Linking Brain Circuitry and Neural Plasticity in Antidepressant Response: The mPFC-Reuniens-Hippocampus Pathway.

The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view that links these processes remains elusive. Here, using a combination of circuit manipulation, electrophysiology, behavior, and fiber photometry, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) is sufficient to exert rapid antidepressant effects across multiple behavioral domains in a mouse model of stress-induced depression and exerts top-down control over hippocampal plasticity and processing. We show that IL stimulation enhances structural plasticity, restores long-term potentiation and improves state-dependent network dynamics in the hippocampus (HIP). We identified the nucleus reuniens (RE) as a necessary mediator of these effects. Notably, RE inhibition blocks not only IL stimulation-induced antidepressant response but also the therapeutic and neuroplastic effects of ketamine. Our findings demonstrate that the functional IL → RE → ventral HIP circuit plays a central role in the antidepressant response, linking circuit activity, HIP plasticity, and depressive-like behaviors.