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

社会威胁引发骨髓祖细胞和小胶质细胞：在焦虑中的作用

• 批准号: 8237863
• 负责人: John F Sheridan
• 金额: $ 38.13万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-15 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8237863
• 关键词: Address; Adrenergic Agents; Adrenergic Receptor; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Attenuated; Behavior; Blood Circulation; Bone Marrow; Brain; Brain region; CD14 gene; Catecholamines; Cells; Chimera organism; Chronic stress; Data; Dendritic Cells; Development; Exposure to; FK506 binding protein 5; FOS gene; Fright; Genes; Glucocorticoids; Goals; Health; Human; ITGAM gene; ITGAX gene; Immune; Immune response; Immunity; Infiltration; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukins; Intervention; Lead; Link; Macrophage Activation; Mediating; Mediator of activation protein; Mental Depression; Mental Health; Mental disorders; Messenger RNA; Metalloproteases; Microglia; Mitogens; Modeling; Mus; Myelogenous; Myeloid Progenitor Cells; Myelopoiesis; Neurons; Neurosciences; Neurosecretory Systems; Pathway interactions; Pattern; Peripheral; Phenotype; Population; Prevalence; Production; Quality of life; Receptor Activation; Regulation; Reporting; Role; Series; Signal Transduction; Spleen; Staining method; Stains; Stress; Surface; Sympathetic Nervous System; TLR4 gene; Testing; Time; Work; adrenergic; chemokine; cytokine; design; hypothalamic-pituitary-adrenal axis; inflammatory marker; macrophage; mouse model; neurobehavioral; neuroinflammation; novel; psychological stressor; research study; response; social; social model; social stress; stressor; trafficking

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. PUBLIC HEALTH RELEVANCE: In humans, chronic stress is associated with an increased prevalence of mental health disorders including anxiety and depression. While it is well known that stress-associated conditions significantly influence health and the quality of life, the mechanisms involved are not completely understood. We propose that stress- induced anxiety-like behavior is exacerbated by inflammatory changes in the brain mediated by the infiltration of bone marrow-derived myeloid progenitor cells (MPCs) into the brain parenchyma. The trafficking of MPCs is regionally specific, and occurs in response to neuronal activation. In this proposal, a murine model of social threat will be used to test the hypothesis that social stress promotes the activation of catecholamine circuits that stimulate bone marrow-derived MPCs to traffic to the brain and produce cytokines that cause prolonged anxiety-like behavior.

描述（由申请人提供）：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患病率增加有关，包括焦虑和抑郁。虽然众所周知，这些与压力相关的条件会显著影响健康和生活质量，但所涉及的机制尚未完全了解。在本文中，我们提出了新的数据，表明暴露于社会破坏（SDR）（一种社会压力模型）引起的焦虑样行为与骨髓（BM）衍生的糖皮质激素（GC）不敏感骨髓祖细胞（MPCs）的输出和贩运有关。此外，在SDR之后，我们发现这些骨髓来源的MPCs （CD11b+/ ly6high /CCR2+）运输到特定的大脑区域。先前的报道表明，从暴露于SDR的小鼠脾脏中收集的MPC群体，包括树突状细胞（CD11c+/CD11b+）和巨噬细胞（CD11b+），对gc提供的抗炎调节不敏感。这是相关的，因为gc不敏感的MPCs与高炎症免疫反应有关。随着脑脊髓型髓系人群的变化，社会威胁增加了大脑中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显示了一种启动表型，几种炎症标志物的表面表达增加，包括CD86、TLR4和CD14 （J. Neuroscience, 2011, in press）。与它们的启动表型相对应，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症细胞因子。因此，本项目的首要目标是验证这样的假设，即社会威胁激活儿茶酚胺能通路，从而增加常驻小胶质细胞的激活，增加MPCs的浸润，从而延长焦虑样行为。为了解决这一假设，我们提出了三个具体目标，使用小鼠社会威胁模型，导致与威胁评估和恐惧/焦虑样反应相关的神经回路的激活。在第一个目标中，我们将阐明在社会威胁后促进gc不敏感MPCs从骨髓发育和输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MPCs招募到特定大脑区域的机制。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募集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免疫细胞激活如何导致焦虑样行为有关，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。