The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response
- 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
2026-09-01
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.