Background. The medial prefrontal cortex (mPFC) is part of a complex circuit controlling stress responses by sending projections to different limbic structures including the nucleus accumbens (NAc) and ventral tegmental area (VTA). However, the impact of chronic stress on NAc- and VTA-projecting mPFC neurons is still unknown and the distinct contribution of these pathways to stress responses in males and females is unclear. Methods. Behavioral stress response in both sexes was induced by 21 days of chronic variable stress (CVS). We used an inter-sectional viral approach to label both pathways and assess the functional, morphological, and transcriptional adaptations in NAc- and VTA-projecting mPFC neurons in stressed males and females. Using chemogenetic approaches, we modified neuronal activity of NAc-projecting mPFC neurons to decipher their contribution to stress phenotypes in both sexes. Results. CVS induced depressive-like behaviors in males and females. NAc- and VTA-projecting mPFC neurons exhibited sex-specific functional, morphological, and transcriptional alterations. The functional changes were more important in females in NAc-projecting mPFC neurons while males exhibited a more drastic reduction in dendritic complexity in VTA-projecting mPFC neurons after CVS. Finally, chemogenetic overactivation of the cortico-accumbal pathway triggered anxiety and behavioral despair in both sexes while its inhibition rescued the phenotype only in females. Conclusions. Our results suggest that chronic stress impacts the cortico-accumbal and cortico-tegmental pathways differently in males and females through sex-specific functional, morphological, and transcriptional alterations in mPFC neurons. Furthermore, our results suggest that the cortico-accumbal pathway contributes to the expression of anxiety and behavioral despair in females.
bioRxiv Subject Collection: Neuroscience