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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社会压力会诱发神经血管病理，从而促进抑郁。

研究表明，周围炎症加剧导致重度抑郁症的发病机制。我们研究了慢性社交失败压力（抑郁症小鼠模型）对血脑屏障（BBB）通透性和外周免疫信号渗透的影响。我们发现应激敏感但非应激小鼠的伏隔核（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。抑郁症患者的 NAc 中 CLDN5 表达也降低。Cldn5 下调足以在阈下社会压力后诱发抑郁样行为，而长期抗抑郁治疗可以挽救 Cldn5 损失并提高恢复能力。应激敏感小鼠或注射了表达针对 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，并随后出现抑郁样行为。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 BBB 完整性，促进外周 IL-6 穿过 BBB 并导致抑郁。