期刊
NATURE NEUROSCIENCE
卷 20, 期 12, 页码 1752-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41593-017-0010-3
关键词
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资金
- Mental Health grants [RO1 MH090264, P50 MH096890, P50 AT008661-01, RO1 MH114882, RO1 MH104559]
- NIH/NHLBI [P01 HL131478, T32 MH087004, T32 MH096678, F30 MH100835, F31 MH105217]
- Janssen/IMHRO Rising Star Translational Research Award
- Swiss National Science Foundation
- Brain and Behavior Research Foundation NARSAD Young Investigator Award
- Brain and Behavior Research Foundation NARSAD Young Investigator Grant - PS Fund
- Grants-in-Aid for Scientific Research [15K12773] Funding Source: KAKEN
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.
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