Authors
Priyam Narain, Marko Šušić, Aleksa Petković, Giuseppe Antonio-Saldi, Marc Arnoux, Mehar Sultana, Beemnet Andualem Belete, Dipesh Chaudhury
Published in
Molecular psychiatry. Sep 08, 2026. Epub Sep 08, 2026.
Abstract
Major depressive disorder (MDD) is characterized by substantial heterogeneity, which hinders attempts to associate distinct symptoms with specific neural mechanisms. The lateral habenula (LHb) is a key brain region involved in negative affect and reward processing, but the molecular changes in the LHb that lead to mood disorders remain unclear. Here, we combined chronic social defeat stress (CSDS), behavioural phenotyping, and single-cell RNA sequencing to examine cell-type and subregion-specific transcriptional changes in the mouse habenula. Mice were classified into behavioural phenotypes reflecting social avoidance, anhedonia, passive coping, resilience, or susceptibility. We identified nine major habenular cell classes and found distinct phenotype-associated transcriptional signatures across both neurons and glia. Distinct transcriptional signatures were observed in LHb neurons of susceptible animals and in oligodendrocytes of resilient animals. Subregional analysis revealed that the oval-medial LHb accounted for most stress-related transcriptional changes, while the HbX subregion displayed a unique molecular signature associated with passive coping behaviour. These findings highlight the cellular heterogeneity of stress responses within the habenula and will pave the way for identifying potential targets for precision psychiatry approaches in depression.
PMID:
42711407
Bibliographic data and abstract were imported from PubMed on 09 Sep 2026.
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