Mechanistic role of vascular dysfunction in TBI-mediated cognitive dysfunction

摘要 轻度创伤性脑损伤(MTBI)是导致死亡和发病的主要原因，尤其是在服役期间。 会员和退伍军人。MTBI与阿尔茨海默氏症等痴呆症的长期发展有关 疾病和相关疾病，但确切的病理生理机制仍不清楚。血管 疾病和心血管风险因素与痴呆症密切相关。我们建议检验这个假设 长期的mTBI导致的认知功能障碍至少部分是由于持续性的脑血管功能障碍。 我们还将检验这一假设，即早期发生的mTBI和后来的高血压发展将具有协同作用。 与高血压或单纯mTBI相比，对脑血管和认知功能障碍的影响。在目标1中，我们将 测量大鼠模型脑血管和认知功能的时间变化(亚急性和慢性) 在建立脑血管功能障碍在mTBI诱导认知中的机制作用 减损。在Spraogue-Dawley大鼠的中线液压冲击损伤或假手术后，我们将测量 亚急性(8周)和慢性(12个月)脑血管功能(通过脑对比MRI进行体内和体外 通过测量大脑动脉血管反应性)和认知功能，并建立它们之间的关系。我们还将 确定是早期(从受伤后2周开始)还是延迟(从受伤后10个月开始)有氧运动 训练会改善脑血管功能，导致认知功能的改善。我们将确定 脑血管功能调节重型颅脑损伤认知功能的分子机制 内皮功能在脑源性神经营养因子调节中的作用。在目标2中，我们将探讨 慢性脑血管疾病早发脑挫伤与晚期高血压的相互作用 认知功能障碍。在这里，我们将使用遗传上易患高血压(自发)的大鼠 高血压大鼠)，观察早期mTBI对慢性脑血管病变的调节作用 认知功能。我们还将有一个探索性的目标，看看mTBI在斯普拉格-道利和 对高血压大鼠心脏结构和功能及冠状动脉功能的影响。该提案可能会提供 对脑外伤后血管功能障碍的机制及其在脑损伤中的作用的关键和新见解 认知功能障碍的发展。

Abstract Mild traumatic brain injury (mTBI) is a major cause of mortality and morbidity especially among service- members and veterans. mTBI is linked to long-term development of dementia conditions such as Alzheimer's disease and related disorders, but the exact pathophysiologic mechanisms remain poorly-defined. Vascular disease and cardiovascular risk factors are strongly linked with dementia. We propose to test the hypothesis that long-term mTBI-induced cognitive dysfunction is due to, at least in part, persistent cerebrovascular dysfunction. We will also test the hypothesis that early onset mTBI and later development of hypertension will have synergistic effects on cerebrovascular and cognitive dysfunction compared to hypertension or mTBI alone. In Aim 1, we will measure the temporal changes (subacute and chronic) in cerebrovascular and cognitive function in a rat model of mTBI while establishing the mechanistic role of cerebrovascular dysfunction in mTBI-induce cognitive impairment. Following midline fluid percussion injury or sham surgery in Sprague-Dawley rats, we will measure subacute (8 weeks) and chronic (12 months) cerebrovascular function (in-vivo by brain contrast MRI and ex-vivo by measuring cerebral artery vasoreactivity) and cognitive function and establish their relationship. We will also determine if early (starting at 2 weeks post-injury) or late (starting at 10 months post-injury) aerobic exercise training will improve cerebrovascular function leading to improvement in cognitive function. We will identify molecular mechanisms by which cerebrovascular function modulates cognitive function in mTBI by investigating the role of endothelial function in the regulation of brain-derived neurotrophic factor. In Aim 2, we will probe the interaction between early onset mTBI and later development of hypertension in chronic cerebrovascular and cognitive dysfunction. Here we will use rats genetically prone to develop hypertension (spontaneously hypertensive rats) to determine the effects of early onset mTBI in modulating chronic cerebrovascular and cognitive function. We will also have an exploratory aim to look at effects of mTBI in Sprague-Dawley and hypertensive rats on cardiac structure and function and coronary artery function. The proposal could provide critical and novel insights on the mechanisms underlying vascular dysfunction in TBI and their role in the development of cognitive dysfunction.