Single-cell transcriptomics reveals Sox6 positive interneurons enriched in the prefrontal cortex of female mice vulnerable to chronic social stress.

Major depressive disorder (MDD) is a prevalent mental illness that significantly impacts global health, with women showing twice the prevalence of men. This study employed the chronic social defeat stress (CSDS) model in female mice to investigate cellular and molecular changes in the prefrontal cortex (PFC) associated with depressive-like behaviors. Using single-nucleus RNA sequencing (snRNA-Seq), we examined transcriptomic alterations across various cell types in the PFC. Our results revealed that interneurons exhibited the most significant transcriptomic changes among all analyzed cell types. Notably, we found the Sox6 interneurons (Sox6Int) were enriched in the CSDS susceptible group. This enrichment was associated with enhanced inflammatory and immune responses, as well as alterations in synaptic function and mitochondrial pathways. Furthermore, we observed significant changes in cell-cell communication patterns, particularly between Sox6Int and oligodendrocyte precursor cells (OPC). Weighted gene co-expression network analysis (WGCNA) identified several gene modules in Sox6Int associated with specific depressive-like behaviors, implicating pathways related to inflammation, autophagy, and synaptic function. In particular, specific knockdown of Sox6 in neurons reversed the depressive-like behaviors. These findings provide novel insights into the cellular and molecular mechanisms underlying MDD in females, highlighting the potential role of Sox6Int in stress-induced depression. Our study not only extends our understanding of the neurobiological basis of depression but also identifies potential therapeutic targets for sex-specific interventions in MDD treatment.