Social stress induces neurovascular pathology promoting depression. (December 2017)

• Record Type: Journal Article
• Authors: Menard, Caroline; Pfau, Madeline; Hodes, Georgia; Kana, Veronika; Wang, Victoria; Bouchard, Sylvain; Takahashi, Aki; Flanigan, Meghan; Aleyasin, Hossein; LeClair, Katherine; Janssen, William; Labonté, Benoit; Parise, Eric; Lorsch, Zachary; Golden, Sam; Heshmati, Mitra; Tamminga, Carol; Turecki, Gustavo; Campbell, Matthew; Fayad, Zahi A.; Tang, Cheuk; Merad, Miriam; Russo, Scott
• Is Part Of: Nature neuroscience. Volume 20:Number 12(2017)
• Page Start: 1752
• Page End: 1760
• Publication Date: 2017-12
• Subjects: Neurosciences -- Periodicals; 573.8
• DOI: 10.1038/s41593-017-0010-3
• Languages: English
• ISSNs: 1097-6256

Abstract

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. Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.