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一种无声的流行病，每年影响100多万年轻健康人群。脑震荡运动员、退伍军人和其他人反复轻度脑外伤的长期神经后果和长期病理改变最近引起了公众的注意，这些报道涉及职业足球运动员和创伤性脑损伤士兵。不幸的是，关于反复轻度TBI后导致急性和慢性脑损伤的具体机制几乎一无所知，除了休息之外，没有其他特定的治疗方法可以减少反复轻度TBI的长期认知和其他后遗症。因此，在遭受一次或多次震荡性脑损伤后，“重返赛场/战场”指导方针的长期安全性在实验上并没有得到很好的证明。为了开始解决这些知识空白，我们最近描述了一种新的脑震荡脑损伤模型，该模型在没有明显的急性和慢性细胞死亡/损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闭合性头部损伤（rCHI）模型，在这种模型中，每天都会发生损伤，

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.