A nucleus accumbens-projecting prefrontal cortex circuit underlies chronic social stress-induced depression-like...

Major depressive disorder (MDD) is a prevalent and debilitating psychiatric illness with limited treatment success. While chronic social stress is a well-established risk factor, the neural circuits that determine individual susceptibility or resilience to MDD remain poorly defined. Here, we identify a distinct subpopulation of layer 5 neurons in the medial prefrontal cortex (mPFC) that project to the nucleus accumbens (NAc) that are selectively activated by chronic social defeat stress (cSDS) in male mice. Using activity-dependent genetic tagging (TRAP), retrograde tracing, and electrophysiology recordings, we demonstrate that these stress-responsive mPFC-NAc neurons exhibit circuit-specific synaptic dysfunction-characterized by reduced excitatory postsynaptic currents, impaired local excitatory connectivity, and dendritic spine loss-in mice susceptible to stress, but not in resilient individuals. Optogenetic modulation further reveals a causal role for this pathway: activation of the mPFC-NAc circuit during cSDS promotes resilience, whereas inhibition increases susceptibility to stress. Together, these findings define a functionally distinct corticolimbic circuit that regulates depression-like behaviors and highlight a potential target for circuit-based interventions in MDD.