The discovery that the adult mammalian brain creates new neurons from pools of stemlike cells was a breakthrough in neuroscience. Interestingly, this particular new form of structural brain plasticity seems specific to discrete brain regions, and most investigations concern the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampal formation (HF). Overall, two main lines of research have emerged over the last two decades: the first aims to understand the fundamental biological properties of neural stemlike cells (and their progeny) and the integration of the newly born neurons into preexisting networks, while the second focuses on understanding its relevance in brain functioning, which has been more extensively approached in the DG. Here, we propose an overview of the current knowledge on adult neurogenesis and its functional relevance for the adult brain. We first present an analysis of the methodological issues that have hampered progress in this field and describe the main neurogenic sites with their specificities. We will see that despite considerable progress, the levels of anatomic and functional integration of the newly born neurons within the host circuitry have yet to be elucidated. Then the intracellular mechanisms controlling neuronal fate are presented briefly, along with the extrinsic factors that regulate adult neurogenesis. We will see that a growing list of epigenetic factors that display a specificity of action depending on the neurogenic site under consideration has been identified. Finally, we review the progress accomplished in implicating neurogenesis in hippocampal functioning under physiological conditions and in the development of hippocampal-related pathologies such as epilepsy, mood disorders, and addiction. This constitutes a necessary step in promoting the development of therapeutic strategies.

Early experiences such as prenatal stress significantly influence the development of the brain and the organization of behavior. In particular, prenatal stress impairs memory processes but the mechanism for this effect is not known. Hippocampal granule neurons are generated throughout life and are involved in hippocampaldependent learning. Here, we report that prenatal stress in rats induced lifespan reduction of neurogenesis in the dentate gyrus and produced impairment in hippocampal-related spatial tasks. Prenatal stress blocked the increase of learning-induced neurogenesis. These data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for psychopathological vulnerabilities in aging. It is well documented from animal studies that during the perinatal period, the development of an organism is subjected to complex environmental influences. Deleterious life events during pregnancy induce neurobiological and behavioral defects in offspring, some of them involving the hippocampal formation (1-5). Indeed, prenatal stress results in an enhanced production of stress hormones by the mother during critical periods of fetal brain development and provokes a definitively longer corticosterone response to stress in the offspring associated with a reduction in the number of hippocampal corticosteroid receptors (1,3,5). Behaviorally, the progeny, from adulthood to senescence, exhibit memory deficits in a hippocampal-dependent task (2, 4, 5).Recently, it has been hypothesized that hippocampal-mediated learning (6) may be related to the generation of new neurons in the adult dentate gyrus (7,8,9). These newborn cells migrate in the granule cell layer, and differentiate in granule neurons whose projections, the mossy fibers, extend to the CA3 hippocampal region (10, 11). Furthermore, the size of the mossy fibers' projections correlates with variations in performances in spatial memory tests (12, 13). Finally, glucocorticoid levels regulate de novo cell proliferation in the dentate gyrus. Indeed, adrenalectomy performed in young or aged rats increases neurogenesis, an effect that is prevented by glucocorticoid treatment (14,15,16). These results raised the critical question as to whether prenatal stress can impair neurogenesis and, if so, whether it is related to learning ability.To test this hypothesis, we first examined cell proliferation in the progeny of stressed mothers with 5-bromo-2Ј-deoxyuridine (BrdUrd), a thymidine analogue incorporated into genetic material during synthetic DNA phase (S phase) of mitotic division. Cellspecific markers were used to phenotype the newly born neurons after longer survival times. We next examined whether the structural hippocampal defects resulting from prenatal stress had functional consequences on learning abilities. Finally, we examined whether the reduction in cell proliferation in the dentate gyrus had an impact on spatial memory, a hypothesis supported by others (17). MethodsHousing Conditions. Adult virgin Sprague-Dawley female rats (Iffa Credo) ...

The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning.