The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response
Maxime Veleanu, Louise E. Schuberth, Antje Kilias, Jakob Weber, Jan Warneke, Lovis M. Würz, Tim Schwär, Rebecca Heck, Joelle Müller, David H. Sarrazin, Marguerite Anselin, Lukas Rutke, Guillermo A. Suárez, S. 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
Nature Communications September 1, 2026 DOI: 10.1038/s41467-026-77248-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical study Peer reviewed |
|---|---|
| Population | Mouse model of stress-induced depression |
| Intervention | Ketamine |
| Topics | Neuroplasticity |
| Key points | Chemogenetic activation of the infralimbic cortex produces rapid antidepressant-like effects in stressed mice, mediated by the thalamic nucleus reuniens and ventral hippocampus. Inhibiting RE or its IL inputs or vHIPP projections blocks both IL-induced and ketamine-induced antidepressant and neuroplastic effects, indicating the IL→RE→vHIPP circuit is central to antidepressant response. |
Abstract
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.