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

描述（由申请人提供）：心理社会压力与心理健康并发症（包括焦虑和抑郁）的患病率增加有关。虽然已知慢性压力源对健康和生活质量有负面影响，但这些神经行为缺陷的机制尚未得到很好的理解。在这个提议中，我们提出了新的数据，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）不敏感的骨髓细胞的出口和贩运到大脑。此外，RSD促进CD 11b +/Ly 6Chigh/CCR 2+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-1 R1）和<$-肾上腺素能受体（<$-ADR）依赖性途径是关键的行为和免疫学改变的RSD促进的发展。此外，RSD促进外周骨髓细胞中糖皮质激素（GC）的不敏感性。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，表明脑中的CD 11b+细胞（常驻小胶质细胞和浸润性髓样细胞）对GC的敏感性较低。这个为期5年的项目的目标是测试这样一个假设，即反复的社会失败刺激从骨髓到大脑中的恐惧和威胁评估区域的启动GC不敏感，CD 11b +/LyC 6 high/CCR 2+骨髓细胞的运输，以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促进容许性神经血管单位发展的程度，以引起脑区域依赖性CD 11b +/Ly 6Chigh/CCR 2+髓样细胞浸润。我们将重点关注<$-ADR和中枢IL-1 R1通路在RSD诱导的髓系细胞募集中的作用。此外，将浸润的髓样细胞与RSD后的常驻小胶质细胞群体进行比较和对比是至关重要的。2）。将测定RSD后这些细胞的表型、GC敏感性和增殖能力。这些实验还将确定RSD后这些骨髓细胞群中的时间和脑区域依赖性差异。虽然已经确定，在CNS中的炎症条件下，循环骨髓细胞将运输到组织损伤部位，但是在不存在显著CNS创伤的心理社会应激模型中，这种特定骨髓细胞群向脑的释放和运输是独特的。3）。将确定趋化因子受体-2（CCR 2）的阻断可预防CD 11b +/Ly 6Chigh/CCR 2+髓样细胞浸润并逆转与RSD相关的长期焦虑样行为的程度。了解与压力相关的促进骨髓细胞贩运如何有助于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贩运的新干预措施，并减轻与慢性压力相关的长期神经行为并发症。

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.