Chronic stress induces sex-specific functional and morphological alterations in cortico-accumbal and cortico-tegmental pathways

Abstract

BackgroundThe 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. MethodsBehavioral stress responses were induced by 21 days of chronic variable stress (CVS) in male and female C57BL6 mice. An inter-sectional viral approach was used 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. ResultsCVS 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 severe in females in NAc-projecting mPFC neurons while males exhibited more drastic reductions 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. ConclusionsOur results suggest that by changing the activity of transcriptional programs controlling neuronal plasticity, CVS interferes with the morphological and synaptic properties of the cortico-accumbal and tegmental pathways differently in males and females contributing to the expression of anxiety and depressive-like behaviors distinctly in a sex-specific fashion.