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

点击翻译按钮获取中文摘要

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.