The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant 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. 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.
Authors
- Katharina Domschke (ORCID: https://orcid.org/0000-0002-2550-9132)
- Antje Kilias (ORCID: https://orcid.org/0000-0001-6691-7194)
- Tsvetan Serchov (ORCID: https://orcid.org/0000-0002-2234-2875)
- Marlene Bartos (ORCID: https://orcid.org/0000-0001-9741-1946)
- Claus Normann (ORCID: https://orcid.org/0000-0001-5693-8936)
- Guillermo A. Suárez (ORCID: https://orcid.org/0009-0005-6219-0174)
- Stefan Vestring (ORCID: https://orcid.org/0000-0001-9150-8712)
- Rebecca Heck
- Thibault Cholvin (ORCID: https://orcid.org/0000-0002-9964-7693)
- Maxime Veleanu (ORCID: https://orcid.org/0000-0001-6760-3488)
- Yaroslav Sych (ORCID: https://orcid.org/0000-0002-1822-8631)
- David H. Sarrazin (ORCID: https://orcid.org/0000-0003-1326-3232)
- Martin Balzinger
- S. Zimmermann
- Zoe Borgeest
- Alina Blendinger
- Anna Catarata
- Samira Assaad Dib
- Tim Schwär
- Louise E. Schuberth (ORCID: https://orcid.org/0009-0005-1338-7261)
- Marguerite Anselin
- Lukas Rutke
- Jan Warneke
- Jakob Weber
- Lovis Würz
- Joelle Müller
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Freiburg (DE)
- University Medical Center Freiburg (DE)
- Institut des Neurosciences Cellulaires et Intégratives (FR)
- German Centre for Cardiovascular Research (DE)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-01
- DOI
- https://doi.org/10.1038/s41467-026-77248-y
- Primary Topic
- Neurotransmitter Receptor Influence on Behavior
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Deutsche Forschungsgemeinschaft
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Albert-Ludwigs-Universität Freiburg
- Université de Strasbourg
- Centre National de la Recherche Scientifique
- Medizinische Fakultät der Albert-Ludwigs-Universität Freiburg