Social stress induces neurovascular pathology promoting depression

• DOI: 10.1038/s41593-017-0010-3
• Publication Date: 2017-11-09T15:25:52Z
• Authors: 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
• Keywords: Male; Imipramine; 0303 health sciences; Tight Junction Proteins; Adrenergic Uptake Inhibitors; Behavior, Animal; Depression; Interleukin-6; Feeding Behavior; Anxiety; Social Environment; Article; Nucleus Accumbens; 3. Good health; Mice, Inbred C57BL; Food Preferences; Mice; 03 medical and health sciences; Blood-Brain Barrier; Animals; Claudin-5; Stress, Psychological; Swimming

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.