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.

中文翻译：

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社会压力导致神经血管病变促进抑郁症

研究表明，周围炎症的加剧是造成重度抑郁症的原因。我们研究了慢性社会挫败压力，一种抑郁症的小鼠模型对血脑屏障（BBB）渗透性和周围免疫信号浸润的影响。我们发现应激易感小鼠的伏伏核（NAc）中内皮细胞紧密连接蛋白claudin-5（Cldn5）的表达减少，血管形态异常。抑郁患者的NAc中CLDN5表达也降低。5号在低于阈值的社会压力下，下调足以诱导抑郁症样的行为，而长期抗抑郁治疗挽救了Cldn5的丢失并增强了适应力。应激反应或注射了针对Cldn5的shRNA的腺相关病毒的小鼠的NAc中BBB完整性降低，导致外周细胞因子白细胞介素6（IL-6）渗入脑实质，并随后表现出抑郁样行为。这些发现表明，慢性社会压力通过紧密连接蛋白Cldn5的丧失改变了血脑屏障的完整性，从而促进外周血IL-6穿过血脑屏障和抑郁症。