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The Habenula’s role in major depressive disorder: recent insights from preclinical and human studies
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  • Review Article
  • Open access
  • Published: 07 February 2026

The Habenula’s role in major depressive disorder: recent insights from preclinical and human studies

  • Lin Feiteng1,
  • Kayleigh Casmey  ORCID: orcid.org/0009-0007-0539-76242,
  • Sierra A. Codeluppi-Arrowsmith3 &
  • …
  • Gustavo Turecki  ORCID: orcid.org/0000-0003-4075-27361,2,3 

Translational Psychiatry , Article number:  (2026) Cite this article

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We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Depression
  • Molecular neuroscience

Abstract

The habenula is a small epithalamic structure composed of two distinct subregions, the medial (MHb) and lateral (LHb) habenula. It serves as a critical hub for integrating fronto-limbic and brainstem signals to regulate motivation, mood, and reward processing. Therefore, it is unsurprising that dysfunction of the habenula has been implicated in several mood disorders including major depressive disorder (MDD), a debilitating mood disorder marked by low mood and feelings of hopelessness. This review synthesizes recent advances in understanding the habenula’s neurocircuitry, molecular landscape, and role in MDD pathophysiology, while evaluating its potential as a therapeutic target. Specifically, emerging evidence highlights subregion-specific pathology. Indeed, in MDD and in animal models of depression, the MHb has been shown to exhibit marked downregulation of calcium-dependent activator protein for secretion 2 (CAPS2) and deficits in nicotinic acetylcholine receptor-mediated signaling. While in the LHb, dysregulated expression profiles of inward-rectifying potassium channel Kir4.1, the β isoform of calcium/calmodulin-dependent protein kinase II (CaMKIIβ), protein phosphatase 2 A (PP2A), and small nucleolar RNA SNORA69 have been found in animal models of depression and MDD postmortem studies. Structural imaging and postmortem neurohistological studies in MDD patients have further revealed habenular volume changes, reduced neuronal cell counts, diminished cell area, and abnormal functional connectivity. As research unravels the habenula’s complexities, its potential in treating mood disorders grows increasingly salient, offering new avenues for intervention in mental health.

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Acknowledgements

We would like to thank all the members of the McGill Group for Suicide Studies (MGSS) for their valuable input and support in this work. This project was supported by grants from the Canadian Institutes of Health Research (CIHR) and the National Institutes of Health (NIH). Financial support was also provided by Health Canada through the Canada Brain Research Fund, an innovative partnership between the Government of Canada (through Health Canada) and Brain Canada. Additional funding was contributed by the Canada First Research Excellence Fund, awarded to McGill University for the Healthy Brains for Healthy Lives initiative, as well as by the Fonds de recherche du Québec - Santé (FRQS) through the Quebec Network on Suicide, Mood Disorders, and Related Disorders.

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Authors and Affiliations

  1. Department of Human Genetics, McGill University, Montréal, Canada

    Lin Feiteng & Gustavo Turecki

  2. Integrated Program in Neuroscience, McGill University, Montréal, QC, Canada

    Kayleigh Casmey & Gustavo Turecki

  3. McGill Group for Suicide Studies, Douglas Institute, Department of Psychiatry, McGill University, Montréal, QC, Canada

    Sierra A. Codeluppi-Arrowsmith & Gustavo Turecki

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  1. Lin Feiteng
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  4. Gustavo Turecki
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Contributions

Feiteng Lin led the literature search, defined the structural framework, and wrote the original draft and subsequent revisions. Kayleigh Casmey provided critical feedback and editing on the draft. Sierra Codeluppi-Arrowsmith contributed to the literature search, suggested key references, and provided revisions to the drafts. Gustavo Turecki provided senior oversight, contributed to the structural framework and conceptual scope of the review, and performed the final critical revision. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Gustavo Turecki.

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Lin, F., Casmey, K., Codeluppi-Arrowsmith, S.A. et al. The Habenula’s role in major depressive disorder: recent insights from preclinical and human studies. Transl Psychiatry (2026). https://doi.org/10.1038/s41398-026-03867-0

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  • Received: 09 October 2024

  • Revised: 17 December 2025

  • Accepted: 28 January 2026

  • Published: 07 February 2026

  • DOI: https://doi.org/10.1038/s41398-026-03867-0

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