The Role of Microglia in Prolonged Anxiety-like Behavior following Social Stress

描述(由申请人提供)：心理社会压力可以深刻地影响免疫力和行为。在临床研究中，压力与炎症状况和早期死亡率有关。此外，压力与包括焦虑和抑郁在内的精神健康并发症的患病率增加有关。不幸的是，压力导致免疫和行为后果的机制还不完全清楚。在一种特殊的社会应激小鼠模型中，称为(Pt.2)重复社会失败(RSD)，外周血髓系细胞和单核细胞(CD11b+)的炎症潜能增强，在免疫刺激后，这些细胞产生更多促炎细胞因子。此外，RSD增加了循环中的髓系细胞对炎症周围组织的募集，导致了夸大的炎症和病理。(Pt.1)最近，我们发表了一篇文章，指出暴露于RSD的小鼠表现出脑部炎症加剧，这与预置的小胶质细胞的增加相对应，小胶质细胞是大脑中驻留的CD11b+细胞。启动的小胶质细胞与增加的神经炎症有关。与衰老和神经系统疾病的模型相似，RSD启动小胶质细胞的激活，导致其炎症能力的增加。例如，从RSD小鼠分离的小胶质细胞的体外免疫刺激导致炎性细胞因子和趋化因子的产生放大，如肿瘤坏死因子-β、CCL2(MCP-1)和IL-6。此外，RSD还增加了Ly6Chigh/CCR2+巨噬细胞(CD11b+/CD45High)向脑内的转运。Ly6Chigh/CCR2+巨噬细胞很容易进入炎症部位，启动或维持免疫反应。此外，RSD会导致长时间的焦虑样行为，这种行为在应激源停止后长达8天都很明显。由于炎症和焦虑密切相关，RSD可能会激活小胶质细胞，并将巨噬细胞招募到大脑中，这会使炎症持续存在，并导致长期的焦虑样行为。在这项应用中，RSD将被用来测试这一假设，即社会应激启动小胶质细胞并将巨噬细胞招募到大脑，这些炎性变化有助于延长焦虑样行为。 公共卫生相关性：心理社会压力与炎症性疾病增加、早期死亡率和包括焦虑在内的心理障碍有关。与大脑相关的预置免疫细胞增加炎症介质，从外周招募反应细胞群，可能是长期行为变化的重要决定因素。了解与大脑相关的免疫细胞如何对神经炎症起作用，有助于揭示心理社会应激导致长期焦虑的机制，并导致新的治疗策略，以减轻应激引起的心理健康并发症。

DESCRIPTION (provided by applicant): Psychosocial stress can profoundly influence immunity and behavior. In clinical studies stress is associated with inflammatory conditions and earlier mortality. In addition, stress is associated with an increased prevalence of mental health complications including anxiety and depression. Unfortunately, the mechanisms by which stress causes immunological and behavioral consequences are not completely understood. In a particular murine model of social stress, called (Pt.2) repeated social defeat (RSD), the inflammatory potential of peripheral myeloid-lineage cells and monocytes (CD11b+) is enhanced and following immune stimulation these cells produce more pro-inflammatory cytokines. In addition, RSD increased the recruitment of circulating, myeloid-lineage cells to inflamed peripheral tissues causing exaggerated inflammation and pathology. (Pt.1) More recently we published that mice exposed to RSD demonstrate enhanced inflammation in the brain that corresponds to an increase in primed microglia, which are resident CD11b+ cells in the brain. Primed microglia are associated with increased neuroinflammation. Similar to models of aging and neurological disease, RSD initiates microglia activation that leads to an increase in their inflammatory capacity. For example, ex vivo immune stimulation of microglia isolated from RSD mice causes amplified production of inflammatory cytokines and chemokines, such as TNF-¿, CCL2 (MCP-1), and IL-6. In addition, RSD increased the trafficking of Ly6Chigh/CCR2+ macrophages (CD11b+/CD45high) to the brain. Ly6Chigh/CCR2+ macrophages readily traffic to sites of inflammation and initiate or perpetuate immune responses. Furthermore, RSD induces prolonged anxiety-like behavior that is apparent up to 8 days after the cessation of the stressor. Since inflammation and anxiety are intimately linked, it is plausible that RSD primes microglia and recruits macrophages to the brain, which perpetuates inflammation and leads to prolonged anxiety-like behavior. In this application, RSD will be used to test the hypothesis that social stress primes microglia and recruits macrophages to the brain and these inflammatory changes contribute to prolonged anxiety-like behavior. PUBLIC HEALTH RELEVANCE: Psychosocial stress is associated with increased inflammatory conditions, earlier mortality, and psychological disorders, including anxiety. Primed immune cells associated with the brain increase inflammatory mediators, recruit reactive cell populations from the periphery, and are likely an important determinant in prolonged behavioral changes. Understanding how primed immune cells associated with the brain contribute to neuroinflammation can help delineate mechanisms by which psychosocial stress can induce prolonged anxiety and lead to novel therapeutic strategies to alleviate mental health complications caused by stress.