@article{002e9a11ca14454fbec145c9c33d7f4d,
title = "Molecular adaptations of the blood–brain barrier promote stress resilience vs. Depression",
abstract = "Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.",
keywords = "Antidepressant, Epigenetic, Inflammation, Mood disorders, Vascular",
author = "Dudek, {Katarzyna A.} and Laurence Dion-Albert and Manon Lebel and Katherine LeClair and Simon Labrecque and Ellen Tuck and Perez, {Carmen Ferrer} and Golden, {Sam A.} and Carol Tamminga and Gustavo Turecki and Naguib Mechawar and Russo, {Scott J.} and Caroline Menard",
note = "Funding Information: ACKNOWLEDGMENTS. This research was supported by grants from the Sentinel North Initiative funded by Canada First Research Excellence Fund (Research Chair on the Neurobiology of Stress and Resilience to C.M.), Brain and Behavior Research Foundation (Young Investigator Grant to C.M.), a Fonds de recherche du Quebec (FRQS) Junior 1 salary award (C.M.), and a Foundation Helene-Halle of Universit{\'e} Laval New Investigator Grant (C.M.). K.A.D., L.D.-A., and E.T. are supported by scholarships from the CERVO Foundation sponsored by Desjardins, Sentinel North, Universit{\'e} Laval Faculty of Medicine, and the A.W.B. Vincent Scholarship, Trinity College Dublin. Other support includes grants from NIH and Conte Center to S.J.R. (R01 MH 104559, P50 MH 096890). The Douglas Bell-Canada Brain Bank is funded by platform support grants from the R{\'e}seau Qu{\'e}b{\'e}cois sur le Suicide, les troubles de l{\textquoteright}Humeur et les troubles Associ{\'e}s, and Healthy Brain, Healthy Lives (McGill University). We thank the individuals and their families who generously gave their brains for science. Funding Information: This research was supported by grants from the Sentinel North Initiative funded by Canada First Research Excellence Fund (Research Chair on the Neurobiology of Stress and Resilience to C.M.), Brain and Behavior Research Foundation (Young Investigator Grant to C.M.), a Fonds de recherche du Quebec (FRQS) Junior 1 salary award (C.M.), and a Foundation Helene-Halle of Universit? Laval New Investigator Grant (C.M.). K.A.D., L.D.-A., and E.T. are supported by scholarships from the CERVO Foundation sponsored by Desjardins, Sentinel North, Universit? Laval Faculty of Medicine, and the A.W.B. Vincent Scholarship, Trinity College Dublin. Other support includes grants from NIH and Conte Center to S.J.R. (R01 MH 104559, P50 MH 096890). The Douglas Bell-Canada Brain Bank is funded by platform support grants from the R?seau Qu?b?cois sur le Suicide, les troubles de l?Humeur et les troubles Associ?s, and Healthy Brain, Healthy Lives (McGill University). We thank the individuals and their families who generously gave their brains for science. Publisher Copyright: {\textcopyright} 2020 National Academy of Sciences. All rights reserved.",
year = "2020",
month = feb,
day = "11",
doi = "10.1073/pnas.1914655117",
language = "English (US)",
volume = "117",
pages = "3326--3336",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "6",
}