in rates of dentate neurogenesis with memory abilities. One study based on subchronic treatment with the toxin methylazoxymethanol acetate (MAM) has provided causal evidence that neurogenesis is involved in hippocampal-dependent trace conditioning. In contrast, spatial learning is not impaired following MAM treatment. We hypothesized that this was due to the small residual number of new cells produced following MAM treatment. In the present experiment, we attempted to achieve a higher level of reduction of adult-generated cells following MAM treatment in young and aged rats. We found only a partial reduction of adult-generated cells in the DG. More importantly, independently of the age of the animals, MAM treatment at a dose necessary to reduce neurogenesis altered the overall health of the animals. In conclusion, the behavioural results obtained following subchronic treatment with high doses of MAM in adulthood must be interpreted with extreme caution.     

Environmental enrichment enhances neurogenesis and improves functional outcome after cranial irradiation

Radiation therapy is a widely used treatment for brain tumors but it can cause delayed progressive cognitive decline and memory deficits. Previous studies suggested that this neurocognitive dysfunction might be linked to the impairment of hippocampal neurogenesis. However, little is known regarding how to reduce the cognitive impairment caused by radiation therapy. To investigate whether environmental enrichment (EE) promotes neurogenesis and cognitive function after irradiation, irradiated gerbils were housed in EE for 2 months and evaluated by neurobehavioral testing for learning and memory function, and immunohistochemical analysis for neurogenesis. Our results demonstrated that even relatively low doses (5-10 Gy) of irradiation could acutely abolish precursor cell proliferation in the dentate gyrus by more than 90%. This reduction in precursor proliferation was persistent and led to a significant decline in the granule cell population 9 months later. EE housing enhanced the number of newborn neurons and increased residual neurogenesis. EE also significantly increased the total number of immature neurons in the dentate gyrus. Furthermore, irradiated animals after EE housing showed a significant improvement in spatial learning and memory during the water-maze test and in rotorod motor learning over a 5-day training paradigm. In conclusion, EE has a positive impact on hippocampal neurogenesis and functional recovery in irradiated adult gerbils. Our data suggest that there is still a considerable amount of plasticity remaining in the hippocampal progenitor cells in adult animals after radiation injury, which can become a target of therapeutic intervention for radiation-induced cognitive dysfunction.     

Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis

Exposure to an enriched environment and physical activity, such as voluntary running, increases neurogenesis of granule cells in the dentate gyrus of adult mice. These stimuli are also known to improve performance in hippocampus-dependent learning tasks, but it is unclear whether their effects on neurogenesis are exclusive to the hippocampal formation. In this study, we housed adult mice under three conditions (enriched environment, voluntary wheel running and standard housing), and analysed proliferation in the lateral ventricle wall and granule cell neurogenesis in the olfactory bulb in comparison to the dentate gyrus. Using bromodeoxyuridine to label dividing cells, we could not detect any difference in the number of newly generated cells in the ventricle wall. When giving the new cells time to migrate and differentiate in the olfactory bulb, we observed no changes in the number of adult-generated olfactory granule cells; however, voluntary running and enrichment produced a doubling in the amount of new hippocampal granule cells. The discrepancy between the olfactory bulb and the dentate gyrus suggests that these living conditions trigger locally through an as yet unidentified mechanism specific to neurogenic signals in the dentate gyrus.     

Adult hippocampal neurogenesis, synaptic plasticity and memory: facts and hypotheses

