Maxime Veleanu, Louise Schuberth, Antje Kilias, Jakob Weber, Jan Warneke, Lovis Würz, Tim Schwär, Rebecca Heck, Joelle Müller, David H Sarrazin, Marguerite Anselin, Lukas Rutke, Guillermo Suarez Marchi, Stella Zimmermann, Zoe Borgeest, Martin Balzinger, Alina Blendinger, Anna Catarata, Samira Assaad Dib, Yaroslav Sych, Thibault Cholvin, Marlene Bartos, Katharina Domschke, Claus Normann, Stefan Vestring, Tsvetan Serchov
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. Our findings demonstrate that the functional IL → RE→vHIPP circuit plays a central role in the antidepressant response, linking circuit activity, hippocampal plasticity, and depressive-like behaviors.