Activity of VMS-projecting mPFC neurons encodes individual vulnerability to chronic restraint stress in male mice

The medial prefrontal cortex (mPFC) is critically involved in stress-related behaviors, specifically via the subpopulation of neurons that project to the ventromedial striatum (VMS). However, whether VMS-projecting mPFC neurons contribute to individual differences in behavioral responses to chronic stress remains unclear. Here, using a chronic restraint stress (CRS) model, we observed heterogeneous CRS-induced behavioral responses and stratified mice into relatively susceptible (SUS) and resilient (RES) subgroups based on a composite stress-related behavioral profile. To investigate the underlying neural basis, we performed in vivo fiber photometry to monitor calcium dynamics of VMS-projecting mPFC excitatory neurons before (baseline), during, and after CRS. We found that SUS mice exhibited significantly higher peak ΔF/F signals compared to RES mice even prior to stress exposure, and displayed persistently elevated activity during and after CRS. To further assess cellular mechanisms, we performed ex vivo whole-cell recordings from projection-defined neurons and found that VMS-projecting mPFC neurons in SUS mice exhibit increased intrinsic excitability, characterized by enhanced firing responses to depolarizing current injection. Chemogenetic activation of these neurons increased stress-related behaviors, whereas their inhibition attenuated CRS-associated behavioral abnormalities in susceptible mice. What's more, future studies are needed to determine whether these mPFC-VMS circuit features generalize to females. Together, these findings support the VMS-projecting mPFC neurons as a candidate neural substrate associated with individual differences in stress-related behavioral vulnerability.