Abstract
Chronic stress promotes blood-brain barrier (BBB) integrity loss leading to passage of inflammatory mediators in mood-regulating brain areas and establishment of depressive behaviors. Conversely, neurovascular adaptations favoring stress resilience and preventive strategies to promote them are undetermined. We report that environmental enrichment dampens stress-induced loss of endothelial tight junction Claudin-5 (Cldn5) along with anxiety- and depression-like behaviors in male mice via an increase in fibroblast growth factor 2 (Fgf2). Coping with voluntary physical exercise also protects the BBB from stress deleterious effects by increasing Fgf2. Fgf2 is mostly expressed by glial cells, and viral-mediated astrocyte-specific Fgf2 upregulation prevents stress-induced social avoidance while downregulation increases stress susceptibility and blunts physical exercise benefits. Treatment of mouse and human endothelial cells with Fgf2 prior an immune challenge reduces BBB dysfunction, Cldn5 loss, and altered signaling supporting its protective role. Circulating FGF2 level is linked with depression severity and symptomatology in men and women reinforcing involvement of this growth factor in mood disorders.
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Acknowledgements
This research was supported by the Canadian Institutes for Health Research (CIHR, Project Grant #427011 and #495641 to C.M.), Fonds de recherche du Quebec—Santé (FRQS, Junior 2 salary award to C.M.) and C.M. Sentinel North Research Chair funded by Canada First Research Excellence Fund. S.E.J.P., J.L.S., A.Cadoret, A.Collignon, L.B.B., B.D., L.M.B., L.D.A., K.A.D. are supported by scholarships from CIHR, Réseau québécois sur le suicide, les troubles de l’humeur et les troubles associés (RQSHA), Natural Sciences and Engineering Research Council of Canada (NSERC), NeuroQuebec and FRQS. The Signature Consortium acknowledges contributions to the Biobank Signature of the CR-IUSMM (www.banquesignature.ca). The Biobank Signature received funding from the Fondation de l’Institut Universitaire de Santé Mentale de Montréal, Bell cause pour la cause, and the RQSHA. The authors would like to sincerely thank Dr. Jack McGugan from the Department of Anesthesiology and Perioperative Medicine at Queen’s University, who performed the 3D printing of our scratch wound template.
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S.E.J.P. and C.M. designed the research. S.E.J.P., J.L.S., A.Cadoret, A.Collignon, L.B.B., B.D., L.M.B., E.R., F.C.R., L.D.A., K.A.D., and M.L. performed the research, including behavioral experiments, molecular, biochemical, and morphological analysis. The Signature Consortium contributed the human blood samples and related demographic and sociodemographic data. S.E.J.P., J.L.S. and C.M. analyzed the data and wrote the manuscript, which was edited by all authors.
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Paton, S.E.J., Solano, J.L., Cadoret, A. et al. Environmental enrichment and physical exercise prevent stress-induced social avoidance and blood-brain barrier alterations via Fgf2. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68058-9
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DOI: https://doi.org/10.1038/s41467-025-68058-9
