Adult neurogenesis is regulated by the neurogenic niche, through mechanisms that remain poorly defined. Here, we investigated whether niche-constituting astrocytes influence the maturation of adult-born hippocampal neurons using two independent transgenic approaches to block vesicular release from astrocytes. In these models, adult-born neurons but not mature neurons showed reduced glutamatergic synaptic input and dendritic spine density that was accompanied with lower functional integration and cell survival. By taking advantage of the mosaic expression of transgenes in astrocytes, we found that spine density was reduced exclusively in segments intersecting blocked astrocytes, revealing an extrinsic, local control of spine formation. Defects in NMDA receptor (NMDAR)-mediated synaptic transmission and dendrite maturation were partially restored by exogenous D-serine, whose extracellular level was decreased in transgenic models. Together, these results reveal a critical role for adult astrocytes in local dendritic spine maturation, which is necessary for the NMDAR-dependent functional integration of newborn neurons.

Summary Mossy cells (MCs) represent a major population of excitatory neurons in the adult dentate gyrus, a brain region where new neurons are generated from radial neural stem cells (rNSCs) throughout life. Little is known about the role of MCs in regulating rNSCs. Here we demonstrate that MC commissural projections structurally and functionally interact with rNSCs through both direct glutamatergic MC-rNSC pathway and indirect GABAergic MC-local interneuron-rNSC pathway. Specifically, moderate MC activation increases rNSC quiescence through dominant indirect pathway; while high MC activation increases rNSC activation through dominant direct pathway. In contrast, MC inhibition or ablation leads to a transient increase of rNSC activation, but rNSC depletion only occurs after chronic ablation of MCs. Together, our study identifies MCs as a critical stem cell niche component that dynamically controls adult NSC quiescence and maintenance under various MC activity states through a balance of direct glutamatergic and indirect GABAergic signaling onto rNSCs.

Adult neurogenesis is tightly regulated by the neurogenic niche. Cellular contacts between niche cells and neural stem cells are hypothesized to regulate stem cell proliferation or lineage choice. However, the structure of adult neural stem cells and the contact they form with niche cells are poorly described. Here, we characterized the morphology of radial glia-like (RGL) cells, their molecular identity, proliferative activity, and fate determination in the adult mouse hippocampus. We found the coexistence of two morphotypes of cells with prototypical morphological characteristics of RGL stem cells: Type α cells, which represented 76% of all RGL cells, displayed a long primary process modestly branching into the molecular layer and type β cells, which represented 24% of all RGL cells, with a shorter radial process highly branching into the outer granule cell layer-inner molecular layer border. Stem cell markers were expressed in type α cells and coexpressed with astrocytic markers in type β cells. Consistently, in vivo lineage tracing indicated that type α cells can give rise to neurons, astrocytes, and type β cells, whereas type β cells do not proliferate. Our results reveal that the adult subgranular zone of the dentate gyrus harbors two functionally different RGL cells, which can be distinguished by simple morphological criteria, supporting a morphofunctional role of their thin cellular processes. Type β cells may represent an intermediate state in the transformation of type α, RGL stem cells, into astrocytes.

Adult hippocampal neurogenesis relies on the activation of neural stem cells in the dentate gyrus, their division, and differentiation of their progeny into mature granule neurons. The complex morphology of radial glia-like (RGL) stem cells suggests that these cells establish numerous contacts with the cellular components of the neurogenic niche that may play a crucial role in the regulation of RGL stem cell activity. However, the morphology of RGL stem cells remains poorly described. Here, we used light microscopy and electron microscopy to examine Nestin-GFP transgenic mice and provide a detailed ultrastructural reconstruction analysis of Nestin-GFP-positive RGL cells of the dentate gyrus. We show that their primary processes follow a tortuous path from the subgranular zone through the granule cell layer and ensheathe local synapses and vasculature in the inner molecular layer. They share the ensheathing of synapses and vasculature with astrocytic processes and adhere to the adjacent processes of astrocytes. This extensive interaction of processes with their local environment could allow them to be uniquely receptive to signals from local neurons, glia, and vasculature, which may regulate their fate.adult neurogenesis | adult neural stem cell | neurogenic niche | electron microscopy | hippocampus N eurogenesis in the adult mouse brain primarily occurs within discrete niches, the subventricular zone (SVZ), and the subgranular zone (SGZ) of the dentate gyrus, supplying new neurons to the olfactory bulb and the dentate gyrus, respectively (1-3). Neural stem cells of these niches can be activated to divide and generate other stem cells, astrocytes, or new neurons (4, 5). Newborn neurons of the dentate gyrus have the capacity to integrate into the existing hippocampal circuitry (6-8), influencing processes such as learning and memory (9-11) as well as stress and depression (12).Radial glia-like (RGL) neural stem cells of the SVZ, which supply the olfactory bulb with newborn neurons and astrocytes, express astrocytic markers and form elegant pinwheel structures (13-16). RGL neural stem cells of the adult dentate gyrus also express astrocytic markers, but comprise a heterogeneous population based on the molecular markers they express, the morphologies they exhibit (17-22), and their fate (23-28). Nestin-GFP-positive RGL stem cells account for more than 70% of RGL stem cells in the SGZ of the dentate gyrus (24), but it was recently found that not all Nestin-GFP-positive cells with RGL morphology have stem cell properties (29): type β cells, which arborize in the granule cell layer (GCL) but do not reach the molecular layer (ML) of the dentate gyrus, account for 26% of Nestin-GFP-positive RGL stem cells. They express stem cell (Sox1, Sox2, Prominin 1, GFAP, and Nestin) and astrocytic [GFAP, glial glutamate tranporter 1 (GLT1), and S100β] markers but do not proliferate. In contrast, type α cells, which extend across the GCL and arborize in the inner ML, account for 74% of Nestin-GFP-positive RGL cells. They express stem...

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.

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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.

Aging is associated with increased inflammation and reduced hippocampal neurogenesis, which may in turn contribute to cognitive impairment. Taurine is a free amino acid found in numerous diets, with anti-inflammatory properties. Although abundant in the young brain, the decrease in taurine concentration with age may underlie reduced neurogenesis. Here, we assessed the effect of taurine on hippocampal neurogenesis in middle-aged mice. We found that taurine increased cell proliferation in the dentate gyrus through the activation of quiescent stem cells, resulting in increased number of stem cells and intermediate neural progenitors. Taurine had a direct effect on stem/progenitor cells proliferation, as observed in vitro, and also reduced activated microglia. Furthermore, taurine increased the survival of newborn neurons, resulting in a net increase in adult neurogenesis. Together, these results show that taurine increases several steps of adult neurogenesis and support a beneficial role of taurine on hippocampal neurogenesis in the context of brain aging.