Nucleus accumbens neuron subtype translatome signatures in socially stressed females.

Major depressive disorder (MDD) disproportionately affects women, yet the molecular mechanisms underlying female vulnerability remain poorly understood. The nucleus accumbens (NAc), a reward circuitry hub, is central to stress- and depression-related pathology. While NAc medium spiny neuron (MSN) transcriptional adaptations have been characterized in stressed male rodents, much less is known about female adaptations. To address this, we exposed female D1-Cre-RiboTag and A2A-Cre-RiboTag mice to chronic witness defeat stress (CWDS) and classified them as high- or low-social interactors. Ribosome-associated mRNA was isolated from MSN subtypes and analyzed by RNA sequencing, differential gene expression analysis (DEG), and weighted gene co-expression network analysis (WGCNA). Cross-species consensus WGCNA with male mouse and human transcriptomic datasets was performed to identify conserved, sex-specific signatures. We detected 9 differentially expressed genes (DEGs) in D1-MSNs and 630 in A2A-MSNs (FDR < 0.05). In D1-MSNs, DEGs were primarily upregulated in low interactors and enriched for energy homeostasis and cell adhesion. A2A-MSN DEGs included upregulated structural genes and downregulated neurotransmission-related genes. WGCNA identified 9 significant D1- and 5 significant A2A-MSN modules, with the most impacted enriched for PI3K-Akt-mTOR signaling and regulated by Nf1. Consensus analysis revealed a stress-associated, sex- and subtype-specific module enriched for PI3K-Akt-mTOR signaling conserved across mice and humans. These findings reveal female-specific MSN transcriptional adaptations to chronic social stress and implicate PI3K-Akt-mTOR signaling as a convergent molecular pathway. By highlighting MSN subtype-specific vulnerabilities, this work suggests potential therapeutic targets for alleviating stress-induced pathology in women with MDD.