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Nat Neurosci. 2017 Dec;20(12):1752-1760. doi: 10.1038/s41593-017-0010-3. Epub 2017 Nov 13.

Social stress induces neurovascular pathology promoting depression.

Author information

1
Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
2
Département de psychiatrie et neurosciences, Faculté de médecine and CERVO Brain Research Centre, Université Laval, Quebec City, QC, Canada.
3
Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
Department of Radiology, Translational and Molecular Imaging Institute at Mount Sinai, New York, NY, USA.
5
University of Tsukuba, Tsukuba, Japan.
6
Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
7
Douglas Mental Health University Institute and McGill University, Montreal, QC, Canada.
8
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
9
Fishberg Department of Neuroscience and the Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. scott.russo@mssm.edu.

Abstract

Studies suggest that heightened peripheral inflammation contributes to the pathogenesis of major depressive disorder. We investigated the effect of chronic social defeat stress, a mouse model of depression, on blood-brain barrier (BBB) permeability and infiltration of peripheral immune signals. We found reduced expression of the endothelial cell tight junction protein claudin-5 (Cldn5) and abnormal blood vessel morphology in nucleus accumbens (NAc) of stress-susceptible but not resilient mice. CLDN5 expression was also decreased in NAc of depressed patients. Cldn5 downregulation was sufficient to induce depression-like behaviors following subthreshold social stress whereas chronic antidepressant treatment rescued Cldn5 loss and promoted resilience. Reduced BBB integrity in NAc of stress-susceptible or mice injected with adeno-associated virus expressing shRNA against Cldn5 caused infiltration of the peripheral cytokine interleukin-6 (IL-6) into brain parenchyma and subsequent expression of depression-like behaviors. These findings suggest that chronic social stress alters BBB integrity through loss of tight junction protein Cldn5, promoting peripheral IL-6 passage across the BBB and depression.

Comment in

PMID:
29184215
PMCID:
PMC5726568
DOI:
10.1038/s41593-017-0010-3
[Indexed for MEDLINE]
Free PMC Article

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