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TitleMolecular adaptations of the blood-brain barrier promote stress resilience vs. depression.
Publication TypeJournal Article
Year of Publication2020
AuthorsDudek, Katarzyna A., Laurence Dion-Albert, Manon Lebel, Katherine LeClair, Simon Labrecque, Ellen Tuck, Carmen Ferrer Perez, Sam A. Golden, Carol Tamminga, Gustavo Turecki, Naguib Mechawar, Scott J. Russo, and Caroline Menard
JournalProc Natl Acad Sci U S A
Date Published2020 02 11
KeywordsAnimals, Antidepressive Agents, Blood-Brain Barrier, Claudin-5, Depression, Depressive Disorder, Major, Disease Models, Animal, Epigenesis, Genetic, Histone Deacetylase 1, Humans, Inflammation, Male, Mice, Mice, Inbred C57BL, Nucleus Accumbens, Signal Transduction, Stress, Psychological

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 expression and low endothelium expression of repressive cldn5-related transcription factor 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 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued expression in the NAc and promoted resilience. Importantly, we confirmed changes in expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious -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.

Alternate JournalProc Natl Acad Sci U S A
PubMed ID31974313
PubMed Central IDPMC7022213
Grant ListR00 DA045662 / DA / NIDA NIH HHS / United States
R01 MH104559 / MH / NIMH NIH HHS / United States
P50 MH096890 / MH / NIMH NIH HHS / United States