Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue

Laurence Dion-Albert, Alice Cadoret, Ellen Doney, Fernanda Neutzling Kaufmann, Katarzyna A. Dudek, Beatrice Daigle, Lyonna F. Parise, Flurin Cathomas, Nalia Samba, Natalie Hudson, Manon Lebel, Matthew Campbell, Gustavo Turecki, Naguib Mechawar and Caroline Menard ()
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Laurence Dion-Albert: Université Laval and CERVO Brain Research
Alice Cadoret: Université Laval and CERVO Brain Research
Ellen Doney: Université Laval and CERVO Brain Research
Fernanda Neutzling Kaufmann: Université Laval and CERVO Brain Research
Katarzyna A. Dudek: Université Laval and CERVO Brain Research
Beatrice Daigle: Université Laval and CERVO Brain Research
Lyonna F. Parise: Icahn School of Medicine at Mount Sinai
Flurin Cathomas: Icahn School of Medicine at Mount Sinai
Nalia Samba: Sorbonne Université
Natalie Hudson: Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate
Manon Lebel: Université Laval and CERVO Brain Research
Matthew Campbell: Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate
Gustavo Turecki: McGill University and Douglas Mental Health University Institute
Naguib Mechawar: McGill University and Douglas Mental Health University Institute
Caroline Menard: Université Laval and CERVO Brain Research

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27604-x

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