Understanding Repetitive Concussion

了解重复性脑震荡

• 批准号: 9341370
• 负责人: MICHAEL J WHALEN
• 金额: $ 20.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9341370
• 关键词: Acceleration; Acute; Address; Adolescence; Adolescent; Adult; Affect; Amyloid beta-Protein; Anatomy; Animal Model; Anxiety; Atrophic; Attention; Attention deficit hyperactivity disorder; Attentional deficit; Behavior; Behavioral; Biological Markers; Blood - brain barrier anatomy; Brain; Brain Concussion; Brain Edema; Brain Injuries; Breathing; Carbon Dioxide; Cell Count; Cell Death; Cerebrovascular Circulation; Characteristics; Child; Childhood; Chronic; Chronic Brain Injury; Clinical; Clinical Research; Closed head injuries; Cognitive; Cognitive deficits; Data; Development; Edema; Elderly; Electron Microscopy; Employee Strikes; Epidemic; Extinction (Psychology); Functional Magnetic Resonance Imaging; Future; Glial Fibrillary Acidic Protein; Gliosis; Goals; Height; Hemorrhage; Hippocampus (Brain); Histocytochemistry; Histologic; Histopathology; Human; Hyperactive behavior; Image Analysis; Immunoglobulin G; Immunohistochemistry; Impaired cognition; In Situ Nick-End Labeling; Incidence; Injury; Knowledge; Link; Locomotion; Longitudinal Studies; Male Adolescents; Manufactured football; Measures; Mental Depression; Methods; Modeling; Molecular; Mus; Nerve Degeneration; Neurofibrillary Tangles; Neurologic; Neurologic Deficit; Neurologic Dysfunctions; Pathologic; Persons; Phenotype; Physiological; Post-Traumatic Stress Disorders; Public Health; Reporting; Rest; Rotation; Senile Plaques; Silver Staining; Social Dominance; Social Interaction; Socialization; Soldier; Speed; Sports; Staining method; Stains; Swimming; Testing; Time; Traumatic Brain Injury; Tube; Unconscious State; United States; War; Weight; Work; anxiety symptoms; axon injury; brain tissue; cerebral atrophy; cerebrovascular; chronic traumatic encephalopathy; cognitive function; conditioned fear; depressive symptoms; experimental study; field study; fluoro jade; gender difference; head impact; locomotor deficit; male; mild traumatic brain injury; morris water maze; mouse model; neuron loss; potential biomarker; prevent; psychiatric symptom; tau Proteins; therapeutic target; therapy development; treatment strategy

Mild traumatic brain injury (TBI) is a silent epidemic in adults and children in the United States affecting over a million young healthy persons annually. The long term neurological consequences and long term pathological changes of repeated mild TBI have recently come to the public's attention through high-profile reports involving professional football players and soldiers with traumatic brain injury. Unfortunately, almost nothing is known about the specific mechanisms leading to acute and chronic brain injury after repeated mild TBI, and no specific therapy other than rest exists to reduce long term cognitive and other sequelae of repeated mild TBI. Several clinical reports suggest that adolescents who suffer one or more concussions may develop cognitive and behavioral sequelae as they mature. However, mechanisms of how concussive TBI in adolescence affects future brain development remain unknown, as few longitudinal studies have been done to examine this question in animal models. To begin to address these knowledge gaps, we have begun development of a repetitive closed head injury (rCHI) model in adolescent mice that produces long term (> 1 year) cognitive and locomotor deficits, as well as deficits in cerebrovascular reactivity to inhaled carbon dioxide, in the absence of structural brain damage. We now propose to develop this adolescent rCHI model with respect to short- and long-term cognitive deficits and histopathology with the following Specific Aims: Aim 1A: Characterize the cognitive deficits associated with repetitive closed head injury (rCHI, height = 48 in, weight = 53 g, 1, 3, 5, or 7 daily CHIs) using a battery of well characterized tests in male mice; Aim 1B: Determine anatomical correlates to the behavioral deficits by characterizing histopathological changes in brain including cell death, gliosis, axonal damage, brain atrophy, edema, and blood-brain barrier damage. Aim 2: Using fMRI/BOLD, characterize the effects of single and 3 hit daily (3HD) vs. 3 hit weekly (3HW) CHI on cerebrovascular reactivity (CVR) at acute and chronic time points after injury. Test the hypothesis that abnormal reactivity of cerebral blood flow to inhaled CO2 is a physiological biomarker of repetitive concussions that occur within a vulnerable time period and are associated with long-term cognitive dysfunction. The proposed studies would lay the groundwork for future mechanistic/treatment studies of repetitive concussive TBI in adolescents.

轻度创伤性脑损伤（TBI）是美国成人和儿童的一种无声流行病， 每年有100万健康的年轻人。长期的神经学后果和长期的病理 反复轻度TBI的变化最近通过高调报道引起了公众的注意， 职业橄榄球运动员和脑外伤士兵不幸的是，几乎什么都不知道 关于反复轻度TBI后导致急性和慢性脑损伤的具体机制， 存在除休息之外的特定疗法以减少反复轻度TBI的长期认知和其它后遗症。 一些临床报告表明，遭受一次或多次脑震荡的青少年可能会出现认知障碍， 和行为后遗症。然而，青少年脑震荡性脑损伤的机制 对未来大脑发育的影响仍然未知，因为很少有纵向研究来研究这一点 动物模型中的问题。为了开始解决这些知识差距，我们已经开始开发 在青少年小鼠中的重复性闭合性头部损伤（rCHI）模型，其产生长期（> 1年）的认知和 运动缺陷，以及脑血管对吸入二氧化碳的反应性缺陷，在缺乏 结构性脑损伤我们现在建议开发这个青少年rCHI模型， 长期认知缺陷和组织病理学，具体目的如下：目的1A： 与重复性闭合性头部损伤相关的认知缺陷（rCHI，身高= 48英寸，体重= 53克，1，3， 5或7次每日CHI），在雄性小鼠中使用一组充分表征的试验;目的1B：确定解剖学 通过表征脑组织病理学变化（包括细胞）与行为缺陷相关 死亡、神经胶质增生、轴突损伤、脑萎缩、水肿和血脑屏障损伤。目标2：使用 fMRI/BOLD，表征单次和每日3次（3 HD）与每周3次（3 HW）CHI对 脑血管反应性（CVR）在急性和慢性时间点损伤后。测试的假设 脑血流对吸入CO2的异常反应是反复脑震荡的生理学生物标志物 发生在脆弱时期，并与长期认知功能障碍有关。的 拟议的研究将为未来重复性脑震荡的机制/治疗研究奠定基础。 青少年TBI