Contribution of Microglia to Axonal Injury following Repetitive Concussion in Mou

小胶质细胞对反复脑震荡后轴突损伤的贡献

• 批准号: 8305833
• 负责人: Rachel Elise Bennett
• 金额: $ 2.84万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8305833
• 关键词: Action Potentials; Acute; Address; Alzheimer' s disease risk; Animals; Appearance; Area; Autopsy; Axon; Brain; Brain Concussion; Brain Injuries; Cell Surface Receptors; Cells; Chronic; Chronic Phase; Corpus Callosum; Data; Dementia; Electron Microscopy; Electrophysiology (science); FCGR3B gene; Flow Cytometry; Head; Hour; Human; Immune; Immunohistochemistry; Impaired cognition; Impairment; Incidence; Individual; Inflammatory Response; Injury; Interleukin-1; Interleukin-6; Invaded; Ipsilateral; Knowledge; Lead; Lesion; Little' s Disease; Macrophage-1 Antigen; Magnetic Resonance Imaging; Measurement; Measures; Methods; Microglia; Modeling; Mus; Neurites; Neurons; Operative Surgical Procedures; Pathologic Processes; Pathology; Pattern; Phase; Phenotype; Poison; Population; Positron-Emission Tomography; Production; Role; Sampling; Silver Staining; Slice; Sports; Surface; Techniques; Therapeutic; Time; Tissues; Toxin; Training; Trauma; Traumatic Brain Injury; Up-Regulation; Work; axonal degeneration; brain cell; cranium; cytokine; extracellular; injured; mouse model; nervous system disorder; neurosurgery; research study; response; white matter

DESCRIPTION (provided by applicant): There are an estimated 1.6-3.8 million sports-related concussions each year. Human concussions do not usually cause macroscopic lesions visible by CT or MRI, but multiple concussions can lead to axonal injury, long-term cognitive impairments, and neurological disease. These long- term changes are best described in professional athletes, termed "dementia pugilistica" in boxers and chronic traumatic encephalopathy in other athletes. Studies in these individuals have shown that activation of the brain's resident immune cells, microglia, occurs after traumatic brain injury in areas of axonal injury. Microglial activation in white matter has also been noted after concussion in post- mortem-samples. Whether this response contributes to ongoing axonal injury, protects against further damage, or is neutral in concussion is not known. To fill this knowledge gap, our lab has developed a reproducible model of repetitive concussive injury in mouse similar to Longhi and colleagues (Neurosurgery 2005). In this model, two closed-skull impacts delivered 24 hours apart result in a consistent pattern of axon degeneration and microglial activation without neuronal cell loss. The central hypothesis of this proposal is that persistent microglial activatio following repetitive concussive injury in mouse results in axon degeneration and electrophysiological compromise. To address this hypothesis, the phenotype of microglia within white matter will be compared across time points. A microglial-specific toxin will be administered to determine how elimination of microglia effects axonal degeneration in both the acute and chronic injury phase. If successful, these experiments will greatly increase our knowledge of the role of activated microglia in axonal injury in this mouse model of repetitive concussive trauma. These results may deepen our understanding of the pathological processes that cause cognitive impairments in concussed individuals and could have important implications for therapeutics. For these experiments the applicant will be trained in multiple techniques including small animal surgery, immunohistochemistry, stereology, flow cytometry, qPCR, extracellular brain slice electrophysiology, and statistical analysis of quantitative data. PUBLIC HEALTH RELEVANCE: There are an estimated 1.6-3.8 million sports-related concussions each year and mounting evidence that multiple concussions result in long-term cognitive impairments and increased risk for Alzheimer's disease. After brain injury microglia, the immune cells of the brain, invade injured regions and may produce toxic compounds that result in tissue damage. This proposal is aimed at determining how microglia contribute to concussive injury, which could ultimately lead to therapeutics that reduce lasting impairments in concussed individuals.

描述（由申请人提供）：估计每年有160万至380万与运动有关的脑震荡。人类脑震荡通常不会引起CT或MRI可见的宏观病变，但多发性脑震荡可导致轴突损伤，长期认知障碍和神经系统疾病。这些长期变化在职业运动员中描述得最好，在拳击手中称为“拳击员痴呆”，在其他运动员中称为慢性创伤性脑病。对这些个体的研究表明，在轴突损伤区域的创伤性脑损伤后，大脑的常驻免疫细胞小胶质细胞发生激活。在死后样本中的脑震荡后也注意到白色物质中的小胶质细胞活化。这种反应是否会导致持续的轴突损伤，防止进一步的损伤，或者在脑震荡中是中性的尚不清楚。为了填补这一知识空白，我们的实验室开发了一种类似于Longhi及其同事的重复性脑震荡损伤小鼠模型（Neurosurgery 2005）。在该模型中，相隔24小时的两次闭合颅骨撞击导致轴突变性和小胶质细胞活化的一致模式，而没有神经元细胞损失。该建议的中心假设是，小鼠反复脑震荡损伤后持续的小胶质细胞激活导致轴突变性和电生理损害。为了解决这一假设，将在不同时间点比较白色物质内小胶质细胞的表型。将给予小胶质细胞特异性毒素以确定小胶质细胞的消除如何影响急性和慢性损伤阶段的轴突变性。如果成功的话，这些实验将大大增加我们对反复脑震荡创伤小鼠模型中激活的小胶质细胞在轴突损伤中的作用的认识。这些结果可能会加深我们对脑震荡患者认知障碍的病理过程的理解，并可能对治疗产生重要影响。对于这些实验，申请人将接受多种技术培训，包括小动物手术、免疫组织化学、体视学、流式细胞术、qPCR、细胞外脑切片电生理学和定量数据的统计分析。 公共卫生相关性：据估计，每年有160万至380万起与运动有关的脑震荡，越来越多的证据表明，多发性脑震荡会导致长期认知障碍，并增加患阿尔茨海默病的风险。脑损伤后，小胶质细胞，大脑的免疫细胞，侵入受伤区域，并可能产生有毒化合物，导致组织损伤。该提案旨在确定小胶质细胞如何促进脑震荡损伤，这可能最终导致减少脑震荡个体持久损伤的治疗方法。