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

项目摘要/摘要 至少30%的阿富汗和伊拉克退伍军人患有严重抑郁障碍(MDD)，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 药物治疗导致50%的患者暂时缓解；因此，迫切需要 针对MDD和心理应激相关情绪障碍的新治疗方法。流行率 在心血管疾病患者中，MDD的发病率增加两到三倍，MDD与80%相关 增加心血管疾病发病率和死亡率的风险。临床研究报告更高水平的循环前- 炎性细胞因子在MDD患者中的表达，并已在临床前动物研究中复制 抑郁症。调节细胞因子释放的个体差异(最显著的是IL-6)与 小鼠对慢性社会压力的敏感性与恢复力。慢性炎症和循环增加 与应激性抑郁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，可能是心血管疾病的致病因素。的确， 免疫调节方法中和外周的炎性细胞因子产生抗抑郁药- 慢性社会失败应激(CSDS)对小鼠和人类的类似行为影响 抑郁症和慢性炎症。复原力的概念，即保持正常心理的能力 以及避免严重精神疾病的身体机能在退伍军人中引起了极大的兴趣 暴露于心理压力后的部署后。最近，与CSDS相关的抑郁症 与血脑屏障(BBB)损害有关的是一系列保护层，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通透性方面发挥关键作用 薄壁组织。拟议的验证研究表明，血脑屏障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 应激如何影响应激性情绪障碍中血脑屏障的区域依赖性损害，如 我们的合作者Scott Russo、Anne Schaefer和Miriam Merad之前在他们的出版物中报道过 “社会应激导致神经血管病变，促进抑郁”。使用具有良好特征的CSDS 小鼠心理应激模型，概括了MDD的许多症状，包括社交 退缩、快感缺乏和焦虑，我们将通过新的技术方法探索慢性 心理压力会损害血脑屏障。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)小鼠探索应激诱导的多基因转录模式 情绪相关的大脑区域决定了心理压力的转录模式。进一步探索如何 心理应激会损害血脑屏障，我们将利用一种创新的质量细胞术(CyTOF)来确定 易感小鼠与恢复能力小鼠的外周和脑组织中的免疫细胞图谱，并了解如何 心理压力会调动先天免疫系统，并导致细胞因子渗入大脑。 总而言之，这项验证研究功绩回顾奖中的建议对退伍军人健康很重要。 退伍军人事务部荣誉评审奖是为了验证我们的合作者最近的发现，表明心理学 抑郁症模型中的压力会损害血脑屏障的通透性，并将我们的知识扩展到压力是如何诱导的 区域特异性内皮基因表达改变，导致血管损伤和抑郁相关 慢性炎症。我们的研究结果将为诺维特的临床前研究提供证据。 治疗退伍军人应激相关MDD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.