ROLE OF THE PFC-REUNIENS-HIPPOCAMPUS PATHWAY IN PLASTICITY AND ANTIDEPRESSANT RESPONSE

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 hippocampal long-term potentiation at the CA1-Schaffer Collateral synapses, and improves state-dependent network dynamics in the hippocampus (HIP). We identified the nucleus reuniens (RE) as a necessary mediator of these effects. Notably, inhibition of the RE, or of the IL → RE projections blocks not only the antidepressant response induced by IL stimulation but also the therapeutic and neuroplastic effects of ketamine. Our results 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. Our study unifies two prominent theoretical frameworks for understanding depression pathophysiology: the circuitry hypothesis and the neuroplasticity hypothesis, and paves the way for a better understanding and targeting of brain stimulation techniques such as DBS or TMS.