The Role of Reactive Brain Endothelium in Modulating Stress-Induced Immunological and Behavioral Changes

反应性脑内皮细胞在调节应激引起的免疫和行为变化中的作用

• 批准号: 10075224
• 负责人: Caroline Sawicki
• 金额: $ 3.37万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10075224
• 关键词: Address; Amygdaloid structure; Antibodies; Anxiety; Anxiety Disorders; Attenuated; Behavior; Behavioral; Blood Vessels; Bone Marrow; Brain; Brain region; Cell Adhesion Molecules; Cytokine Signaling; Data; Development; Endocrine; Endothelial Cells; Endothelium; Extravasation; Fright; Functional disorder; Gene Expression; High Prevalence; Human; Immune System Diseases; Immunologics; Inflammation; Inflammation Mediators; Inflammatory; Intercellular adhesion molecule 1; Interleukin-1 beta; Interleukins; Intervention; Knowledge; Lead; Ligands; Macrophage Colony-Stimulating Factor Receptor; Mediating; Mediator of activation protein; Mental Health; Microglia; Minocycline; Modeling; Mus; Neurobiology; Neurons; Neurosecretory Systems; Pathway interactions; Physiological; Prefrontal Cortex; Psychosocial Stress; Receptor Signaling; Recurrence; Rodent; Role; Selectins; Signal Transduction; Source; Stress; Testing; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Vascular Endothelium; anxiety-like behavior; behavioral response; biological adaptation to stress; brain parenchyma; cell type; chemokine; chronic inflammatory disease; cytokine; design; monocyte; mortality; mouse model; neurobehavioral; neuroinflammation; neurovascular; neurovascular unit; neutralizing antibody; novel; novel therapeutics; prevent; protein expression; receptor; recruit; response; social defeat; social stress; stressor; trafficking

Project Summary: Immunological adaptations to psychosocial stress may promote the pathophysiology of chronic inflammatory diseases. In humans, social stress activates neuronal and neuroendocrine pathways that result in significant physiological, immunological, and behavioral consequences associated with the development and recurrence of mental health complications, including anxiety. Repeated social defeat (RSD) is a murine stressor that replicates many aspects of the human stress response, including increased circulating cytokines, monocyte trafficking, and prolonged anxiety-like behavior. In both humans and rodents, the brain interprets physiological stress within fear and threat appraisal circuitry. My lab has shown that RSD induces activation of microglia within discrete stress-responsive brain regions, such as the prefrontal cortex. This is relevant because stress- induced recruitment of circulating monocytes to these brain regions promotes the development of anxiety-like behavior. Emerging evidence suggests that microglia propagate neuroinflammatory signaling that modulates neuronal and endocrine responses to stress. For example, microglia are the primary source of pro- inflammatory cytokines, including interleukin (IL)-1β. Unfortunately, the mechanisms that underlie stress- induced monocyte recruitment and subsequent neurobehavioral deficits are not completely understood. Monocyte recruitment to the brain after RSD likely involves dynamic interactions among cell types that comprise the neurovascular unit, including endothelial cells and microglia. In support of this, RSD induces the expression of key adhesion molecules on vascular endothelial cells within the same brain regions where previous findings of microglial activation and monocyte trafficking occurred. Additionally, I show novel data that inhibition of microglial activation with minocycline attenuates RSD-induced neuroinflammatory gene expression, monocyte trafficking to the brain, and development of anxiety-like behavior. Therefore, it is plausible that stress-induced microglial activation and brain cytokine signaling enhance neuroendocrine outflow that may further reinforce stress-related behaviors. Here, I will use a murine model of stress to test the hypothesis: microglia-derived IL-1β signaling activates vascular endothelial cells after RSD, which facilitate region-specific monocyte recruitment to the brain via neurovascular adhesion molecule expression to promote anxiety-like behavior. I propose three specific aims to address this hypothesis. The first aim defines the role of microglia in activating brain region-specific vascular endothelium after RSD. The second aim characterizes the degree of endothelial activation by microglia-derived IL-1β signaling after RSD. The third aim determines if adhesion molecule blockade prevents RSD-induced neuroinflammation and anxiety. Overall, this proposal will advance our knowledge on the role of reactive brain endothelium in modulating stress-induced immunological and behavioral changes, and may lead to the development of novel therapies to treat inflammation and anxiety.

项目摘要： 对社会心理压力的免疫学适应可能促进慢性炎症的病理生理学 疾病。在人类中，社会压力激活神经元和神经内分泌途径，导致重要 与发展和复发有关的身体，免疫和行为后果 心理健康并发症，包括焦虑。反复的社交失败（RSD）是一种鼠压力源 复制人类压力反应的许多方面，包括增加的循环细胞因子，单核细胞 贩运和延长类似动画的行为。在人类和啮齿动物中，大脑都可以解释生理 恐惧和威胁评估循环中的压力。我的实验室表明，RSD诱导小胶质细胞的激活 在离散应力响应性的大脑区域中，例如前额叶皮层。这很重要，因为压力 - 诱导将循环单核细胞募集到这些大脑区域可促进动画样的发展 行为。新兴证据表明，小胶质细胞传播了调节的神经炎症信号传导 神经元和内分泌对压力的反应。例如，小胶质细胞是亲胶质细胞的主要来源 炎性细胞因子，包括白介素（IL）-1β。不幸的是，压力的基础的机制 尚未完全了解诱导的单核细胞募集和随后的神经行为定义。 RSD后，单核细胞募集到大脑可能涉及细胞类型之间的动态相互作用 包括内皮细胞和小胶质细胞在内的神经血管单元。为此，RSD引起了 在同一大脑区域内血管内皮细胞上关键广告分子的表达 先前关于小胶质激活和单核细胞运输的发现。此外，我展示了新颖的数据 用米诺环素抑制小胶质细胞激活RSD诱导的神经炎症基因 表达，单核细胞运输到大脑以及动画样行为的发展。因此，是 应力诱导的小胶质细胞激活和脑细胞因子信号的合理可增强神经内分泌出口流动 这可能会进一步加强与压力相关的行为。在这里，我将使用压力的鼠模型来测试 假设：小胶质细胞衍生的IL-1β信号传导在RSD之后激活血管内皮细胞（该设施） 通过神经血管粘合分子表达向大脑的区域特异性单核细胞募集以促进 焦虑般的行为。我提出了三个特定的目的来解决这一假设。第一个目标定义了 RSD后激活大脑区域特异性血管内皮的小胶质细胞。第二个目标是 RSD后，小胶质细胞衍生的IL-1β信号传导的内皮激活程度。第三个目标决定了是否 粘附分子阻断可防止RSD诱导的神经炎症和动画。总体而言，该建议将 促进我们对反应性脑内皮在调节压力诱导的免疫学中作用的知识 和行为的改变，并可能导致发展新型疗法以治疗感染和 焦虑。