The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in 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.
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BibTeX
@article{veleanu2026mpfcreunienshippocampus,
title = {{The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response}},
author = {Maxime Veleanu and Louise Schuberth and Antje Kilias and Jakob Weber and Jan Warneke and Lovis Würz and Tim Schwär and Rebecca Heck and Joelle Müller and David H Sarrazin and Marguerite Anselin and Lukas Rutke and Guillermo Suarez Marchi and Stella Zimmermann and Zoe Borgeest and Martin Balzinger and Alina Blendinger and Anna Catarata and Samira Assaad Dib and Yaroslav Sych and Thibault Cholvin and Marlene Bartos and Katharina Domschke and Claus Normann and Stefan Vestring and Tsvetan Serchov},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77248-y},
url = {https://hal.science/hal-05774532v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - The mPFC-reuniens-hippocampus pathway links brain circuitry and neural plasticity in antidepressant response
AU - Maxime Veleanu
AU - Louise Schuberth
AU - Antje Kilias
AU - Jakob Weber
AU - Jan Warneke
AU - Lovis Würz
AU - Tim Schwär
AU - Rebecca Heck
AU - Joelle Müller
AU - David H Sarrazin
AU - Marguerite Anselin
AU - Lukas Rutke
AU - Guillermo Suarez Marchi
AU - Stella Zimmermann
AU - Zoe Borgeest
AU - Martin Balzinger
AU - Alina Blendinger
AU - Anna Catarata
AU - Samira Assaad Dib
AU - Yaroslav Sych
AU - Thibault Cholvin
AU - Marlene Bartos
AU - Katharina Domschke
AU - Claus Normann
AU - Stefan Vestring
AU - Tsvetan Serchov
PY - 2026
DA - 2026/10/01
JO - Nature Communications
DO - 10.1038/s41467-026-77248-y
UR - https://hal.science/hal-05774532v1
AB - 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.
SN - 2041-1723
SN - 2041-1723
ER -