Left-to-right dorsomedial prefrontal cortex interhemispheric projections mediate psychosocial stress vulnerability

ABSTRACT Functional asymmetries in the medial prefrontal cortex (mPFC) are significant attributes of this brain area, implicated in its role in emotional processing and executive function. Evidence suggests that, under normal conditions, there is a tonic inhibition of the right (R) mPFC by the left (L) mPFC, and a dysregulation of this hemispheric functional lateralization is implicated in detrimental chronic stress effects. Considering the wide interhemispheric connection and the inhibitory tone from the LmPFC to the RmPFC, we hypothesize that alterations in the activity of the direct projections between the mPFC hemispheres during stressful situations are related to stress vulnerability. To address this question, we used a chemogenetic approach to modulate the activity of L-to-R dorsomedial prefrontal cortex (dmPFC) monosynaptic projections during psychosocial stress (PSS) exposure in mice. We found that activating LdmPFC projections during a repeated PSS protocol prevents stress-induced apathy-like behavior in females and males and social avoidance in male mice. On the other hand, inhibiting such projections during a single session of PSS increases vulnerability to stress effects in male mice, increasing social avoidance and anxiety-like behaviors. Both glutamatergic and GABAergic cells compose the projecting interhemispheric neurons in the dmPFC. However, the LdmPFC showed a higher density of glutamatergic projections to the RdmPFC than the opposite. In conclusion, our results revealed an involvement of the monosynaptic projections from the LdmPFC to RdmPFC in the vulnerability to the behavioral alterations induced by PSS in female and male mice.