Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice

Yan-Jia Luo; Hechen Bao; Andrew Crowther; Ya-Dong Li; Ze-Ka Chen; Dalton S Tart; Brent Asrican; Libo Zhang; Juan Song

doi:10.1016/j.celrep.2024.114140

Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice

Cell Rep. 2024 Apr 23;43(5):114140. doi: 10.1016/j.celrep.2024.114140. Online ahead of print.

Authors

Yan-Jia Luo¹, Hechen Bao², Andrew Crowther³, Ya-Dong Li⁴, Ze-Ka Chen², Dalton S Tart⁵, Brent Asrican², Libo Zhang⁵, Juan Song⁶

Affiliations

¹ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Anesthesiology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
² Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
³ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Curriculum, University of North Carolina, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA; Songjiang Research Institute, Songjiang Hospital Affiliated with Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Emotions and Affective Disorders, Shanghai 201699, China.
⁵ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
⁶ Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: juansong@email.unc.edu.

PMID: 38656873
DOI: 10.1016/j.celrep.2024.114140

Abstract

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.

Keywords: CP: Cell biology; CP: Neuroscience; adult hippocampal neurogenesis; neural stem cell; serotonin; serotonin receptor; sex difference; stress.