Nucleus accumbens neuron subtype translatome signatures in socially stressed females.

Background: The nucleus accumbens (NAc) is a reward circuitry hub associated with major depressive disorder (MDD) and chronic stress in rodents. While transcriptional adaptations in NAc medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor 1(D1) or dopamine receptor 2 (D2) and adenosine 2a receptor (A2A) are well characterized in socially stressed male rodents, there is less knowledge of MSN subtype adaptations in socially stressed females. Methods: Chronic witness defeat stress (CWDS) was performed in female D1-Cre-RiboTag and A2A-Cre-RiboTag mice. After stress, mice were separated into high- and low-social interactors with a three Chamber Social Interaction test. Following isolation of ribosome-associated mRNA, MSN subtype-specific gene expression profiles were determined with RNA sequencing followed by differential gene expression analysis (DEG) and weighted gene co-expression network analysis (WGCNA). Consensus WGCNA with male mouse social defeat stress and clinically relevant human transcriptomic datasets was performed to examine the translational sex-specific molecular signatures. Results: 9 DEGs in D1-MSNs and 630 in A2A-MSNs were identified in female stress groups (FDR < 0.05). D1-MSN DEGs were mostly upregulated in CWDS low vs high interactors and were enriched for functions related to energy homeostasis and cell adhesion. A2A-MSN DEGs upregulated in low interactors involved structural molecules while downregulated genes involved neurotransmission. WGCNA identified 9 significant D1- and 5 significant A2A-MSN modules related to cell structure, protein synthesis, synapse and mitochondria. The most impacted modules from each subtype (based on DEG count) were enriched for PI3K-Akt-mTOR signaling pathway and regulated by the Nf1 transcription factor. Consensus module analysis identified a module significantly associated with social stress in a sex- and subtype-specific manner in both mice and humans enriched for genes involved in the PI3K-Akt-mTOR signaling pathway. Conclusion: Chronic social stress-induced sex-specific molecular signatures were uncovered in female subjects. Consensus modules across stress and clinical populations implicate alterations in MSN subtypes could contribute to MDD signatures among female populations.