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Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression

Laurence Dion-Albert, Alice Cadoret, Ellen Doney, Fernanda Neutzling Kaufmann, Katarzyna A. Dudek, Lyonna F. Parise, Flurin Cathomas, Nalia Samba, Natalie Hudson, Manon Lebel, Signature Consortium, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, View ORCID ProfileCaroline Menard
doi: https://doi.org/10.1101/2021.04.23.441142
Laurence Dion-Albert
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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Alice Cadoret
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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Ellen Doney
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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Fernanda Neutzling Kaufmann
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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Katarzyna A. Dudek
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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Lyonna F. Parise
2Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Flurin Cathomas
2Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Nalia Samba
3Sorbonne Université, Paris (France)
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Natalie Hudson
4Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate, Dublin 2 (Ireland)
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Manon Lebel
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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5Institut universitaire en santé mentale de Montréal, Centre intégré universitaire de santé et service sociaux Est, Montreal, QC (Canada)
Matthew Campbell
4Smurfit Institute of Genetics, Trinity College Dublin, Lincoln Place Gate, Dublin 2 (Ireland)
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Gustavo Turecki
6Department of Psychiatry, McGill University and Douglas Mental Health University Institute, Montreal, QC (Canada)
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Naguib Mechawar
6Department of Psychiatry, McGill University and Douglas Mental Health University Institute, Montreal, QC (Canada)
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Caroline Menard
1Department of Psychiatry and Neuroscience, Université Laval and CERVO Brain Research Center, 2601 de la Canardiere, Quebec City, QC (Canada)
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  • ORCID record for Caroline Menard
  • For correspondence: caroline.menard@fmed.ulaval.ca
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Abstract

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 Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 24, 2021.
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Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression
Laurence Dion-Albert, Alice Cadoret, Ellen Doney, Fernanda Neutzling Kaufmann, Katarzyna A. Dudek, Lyonna F. Parise, Flurin Cathomas, Nalia Samba, Natalie Hudson, Manon Lebel, Signature Consortium, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, Caroline Menard
bioRxiv 2021.04.23.441142; doi: https://doi.org/10.1101/2021.04.23.441142
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Sex-specific blood-brain barrier alterations and vascular biomarkers underlie chronic stress responses in mice and human depression
Laurence Dion-Albert, Alice Cadoret, Ellen Doney, Fernanda Neutzling Kaufmann, Katarzyna A. Dudek, Lyonna F. Parise, Flurin Cathomas, Nalia Samba, Natalie Hudson, Manon Lebel, Signature Consortium, Matthew Campbell, Gustavo Turecki, Naguib Mechawar, Caroline Menard
bioRxiv 2021.04.23.441142; doi: https://doi.org/10.1101/2021.04.23.441142

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