Connectome Analysis of the Nigrostriatal Neuronal Tract after Blast TBI

冲击波 TBI 后黑质纹状体神经元束的连接组分析

• 批准号: 10015797
• 负责人: C EDWARD DIXON
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-10-01 至 2022-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015797
• 关键词: Affect; Afghanistan; Amygdaloid structure; Area; Behavioral; Brain; Carrier Proteins; Catecholamines; Chronic; Cognition; Cognitive; Corpus striatum structure; Craniocerebral Trauma; Data; Diffusion Magnetic Resonance Imaging; Dopamine; Exposure to; Fiber; Freedom; Funding; Goals; Grant; Hippocampus (Brain); Image; Impaired cognition; Impairment; Iraq; Measures; Memory impairment; Midbrain structure; Military Personnel; Motor; Neurologic Deficit; Neurons; Neurotransmitters; Pathology; Pathway Analysis; Pathway interactions; Physical Function; Proteins; Rattus; Reporter; Research; Research Personnel; Role; Severities; Shock; Shoulder; Stress; System; Testing; Training; Traumatic Brain Injury; Tube; Ventral Tegmental Area; Veterans; War; addiction; base; behavioral outcome; cognitive function; connectome; emotional functioning; functional outcomes; high risk; nigrostriatal pathway; operation; pressure; response; spatial memory; tractography; weapons; white matter

Military personnel deployed to the wars in Afghanistan (Operation Enduring Freedom; OEF) and Iraq (Operation Iraqi Freedom; OIF) are at high risk of sustaining a traumatic brain injury (TBI) from exposures to a blast (bTBI) and other types of head injuries. Furthermore, exposure to blast waves from firing shoulder-fired weapons can affect the brain, even during training. TBI of all severities can result in chronic post-deployment disturbances of cognitive, behavioral, emotional, and physical functioning. There is extensive evidence that traumatic brain injury (TBI) produces chronic deficits in the dopaminergic system that may contribute to postinjury cognitive function. The goal of this SPiRE grant is to evaluate the use of diffusion MRI tractography and network analysis to determine the effects of single and repetitive simulated blast (shock tube) exposures on the integrity of nigrostriatal-associated tracts. hTH-GFP reporter rats will be exposed to single or repeated pressure waves at either peak pressure of 30psi or 40psi. These pressures are based on preliminary data demonstrating greater spatial memory deficits in the 40psi vs. 30psi. A battery of behavioral outcome tests to assess motor, cognitive, and stress-related function will be measured. At 4-weeks post-simulated blast, ex-vivo high-definition fiber tracking (HDFT) in conjunction with network topology analysis will be performed to characterize the integrity of substantia nigral and striatal neuronal network pathways. Ventral tegmental area tracts will also be assessed. Preliminary connectome analyses indicate that midbrain and striatal connectivity is impaired after bTBI. Loss of dopaminergic transporter protein was preliminarily observed after 4-week post-bTBI. Preliminary imaging network topological analysis showed that the nigrostriatal pathway underwent larger neuronal network re- organization after bTBI than hippocampal or amygdala regions. Immunohistochemical analyses of dopamine- related proteins will be assessed after imaging. The overall hypothesis is that exposure to varying simulated blast overpressures will result in graded reductions in nigrostriatal integrity, dopaminergic markers, and behavioral function. The application is in line with the SPiRE purpose to support senior investigators seeking to explore new research approaches in areas where they have not previously been funded.

部署到阿富汗战争（持久自由行动；OEF）和伊拉克战争（行动）的军事人员 伊拉克自由； OIF）因暴露于爆炸（bTBI）而遭受创伤性脑损伤（TBI）的风险很高 和其他类型的头部受伤。此外，暴露于肩扛式武器发射的爆炸波可能会 即使在训练期间也会影响大脑。所有严重程度的 TBI 都可能导致部署后的慢性干扰 认知、行为、情感和身体功能。有大量证据表明创伤性脑损伤 (TBI) 会导致多巴胺能系统慢性缺陷，这可能有助于损伤后认知功能。 SPiRE 资助的目标是评估扩散 MRI 纤维束成像和网络分析的使用 确定单次和重复模拟爆炸（激波管）暴露对完整性的影响 黑质纹状体相关束。 hTH-GFP 报告大鼠将暴露于单次或重复的压力波 峰值压力为 30 psi 或 40 psi。这些压力是基于初步数据表明更大 40psi 与 30psi 的空间记忆缺陷。一系列行为结果测试，用于评估运动、认知、 并将测量与压力相关的功能。模拟爆炸后 4 周，离体高清光纤 将执行跟踪（HDFT）与网络拓扑分析相结合来表征网络的完整性 黑质和纹状体神经元网络通路。还将评估腹侧被盖区束。 初步连接组分析表明，bTBI 后中脑和纹状体连接受损。损失 bTBI后4周初步观察到多巴胺能转运蛋白。初步成像 网络拓扑分析表明黑质纹状体通路经历了更大的神经元网络重构 bTBI 后的组织比海马或杏仁核区域更重要。多巴胺的免疫组织化学分析 相关蛋白质将在成像后进行评估。总体假设是，暴露于不同的模拟环境中 爆炸超压将导致黑质纹状体完整性、多巴胺能标记物和 行为功能。该申请符合 SPiRE 的目的，即支持高级研究人员寻求 在以前未曾获得资助的领域探索新的研究方法。