Chronic stress induces neural stem cell quiescence in the hippocampus by repressing Ascl1 expression [RNA-seq]

Chronic stress inhibits neurogenesis, yet its impact on neural stem cells (NSCs) remains poorly understood. Here, using the 5-bromo-2′-deoxyuridine (BrdU) label-retaining assay, we found that chronic restraint stress (CRS) in adult mice promoted quiescence in hippocampal NSCs (i.e. radial-glial-like cells, RGLs). Long-term administration of the synthetic stress hormone agonist dexamethasone (Dex) to adult mice recapitulated the phenotype. Moreover, pre-administration of the antagonist mifepristone (RU486) prevented RGLs from quiescence. At the cellular level, Dex induced reversible quiescence in hippocampal NSCs (HpNSCs) in a manner similar to the quiescence-promoting signal BMP4 in vitro. However, Dex and BMP4 regulated overlapping yet distinct NSC quiescence programs, with their co-regulation primarily being synergistic. Mechanistically, Dex downregulated the expression of achaete-scute homolog 1 (Ascl1) by repressing a distal enhancer. These data suggest that chronic stress induces quiescence in RGLs by repressing the transcription of the quiescence regulator gene Ascl1, and that synthetic glucocorticoid antagonists may have therapeutic value in correcting abnormalities of NSC activity in conditions associated with elevated cortisol levels, including psychological and mental health conditions.