Dynamic Cellular Interactions Associated with Inflammatory Monocyte Accumulation in the Neurovasculature with Social Stress

项目总监/首席调查员(Sheridan，JF&Godout JP)： 项目摘要/摘要： 大脑中的动态炎症信号可能是导致焦虑的原因之一。我们反复报告说 小鼠社会挫败(RSD)诱导交感神经介导的骨髓单核细胞释放 它们被积极地招募到大脑中。总而言之，我们表明，RSD促进了长期的焦虑 依赖于小胶质细胞的激活和炎性单核细胞的招募来评估威胁的行为 大脑的不同区域。这一应用表明，小胶质细胞募集产生IL-1β的单核细胞 神经血管内皮细胞对社会反应中焦虑样行为的增强是必需的 压力。尽管有这些知识，但仍有三个关键的机械问题有待回答，这将使 治疗与应激相关的神经精神并发症的新干预措施的开发： 1)RSD如何激活威胁评估区域的小胶质细胞？2)炎性单核细胞如何 威胁评估区域对神经血管内皮细胞的选择性招募？3)关键因素是什么 由神经血管内皮细胞产生，会加剧神经炎症和焦虑吗？我们证明了 小胶质细胞对RSD的反应依赖于威胁评估区域内神经元的激活。 此外，初步证据表明，这是通过激活嘌呤能受体P2RX7来调节的， 在小胶质细胞上。这里提供的新数据表明，单核细胞招募和焦虑症样的发展 RSD后的行为需要小胶质细胞的激活。此外，细胞特异性转录图谱表明 小胶质细胞通过分泌趋化因子配体(CCL2)将单核细胞招募到脑内。这些人招募了 单核细胞产生IL-1，并通过内皮细胞IL-1受体-1激活促进焦虑样行为。值得注意的是， 这种IL-1R1的激活与COX2神经血管表达的增加有关，COX2是一种能够 合成神经活性前列腺素。因此，这个项目的目标是检验招聘的假设 随后炎性单核细胞与神经血管内皮细胞的相互作用对 RSD后神经炎症加重和焦虑样行为增强。要解决这个问题 假设，提出了三个具体目标。在AIM-1中，我们将确定区域可持续发展导致的 小胶质细胞的激活依赖于P2RX7嘌呤能受体的刺激。在AIM-2中，我们将确定 单核细胞募集到威胁评估所需的小胶质细胞产生CCL2的程度 区域与RSD后焦虑样行为的诱导。在AIM-3中，我们将评估内皮细胞的作用 COX2跟随RSD，并确定IL-1R1刺激的内皮细胞产生的其他关键因子 促进RSD后焦虑样行为。了解小胶质细胞募集如何产生IL-1β 单核细胞到威胁评估区域加重神经炎症和焦虑样行为将导致新的 与应激相关的神经精神并发症的干预。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator (Sheridan, JF & Godbout JP): PROJECT SUMMARY/ABSTRACT: Dynamic inflammatory signaling in the brain may have a causative role in anxiety. We report that repeated social defeat (RSD) in mice induces sympathetic-mediated release of primed monocytes from the bone marrow that are actively recruited to the brain. Collectively, we show that RSD promotes prolonged anxiety-like behavior that depends on activation of microglia and recruitment of inflammatory monocytes to threat appraisal regions of the brain. This application demonstrates that microglial recruitment of IL-1β producing monocytes to neurovascular endothelium is necessary for the potentiation of anxiety-like behavior in response to social stress. Despite this knowledge, three key mechanistic questions remain to be answered, which will allow for the development of novel interventions for treatment of neuropsychiatric complications associated with stress: 1) How does RSD activate microglia in threat appraisal regions? 2) How are inflammatory monocytes selectivity recruited to neurovascular endothelium in threat appraisal regions? 3) What are the key factors produced by neurovascular endothelia cells that potentiate neuroinflammation and anxiety? We show that microglial activation in response to RSD depends on neuronal activation within threat appraisal regions. Moreover, preliminary evidence suggests that this is mediated by activation of the purinergic receptor, P2RX7, on microglia. Novel data presented here show that monocyte recruitment and the development of anxiety-like behavior after RSD requires microglial activation. Furthermore, cell-specific transcriptional profiling indicates that microglia recruit monocytes to the brain via chemokine ligand (CCL2) secretion. These recruited monocytes produce IL-1and promote anxiety-like behavior by endothelial IL-1 Receptor-1 activation. Notably, this IL-1R1 activation is associated with increased neurovascular expression of COX2, the enzyme that synthesizes neuroactive prostaglandins. Thus, the goal of this project is to test the hypothesis that recruitment and subsequent interaction of inflammatory monocytes with neurovascular endothelial cells is critical for the augmentation of neuroinflammation and potentiation of anxiety-like behavior following RSD. To address this hypothesis, three specific aims are proposed. In Aim-1, we will ascertain the extent to which RSD-induced microglial activation is dependent on stimulation of the P2RX7 purinergic receptor. In Aim-2, we will determine the degree to which microglial production of CCL2 is required for monocyte recruitment to threat appraisal regions and the induction of anxiety-like behavior after RSD. In Aim-3, we will assess the role of endothelial COX2 following RSD and determine other key factors produced by IL-1R1-stimulated endothelial cells that facilitate anxiety-like behavior after RSD. Understanding how microglial recruitment of IL-1β producing monocytes to threat appraisal regions potentiates neuroinflammation and anxiety-like behavior will lead to new interventions for neuropsychiatric complications associated with stress. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page