Single-nucleus transcriptomic atlas of sexually dimorphic molecular responses to sub-chronic variable stress in the mouse hippocampus.

Overview

1. Department of Psychology, The Fourth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang China
2. Department of Cardiology, Renmin Hospital of Wuhan University, Hubei Zhang Road (formerly Ziyang Road), Wuchang District No. 99, Jiefang Road 238, Wuhan, Hubei China
3. The Fourth Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang China

Abstract

Background: Major depressive disorder (MDD) exhibits a higher prevalence in women, yet the underlying cellular mechanisms for this clinical disparity remain elusive. To investigate sex-specific molecular mechanisms, we profiled sex-specific molecular responses to sub-chronic stress in the mouse hippocampus at single-nucleus resolution.

Methods: Male and female C57BL/6N mice were exposed to sub-chronic variable stress (SCVS). Anhedonia was assessed via sucrose preference and novelty-suppressed feeding. We employed single-nucleus RNA sequencing (snRNA-seq) to map sex-specific hippocampal responses to sub-chronic variable stress (SCVS) in mice.

Results: Female mice displayed significantly exacerbated anhedonia and selective depletion of plasma serotonin (5-HT) following SCVS exposure, contrasting with minimal behavioral changes in males. Single-nucleus RNA sequencing of 31,256 hippocampal cells revealed profound sex-dimorphic transcriptional reprogramming: females exhibited a 3-fold greater number of differentially expressed genes (DEGs) than males with minimal overlap. Key mechanistic findings included: (1) Females exhibited oligodendrocyte-specific upregulation of mitochondrial genes (mt-Atp6, mt-Co3), increasing oxidative stress susceptibility. Concurrently, stress depleted their baseline oligodendrocyte predominance, potentially disrupting hippocampal synchrony underlying anhedonia.; (2) Females exhibit broad Mef2c upregulation, while males show astrocyte/cholinergic neuron NRG-1 upregulation and astrocyte Slc6a11 downregulation; (3) Females display suppressed oxytocin signaling and coordinated dampening of glutamatergic signaling, astrocytic K⁺ buffering, and cell adhesion; males exhibit dysregulated kinase/phosphatase activity.

Conclusion: This study presents the single-nucleus atlas of hippocampal sexual dimorphism in stress response, identifying oligodendrocyte mitochondrial dysfunction, pan-cellular Mef2c upregulation, and oxytocin suppression as potential female-specific therapeutic targets for depression. Our findings reveal fundamental sex-divergent molecular adaptations to stress, providing a roadmap for novel, sex-stratified treatments for MDD.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Code reported in this paper will be shared by the lead contact upon request.

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Data availability

All data reported in this paper will be shared by the lead contact upon request. All raw sequencing data generated by this study are available in the Gene Expression Omnibus (GEO) repository under the accession number GSE303470.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 2 keywords, 13 MeSH terms, 1 funder, 56 references.

Cite

This paper

Liang, L., Yuan, Y.-p., Chang, C.-l., Zhang, J., & Liang, C. (2026). Single-nucleus transcriptomic atlas of sexually dimorphic molecular responses to sub-chronic variable stress in the mouse hippocampus. Translational psychiatry, 16(1), 456. https://doi.org/10.1038/s41398-026-04202-3

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