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A pathway from the anterior cingulate cortex to the lateral habenula controls chronic pain-induced depression in male mice

Neuropsychopharmacology (2026)Cite this article

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Abstract

Chronic pain induces long-lasting changes in the anterior cingulate cortex (ACC) activity that contribute to the development of comorbid mood disorders. However, how such alterations propagate throughout the ACC connectome remains to be elucidated. Here, we aimed to study the role of the ACC neurons projecting to the lateral habenula (LHb) (ACC→LHb) in chronic pain-induced depression (CPID). CPID was induced using sciatic nerve cuffing in male C57BL/6J mice, and anxiodepressive-like behaviors were evaluated using a battery of behavioral tests. Fiber photometry was used to study the Ca2+ dynamics in the ACC, LHb, and ACC→LHb neurons. We combined viral Translating Ribosome Affinity Purification (vTRAP) and RNA sequencing to study the molecular alterations in the ACC→LHb neurons. Finally, we used an optogenetic approach to study the functional role of this pathway in CPID. Our results confirmed a functional connectivity between the ACC and LHb and demonstrated that this connection plays a critical role in emotional processing. Activation of ACC→LHb neurons elicited Ca2+ responses in the LHb and induced anxiodepressive-like behaviors in naive mice. Cell-type specific transcriptomic analysis revealed that CPID altered the expression of genes involved in neuronal excitability, such as genes related to sphingolipid metabolism, glycophospholipid,s and Ca2+ channels in ACC→LHb neurons. Interestingly, inhibition of this hyperactivity alleviated chronic pain- but not stress-induced anxiodepressive-like behaviors, demonstrating that the ACC→LHb pathway selectively contributed to nerve-injury induced emotional dysregulation. These results reveal that hyperactivity of the neuronal pathway linking the ACC to the LHb is essential for CPID in male mice.

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Fig. 1: ACC and LHb dynamics and interplay in emotional processing in male mice.
Fig. 2: Chronic but not acute ACC→LHb optogenetic activation is sufficient to trigger anxiodepressive-like behaviors in male mice.
Fig. 3: Chronic neuropathic pain affects the ACC-LHb functional connectivity in male mice.
Fig. 4: Neuropathic pain alters sphingolipids in the ACC→LHb neurons in male mice.
Fig. 5: Optogenetic inhibition of the ACC→LHb pathway prevents chronic pain- but not stress-induced anxiodepressive-like consequences in male mice.

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Acknowledgements

We thank the UAR3415 Chronobiotron for animal care, the In Vitro UAR3156 imaging platform, Pascale Koebel and Paola Rossolillo from IGBMC for virus preparations, Noémie Willem, Maxime Thouaye and Quentin Leboulleux for technical support as well as Dr. Lucas Lecourtier for the rgAAV-GCaMP. Behavioral and microscopy platforms were supported by the Région Grand-Est (Fonds Régional de Coopération pour la Recherche, CLueDol project). Sequencing was performed by the GenomEast platform, a member of the ‘France Génomique’ consortium (ANR-10-INBS-0009). We thank the imaging platform (IRIS) of the ICube Lab at University of Strasbourg where the brain MRI data was acquired as well as Dr. Laetitia Degiorgis, Dr. Marion Sourty, Marion Rame, and Vanessa Vanderberghe for technical support in data acquisition and analysis. We acknowledge that drawings were adapted from “Mouse brain (sagittal cut)”, “Mouse brain (coronal cut)”, and “Brain (sagittal cut)” by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates.

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  1. These authors contributed equally: Sarah H. Journée, Victor P. Mathis.

Authors and Affiliations

  1. Université de Strasbourg, Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Intégratives, Strasbourg, France

    Sarah H. Journée, Victor P. Mathis, Robin Waegaert, Sebahat Ozkan, Enora Langlois, Beyza Ayazgok, Léa J. Becker, Mithil Gaikwad, Michel Barrot, Sylvain Hugel, Pierre-Eric Lutz & Ipek Yalcin

  2. Laboratory of Engineering, Informatics and Imaging (ICube), Integrative multimodal imaging in healthcare (IMIS), CNRS, UMR 7357, University of Strasbourg, Strasbourg, France

    Pilar Ortiz-Teba & Laura Harsan

  3. Hacettepe University, Faculty of Pharmacy, Department of Biochemistry, Ankara, Turkey

    Beyza Ayazgok

  4. Department of Psychiatry and Neuroscience, Université Laval, Québec, QC, Canada

    Mithil Gaikwad & Ipek Yalcin

  5. Douglas Mental Health University Institute, Montreal, QC, Canada

    Pierre-Eric Lutz

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Contributions

SHJ and IY contributed to the design of the study. SHJ, VM, IY, RW, SO, EL, LJB, BA, SH and POT conducted experiments. MG, PEL, LH participated in data analyses. SH and VM wrote the first draft of the paper. MB, IY and PEL revised the manuscript. All authors reviewed and edited the final manuscript. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

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Correspondence to Ipek Yalcin.

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Journée, S.H., Mathis, V.P., Waegaert, R. et al. A pathway from the anterior cingulate cortex to the lateral habenula controls chronic pain-induced depression in male mice. Neuropsychopharmacol. (2026). https://doi.org/10.1038/s41386-026-02346-w

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