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，压力与心理健康并发症的发病率增加有关，包括焦虑和抑郁。不幸的是，应激引起免疫和行为后果的机制尚未完全了解。在一个特定的社会应激小鼠模型中，称为（Pt.2）反复社交失败（RSD），外周骨髓系细胞和单核细胞（CD 11b+）的炎症潜能增强，免疫刺激后，这些细胞产生更多的促炎细胞因子。此外，RSD增加了循环骨髓系细胞向发炎外周组织的募集，导致过度炎症和病理学。（Pt.1）最近，我们发表了暴露于RSD的小鼠表现出大脑中炎症的增强，这对应于引发的小胶质细胞的增加，小胶质细胞是大脑中的常驻CD 11b+细胞。引发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模型相似，RSD启动小胶质细胞活化，导致其炎症能力增加。例如，从RSD小鼠中分离的小胶质细胞的离体免疫刺激导致炎性细胞因子和趋化因子如TNF-α、CCL 2（MCP-1）和IL-6的扩增产生。此外，RSD增加了Ly 6Chigh/CCR 2+巨噬细胞（CD 11b +/CD 45 high）向脑的运输。Ly 6Chigh/CCR 2+巨噬细胞容易运输到炎症部位并启动或维持免疫应答。此外，RSD诱导延长的焦虑样行为，这是明显的长达8天后停止的压力。由于炎症和焦虑是密切相关的，这是合理的，RSD引发小胶质细胞和招募巨噬细胞到大脑，这使炎症持续存在，并导致长期的焦虑样行为。在本申请中，RSD将用于检验以下假设：社会压力引发小胶质细胞并向大脑招募巨噬细胞，这些炎症变化有助于延长焦虑样行为。

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.