The role of the brain endothelium in neuroinflammatory responses to social stress

项目总结/摘要 心理社会应激后的炎症信号可能介导适应不良的生理和行为 对压力的反应。例如，焦虑或抑郁患者的促炎性细胞因子水平通常会增加， 循环中的细胞因子和改变的白细胞功能，这与疾病的严重程度和对 治疗重复的社会失败（RSD）是一种心理社会压力的小鼠模型， 人类对慢性社会压力反应的组成部分，包括循环细胞因子的增加， 促炎性单核细胞，以及焦虑样行为的发展。我们以前已经表明，RSD 改变大脑和免疫系统之间的双向信号，特别是在大脑相关区域， 威胁评估和对压力的行为反应，如杏仁核和前边缘皮层。内 在这些区域，小胶质细胞被激活，并招募循环促炎单核细胞到神经血管 内皮细胞单核细胞通过白细胞介素（IL）-1 β受体（IL-1R1）向内皮细胞发出信号至关重要 在压力下产生类似焦虑的行为。目前，内皮细胞对单核细胞源性 IL-1 β未知。在这里，我展示了IL-1 β可以减少内皮紧密连接蛋白的初步数据， 表达并诱导环氧化酶-2，一种参与前列腺素产生的酶。这项建议会 研究应激后神经血管内皮功能的变化， 信号传导影响血脑屏障的通透性，并揭示内皮源性 胡枝子素影响中枢神经系统（CNS）的其他细胞。我提出了三个目标来测试 假设通过内皮细胞IL-1R1的IL-1 β信号传导破坏了参与细胞凋亡的区域中的紧密连接完整性， 恐惧和威胁评估，并刺激内皮细胞产生的肾上腺素，信号中枢神经系统细胞， 影响对压力的行为反应。首先，我将确定是否RSD减少紧密连接蛋白 IL-1R1+内皮细胞的表达以及RSD是否增加血脑屏障通透性。接下来我会 表征神经血管内皮细胞的恐惧反应区域内的转录谱， 在有和没有来自单核细胞的IL-1 β信号的情况下，RSD后的脑。最后，我会抑制前列腺素的产生 使用药理学干预和基因敲除来阐明内皮源性 野牡丹素对RSD后神经元和小胶质细胞活化和行为缺陷的影响。总的来说，这将揭示一个 新的机制，压力可以扰乱中枢神经系统的免疫信号，最终影响行为。 了解压力反应的生物学对于理解心理健康障碍至关重要， 在人口中普遍存在。神经血管内皮细胞是治疗干预的潜在靶点， 预防和治疗焦虑和抑郁等疾病。

PROJECT SUMMARY / ABSTRACT Inflammatory signaling after psychosocial stress may mediate maladaptive physiologic and behavioral responses to stress. For example, patients with anxiety or depression often have increased pro-inflammatory cytokines in circulation and altered leukocyte function, which correlates with disease severity and resistance to treatment. Repeated social defeat (RSD) is a murine model of psychosocial stress that recapitulates key components of the human response to chronic social stress, including increased circulating cytokines, production of pro-inflammatory monocytes, and development of anxiety-like behaviors. We have previously shown that RSD alters bidirectional signaling between the brain and immune system specifically in regions of the brain associated with threat appraisal and behavioral responses to stress, such as the amygdala and prelimbic cortex. Within these regions, microglia become activated, and recruit circulating pro-inflammatory monocytes to neurovascular endothelial cells. Monocyte signaling to endothelial cells through the interleukin(IL)-1β receptor (IL-1R1) is critical for the development of anxiety-like behavior after stress. Currently, the endothelial response to monocyte-derived IL-1β is unknown. Here, I show preliminary data that IL-1β may decrease endothelial tight junction protein expression and induce cyclooxegenase-2, an enzyme involved in prostaglandin production. This proposal will investigate how neurovascular endothelial function changes after stress by addressing whether inflammatory signaling impacts the permeability of the blood-brain barrier and revealing whether endothelial-derived prostaglandins impact other cells of the central nervous system (CNS). I propose three aims to test the hypothesis that IL-1β signaling through endothelial IL-1R1 disrupts tight junction integrity in regions involved in fear and threat appraisal, and stimulates endothelial production of prostaglandins which signal to CNS cells to impact behavioral responses to stress. First, I will determine whether RSD decreases tight junction protein expression in IL-1R1+ endothelial cells and if RSD increases blood-brain barrier permeability. Next, I will characterize the transcriptional profile of neurovascular endothelial cells within fear-responsive regions of the brain after RSD with and without the IL-1β signal from monocytes. Finally, I will inhibit prostaglandin production using pharmacologic interventions and genetic knockouts to elucidate the effects of endothelial-derived prostaglandins on neuronal and microglial activation and behavioral deficits after RSD. Overall, this will reveal a novel mechanism by which stress can perturb immune signaling in the CNS which ultimately impacts behavior. Understanding the biology of stress responses is vital to understanding mental health disorders, which are highly prevalent in the population. Neurovascular endothelial cells are a potential target for therapeutic intervention to prevent and treat disorders such as anxiety and depression.