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Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability. [Display omitted] • Adult mouse Ascl1-NSCs express 5HT1ARs in females, while they express 5HT7Rs in males • 5HT1AR deletion in Ascl1-NSCs of females impairs NSCs via upregulation of 5HT7Rs • Stress upregulates 5HT7Rs in Ascl1-NSCs of females and reduces NSCs via 5HT1ARs • Stress downregulates 5HT7Rs in Ascl1-NSCs of males, and NSCs are maintained Luo et al. report sex-specific expression of distinct 5HTRs in adult mouse neural stem cells (NSCs) and their differential interaction with stress in regulating NSCs. Specifically, stress upregulates 5HT7Rs in NSCs of females and reduces the NSC pool via 5HT1ARs, while it downregulates 5HT7Rs in NSCs of males and maintains the NSC pool. [ABSTRACT FROM AUTHOR]