Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression

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 pas...

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Veröffentlicht in:	Proceedings of the National Academy of Sciences - PNAS Jg. 117; H. 6; S. 3326
Hauptverfasser:	Dudek, Katarzyna A, Dion-Albert, Laurence, Lebel, Manon, LeClair, Katherine, Labrecque, Simon, Tuck, Ellen, Ferrer Perez, Carmen, Golden, Sam A, Tamminga, Carol, Turecki, Gustavo, Mechawar, Naguib, Russo, Scott J, Menard, Caroline
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States 11.02.2020
Schlagworte:	Animals Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Blood-Brain Barrier - metabolism Claudin-5 - metabolism Depression - drug therapy Depression - metabolism Depressive Disorder, Major - metabolism Disease Models, Animal Epigenesis, Genetic - drug effects Epigenesis, Genetic - physiology Histone Deacetylase 1 - metabolism Humans Inflammation - metabolism Male Mice Mice, Inbred C57BL Nucleus Accumbens - metabolism Signal Transduction - drug effects Signal Transduction - physiology Stress, Psychological - metabolism epigenetic inflammation vascular mood disorders antidepressant
ISSN:	1091-6490, 1091-6490
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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 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.
AbstractList	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.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. 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.
Author	Dudek, Katarzyna A Menard, Caroline Tamminga, Carol Mechawar, Naguib Tuck, Ellen LeClair, Katherine Labrecque, Simon Golden, Sam A Ferrer Perez, Carmen Dion-Albert, Laurence Russo, Scott J Turecki, Gustavo Lebel, Manon
Author_xml	– sequence: 1 givenname: Katarzyna A orcidid: 0000-0003-4894-5268 surname: Dudek fullname: Dudek, Katarzyna A organization: CERVO Brain Research Center, Quebec, QC G1J 2G3, Canada – sequence: 2 givenname: Laurence orcidid: 0000-0002-7051-6390 surname: Dion-Albert fullname: Dion-Albert, Laurence organization: CERVO Brain Research Center, Quebec, QC G1J 2G3, Canada – sequence: 3 givenname: Manon orcidid: 0000-0003-1649-1214 surname: Lebel fullname: Lebel, Manon organization: CERVO Brain Research Center, Quebec, QC G1J 2G3, Canada – sequence: 4 givenname: Katherine surname: LeClair fullname: LeClair, Katherine organization: Center for Affective Neuroscience, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674 – sequence: 5 givenname: Simon surname: Labrecque fullname: Labrecque, Simon organization: CERVO Brain Research Center, Quebec, QC G1J 2G3, Canada – sequence: 6 givenname: Ellen orcidid: 0000-0001-6997-8056 surname: Tuck fullname: Tuck, Ellen organization: Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland – sequence: 7 givenname: Carmen surname: Ferrer Perez fullname: Ferrer Perez, Carmen organization: Department of Psychobiology, University of Valencia, 46010 Valencia, Spain – sequence: 8 givenname: Sam A surname: Golden fullname: Golden, Sam A organization: Department of Biological Structure, University of Washington, Seattle, WA 98195 – sequence: 9 givenname: Carol surname: Tamminga fullname: Tamminga, Carol organization: Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390 – sequence: 10 givenname: Gustavo surname: Turecki fullname: Turecki, Gustavo organization: Douglas Hospital Research Centre, Montreal, QC H4H 1R3, Canada – sequence: 11 givenname: Naguib surname: Mechawar fullname: Mechawar, Naguib organization: Douglas Hospital Research Centre, Montreal, QC H4H 1R3, Canada – sequence: 12 givenname: Scott J orcidid: 0000-0002-6470-1805 surname: Russo fullname: Russo, Scott J organization: Center for Affective Neuroscience, Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029-5674 – sequence: 13 givenname: Caroline orcidid: 0000-0001-8202-7378 surname: Menard fullname: Menard, Caroline email: Caroline.Menard@fmed.ulaval.ca organization: CERVO Brain Research Center, Quebec, QC G1J 2G3, Canada
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/31974313$$D View this record in MEDLINE/PubMed
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Snippet	Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic...
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SubjectTerms	Animals Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Blood-Brain Barrier - metabolism Claudin-5 - metabolism Depression - drug therapy Depression - metabolism Depressive Disorder, Major - metabolism Disease Models, Animal Epigenesis, Genetic - drug effects Epigenesis, Genetic - physiology Histone Deacetylase 1 - metabolism Humans Inflammation - metabolism Male Mice Mice, Inbred C57BL Nucleus Accumbens - metabolism Signal Transduction - drug effects Signal Transduction - physiology Stress, Psychological - metabolism
Title	Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression
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