The demonstration that progenitor cells in regions of the adult mammalian brain such as the dentate gyrus of the hippocampus can undergo mitosis and generate new cells that differentiate into functionally integrated neurons throughout life has marked a new era in neuroscience. In recent years, a wide range of investigations has been directed at understanding the physiological mechanisms and functional relevance of this form of brain plasticity. Our current knowledge of adult hippocampal neurogenesis indicates that the production of new cells in the brain follows a multi-step process during which newborn cells are submitted to various regulatory factors that influence cell proliferation, maturation, fate determination and survival. As details of the dynamics of morphological maturation and functional integration of newborn neurons in corticohippocampal circuits have become clearer, an increasing number of studies have examined how environmental and/or behavioural factors can modulate neurogenesis and affect hippocampal-dependent learning and memory. In this article we present an overview of recent literature that relates neurogenesis to hippocampal function on the basis of correlative studies investigating the modulation of neurogenesis by learning and behavioural experience, and the consequences of the loss of hippocampal neurogenesis for memory function. We also highlight experimental evidence that immature neurons exhibit unique electrophysiological characteristics and therefore may constitute a specific cell population particularly inclined to undergo activity-dependent plasticity. Moreover, we review recent work that reveals an unsuspected mechanistic link between synaptic plasticity and the proliferation and survival of new hippocampal neurons. From the present background of research, we argue that the incorporation of functional adult-generated neurons into existing neural networks provides a higher capacity for plasticity, which may favour the encoding and storage of certain types of memories. Depending on their birth date and maturation stage, new neurons might be implicated in the encoding/storage process of the task at hand or may help future learning experience. Finally, we highlight critical issues to be addressed in order to decipher the exact contribution of newly generated neurons to cognitive functions.     

NADPH oxidase mediates β-amyloid peptide-induced activation of ERK in hippocampal organotypic cultures

Newborn neurons in the subgranular zone (SGZ) of the hippocampus incorporate into the dentate gyrus and mature. Numerous studies have focused on hippocampal neurogenesis because of its importance in learning and memory. However, it is largely unknown whether hippocampal neurogenesis is involved in memory extinction per se. Here, we sought to examine the possibility that hippocampal neurogenesis may play a critical role in the formation and extinction of hippocampus-dependent contextual fear memory. By methylazoxymethanol acetate (MAM) or gamma-ray irradiation, hippocampal neurogenesis was impaired in adult mice. Under our experimental conditions, only a severe impairment of hippocampal neurogenesis inhibited the formation of contextual fear memory. However, the extinction of contextual fear memory was not affected. These results suggest that although adult newborn neurons contribute to contextual fear memory, they may not be involved in the extinction or erasure of hippocampus-dependent contextual fear memory.     

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.     

Short‐term environmental enrichment,in the absence of exercise,improves memory,and increases NGF concentration,early neuronal survival,and synaptogenesis in the dentate gyrus in a time‐dependent manner

Environmental manipulations can enhance neuroplasticity in the brain, with enrichment‐induced cognitive improvements being linked to increased expression of growth factors, such as neurotrophins, and enhanced hippocampal neurogenesis. There is, however, a great deal of variation in environmental enrichment protocols used in the literature, making it difficult to assess the role of particular aspects of enrichment upon memory and the underlying associated mechanisms. This study sought to evaluate the efficacy of environmental enrichment, in the absence of exercise, as a cognitive enhancer and assess the role of Nerve Growth Factor (NGF), neurogenesis and synaptogenesis in this process. We report that rats housed in an enriched environment for 3 and 6 weeks (wk) displayed improved recognition memory, while rats enriched for 6 wk also displayed improved spatial and working memory. Neurochemical analyses revealed significant increases in NGF concentration and subgranular progenitor cell survival (as measured by BrdU+ nuclei) in the dentate gyrus of rats enriched for 6 wk, suggesting that these cellular changes may mediate the enrichment‐induced memory improvements. Further analysis revealed a significant positive correlation between recognition task performance and BrdU+ nuclei. In addition, rats enriched for 6 wk showed a significant increase in expression of synaptophysin and synapsin I in the dentate gyrus, indicating that environmental enrichment can increase synaptogenesis. These data indicate a time‐dependent cognitive‐enhancing effect of environmental enrichment that is independent of physical activity. These data also support a role for increased concentration of NGF in dentate gyrus, synaptogenesis, and neurogenesis in mediating this effect. © 2013 Wiley Periodicals, Inc.     

