Female mice exhibit exacerbated anhedonia and 3-fold more hippocampal gene changes than males after stress

Major depressive disorder (MDD) disproportionately affects women, yet the specific cellular and molecular mechanisms driving this sex disparity remain poorly understood. Current treatments often lack sex-specific efficacy, highlighting a critical gap in understanding how stress impacts the brain differently in males and females. The hippocampus, a brain region crucial for mood regulation and stress response, is a key area for investigating these sex-specific molecular adaptations. Unraveling these differences could lead to more targeted and effective therapies for stress-related psychiatric conditions.

Researchers exposed male and female C57BL/6N mice to sub-chronic variable stress (SCVS) to model chronic stress. Anhedonia, a core symptom of depression, was quantified using sucrose preference and novelty-suppressed feeding tests. To map sex-specific molecular responses, single-nucleus RNA sequencing (snRNA-seq) was performed on 31,256 hippocampal cells, comparing transcriptional profiles between stressed males and females. Plasma serotonin (5-HT) levels were also measured to assess neurochemical changes.

Female mice exhibited 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 showed a 3-fold greater number of differentially expressed genes (DEGs) than males, with minimal overlap in gene sets. Key mechanistic findings included:

Females displayed oligodendrocyte-specific upregulation of mitochondrial genes (mt-Atp6, mt-Co3), increasing oxidative stress susceptibility, alongside a stress-induced depletion of baseline oligodendrocyte predominance, potentially disrupting hippocampal synchrony underlying anhedonia. Females also exhibited broad Mef2c upregulation, while males showed astrocyte/cholinergic neuron NRG-1 upregulation and astrocyte Slc6a11 downregulation. Furthermore, females displayed suppressed oxytocin signaling and coordinated dampening of glutamatergic signaling, astrocytic K+ buffering, and cell adhesion, whereas males exhibited dysregulated kinase/phosphatase activity.