SUMMARY Adult hippocampal neurogenesis is believed to maintain a range of cognitive functions, many of which decline with age. We recently reported that radial neural stem cells (rNSCs) in the hippocampus undergo activation-dependent conversion into astrocytes, a mechanism that over time contributes to a reduction in the rNSC population. Here, we injected low and high levels of kainic acid (KA) in the dentate gyrus to assess whether neuronal hyperexcitation, a hallmark of epileptic disorders, could accelerate this conversion. At low levels of KA, generating epileptiform activity without seizures, we indeed found increased rNSC activation and conversion into astrocytes. At high levels, generating sustained epileptic seizures, however, we find that rNSCs divide symmetrically and that both mother and daughter cells convert into reactive astrocytes. Our results demonstrate that a threshold response for neuronal hyperexcitation provokes a dramatic shift in rNSCs function, which impairs adult hippocampal neurogenesis in the long term.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain.

Adult neurogenesis persists in the hippocampus of most mammal species during postnatal and adult life, including humans, although it declines markedly with age. The mechanisms driving the age‐dependent decline of hippocampal neurogenesis are yet not fully understood. The progressive loss of neural stem cells (NSCs) is a main factor, but the true neurogenic output depends initially on the actual number of activated NSCs in each given time point. Because the fraction of activated NSCs remains constant relative to the total population, the real number of activated NSCs declines in parallel to the total NSC pool. We investigated aging‐associated changes in NSCs and found that there are at least two distinct populations of NSCs. An alpha type, which maintains the classic type‐1 radial morphology and accounts for most of the overall NSC mitotic activity; and an omega type characterized by increased reactive‐like morphological complexity and much lower probability of division even under a pro‐activation challenge. Finally, our results suggest that alpha‐type NSCs are able to transform into omega‐type cells overtime and that this phenotypic and functional change might be facilitated by the chronic inflammation associated with aging.

The generation of new neurons from neural stem cells (NSCs) throughout adult life in the mammalian brain is a biological process that fascinates scientists for its uniqueness and restorative potential. In the dentate gyrus (DG) of the hippocampus NSCs are able to self-renew and generate new granule cells and astrocytes through a complex and plastic mechanism that can be regulated by endogenous and exogenous cues at different levels. Unexpected recent findings suggest that the population of NSCs is heterogeneous in morphology and behavior. We herein explore the hypothesis that NSC heterogeneity and the neurogenic potential of the DG depends on their developmental origin. We provide an up-to-date picture of the process of neurogenesis in the adult hippocampus with an especial focus on NSCs and outline key unsolved aspects. Further, we discuss the origin of NSCs in the adult DG from a developmental perspective and explore the possibility of NSC heterogeneity being determined from early postnatal periods and being responsible for the neurogenic output of the DG in the long term.