Neurogenesis in the adult mammalian brain

The production of neurons in the mammalian brain is typically restricted to a discrete developmental period ending, for the most part, prior to parturition. However, in certain regions of the brain, including the dentate gyrus, new neurons continue to be produced well into adulthood. In the adult brain, new cells arise from progenitors located within the hilus and subgranular zone of the dentate gyrus, and then migrate into the dentate granule cell layer. Morphological, biochemical, and ultrastructural evidence indicate that many of these new cells become granule neurons, the principal projection neuron of the dentate gyrus. Anatomic studies have demonstrated that adult-generated granule neurons contribute axonal projections to area CA3 of Ammon's horn, while electron microscopy studies have revealed that these cells possess dendritic processes that extend into the dentate molecular layer to form synapses. Collectively, these data indicate that adult-generated granule neurons become functionally incorporated into the pre-existing neural circuitry of the dentate gyrus. The production and survival of adult-generated granule neurons are significantly influenced by experiential and neuroendocrine factors, suggesting that adult neurogenesis represents a substrate by which the environment may affect the structure and function of the adult brain. Although the precise function of adult-generated granule neurons is unknown, the formation of entirely novel neural circuits, and the regulation of this process by neuroendocrine and experiential factors, is likely to represent an important mode of neural plasticity. Moreover, the persistence of neural progenitors within the adult brain provides hope that an understanding of the process of adult neurogenesis may ultimately be of therapeutic relevance.     

Posttraining ablation of adult-generated neurons degrades previously acquired memories

New neurons are continuously generated in the subgranular zone of the adult hippocampus and, once sufficiently mature, are thought to integrate into hippocampal memory circuits. However, whether they play an essential role in subsequent memory expression is not known. Previous studies have shown that suppression of adult neurogenesis often (but not always) impairs subsequent hippocampus-dependent learning (i.e., produces anterograde effects). A major challenge for these studies is that these new neurons represent only a small subpopulation of all dentate granule cells, and so there is large potential for either partial or complete compensation by granule cells generated earlier on during development. A potentially more powerful approach to investigate this question would be to ablate adult-generated neurons after they have already become part of a memory trace (i.e., retrograde effects). Here we developed a diphtheria toxin-based strategy in mice that allowed us to selectively ablate a population of predominantly mature, adult-generated neurons either before or after learning, without affecting ongoing neurogenesis. Removal of these neurons before learning did not prevent the formation of new contextual fear or water maze memories. In contrast, removal of an equivalent population after learning degraded existing contextual fear and water maze memories, without affecting nonhippocampal memory. Ablation of these adult-generated neurons even 1 month after learning produced equivalent memory degradation in the water maze. These retrograde effects suggest that adult-generated neurons form a critical and enduring component of hippocampal memory traces.     

Stimulation of Hippocampal Neurogenesis by Transcranial Focused Ultrasound and Microbubbles in Adult Mice

Transcranial focused ultrasound (FUS) and microbubble contrast agent, applied at parameters known to transiently increase blood-brain barrier permeability, were tested for the potential to stimulate hippocampal neurogenesis. In adult mice, FUS treatment significantly increased the number of proliferating cells and newborn neurons in the dentate gyrus of the dorsal hippocampus. This provides evidence that FUS with microbubbles can stimulate hippocampal neurogenesis, a process involved in learning and memory and affected in neurological disorders, such as Alzheimer's disease.     

Brain-derived neurotrophic factor (BDNF) is required for the enhancement of hippocampal neurogenesis following environmental enrichment

Neurogenesis continues to occur in the adult mammalian hippocampus and is regulated by both genetic and environmental factors. It is known that exposure to an enriched environment enhances the number of newly generated neurons in the dentate gyrus. However, the mechanisms by which enriched housing produces these effects are poorly understood. To test a role for neurotrophins, we used heterozygous knockout mice for brain-derived neurotrophic factor (BDNF+/-) and mice lacking neurotrophin-4 (NT-4-/-) together with their wild-type littermates. Mice were either reared in standard laboratory conditions or placed in an enriched environment for 8 weeks. Animals received injections of the mitotic marker bromodeoxyuridine (BrdU) to label newborn cells. Enriched wild-type and enriched NT-4-/- mice showed a two-fold increase in hippocampal neurogenesis as assessed by stereological counting of BrdU-positive cells in the dentate gyrus and double labelling for BrdU and the neuronal marker NeuN. Remarkably, this enhancement of hippocampal neurogenesis was not seen in enriched BDNF+/- mice. Failure to up-regulate BDNF accompanied the lack of a neurogenic response in enriched BDNF heterozygous mice. We conclude that BDNF but not NT-4 is required for the environmental induction of neurogenesis.     

