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

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.