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: 8997117
• 负责人: John F Sheridan
• 金额: $ 41.96万
• 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/8997117
• 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; anxiety-like behavior; base; chemokine; chemokine receptor; design; mRNA Expression; macrophage; neurobehavioral; neuroinflammation; neurovascular unit; novel; paraventricular nucleus; precursor cell; prevent; psychosocial; 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）：心理社会压力源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。众所周知，慢性压力源会对健康和生活质量产生负面影响，但这些神经行为缺陷背后的机制尚不清楚。在这项提议中，我们提出了新的数据，即反复的社会失败（RSD）诱导的焦虑样行为与骨髓（BM）衍生的糖皮质激素（GC）不敏感的髓样细胞向大脑的输出和贩运有关。此外，RSD促进CD11b+/ ly6high /CCR2+骨髓细胞浸润到与恐惧和威胁评估相关的特定脑区。我们的数据还表明，IL-1受体1型（IL-1R1）和肾上腺素能受体（adr）依赖通路在RSD促进的行为和免疫改变的发展中至关重要。此外，RSD可促进外周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会高度炎症，也就是说，它们表达高水平的促炎基因。本研究也提供了证据，表明脑中的CD11b+细胞（常驻小胶质细胞和浸润性髓细胞）是启动的，对GC的敏感性较低。这个为期5年的项目的目标是验证这样一个假设，即反复的社会失败会刺激骨髓中启动的gc不敏感、CD11b+/ lyc6高/CCR2+髓样细胞向大脑中的恐惧和威胁评估区域转移，从而促进长时间的焦虑样行为。为了解决这一假设，提出了三个具体目标：1)。我们将确定RSD在多大程度上促进容许性神经血管单元的发展，从而引发CD11b+/ ly6high /CCR2+骨髓细胞的脑区域依赖性浸润。我们将重点关注¿-ADR和中央IL-1R1通路在rsd诱导的髓细胞募集中的作用。此外，在RSD后，将浸润的髓细胞与常驻的小胶质细胞群进行比较和对比是至关重要的。2）. 这些细胞在RSD后的表型、GC敏感性和增殖能力将被确定。这些实验还将确定在RSD后这些髓系人群的时间和脑区域依赖性差异。虽然已经确定，在中枢神经系统的炎症条件下，循环髓细胞会运输到组织损伤的部位，但在没有显著中枢神经系统创伤的社会心理应激模型中，这种特定髓细胞群的释放和运输是独特的。3）. 趋化因子受体-2 （CCR2）阻断阻断CD11b+/ ly6high /CCR2+骨髓细胞浸润和逆转与RSD相关的长时间焦虑样行为的程度将被确定。了解与压力相关的髓细胞运输促进如何促进神经炎症和促进持久的焦虑样行为，可能会导致针对髓细胞运输和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。