Astrocytic cannabinoid receptor 1 promotes resilience by dampening stress-induced blood–brain barrier alterations
Blood-brain barrier (BBB) alterations contribute to stress vulnerability and the development of depressive behaviors. In contrast, neurovascular adaptations underlying stress resilience remain unclear. Here we report that high expression of astrocytic cannabinoid receptor 1 (CB1) in the nucleus accumbens (NAc) shell, particularly in the end-feet ensheathing blood vessels, is associated with resilience during chronic social stress in adult male mice. Viral-mediated overexpression of Cnr1 in astrocytes of the NAc shell results in baseline anxiolytic effects and dampens stress-induced anxiety- and depression-like behaviors in male mice. It promotes the expression of vascular-related genes and reduces astrocyte inflammatory response and morphological changes following an immune challenge with the cytokine interleukin-6, linked to stress susceptibility and mood disorders. Physical exercise and antidepressant treatment increase the expression of astrocytic Cnr1 in the perivascular region in male mice. In human tissue from male donors with major depressive disorder, we observe loss of CNR1 in the NAc astrocytes. Our findings suggest a role for the astrocytic endocannabinoid system in stress responses via modulation of the BBB.
Authors
- Gustavo Turecki (ORCID: https://orcid.org/0000-0003-4075-2736)
- Luisa Bandeira Binder (ORCID: https://orcid.org/0000-0003-2372-8689)
- Olivier Lavoie (ORCID: https://orcid.org/0000-0002-0545-6993)
- Vincenzo Di Marzo (ORCID: https://orcid.org/0000-0002-1490-3070)
- Matthew E. Campbell (ORCID: https://orcid.org/0000-0003-3325-240X)
- Alice Cadoret (ORCID: https://orcid.org/0000-0001-8228-3320)
- Laurence Dion‐Albert (ORCID: https://orcid.org/0000-0002-7051-6390)
- Jonathan Bouchard (ORCID: https://orcid.org/0000-0002-8976-1847)
- Sam E.J. Paton (ORCID: https://orcid.org/0000-0001-6388-5705)
- Claudia Manca (ORCID: https://orcid.org/0000-0002-4081-9550)
- Cristoforo Silvestri (ORCID: https://orcid.org/0000-0001-5635-1545)
- Naguib Mechawar (ORCID: https://orcid.org/0000-0003-4960-756X)
- Valérie Clavet-Fournier
- Adeline Collignon (ORCID: https://orcid.org/0009-0005-5086-5648)
- Nicolas Flamand (ORCID: https://orcid.org/0000-0001-5944-7200)
- Flavie Lavoie‐Cardinal (ORCID: https://orcid.org/0000-0002-4496-5088)
- Katarzyna Dudek (ORCID: https://orcid.org/0000-0003-4894-5268)
- Fernanda Neutzling Kaufmann (ORCID: https://orcid.org/0000-0002-8175-8600)
- Manuel Guzmán (ORCID: https://orcid.org/0000-0001-7475-118X)
- Caroline Ménard (ORCID: https://orcid.org/0000-0001-8202-7378)
- Manon Lebel (ORCID: https://orcid.org/0000-0003-1649-1214)
Institutions
- Universidad Complutense de Madrid (ES)
- Trinity College Dublin (IE)
- Douglas Mental Health University Institute (CA)
- Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
- Instituto Ramón y Cajal de Investigación Sanitaria (ES)
- Impact (CA)
- Université Laval (CA)
- McGill University (CA)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2025-02-27
- DOI
- https://doi.org/10.1038/s41593-025-01891-9
- Citations
- 28
- Primary Topic
- Cannabis and Cannabinoid Research
- Type
- article
- Field-Weighted Citation Impact
- 39.05
Funders
- Fondation Brain Canada
- Science Foundation Ireland
- Canada Research Chairs
- Irish Research Council
- Canada Excellence Research Chairs, Government of Canada
- Canada First Research Excellence Fund
- Canadian Institutes of Health Research
- Natural Sciences and Engineering Research Council of Canada
- Fonds de Recherche du Québec - Santé
- European Regional Development Fund