Major Depressive Disorder (MDD) is more frequent in women than men, and sex differences have been reported in symptoms and treatment response. The fact that individuals with cardiovascular disease or stroke are more prone to depression suggests vascular dysfunction may also be involved. New research by Laurence Dion-Albert, PhD student at Université Laval, shows for the first-time alterations in brain barrier integrity in female animals and women with depression that are different from those seen in males and men. They also identified potential biomarkers for depression that could help better diagnose and inform treatment strategies for depressive disorders.
Laurence Dion-Albert won a CAN-CIHR-INMHA Brain Star award for these discoveries.
Exposure to chronic stress induces changes in brain vascular integrity and blood-brain barrier (BBB) leakiness through downregulation of a protein called Claudin-5 in the nucleus accumbens of male mice, a brain region critical for emotional responses. During her Masters degree, Laurence Dion-Albert investigated if sex-specific changes in BBB integrity could underlie sex differences in major depressive disorder. She found that female mice exposed to chronic stress presented major changes in expression of BBB-related genes and loss of Claudin-5 in a different brain region, the prefrontal cortex (PFC), a hub for anxiety and self-perception. Importantly, viral-mediated knockdown of Claudin-5 in the female PFC recapitulated social isolation as well as anxiety- and depressive-like behaviors without prior exposure to stress, highlighting a causal role for Claudin-5 in the establishment of detrimental stress coping behaviors. These findings were confirmed in post-mortem brain samples from depressed individuals of both sexes, adding critical translational value to the findings in animals. Finally, Laurence Dion-Albert explored several markers of vascular dysfunction in blood samples from stressed animals and individuals with MDD. She showed that sE-selectin, an indicator of vascular inflammation, is higher in stressed females and women with MDD, and could serve as a biomarker to assist in diagnosis.
These results, which demonstrate sex-specific neurovascular alterations linked to depression for the first time, may explain sex-specific symptomatology and pave the way for the development of new, more effective treatments. 30-50% of individuals with MDD are unresponsive to traditional neuron-centered antidepressants, and a better understanding of the mechanisms involved in stress responses and mood disorders is essential to achieve breakthrough for them. Moreover, no reliable biomarker has been found for major depression, which is still diagnosed by questionnaires. Although it needs to be evaluated in larger cohorts, this study is the first to propose sE-selectin as a blood marker for MDD.
Following these findings, Laurence Dion-Albert hopes to further decipher the mechanisms underlying the pathogenesis of MDD to produce tangible change for men and women with MDD across the world.
About Laurence Dion-Albert
Laurence Dion-Albert developed the experimental design with her supervisor, Dr. Caroline Menard, researcher at the CERVO Brain Research Centre, affiliated to Université Laval. She organized, optimized, and performed all the experiments included in the article. She also supervised colleagues who helped for surgeries and behavior analysis and helped write the manuscript and prepare figures. Beyond her direct contribution to the study, Laurence Dion-Albert has been actively involved in sharing these results with other scientists and the public through multiple presentations.
Funding Source:
Canadian Institutes of Health Research
Scientific publication :
Dion-Albert, L., Cadoret, A., Doney, E. Neutzling Kaufmann, F., Dudek, KA., Daigle, B., Parise, LF., Cathomas, F., Samba, N., Hudson, N., Lebel, M., Signature Consortium., Campbell, M., Turecki, G., Mechawar, N., Menard, C. Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue. Nat Commun 13, 164 (2022). https://doi.org/10.1038/s41467-021-27604-x
https://www.nature.com/articles/s41467-021-27604-x
More about this story
This discovery was selected as one of the top 10 discoveries of 2022 by Quebec Science magazine:
https://lactualite.com/sante-et-science/depression-une-nouvelle-piste-pour-mieux-traiter-les-femmes/
