Transcriptional profiling of the cortico-accumbal pathway reveals sex-specific alterations underlying stress susceptibility.

Background: Anxiety and depressive disorders, including major depressive disorder (MDD), affect millions of people every year, imposing significant socio-economic burdens and highlighting the need to better understand their molecular mechanisms. The medial prefrontal cortex (mPFC) has been identified as a critical brain region in MDD pathology, displaying altered activity and morphology.

Methods: We used RNA sequencing in RiboTag mice to uncover transcriptional profiles in mPFC neurons projecting to the nucleus accumbens (NAc) in stressed male and female mice after 21 days of chronic variable stress. Sex-specific gene expression changes were evaluated through differential expression and weighted gene co-expression network analyses. We used viral-mediated gene transfer combined with behavioral analysis, electrophysiological recording, and morphological reconstruction to evaluate the role of target gene programs on stress susceptibility in both sexes.

Results: Our analyses revealed distinct transcriptional responses to chronic stress in males and females. Key findings include the identification of the Xlr4b gene as a male-specific hub gene and potential driver for stress susceptibility. The overexpression of Xlr4b in NAc-projecting mPFC neurons induced stress susceptibility in males but not females. Follow-up analyses suggested these effects were mediated by sex-specific changes in the morphological and physiological properties of the cortico-accumbal pathway.

Conclusion: Chronic stress induces sex-specific transcriptional alterations in NAc-projecting mPFC neurons. Some of these alterations change the morphological and functional properties of neuronal pathways, ultimately contributing to the differential manifestation of anxiety-like and depressive-like behaviors in male and female mice.