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.

项目概要： 心理社会应激的免疫适应可能促进慢性炎症性肠病的病理生理学改变。 疾病在人类中，社会压力激活神经元和神经内分泌通路，导致显著的 与发展和复发相关的生理、免疫和行为后果 精神健康并发症包括焦虑重复的社会失败（RSD）是一种鼠应激源， 复制了人类应激反应的许多方面，包括循环细胞因子、单核细胞增加 贩卖人口和长期的焦虑行为在人类和啮齿类动物中， 恐惧和威胁评估回路中的压力。我的实验室已经证明RSD可以激活小胶质细胞 在离散的压力反应大脑区域，如前额叶皮层。这是相关的，因为压力- 循环单核细胞向这些脑区的诱导募集促进了焦虑样 行为新出现的证据表明，小胶质细胞传播神经炎症信号， 神经元和内分泌对压力的反应。例如，小胶质细胞是前- 炎性细胞因子，包括白细胞介素（IL）-1β。不幸的是，压力背后的机制- 诱导的单核细胞募集和随后的神经行为缺陷还不完全清楚。 RSD后单核细胞向脑的募集可能涉及细胞类型之间的动态相互作用， 包括神经血管单位，包括内皮细胞和小胶质细胞。为了支持这一点，区域市政总署 关键粘附分子在同一脑区血管内皮细胞上的表达 出现了小胶质细胞活化和单核细胞运输的先前发现。此外，我还展示了一些新的数据， 米诺环素抑制小胶质细胞活化减弱RSD诱导的神经炎性基因 表达，单核细胞运输到大脑，以及焦虑样行为的发展。因此有 应激诱导的小胶质细胞激活和脑细胞因子信号传导增强神经内分泌流出似乎是合理的 这可能会进一步强化与压力相关的行为。在这里，我将使用一个小鼠模型的压力，以测试 假设：小胶质细胞来源的IL-1β信号在RSD后激活血管内皮细胞， 区域特异性单核细胞通过神经血管粘附分子表达募集到脑中， 类似焦虑的行为我提出了三个具体目标来解决这个假设。第一个目标确定了 小胶质细胞在RSD后激活脑区域特异性血管内皮中的作用。第二个目标的特点是 RSD后通过小胶质细胞衍生的IL-1β信号传导的内皮活化程度。第三个目标决定了， 粘附分子阻断可预防RSD诱导的神经炎症和焦虑。总的来说，这项建议将 促进我们对反应性脑内皮细胞在调节应激诱导的免疫反应中的作用的认识。 和行为变化，并可能导致开发新的疗法来治疗炎症， 焦虑