Chronic neurodegenerative and neurophysiological sequela of closed-head TBI

描述(由申请人提供)： 军事创伤性脑损伤在当前的伊拉克和阿富汗战争中显著增加，可以单独发生，也可以作为严重战场多发伤的组成部分。最近，据估计，有15%-20%的战斗人员(超过30万名士兵)曾在伊拉克或阿富汗服役，至少遭受过轻微的脑外伤。这些数量惊人的饱受创伤的战士使脑外伤的长期影响成为影响我们退伍军人的最紧迫的问题之一。因此，这项建议的总体目标是确定闭合性脑外伤后从急性到慢性病理转变的机制(S)和渐进性变化。我们的中心假设是，单一的严重或重复的轻度闭合性脑损伤在伤后数月至数年内会导致缓慢进行的神经退行性改变。我们认为，这些长期的神经退行性变化将在海马体、黑质纹状体系统、大脑皮层的某些部分和弥漫性白质中最为明显。此外，我们假设这些神经退行性改变的驱动机制是轴突内逐渐积累(并伴随着突触前缺失)α-突触核蛋白--一种淀粉样蛋白--最终导致更广泛的轴突功能障碍、突触效能丧失和神经元变性。最初，这将表现为 神经生理学缺陷影响轴突效能和突触功能，并将导致学习、解决问题和运动功能的神经行为逐渐下降。为了验证这些假说，我们组建了一个多方面的研究团队，他们拥有神经退行性病理学、啮齿动物和猪的脑损伤模型以及神经系统电生理学方面的专业知识。我们将使用致淀粉样变性的转基因小鼠脑损伤模型和闭头旋转加速致脑损伤的猪模型，从力学上评估脑损伤后1个月到2年的病理生理进展。重要的是，转基因小鼠研究(表达人类α-突触核蛋白)将被用于直接比较BLAST-TBI和IMPACT-TBI的病理生理学和神经退行性机制。在小鼠和猪身上，我们将采用一系列全面的测试，包括：(1)评估正在演变的神经退行性变化，包括弥漫性轴索损伤(DAI)、帕金森样路易氏病变、阿尔茨海默氏样淀粉样变性和变应性疾病、突触丢失和神经炎症；(2)学习、记忆、运动和解决问题的神经行为测试；以及(3)使用电生理学技术对敏感的轴突丢失/功能、突触变化和兴奋性变化进行神经生理测量。对同一动物的脑损伤所致的慢性神经退行性变、神经行为和神经生理学的评价是一个独特和强大的实验平台，可以检测细微的神经变化，研究诱发的病理生理学，并建立特定的结构-功能关系。重要的是，这些将在单一的中度或严重伤害后进行评估，或者在反复的轻微伤害之后进行评估。虽然越来越多的证据表明颅脑损伤与早期神经退行性病变有关，但军事上相关的单发或重复闭合性颅脑损伤后这些进行性神经病变的机制尚不清楚。然而，建立病理生理联系对我们退伍军人的长期健康和神经功能至关重要，因此强调了当前提议的重要性和相关性。

DESCRIPTION (provided by applicant): Military traumatic brain injury (TBI) has risen markedly in the current wars in Iraq and Afghanistan, and may occur in isolation or as a component of severe battlefield polytrauma. Recently, there have been estimates of 15-20% of warfighters (over 300,000 soldiers) having served in Iraq or Afghanistan having sustained at least mild TBI. These staggering numbers of afflicted warfighters make the chronic effects of TBI one of the most pressing issues affecting our Veterans. Accordingly, the overall objective of this proposal is to identify the mechanism(s) and progressive changes underlying the transition from acute to chronic pathology following closed-head TBI. Our central hypothesis is that a single severe or repeated mild closed-head TBI induces slowly progressive neurodegenerative changes over months to years post-insult. We believe these long-term neurodegenerative changes will be most apparent in the hippocampus, nigrostriatal system, aspects of the cerebral cortex, and diffuse white matter. Moreover, we hypothesize that a driving mechanism for these neurodegenerative changes is the gradual intra-axonal accumulation (and concomitant pre-synaptic depletion) of alpha-synuclein - an amyloidogenic protein - that eventually leads to more widespread axonal dysfunction, loss of synaptic efficacy, and neuronal degeneration. Initially, this will manifest as neurophysiological deficits affecting axonal efficacy and synaptic function, and will underlie a gradual neurobehavioral decline in learning, problem-solving, and motor function. To test these hypotheses, we have assembled a multi-faceted team of investigators with expertise in neurodegenerative pathologies, rodent and porcine models of TBI, and neural systems electrophysiology. We will use a pro-amyloidogenic transgenic mouse model of TBI and a swine model of closed-head rotational acceleration-induced TBI to mechanistically evaluate the pathophysiological progression from 1 month to 2 years post-injury. Importantly, the transgenic mouse studies (expressing human alpha-synuclein) will be used to directly compare the pathophysiology and neurodegenerative mechanisms in blast-TBI versus impact-TBI. In both mice and pigs, we will employ a comprehensive battery of tests including: (1) assessment of evolving neurodegenerative changes including diffuse axonal injury (DAI), Parkinson's-like Lewy pathology, Alzheimer's-like amyloidosis and tauopathies, synaptic loss, and neuroinflammation; (2) neurobehavior testing of learning, memory, motor, and problem solving; and (3) neurophysiological measurements using electrophysiological techniques sensitive to axonal loss/dysfunction, synaptic changes, and excitability changes. The evaluation of TBI-induced chronic neurodegeneration, neurobehavior, and neurophysiology in the same animals is a unique and powerful experimental platform to detect subtle neurological changes, investigate precipitating pathophysiology, and establish specific structure-function relationships. Importantly, these will be evaluated following either a single moderate or severe injury, or following repeated mild injuries. Although there is mounting evidence for links between TBI and early onset of neurodegenerative pathologies, the mechanisms of these progressive neuropathological changes following militarily relevant single or repetitive closed-head TBI are unknown. However, establishing the pathophysiological links is critical for the long-term health and neurological function of our Veterans, and thus underscores the importance and relevance of the current proposal.