PT - JOURNAL ARTICLE AU - Laurence Dion-Albert AU - Alice Cadoret AU - Ellen Doney AU - Fernanda Neutzling Kaufmann AU - Katarzyna A. Dudek AU - Lyonna F. Parise AU - Flurin Cathomas AU - Nalia Samba AU - Natalie Hudson AU - Manon Lebel AU - Signature Consortium AU - Matthew Campbell AU - Gustavo Turecki AU - Naguib Mechawar AU - Caroline Menard TI - Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression AID - 10.1101/2021.04.23.441142 DP - 2021 Jan 01 TA - bioRxiv PG - 2021.04.23.441142 4099 - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441142.short 4100 - http://biorxiv.org/content/early/2021/04/24/2021.04.23.441142.full AB - Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.Competing Interest StatementThe authors have declared no competing interest.