Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression
Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression
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DOI：
10.1073/pnas.1914655117
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发表时间：
2020-02-11
影响因子：
11.1
通讯作者：
Menard, Caroline
中科院分区：
文献类型：
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作者：
Dudek, Katarzyna A.;Dion-Albert, Laurence;Menard, Caroline
临床前和临床研究表明，炎症和血管功能障碍与重度抑郁症（MDD）的发病机制有关。在雄性小鼠中，慢性社会压力通过丧失紧密连接蛋白cldn5 （cldn5）改变血脑屏障（BBB）的完整性，促进循环促炎细胞因子的传递和抑郁样行为。这种效应在伏隔核（大脑中与情绪调节有关的区域）中表现突出；然而，其中的机制尚不清楚。此外，代偿反应导致适当的行为策略和积极的弹性是未知的。在这里，我们发现血脑屏障内与应激恢复能力相关的活跃分子变化可能对神经血管系统起保护作用。我们还证实了这些变化与人类抑郁症和抗抑郁药物治疗的相关性。我们发现cldn5表达的允许表观遗传调控和抑制cldn5相关转录因子foxo1的内皮低表达与应激恢复有关。区域和内皮细胞特异性全转录组学分析揭示了与应激易损性和恢复力相关的分子特征。我们发现促炎TNF α /NF κ B信号和hdac1是应激敏感性的介质。药物抑制应激诱导的hdac1活性增加，可挽救NAc中cldn5的表达，并促进恢复力。重要的是，我们证实了未经抗抑郁治疗的抑郁症患者NAc中HDAC1表达的变化与CLDN5丢失一致。相反，在接受抗抑郁治疗的受试者死后NAc中，许多这些有害的cldn5相关分子变化减少了。这些发现加强了在抑郁症中考虑压力诱导的神经血管病理的重要性，并为治疗这种情绪障碍和促进恢复力提供了治疗靶点。
Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood-brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNF alpha/NF kappa B signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.