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Abstract
Prevalence, symptoms, and treatment of depression suggest that major depressive disorders (MDD) present sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice; however, this association is unclear in females. Here, we report that chronic social and subchronic variable stress promotes blood-brain barrier (BBB) alterations in mood-related brain regions of female mice. Targeted disruption of the BBB in the female prefrontal cortex (PFC) induces anxiety- and depression-like behaviours. By comparing the endothelium cell-specific transcriptomic profiling of the mouse male and female PFC, we identify several pathways and genes involved in maladaptive stress responses and resilience to stress. Furthermore, we confirm that the BBB in the PFC of stressed female mice is leaky. Then, we identify circulating vascular biomarkers of chronic stress, such as soluble E-selectin. Similar changes in circulating soluble E-selectin, BBB gene expression and morphology can be found in blood serum and postmortem brain samples from women diagnosed with MDD. Altogether, we propose that BBB dysfunction plays an important role in modulating stress responses in female mice and possibly MDD.
The vascular, cellular and molecular changes underlying sex differences in mood disorders are unclear. Here, the authors show that blood-brain barrier dysfunction modulates anxiety- and depressive-like behaviors in female mice and endothelium-specific changes associated with maladaptive responses compared to resilience to stress.
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1 Université Laval and CERVO Brain Research, Department of Psychiatry and Neuroscience, Quebec City, Canada (GRID:grid.23856.3a) (ISNI:0000 0004 1936 8390)
2 Icahn School of Medicine at Mount Sinai, Fishberg Department of Neuroscience and the Friedman Brain Institute, New York, USA (GRID:grid.59734.3c) (ISNI:0000 0001 0670 2351)
3 Sorbonne Université, Paris, France (GRID:grid.462844.8) (ISNI:0000 0001 2308 1657)
4 Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate, Dublin 2, Ireland (GRID:grid.8217.c) (ISNI:0000 0004 1936 9705)
5 Centre intégré universitaire de santé et service sociaux Est, Institut universitaire en santé mentale de Montréal, Montreal, Canada (GRID:grid.414210.2) (ISNI:0000 0001 2321 7657)
6 McGill University and Douglas Mental Health University Institute, Department of Psychiatry, Montreal, Canada (GRID:grid.412078.8) (ISNI:0000 0001 2353 5268)