Neurogenesis within the adult hippocampus under physiological conditions and in depression

Adult neurogenesis can only be observed in some specific brain regions. One of these areas is the dentate gyrus of the hippocampal formation. The progenitor cells located in the subgranular layer of the dentate gyrus proliferate, differentiate, and give rise to young neurons that can become integrated into existing neuronal circuits. Under physiological conditions, hippocampal neurogenesis is linked to hippocampal-dependent learning, whereas deficits in adult hippocampal neurogenesis have been shown to correlate with disturbances in spatial learning and memory. This review summarizes the phenomenon of adult hippocampal neurogenesis and the use of suitable markers for the investigation of adult hippocampal neurogenesis. In addition, we focused on the disturbances in neurogenesis that can be seen in depression. Interestingly, several antidepressants have been found to be capable of increasing the rate of hippocampal neurogenesis. Based on that, it can be speculated that factors, which directly or indirectly increase the rate of hippocampal neurogenesis, may be helpful in the treatment of depression.     

Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus

Throughout the adult life of most mammals, new neurons are continuously generated in the dentate gyrus of the hippocampal formation. Recent work has documented specific cognitive deficits after elimination of adult hippocampal neurogenesis in rodents, suggesting that these neurons may contribute to information processing in hippocampal circuits. Young adult-born neurons exhibit enhanced excitability and have altered capacity for synaptic plasticity in hippocampal slice preparations in vitro. Still, little is known about the effect of adult-born granule cells on hippocampal activity in vivo. To assess the impact of these new neurons on neural circuits in the dentate, we recorded perforant-path evoked responses and spontaneous network activity from the dentate gyrus of urethane-anesthetized mice whose hippocampus had been focally X-irradiated to eliminate the population of young adult-born granule cells. After X-irradiation, perforant-path responses were reduced in magnitude. In contrast, there was a marked increase in the amplitude of spontaneous γ-frequency bursts in the dentate gyrus and hilus, as well as increased synchronization of dentate neuron firing to these bursts. A similar increase in gamma burst amplitude was also found in animals in which adult neurogenesis was eliminated using the GFAP:TK pharmacogenetic ablation technique. These data suggest that young neurons may inhibit or destabilize recurrent network activity in the dentate and hilus. This unexpected result yields a new perspective on how a modest number of young adult-generated granule cells may modulate activity in the larger population of mature granule cells, rather than acting solely as independent encoding units.     

Modification of hippocampal neurogenesis and neuroplasticity by social environments

Synaptic plasticity and neurogenesis in the brain are affected by environmental stimuli. The present study was designed to investigate the effects of social environments on learning and memory, neurogenesis, and neuroplasticity. Twenty-two-day-old rats were housed in isolation or in groups for 4 or 8 weeks and injected intraperitoneally with bromodeoxyuridine to detect proliferation among progenitor cells. The animals were also tested for learning in a water maze and for hippocampal CA1 long-term potentiation in vivo and in vitro. The results show that the number of newborn neurons in the dentate gyrus and the learning in a water maze decreased significantly in rats reared in isolation for 4 or 8 weeks, as compared with grouped controls. Induction of long-term potentiation in the CA1 area of rat hippocampus in vivo and in vitro was also significantly reduced by isolation. Furthermore, the effects of isolation rearing on spatial learning, hippocampal neurogenesis, and long-term potentiation could be reversed by subsequent group rearing. These findings demonstrated that social environments can modify neurogenesis and synaptic plasticity in adult hippocampal regions, which is associated with alterations in spatial learning and memory.     

