Abstract
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.
Highlights
In the dentate gyrus of the adult hippocampus, a resident population of radial glia‐like neural stem cells (NSCs) with astrocytic properties (Seri, García‐Verdugo, McEwen, & Alvarez‐Buylla, 2001) generates neurons throughout adulthood in most mammals including humans (Eriksson et al, 1998; Moreno‐Jiménez et al, 2019; Spalding et al, 2013)
The age‐related decrease of neurogenesis is well described in the dentate gyrus (DG) of experimental animals from rodents to primates (Kuhn et al, 1996; Leuner, Kozorovitskiy, Gross, & Gould, 2007; Ngwenya, Heyworth, Shwe, Moore, & Rosene, 2015; Walter et al, 2011)
That activation of NSCs could translate into their depletion was suggested by the in vivo blockade of inhibiting bone morphoge‐ netic protein (BMP) signaling (Mira et al, 2010)
Summary
In the dentate gyrus of the adult hippocampus, a resident population of radial glia‐like neural stem cells (NSCs) with astrocytic properties (Seri, García‐Verdugo, McEwen, & Alvarez‐Buylla, 2001) generates neurons throughout adulthood in most mammals including humans (Eriksson et al, 1998; Moreno‐Jiménez et al, 2019; Spalding et al, 2013). At all the different age points, α‐ cells accounted for the vast majority of Nestin‐GFP/GFAP cells that incorporated BrdU, while the fraction of BrdU+ Ω‐cells was much lower (Figure 3b) In both cases, the majority of the cells comprising each population remained quiescent, but interestingly, α‐cells were able to increase their activation, in percentage over the total α‐cell population, over time as shown by the significantly higher propor‐ tion of BrdU‐labeled cells among the α‐cells population in aged mice (Figure 3c). When analyzed by subtypes we found that the proportion of activated α‐cells (among the total of BrdU cells) did not change but that the proportion of di‐ viding Ω‐cells was significantly decremented, accounting for the overall reduction in Nestin‐GFP/GFAP cell activation as Ω‐cells are more abundant IFN‐α mice (Figure 5h). These results suggest that even though inflammation might be playing a role in the potential conversion of α‐cells into Ω‐cells but might not be the only factor associated with aging involved
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