Social stress induces neurovascular pathology promoting depression
Caroline Menard, Madeline L Pfau, Georgia E Hodes, Veronika Kana, Victoria X Wang, Sylvain Bouchard, Aki Takahashi, Meghan E Flanigan, Hossein Aleyasin, Katherine B LeClair, William G Janssen, Benoit Labonté, Eric M Parise, Zachary S Lorsch, Sam A Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A Fayad, Cheuk Ying Tang, Miriam Merad, Scott J Russo, Caroline Menard, Madeline L Pfau, Georgia E Hodes, Veronika Kana, Victoria X Wang, Sylvain Bouchard, Aki Takahashi, Meghan E Flanigan, Hossein Aleyasin, Katherine B LeClair, William G Janssen, Benoit Labonté, Eric M Parise, Zachary S Lorsch, Sam A Golden, Mitra Heshmati, Carol Tamminga, Gustavo Turecki, Matthew Campbell, Zahi A Fayad, Cheuk Ying Tang, Miriam Merad, Scott J Russo
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.
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References
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