Molecular adaptations of the blood–brain barrier promote stress resilience vs. depression
| Autor: | Carmen Ferrer Perez, Katarzyna Anna Dudek, Caroline Menard, Simon Labrecque, Naguib Mechawar, Sam A. Golden, Katherine B. LeClair, Scott J. Russo, Laurence Dion-Albert, Manon Lebel, Carol A. Tamminga, Gustavo Turecki, Ellen Tuck |
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| Rok vydání: | 2020 |
| Předmět: |
Male
Histone Deacetylase 1 Inflammation FOXO1 Blood–brain barrier Nucleus Accumbens Epigenesis Genetic Proinflammatory cytokine Mice 03 medical and health sciences 0302 clinical medicine vascular medicine Animals Humans Claudin-5 030304 developmental biology Social stress Depressive Disorder Major 0303 health sciences antidepressant Multidisciplinary Depression business.industry Systems Biology Biological Sciences medicine.disease mood disorders Antidepressive Agents 3. Good health Mice Inbred C57BL Disease Models Animal medicine.anatomical_structure Mood disorders Blood-Brain Barrier Major depressive disorder Antidepressant medicine.symptom business Neuroscience Stress Psychological epigenetic 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1914655117 |
| Popis: | Significance Thirty to fifty percent of depressed individuals are unresponsive to commonly prescribed antidepressant treatments, suggesting that biological mechanisms, such as stress-induced inflammation and blood vessel dysfunction, remain untreated. The blood–brain barrier is the ultimate frontier between the brain and harmful toxins or inflammatory signals circulating in the blood. Depression and vulnerability to chronic social stress are associated with loss of this barrier integrity; however, the mechanisms involved remain poorly understood. Identification of adaptations leading to resilience under stressful conditions could help develop novel treatments. Here we combined behavioral, pharmacological, and cell-specific gene profiling experiments in mice with epigenetic, molecular, and anatomical analysis of human samples to unravel mechanisms with therapeutic potential to protect the brain and promote resilience. 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. |
| Databáze: | OpenAIRE |
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