Neurogenesis in the R6/1 transgenic mouse model of Huntington's disease: effects of environmental enrichment

Previous work has demonstrated that the transgenic R6/1 mouse model of Huntington's disease has decreased proliferation of neural precursor cells (NPCs) in the dentate gyrus of the hippocampus. This study therefore examined the survival and differentiation of NPCs in presymptomatic and symptomatic R6/1 mice and the effects of environmental enrichment on these variables. Here it is demonstrated that the survival of bromodeoxyuridine-positive (BrdU+) NPCs in the dentate gyrus is decreased in the transgenic mice. In addition, the number of doublecortin-positive (DCX+) cells is greatly reduced in these mice, as is the total number of new mature neurons, while the proportion of BrdU+ cells differentiating into mature neurons was not significantly different between genotypes. Furthermore, the DCX+ cells in the R6/1 mice had smaller and irregular-shaped somas, shorter neurites, and migrated a shorter distance into the granular cell layer compared with wild-type mice. Older symptomatic mice housed in an enriched environment had an increased number of BrdU+ and DCX+ cells as well as longer neurites and increased migration of DCX+ cells. There was no significant difference between genotypes or environments in the number of BrdU+ cells in the subventricular zone. These results suggest that decreased neurogenesis might be responsible, in part, for the hippocampal deficits observed in these mice and that environmental enrichment produces morphological changes in newborn granule neurons in both wild-type and R6/1 mice, which could underlie some of the beneficial effects of enrichment.     

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

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.     

Functional recruitment of newborn hippocampal neurons after experimental stroke

The adult brain responds to diverse pathologies such as stroke with increased generation of neurons in the dentate gyrus of the hippocampus. However, only little is known regarding the functional integration of newborn neurons into pre-existing neuronal circuits. In this study, we investigated whether newborn neurons generated after experimental stroke are recruited for different behavioral tasks. Adult mice received photochemical cortical infarcts in the sensorimotor cortex and proliferating cells were labeled using the proliferation marker, bromodeoxyuridine. Eight weeks after stroke induction, the animals were trained to perform either a spatiotemporal task or a sensorimotor task. Immediate early gene expression (c-fos, Zif268) in newborn neurons was analyzed directly after the last session. Using this approach, we demonstrate that post-stroke generated neurons are recruited within the hippocampal networks. The sensorimotor task activates significantly more newborn neurons compared to the spatiotemporal task. Further experiments employing the two well-established stimulators of neurogenesis, enriched environment and voluntary wheel running, both significantly increase post-stroke neurogenesis in the dentate gyrus but do not affect the percentage of recruited neurons compared to controls. Significantly, the spatiotemporal task leads to a higher portion of activated newborn neurons in the granule cell layer, suggesting a specific spatial activation pattern of new neurons in the dentate gyrus.     

Voluntary exercise-induced neurogenesis in the postischemic dentate gyrus is associated with spatial memory recovery from stroke

Spatial cognitive impairment is common after stroke insults. Voluntary exercise could improve the impaired spatial memory. Newly generated neurons in the dentate gyrus are necessary for the acquisition of new hippocampus-dependent memories. However, it is not well known whether voluntary exercise after stroke promotes neurogenesis in the adult dentate gyrus, thereby promoting spatial memory recovery. Here, we examined in mice subjected to focal cerebral ischemia the effect of voluntary or forced exercise on neurogenesis in the ischemic dentate gyrus and spatial memory. Exposure to voluntary wheel running after stroke enhanced newborn cell survival and up-regulated the phosphorylation of cAMP response element binding protein (CREB) in the dentate gyrus and reversed ischemia-induced spatial memory impairment. However, the enhanced newborn cell survival and CREB phosphorylation in the dentate gyrus and improved spatial memory were not observed in the mice exposed to forced swimming. Moreover, there was a significant correlation between the total number of surviving newborn cells in the dentate gyrus and the ability of mice to locate the platform in the Morris water maze. These results suggest that, in the adult mice, exposure to voluntary exercise after ischemic stroke may promote newborn cells survival in the dentate gyrus by up-regulating CREB phosphorylation and consequently restore impaired hippocampus-dependent memory.     

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

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. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.     

Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis

Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.