Development of a repetitive concussion traumatic brain injury model

重复性脑震荡创伤性脑损伤模型的开发

基本信息

批准号：
8303623
负责人：
MICHAEL J WHALEN
金额：
$ 25.28万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8303623
关键词：
Absence Epilepsy Acute Address Adult Affect Amyloid beta-Protein Precursor Attention Axon Behavioral Blood - brain barrier anatomy Brain Brain Concussion Brain Edema Brain Injuries Cell Count Cell Death Cessation of life Child Chronic Chronic Brain Injury Chronic Phase Closed head injuries Cognitive Cognitive deficits Deterioration Development Drops Edema Electron Microscopy Epidemic Evans blue stain Extinction (Psychology)Fright Future Glial Fibrillary Acidic Protein Gliosis Guidelines Height Hematoxylin and Eosin Staining Method Hippocampus (Brain)Histocytochemistry Histopathology Housing Human Image Analysis Immunoglobulin G Immunohistochemistry Impaired cognition In Situ Nick-End Labeling Injury Knowledge Laboratories Learning Lesion Manufactured football Measures Methods Modeling Mus Neurologic Neurons Neurosciences Newsletter Outcome Patients Persons Phenotype Play Post-Traumatic Stress Disorders Propidium Diiodide Public Health Reporting Rest Safety Seizures Short-Term Memory Silver Staining Soldier Speed Sports Staining method Stains Testing Time Traumatic Brain Injury Unconscious State United States Veterans War Weight Work astrogliosis base brain cell brain tissue cell injury clinically relevant conditioned fear fluoro jade in vivo morris water maze mortality neuroinflammation neuron loss novel prevent research study therapeutic target therapy development treatment strategy

项目摘要

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.

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，每年影响超过一百万年轻健康人。最近，通过涉及职业足球运动员和患有创伤性脑损伤的士兵的备受瞩目的报告，脑震荡运动员、退伍军人和其他人反复轻度 TBI 造成的长期神经系统后果和长期病理变化引起了公众的关注。不幸的是，对于反复轻度 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，没有特殊疗法可以减少反复轻度 TBI 的长期认知和其他后遗症。因此，遭受一次或多次脑震荡后“重返比赛/战场”准则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差距，我们最近描述了一种新的脑震荡 TBI 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重复性轻度脑震荡闭合性头部损伤 (rCHI) 模型，每天都会产生损伤，每周或每月一次，在没有癫痫发作、意识丧失和总体结构性脑损伤的情况下，会诱发强烈且长期的认知缺陷。我们现在建议开发这种关于短期和长期认知缺陷和组织病理学的 rCHI 模型，具体目标如下：目标 1：描述与重复 CHI 相关的认知缺陷（rCHI，高度 = 28 英寸，体重 = 53 克），能量水平 = 0.37 J）使用海马依赖和独立学习的三个特征良好的测试：（1）莫里斯水迷宫（MWM）， (2) 使用 MWM 的匹配放置版本的工作记忆，以及 (3) 恐惧调节。目标 2：在目标 1 中评估的 rCHI (0.37 J) 水平上表征大脑中的组织病理学变化：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重复性脑震荡 TBI 的机制/治疗研究奠定基础。公共健康相关性：拟议的工作可能会通过在小鼠中建立新的重复性脑震荡创伤性脑损伤模型来在短期内影响公共健康。从长远来看，这项工作可能会加速预防或减少多发性脑震荡患者长期神经功能缺损的治疗方法的开发。