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，压力与炎症和早期死亡率有关。此外，压力与包括焦虑和抑郁在内的心理健康并发症的患病率增加有关。不幸的是，压力引起免疫和行为后果的机制尚不完全清楚。在一种特殊的小鼠社会压力模型中，称为（Pt.2）重复性社会失败（RSD），外周髓系细胞和单核细胞（CD11b+）的炎症潜力增强，在免疫刺激后，这些细胞产生更多的促炎细胞因子。此外，RSD增加了循环、髓系细胞向炎症外周组织的募集，导致炎症和病理加剧。最近我们发表的研究表明，暴露于RSD的小鼠表现出大脑炎症增强，这与启动小胶质细胞（驻留在大脑中的CD11b+细胞）的增加相对应。引发的小胶质细胞与神经炎症增加有关。与衰老和神经系统疾病模型类似，RSD启动小胶质细胞激活，导致其炎症能力增加。例如，对从RSD小鼠中分离的小胶质细胞进行体外免疫刺激会导致炎症细胞因子和趋化因子（如TNF-¿、CCL2 （MCP-1）和IL-6）的扩增。此外，RSD增加了ly6high /CCR2+巨噬细胞（CD11b+/CD45high）向脑的运输。ly6high /CCR2+巨噬细胞很容易到达炎症部位并启动或延续免疫反应。此外，RSD诱导长时间的焦虑样行为，这种行为在压力源停止后8天内是明显的。由于炎症和焦虑密切相关，RSD启动小胶质细胞并招募巨噬细胞进入大脑，从而使炎症永久化并导致长时间的焦虑样行为是合理的。在这个应用中，RSD将被用来测试社会压力启动小胶质细胞和招募巨噬细胞到大脑的假设，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.