Contribution of adult neurogenesis to epileptogenesis and recovery after TBI

项目摘要 在美国，每年有超过100万人在维持大脑功能后接受治疗。 创伤性脑损伤（TBI）通常伴随着创伤后延迟发展。 癫痫（PTE），对于它有几个有效的疗法。虽然TBI和 虽然癫痫是有据可查的，但旨在预防PTE的治疗在很大程度上是不成功的。中 迄今为止报道的最有希望的抗癫痫治疗集中在抑制哺乳动物的 雷帕霉素（mTOR）通路的（机械）靶标。mTOR在创伤性脑损伤和癫痫发作后被激活， 调节多种细胞活动，包括生长和增殖，特别是在发育中的神经元中。 抑制mTOR活性已经显示出改变啮齿动物模型中癫痫发生进展的希望， 癫痫，包括PTE，但也有一些注意事项，特别是： 已经提出TBI后mTOR可预防癫痫发生，而已经提出mTOR激活 作为改善TBI患者认知恢复的一种手段。mTOR的机制 调制发挥其抗癫痫作用是未知的，新生神经元和 齿状回突触重组对癫痫发生和认知功能的影响存在争议。防止 PTE受到这些基本知识差距的阻碍。这项提案将使用可控的皮质撞击 (CCI)TBI模型，导致细胞丢失，增加神经发生和突触重组， 齿状回，和自发性癫痫发作的延迟发展（即，癫痫发生），以研究 新生神经元对齿状回突触兴奋性变化的影响。负面影响和 mTOR对癫痫发生和认知恢复的正调节也将在以下背景下确定： 脑损伤后的神经发生最重要的假设是，成人出生的神经元有助于突触 TBI后的重组和mTOR活性依赖的神经发生调节改变癫痫发生 以及TBI后的认知恢复。结合电生理学、组织学和行为学技术 利用成年出生神经元的光遗传学和化学遗传学修饰将用于解决三个目标： 1)确定TBI后成年出生的DGC的功能性突触组织; 2）确定mTOR的作用 TBI后齿状回神经发生和突触连接的调节;以及3）确定如何 成年出生的DGC有助于TBI后的功能恢复和癫痫发作。机械地理解 成年出生的神经元有助于DGC电路以及mTOR调节如何改变这些神经元的电路 CCI后的认知功能将在TBI后认知恢复和PTE发展的背景下发展。一 更好地理解成年出生的神经元对TBI后恢复和癫痫发生的作用， 促进预防PTE的治疗方法的发展。

Project Summary More than one million people are treated medically each year in the United States after sustaining a brain injury and traumatic brain injury (TBI) is often accompanied by the delayed development of posttraumatic epilepsy (PTE), for which there are few effective therapies. Although clinical association between TBI and epilepsy is well documented, treatments designed to prevent PTE have been largely unsuccessful. Among the most promising antiepileptogenic treatments reported to date center on inhibition of the mammalian (mechanistic) target of rapamycin (mTOR) pathway. mTOR is activated after TBI and seizures, and it's activity regulates a variety of cellular activities, including growth and proliferation, especially in developing neurons. Inhibiting mTOR activity has shown promise for altering the progression of epileptogenesis in rodent models of epilepsy, including PTE, but several caveats have also been acknowledged, specifically: Suppression of mTOR post-TBI has been proposed to prevent epileptogenesis, whereas mTOR activation has been proposed as a means of improving cognitive recovery after TBI in patients. The mechanisms by which mTOR modulation exerts its anti-epileptogenic effects are not known, and the contribution of newborn neurons and synaptic reorganization in the dentate gyrus to epileptogenesis and cognition are controversial. Preventing PTE is hampered by these fundamental knowledge gaps. This proposal will use the controlled cortical impact (CCI) model of TBI, which results in cell loss, increased neurogenesis and synaptic reorganization in the dentate gyrus, and delayed development of spontaneous seizures (i.e., epileptogenesis) to study the impact of newborn neurons on synaptic excitability changes in the dentate gyrus. The effects of both negative and positive regulation of mTOR on epileptogenesis and cognitive recovery will also be determined in the context of neurogenesis after brain injury. The overarching hypotheses are that adult born neurons contribute to synaptic reorganization after TBI and that mTOR activity-dependent regulation of neurogenesis alters epileptogenesis and post-TBI cognitive recovery. A combination of electrophysiological, histological, and behavioral techniques utilizing optogenetic and chemogenetic modification of adult born neurons will be used to address three aims: 1) Determine the functional synaptic organization of adult born DGCs after TBI; 2) Determine effects of mTOR modulation on neurogenesis and synaptic connectivity in the dentate gyrus after TBI; and 3) Determine how adult born DGCs contribute to functional recovery and seizures after TBI. A mechanistic understanding of how adult born neurons contribute to DGC circuitry and how mTOR modulation alters the circuitry of these neurons after CCI will be developed in the context of both cognitive recovery after TBI and development of PTE. A better understanding of the contribution of adult born neurons to recovery and epileptogenesis after TBI will facilitate the development of treatments to prevent PTE.