Understanding Repetitive Concussion

了解重复性脑震荡

基本信息

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
项目类别：
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

项目摘要

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）是美国成人和儿童中一种无声的流行病，影响了超过每年百万健康青年人。长期神经后果和长期病理后果最近，反复轻度 TBI 的变化通过一些备受瞩目的报道引起了公众的关注，其中涉及职业足球运动员和患有脑外伤的士兵。不幸的是，几乎一无所知关于重复轻度TBI后导致急慢性脑损伤的具体机制，目前尚无除休息外，还存在其他特殊疗法，可减少反复轻度 TBI 的长期认知和其他后遗症。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以及成熟后的行为后遗症。然而，青春期脑震荡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检验这一点动物模型中的问题。为了开始解决这些知识差距，我们已经开始开发青春期小鼠的重复性闭合性头部损伤 (rCHI) 模型可产生长期（> 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种青少年 rCHI 模型长期认知缺陷和组织病理学，具有以下具体目标：目标 1A：表征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, 每天 5 或 7 个 CHI），在雄性小鼠中使用一系列经过充分表征的测试；目标 1B：确定解剖学通过表征大脑（包括细胞）的组织病理学变化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，描述每日单次和 3 次点击 (3HD) 与每周 3 次点击 (3HW) CHI 对 CHI 的影响损伤后急性和慢性时间点的脑血管反应性（CVR）。检验假设脑血流对吸入二氧化碳的异常反应是重复性脑震荡的生理生物标志物发生在脆弱时期并与长期认知功能障碍有关。这拟议的研究将为未来重复性脑震荡的机械/治疗研究奠定基础青少年 TBI。