|Title||Social stress induces neurovascular pathology promoting depression.|
|Publication Type||Journal Article|
|Year of Publication||2017|
|Auteurs||Menard, C, Pfau, ML, Hodes, GE, Kana, V, Wang, VX, Bouchard, S, Takahashi, A, Flanigan, ME, Aleyasin, H, LeClair, KB, Janssen, WG, Labonté, B, Parise, EM, Lorsch, ZS, Golden, SA, Heshmati, M, Tamminga, C, Turecki, G, Campbell, M, Fayad, ZA, Tang, CYing, Merad, M, Russo, SJ|
|Date Published||2017 Dec|
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.