The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response
Researchers have identified a specific brain circuit, the IL-RE-vHIPP pathway, that mediates the rapid antidepressant effects of treatments like ketamine. This discovery provides a new neurobiological framework for understanding depression and developing faster-acting therapeutic interventions.
Why it matters
Mapping the neural circuitry of antidepressant response is a critical step toward creating more effective treatments for major depressive disorder, which currently has high rates of non-response.
The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view linking these processes remains elusive. Here, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) exerts rapid antidepressant-like effects across multiple behavioral domains in a mouse model of stress-induced depression. IL stimulation exerts top-down control over the hippocampus, enhancing structural plasticity, restoring long-term potentiation deficits and improving state-dependent network dynamics in the ventral hippocampus (vHIPP). We identify the thalamic nucleus reuniens (RE) as a necessary mediator of these effects. Notably, direct inhibition of RE, its inputs from IL or projections to vHIPP, blocks both IL stimulation-induced antidepressant response and the therapeutic and neuroplastic effects of ketamine.
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