Validation of Immune Dysfunction in Model of Social Stress: Implications for Major Depression Disorder in Veterans

项目概要/摘要 至少有30%的阿富汗和伊拉克退伍军人受到严重抑郁症（MDD）的影响，20%的人 受创伤后应激障碍（PTSD）和其他与压力相关的情绪障碍的影响。当前存在 药物治疗在<50%的患者中引起暂时缓解;因此，迫切需要 针对MDD和心理压力相关情绪障碍的新治疗方法。之时尚 心血管疾病患者中MDD的发生率高出2 - 3倍，MDD与80%的 心血管疾病发病率和死亡率的风险增加。临床研究报告称， 在MDD患者中的炎性细胞因子，并已在临床前动物研究中复制， 萧条调节细胞因子释放（最显著的是IL-6）的个体差异与 小鼠对慢性社会压力的易感性与恢复力。慢性炎症和循环增加 与压力诱导的抑郁症相关的促炎细胞因子与动脉粥样硬化斑块有关 形成、进展和破裂，可能有助于心血管疾病的发病机制。的确， 中和外周炎症细胞因子的免疫调节方法产生抗抑郁药- 就像慢性社会失败压力（CSDS）对小鼠和人类的行为影响一样， 抑郁症和慢性炎症。心理韧性的概念，保持正常心理的能力 和身体功能，以避免严重的精神疾病有重大利益的主题，在退伍军人期间， 最近，与CSD相关的抑郁症已经被发现， 与血脑屏障（BBB）受损有关，血脑屏障是一系列保护层，包括内皮细胞 和星形胶质细胞，在维持外周和大脑之间的血管不渗透性方面起着关键作用 薄壁组织拟议的验证研究表明，BBB的损害可能是因果关系， 与压力引起的情绪障碍有关特别是，我们将验证和扩大我们的理解， 应激如何影响应激诱导的心境障碍中BBB的区域依赖性损伤， 我们的合作者Scott Russo，Anne Schaefer和Miriam Merad在他们的出版物中先前报道过 社会压力导致神经血管病理学促进抑郁症。使用特征良好的CSDS 小鼠心理应激模型，重现了MDD的许多症状，包括社会 退缩，快感缺乏和焦虑，我们将通过新的技术方法探索慢性 心理压力损害BBB。特别是，我们将利用一种新的内皮特异性翻译， 核糖体亲和纯化（TRAP）小鼠，以探索多种应激诱导的转录模式 情绪相关的大脑区域，以确定转录模式的心理压力。为了进一步探索 心理压力损害血脑屏障，我们将利用创新的质谱仪（CyTOF）来确定 免疫细胞在易感小鼠与弹性小鼠的外周和脑组织中的分布，并了解如何 心理压力调动了先天免疫系统并导致细胞因子渗入大脑。 总而言之，这项验证研究优秀评审奖的提案对退伍军人健康至关重要。 这个VA优秀评论奖是为了验证我们的合作者最近的发现，表明心理 抑郁症模型中的应激损害BBB渗透性，并扩展了我们对应激如何诱导 区域特异性内皮基因表达改变，导致血管损伤和抑郁症相关 慢性炎症我们的研究结果将为新的临床前研究提供证据。 治疗退伍军人压力相关抑郁症的治疗方法。

Project Summary/Abstract At least 30% of Afghanistan and Iraq veterans are affected by Major Depressive Disorder (MDD) and 20% are affected by post-traumatic stress disorder (PTSD) and other stress-related mood disorders. Currently existing pharmacological treatments elicit temporary remission in <50% of patients; thus, there is an urgent need for novel therapeutic approaches to target MDD and psychological stress-related mood disorders. The prevalence of MDD is two- to threefold higher in patients with cardiovascular disease and MDD is associated with 80% increased risk of cardiovascular morbidity and mortality. Clinical studies report higher levels of circulating pro- inflammatory cytokines in patients with MDD and has been replicated in preclinical animal studies of depression. Individual differences in the modulation of cytokine release (most notably IL-6) are associated with susceptibility vs. resilience to chronic social stress in mice. Chronic inflammation and increases in circulatory pro-inflammatory cytokines associated with stress-induced depression is linked with atherosclerotic plaque formation, progression, and rupture, likely contributing to the pathogenesis of cardiovascular disease. Indeed, immune modulatory approaches to neutralize inflammatory cytokines in the periphery produce antidepressant- like behavioral effects following Chronic Social Defeat Stress (CSDS) in mice as well as in humans with depression and chronic inflammation. The concept of resilience, the ability to maintain normal psychological and physical functioning to avoid serious mental illness has topic of significant interest in Veterans during and post-deployment after exposure to psychological stress.Recently, CSDS-associated depression has been linked to impairment of the blood brain barrier (BBB), a series of protective layers including endothelial cells and astrocytes that plays a critical role in maintaining vascular impermeability between the periphery and brain parenchyma. The proposed validation studies implicate that impairment of the BBB may be causally associated with stress-induced mood disorders. In particular, we will validate and expand our understanding how stress influences the region-dependent impairment of the BBB in stress-induced mood disorders, as previously reported by our collaborators Scott Russo, Anne Schaefer, and Miriam Merad in their publication “Social stress induces neurovascular pathology promoting depression”. Using a well-characterized CSDS model of psychological stress in mice that recapitulates many of the symptoms of MDD including social withdrawal, anhedonia, and anxiety, we will explore through novel technological approaches how chronic psychological stress impairs the BBB. In particular, we will utilize a novel endothelial-specific Translating Ribosome Affinity Purification (TRAP) mouse to explore stress-induced transcriptional patterns in multiple mood-related brain regions to determine transcriptomic patterns to psychological stress. To further explore how psychological stress impairs the BBB, we will utilize an innovative mass cytometry (CyTOF) to determine the immune cell profiles in the periphery and brain tissue of susceptible vs. resilient mice and understand how psychological stress mobilizes the innate immune system and causes infiltration of cytokines into the brain. In summary, the proposal in this Merit Review Award for Validation Studies is of importance to Veteran Health. This VA Merit Review Award is to validate recent findings by our collaborators showing that psychological stress in a model of depression impairs BBB permeability and expand our knowledge into how stress induces region-specific endothelial gene expression changes, leading to vascular damage and depression-linked chronic inflammation. The findings of our studies will provide evidence for preclinical studies for novel therapeutic approaches for treating stress-related MDD for Veterans.