Development of a repetitive concussion traumatic brain injury model

描述（由申请人提供）：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，每年影响超过100万年轻健康人。脑震荡运动员、退伍军人和其他人反复轻度TBI的长期神经学后果和长期病理变化最近通过涉及职业足球运动员和创伤性脑损伤士兵的高调报道引起了公众的注意。不幸的是，几乎没有什么是已知的具体机制，导致急性和慢性脑损伤后，反复轻度TBI，并没有具体的治疗以外的休息存在，以减少长期的认知和其他后遗症反复轻度TBI。因此，在遭受一次或多次震荡性TBI后，“返回游戏/战场”指南的长期安全性在实验上没有得到充分证明。为了开始解决这些知识差距，我们最近描述了一种新型的脑震荡性脑外伤模型，该模型在没有明显的急性和慢性细胞死亡/丢失的情况下产生早期认知功能障碍。我们现在已经开始开发一种重复性轻度震荡性闭合性头部损伤（rCHI）模型， 每周或每月给药一次，并且其中在没有癫痫发作、意识丧失和大体结构性脑损伤的情况下诱导强烈和持久的认知缺陷。我们现在建议开发这种rCHI模型，其关于短期和长期认知缺陷和组织病理学，具有以下具体目的：目的1：表征与重复CHI相关的认知缺陷（rCHI，身高= 28英寸，体重= 53克，能量水平= 0.37 J），使用三个充分表征的依赖于营地和独立学习的测试：（1）Morris水迷宫（MWM），（2）使用匹配放置版本的MWM的工作记忆，以及（3）恐惧条件反射。目标二：在目标1中评估的rCHI（0.37 J）水平表征脑组织病理学变化：急性细胞损伤和死亡（Fluoro Jade B、TUNEL、体内碘化丙啶和银染色）、轴突损伤（APP组织化学、电子显微镜和银染色）和神经炎症（GFAP和IBA-1组织化学）。拟议的研究将为未来的机制/治疗反复脑震荡TBI的研究奠定基础。 公共卫生相关性：这项工作可能会在短期内通过建立一种新的小鼠重复性脑震荡创伤性脑损伤模型来影响公共卫生。从长远来看，这项工作可能会加速治疗方法的发展，从而预防或减少多发性脑震荡患者的长期神经功能缺损。

DESCRIPTION (provided by applicant): 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 in concussed athletes, war veterans, and others 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. Thus, the long term safety of "return to play/battlefield" guidelines after suffering one or more concussive TBIs is not well justified experimentally. To begin to address these knowledge gaps, we recently described a novel model of concussive TBI that produces early cognitive dysfunction in the absence of demonstrable acute and chronic cell death/loss. We have now begun development of a repetitive mild concussive closed head injury (rCHI) model in which injury is delivered daily, weekly, or monthly, and in which robust and long lasting cognitive deficits are induced in the absence of seizures, loss of consciousness, and gross structural brain lesions. We now propose to develop this rCHI model with respect to short- and long-term cognitive deficits and histopathology with the following Specific Aims: Aim 1: Characterize the cognitive deficits associated with repetitive CHI (rCHI, height = 28 in, weight = 53 g, energy level = 0.37 J) using three well-characterized tests of hippocampal-dependent and - independent learning: (1) Morris water maze (MWM), (2) working memory using a matching to place version of the MWM, and (3) fear conditioning. Aim 2: Characterize histopathological changes in brain at the level of rCHI (0.37 J) assessed in Aim 1: Acute cellular injury and death (Fluoro Jade B, TUNEL, in vivo propidium iodide, and silver staining), axonal injury (APP histochemistry, electron microscopy, and silver staining), and neuroinflammation (GFAP and IBA-1 histochemistry). The proposed studies would lay the groundwork for future mechanistic/treatment studies of repetitive concussion TBI. PUBLIC HEALTH RELEVANCE: The proposed work could impact public health in the short term by establishing a new repetitive concussive traumatic brain injury model in mice. In the long term, the work may speed development of treatments that would prevent or reduce long term neurological deficits in people with multiple concussions.