Social threat primes myeloid progenitor cells and microglia: role in anxiety

描述(申请人提供)：心理压力源，包括社会压力源，深刻影响免疫力和行为。在人类中，慢性压力与心理健康并发症的增加有关，包括焦虑和抑郁。虽然众所周知，这些与压力相关的疾病会显著影响健康并影响生活质量，但其中涉及的机制还不完全清楚。在这项提案中，我们提出了新的数据，表明暴露于社交破坏(SDR)引起的焦虑样行为与骨髓(BM)来源的、糖皮质激素(GC)不敏感的髓系祖细胞(MPC)的外流和运输有关。此外，在SDR之后，我们发现这些骨髓来源的MPC(CD11b+/Ly6Chigh/CCR2+)流量到特定的大脑区域。以往的报道表明，从SDR暴露的小鼠脾中收集的MPC群体，包括树突状细胞(CD11c+/CD11b+)和巨噬细胞(CD11b+)，对GCs提供的抗炎调节不敏感。这是相关的，因为GC不敏感的MPC与高炎性免疫反应有关。随着骨髓来源髓系群体的变化，社会威胁增加了脑内常驻小胶质细胞的反应性。例如，从SDR小鼠收集的小胶质细胞表现出启动的表型，表面增加了几种炎症标志物的表达，包括CD86、TLR4和CD14(神经科学杂志，2011年出版)。与其启动表型相对应，暴露于SDR的小鼠的小胶质细胞在有丝分裂原刺激后产生更高水平的炎性细胞因子。因此，这个项目的首要目标是检验这一假说，即社会威胁激活儿茶酚胺能通路，从而增加驻留的小胶质细胞的激活，并增加MPC的渗透，以延长焦虑样行为。为了解决这一假设，我们使用一个社会威胁的小鼠模型提出了三个特定的目标，这导致了与威胁评估和恐惧/焦虑样反应相关的神经回路的激活。在第一个目标中，我们将阐明在受到社会威胁后，促进GC不敏感的MPC从骨髓中发展和排出的神经内分泌途径。在第二个目标中，我们将阐明社会威胁促进MPC招募到特定脑区的机制。在第三个目标中，我们将确定社会威胁诱导的小胶质细胞激活和MPC招募如何有助于延长焦虑样行为。这些目标与理解应激相关的先天性免疫细胞激活如何导致焦虑样行为，并可能导致减少神经炎症和延长神经行为并发症的干预措施有关。

DESCRIPTION (provided by applicant): Psychological stressors, including social stressors, profoundly influence immunity and behavior. In humans, chronic stress is associated with an increased prevalence of mental health complications, including anxiety and depression. While it is well known that these stress-associated conditions significantly affect health and influence quality of life, the mechanisms involved are not completely understood. In this proposal, we present novel data that indicate that anxiety-like behavior caused by exposure to social disruption (SDR), a model of social stress, is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid progenitor cells (MPCs). Moreover, following SDR we show that these bone marrow-derived MPCs (CD11b+/Ly6Chigh/CCR2+) traffic to specific brain regions. Previous reports indicate that MPC populations, including dendritic cells (CD11c+/CD11b+) and macrophages (CD11b+) collected from the spleens of mice exposed to SDR were insensitive to the anti- inflammatory regulation provided by GCs. This is relevant because GC-insensitive MPCs are associated with hyper-inflammatory immune responses. Along with changes in BM-derived myeloid populations, social threat increases the reactivity of resident microglia in the brain. For example, microglia collected from SDR mice showed a primed phenotype with increased surface expression of several inflammatory markers, including CD86, TLR4, and CD14 (J. Neuroscience 2011, in press). Corresponding with their primed phenotype, microglia from mice exposed to SDR produced higher levels of inflammatory cytokines following mitogen stimulation. Therefore, the overarching goal of this project is to test the hypothesis that social threat activates catecholaminergic pathways that increase the activation of resident microglia and increase the infiltration of MPCs to prolong anxiety-like behavior. To address this hypothesis we propose three specific aims using a mouse model of social threat that results in the activation of neurocircuitry associated with threat appraisal and fear/anxiety-like responses. In the first aim we will elucidate the neuroendocrine pathways that contribute to the development and egress of GC-insensitive MPCs from the bone marrow after social threat. In the second aim we will elucidate the mechanism by which social threat facilitates the recruitment of MPCs to specific brain regions. In the third aim, we will determine how social threat-induced activation of microglia and MPC recruitment contributes to prolonged anxiety-like behavior. These aims are relevant to understanding how stress-associated activation of innate immune cells contributes to anxiety-like behavior and may lead to interventions that diminish neuroinflammation and prolonged neurobehavioral complications.