Mechanisms of stress-induced neurovascular damage promoting immune infiltration and depression-like behaviors

多项临床研究表明，外周炎症加剧是导致 抑郁症(MDD)的发病机制。炎症性疾病与MDD并存的情况非常普遍， MDD患者患这些疾病的风险更高。据推测，循环中的 炎症分子在慢性应激后释放，穿透血脑屏障(BBB)，以及 影响神经回路，调节应激、脆弱和抑郁。然而，尽管多年来密集地 关于细胞因子在抑郁症中的作用的研究，我们几乎没有直接证据表明细胞因子是如何进入 以及它们在哪些回路中起作用。最近，我们开始调查慢性社会挫败的影响 应激(CSDS)，一种导致抑郁样行为的应激模型，对血脑屏障通透性的影响。 血管内皮细胞和星形胶质细胞在维持血管不通透性方面起着关键作用。内皮细胞，通过 紧密连接蛋白的表达，在血管周围间隙和血管之间建立细胞旁屏障 脑实质。内皮屏障的破坏可导致外周免疫信号的渗透- 例如IL-6，我们之前已经证明了它可以增加应激敏感性。我们的新数据显示，10 天数CSDS下调应激敏感大鼠NAC紧密连接蛋白Cldn5的表达 导致小鼠血管内皮细胞屏障完整性丧失、免疫渗入和表达类抑郁 行为。在这些初步观察的基础上，我们将探索详细的分子和细胞 外周免疫信号与情绪相关大脑回路相互作用以控制的机制 伴随着社会压力而出现的抑郁行为。通过了解慢性压力如何影响血脑屏障，我们可能 能够加强目前的抗抑郁药物治疗或设计新的治疗策略来促进血管 通过防止血脑屏障退化来保持健康。

Multiple clinical studies suggest that heightened peripheral inflammation contributes to major depressive disorder (MDD) pathogenesis. Co-morbidity of inflammatory disease with MDD is highly prevalent, and MDD patients have a higher risk of developing those diseases. It has been hypothesized that circulating inflammatory molecules are released following chronic stress, penetrate the blood brain barrier (BBB), and affect neural circuits, mediating stress vulnerability and depression. However, despite years of intensive research into the role of cytokines in depression, we have very little direct evidence of how cytokines enter the brain and in which circuits they act. Recently, we have begun to investigate the effect of chronic social defeat stress (CSDS), a mouse model of stress that induces depression-like behavior, on BBB permeability. Endothelial cells and astrocytes play critical roles in maintaining vascular impermeability. Endothelial cells, via expression of tight junction proteins, establish the paracellular barrier between the perivascular space and brain parenchyma. Breakdown of the endothelial barrier can lead to infiltration of peripheral immune signals— such as IL-6—that we have shown previously to increase stress susceptibility. Our new data shows that 10 days of CSDS downregulates expression of the tight junction protein Cldn5 in the NAc of stress-susceptible mice leading to loss of integrity of the endothelial barrier, immune infiltration and expression of depression-like behaviors. Expanding upon these preliminary observations, we will probe the detailed molecular and cellular mechanisms by which peripheral immune signals interface with mood-related brain circuitry to control depression-like behaviors following social stress. By understanding how chronic stress affects the BBB we may be able to augment current antidepressant treatment or design new therapeutic strategies promoting vascular health by preventing BBB degeneration.