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

描述(由申请人提供)：心理社会应激源与包括焦虑和抑郁在内的精神健康并发症的发病率增加有关。虽然众所周知，慢性应激源对健康和生活质量有负面影响，但这些神经行为缺陷背后的机制还没有被很好地理解。在这个提案中，我们提出了新的数据，即重复社会失败(RSD)诱导的焦虑样行为与骨髓(BM)来源的、糖皮质激素(GC)不敏感的髓系细胞外流和运输到大脑有关。此外，RSD促进CD11b/Ly6Chigh/CCR2髓样细胞渗透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(IL-1R1)和�-肾上腺素能受体(�-Adr)依赖的通路在RSD促进的行为和免疫改变的发生发展中起关键作用。此外，RSD促进外周髓系细胞对糖皮质激素(GC)的不敏感。这是相关的，因为GC不敏感的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(常驻的小胶质细胞和浸润性髓样细胞)被激活，对GC不那么敏感。这个为期5年的项目的目标是检验这样一个假设，即反复的社会失败会刺激启动的GC不敏感的CD11b/LyC6High/CCR2髓系细胞从骨髓运输到大脑中的恐惧和威胁评估区域，以促进长期的焦虑样行为。针对这一假设，本文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位的发展，以诱导脑区域依赖的CD11b/Ly6Chigh/CCR2髓样细胞的渗透。我们将重点介绍�-adr和中枢IL-1R1通路在雷公藤多甙诱导的髓系细胞募集中的作用。此外，将RSD后浸润的髓系细胞与常驻的小胶质细胞群体进行比较和对比是至关重要的。2)。RSD后这些细胞的表型、GC敏感性和增殖能力将被确定。这些实验还将确定这些髓系群体在RSD后的时间和大脑区域依赖的差异。虽然已证实循环中的髓样细胞会在中枢神经系统炎症条件下运输到组织损伤部位，但这种特定的髓样细胞群的释放和运输到脑中在心理社会应激模型中是独一无二的，因为在那里没有明显的中枢神经系统创伤。3)。阻断趋化因子受体-2(CCR2)在多大程度上阻止CD11b/Ly6Chigh/CCR2髓细胞渗透并逆转与RSD相关的长期焦虑样行为将被确定。了解应激相关的髓系细胞运输的促进如何有助于神经炎症和长期焦虑样行为的促进，可能会导致针对髓系细胞运输的新干预措施，并减轻与慢性应激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.