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： 对社会心理压力的免疫适应可能促进慢性炎症的病理生理学 在人类中，社会压力会激活神经和神经内分泌通路，从而导致严重的疾病。 与发展和复发相关的生理、免疫和行为后果 包括焦虑在内的心理健康并发症（RSD）是一种小鼠应激源。 复制人类应激反应的许多方面，包括增加循环细胞因子、单核细胞 在人类和啮齿类动物中，大脑都会解释生理现象。 我的实验室表明，恐惧和威胁评估回路中的压力会诱导小胶质细胞的激活。 在离散的压力反应大脑区域内，例如前额皮质，这是相关的，因为压力- 诱导循环单核细胞向这些大脑区域的募集促进了焦虑样症状的发展 新的证据表明小胶质细胞传播调节神经炎症信号。 例如，小胶质细胞是应激反应的主要来源。 炎症细胞因子，包括白细胞介素 (IL)-1β 不幸的是，压力的机制- 诱导的单核细胞募集和随后的神经行为缺陷尚不完全清楚。 RSD 后单核细胞招募到大脑可能涉及细胞类型之间的动态相互作用 包含神经血管单元，包括内皮细胞和小胶质细胞，RSD 诱导了这一点。 关键粘附分子在同一脑区血管内皮细胞上的表达 此外，我还展示了之前关于小胶质细胞激活和单核细胞运输的新发现。 用米诺环素抑制小胶质细胞活化可减弱 RSD 诱导的神经炎症基因 表达、单核细胞向大脑的运输以及焦虑样行为的发展。 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，我将使用小鼠压力模型来测试。 假设：小胶质细胞衍生的 IL-1β 信号在 RSD 后激活血管内皮细胞，从而促进 通过神经血管粘附分子表达将区域特异性单核细胞募集至大脑，以促进 我提出了三个具体目标来解决这个假设。 RSD 后小胶质细胞激活大脑区域特异性血管内皮的作用。 第三个目标是确定 RSD 后小胶质细胞衍生的 IL-1β 信号传导对内皮细胞的激活程度。 粘附分子阻断可预防 RSD 引起的神经炎症和焦虑。 我们对先进反应性脑内皮在调节应激诱导的免疫学中的作用的了解 和行为改变，并可能导致治疗炎症和疾病的新疗法的开发 焦虑。