Thermosensitive receptors in neural stem cells link stress-induced hyperthermia to impaired neurogenesis via microglial engulfment

Social stress impairs hippocampal neurogenesis and causes psychiatric disorders such as depression. Recent studies have highlighted the significance of increased body temperature in stress responses; however, whether and how social stress–induced hyperthermia affects hippocampal neurogenesis remains unknown. Here, using transgenic mice in which the thermosensitive transient receptor potential vanilloid 4 (TRPV4) is conditionally knocked out in Nestin-expressing neural stem cells (NSCs), we found that social defeat stress (SDS)–induced hyperthermia activates TRPV4 in NSCs in the dentate gyrus and thereby impairs hippocampal neurogenesis. Specifically, SDS activated TRPV4 in NSCs and induced the externalization of phosphatidylserine in NSCs, which was recognized by the brain-resident macrophage, microglia, and promoted the microglial engulfment of NSCs. SDS-induced impairment of hippocampal neurogenesis was ameliorated by NSC-specific knockout of TRPV4 or pharmacological removal of microglia. Thus, this study reveals a previously unknown role of thermosensitive receptors expressed by NSCs in stress responses.