Understanding Repetitive Concussion

轻度创伤性脑损伤(TBI)是美国成人和儿童中的一种无声流行病，影响着超过 每年有一百万健康的青年。长期神经学后果和长期病理 反复轻度脑外伤的变化最近通过涉及以下内容的高调报道引起了公众的注意 职业足球运动员和患有创伤性脑损伤的士兵。不幸的是，几乎什么都不知道。 关于反复轻度颅脑损伤后急慢性脑损伤的具体机制 除了休息之外，存在其他特定的治疗方法来减少反复轻度脑损伤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发展成认知能力。 以及成熟后的行为后遗症。然而，青春期脑震荡脑损伤的机制 对未来大脑发育的影响尚不清楚，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，我们已经开始开发一种 青春期小鼠重复性闭合性头部损伤(RCHI)模型 运动障碍，以及脑血管对吸入二氧化碳的反应性缺陷 结构性脑损伤。我们现在建议开发这种青少年rCHI模型，涉及到短期和 具有以下具体目标的长期认知缺陷和组织病理学：目标1A：描述 与反复闭合性头部损伤相关的认知障碍(rCHI，身高=48英寸，体重=53g，1，3， 每天5次或7次)，在雄性小鼠身上进行一系列具有良好特征的测试；目标1B：确定解剖学 通过表征包括细胞在内的脑组织病理变化与行为缺陷相关 死亡、神经胶质化、轴突损伤、脑萎缩、水肿和血脑屏障损伤。目标2：使用 FMRI/BOLD，表征单次和每天3次点击(3HD)与每周3次点击(3HW)的效果 伤后急慢性时间点的脑血管反应性(CVR)。检验以下假设 脑血流对吸入二氧化碳的异常反应性是反复脑震荡的生理生物标志物 这些疾病发生在一个脆弱的时期，并与长期的认知功能障碍有关。这个 拟议的研究将为未来反复脑震荡的机制/治疗研究奠定基础 青少年的脑损伤。

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.