Brain region dependent trafficking of myeloid precursor cells in repeated defeat.

大脑区域依赖性骨髓前体细胞的运输屡屡失败。

• 批准号: 8503687
• 负责人: John F Sheridan
• 金额: $ 49.05万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8503687
• 关键词: Address; Adrenergic Agents; Adrenergic Receptor; Affect; Amygdaloid structure; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Area; Astrocytes; Attenuated; Behavior; Behavioral; Blood Circulation; Bone Marrow; Brain; Brain region; CCL2 gene; Cell Adhesion Molecules; Cells; Chimera organism; Chronic; Chronic stress; Critical Pathways; Data; Development; Endothelial Cells; Endothelium; FK506 binding protein 5; Fright; Genes; Genotype; Glucocorticoids; Goals; Health; Hippocampus (Brain); ITGAM gene; Immune response; Infiltration; Inflammatory; Interleukin-1; Interleukin-1 Receptors; Interleukins; Intervention; Lead; Ligands; Limbic System; Macrophage Activation; Mental Depression; Mental Health; Messenger RNA; Metalloproteases; Microglia; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid Progenitor Cells; Neuraxis; Neurons; Pathway interactions; Pattern; Peripheral; Phenotype; Population; Prefrontal Cortex; Prevalence; Psychosocial Stress; Publications; Publishing; Quality of life; Recruitment Activity; Regulation; Resistance; Role; Site; Stress; Testing; Time; Tissues; Traumatic CNS injury; Work; adrenergic; base; chemokine; chemokine receptor; design; mRNA Expression; macrophage; neurobehavioral; neuroinflammation; neurovascular unit; novel; paraventricular nucleus; precursor cell; prevent; psychosocial; public health relevance; receptor; research study; response; social; stressor; trafficking

DESCRIPTION (provided by applicant): Psychosocial stressors are associated with an increased prevalence of mental health complications including anxiety and depression. While it is known that chronic stressors negatively affect health and influence quality of life, the mechanisms that underlie these neurobehavioral deficits are not well understood. In this proposal, we present novel data that repeated social defeat (RSD)-induced anxiety-like behavior is associated with the egress and trafficking of bone marrow (BM)-derived, glucocorticoid (GC)-insensitive myeloid cells to the brain. Moreover, RSD promotes the infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells to specific brain regions associated with fear and threat appraisal. Our data also indicate that IL-1 receptor type-1 (IL-1R1) and ¿-adrenergic receptor (¿-ADR)-dependent pathways are critical in the development of behavioral and immunological alterations promoted by RSD. Additionally, that RSD promotes glucocorticoid (GC) insensitivity in peripheral myeloid cells. This is relevant because GC-insensitive cells are hyper-inflammatory following activation, that is, they express high levels of proinflammatory genes. Here evidence is also provided indicating that CD11b+ cells in the brain (resident microglia and infiltrating myeloid cells) are primed and less sensitive to GC. The goal of this 5 year project is to test the hypothesis that repeated social defeat stimulates trafficking of primed GC-insensitive, CD11b+/LyC6high/CCR2+ myeloid cells from the bone marrow to fear and threat appraisal regions in the brain to promote prolonged anxiety-like behavior. To address this hypothesis, three specific aims are proposed: 1). We will determine the degree to which RSD promotes the development of a permissive neurovascular unit to elicit brain region-dependent infiltration of CD11b+/Ly6Chigh/CCR2+ myeloid cells. We will focus on the role of ¿-ADR and central IL-1R1 pathways in RSD-induced myeloid cell recruitment. Moreover, it is critical to compare and contrast the infiltrating myeloid cells with the resident microglial population after RSD. 2). The phenotype, GC sensitivity, and proliferative capacity of these cells following RSD will be determined. These experiments will also determine time- and brain region-dependent differences in these myeloid populations following RSD. While it is established that circulating myeloid cells will traffic to sites of tissue damage under inflammatory conditions in the CNS, the release and trafficking of this specific myeloid population to the brain is unique in a model of psychosocial stress where significant CNS trauma is absent. 3). The degree to which blockade of the chemokine receptor-2 (CCR2) prevents CD11b+/Ly6Chigh/CCR2+ myeloid cell infiltration and reverses prolonged anxiety-like behavior associated with RSD will be determined. Understanding how stress-associated promotion of myeloid cell trafficking contributes to neuroinflammation and the promotion of long-lasting anxiety-like behavior may lead to novel interventions that target myeloid cell trafficking and attenuate prolonged neurobehavioral complications associated with chronic stress.

描述（由申请人提供）：社会心理压力源与焦虑和抑郁等心理健康并发症的患病率增加有关。虽然众所周知，慢性压力源会对健康产生负面影响并影响生活质量，但这些神经行为缺陷背后的机制尚不清楚。在这项提案中，我们提出了新的数据，表明重复的社交失败（RSD）引起的焦虑样行为与骨髓（BM）来源的、糖皮质激素（GC）不敏感的骨髓细胞向大脑的流出和运输有关。此外，RSD 促进 CD11b+/Ly6Chigh/CCR2+ 骨髓细胞浸润到与恐惧和威胁评估相关的特定大脑区域。我们的数据还表明，IL-1 受体 1 型 (IL-1R1) 和 ¿-肾上腺素受体 (¿-ADR) 依赖性途径对于 RSD 促进的行为和免疫学改变的发展至关重要。此外，RSD 还会促进外周骨髓细胞对糖皮质激素 (GC) 不敏感。这是相关的，因为 GC 不敏感细胞在激活后是高度炎症的，也就是说，它们表达高水平的促炎基因。这里还提供了证据表明大脑中的 CD11b+ 细胞（常驻小胶质细胞和浸润性骨髓细胞）已启动并且对 GC 不太敏感。这个为期 5 年的项目的目标是检验以下假设：反复的社会失败会刺激 GC 不敏感的 CD11b+/LyC6high/CCR2+ 骨髓细胞从骨髓运输到大脑中的恐惧和威胁评估区域，从而促进长期的焦虑样行为。为了解决这一假设，提出了三个具体目标：1）。我们将确定 RSD 在多大程度上促进允许的神经血管单元的发育，以引发 CD11b+/Ly6Chigh/CCR2+ 骨髓细胞的大脑区域依赖性浸润。我们将重点关注 ¿-ADR 和中央 IL-1R1 通路在 RSD 诱导的骨髓细胞募集中的作用。此外，将 RSD 后的浸润性骨髓细胞与常驻小胶质细胞群进行比较和对比至关重要。 2）。 RSD 后这些细胞的表型、GC 敏感性和增殖能力将被确定。这些实验还将确定 RSD 后这些骨髓细胞群的时间和大脑区域依赖性差异。虽然已经确定循环的骨髓细胞在中枢神经系统炎症条件下会运输到组织损伤部位，但这种特定的骨髓细胞群向大脑的释放和运输在不存在严重中枢神经系统创伤的心理社会压力模型中是独特的。 3）。将确定阻断趋化因子受体 2 (CCR2) 阻止 CD11b+/Ly6Chigh/CCR2+ 骨髓细胞浸润并逆转与 RSD 相关的长期焦虑样行为的程度。了解与压力相关的骨髓细胞运输促进如何导致神经炎症和促进持久的焦虑样行为可能会导致针对骨髓细胞运输并减轻与慢性压力相关的长期神经行为并发症的新干预措施。