Contribution of adult neurogenesis to epileptogenesis and recovery after TBI

项目摘要 在美国，每年有100多万人在脑部受损后接受医疗治疗 损伤及创伤性脑损伤常伴有创伤后发育迟缓。 癫痫(PTE)，几乎没有有效的治疗方法。尽管脑外伤和脑外伤的临床相关性 癫痫是有据可查的，旨在预防PTE的治疗基本上都不成功。在这些人中 到目前为止，报道的最有希望的抗癫痫治疗集中在抑制哺乳动物 雷帕霉素(MTOR)途径的(机械)靶点。MTOR在脑创伤和癫痫发作后被激活，其活性 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。 抑制mTOR活性有望改变啮齿动物模型的癫痫发生进展 癫痫，包括PTE，但也有几个警告，具体地说：抑制 脑外伤后mTOR被认为是为了防止癫痫的发生，而mTOR的激活则被提出。 作为促进脑外伤患者认知功能恢复的一种手段。MTOR的机制 调制是否发挥其抗癫痫作用尚不清楚，而新生神经元和 海马齿状回的突触重组对癫痫的发生和认知存在争议。预防 PTE受到这些基本知识差距的阻碍。这项提议将使用受控的皮质影响 (CCI)脑损伤模型，导致脑细胞丢失、神经发生增加和突触重组。 研究齿状回对自发性癫痫的延迟发展(即癫痫发生)的影响。 新生神经元对齿状回突触兴奋性的影响。负面和负面的影响 MTOR对癫痫发生和认知恢复的积极调节也将在以下背景下确定 脑损伤后的神经再生。最重要的假设是成年出生的神经元对突触有贡献。 脑损伤后的重组和mTOR活性依赖的神经发生调节改变癫痫的发生 和颅脑损伤后认知功能恢复。电生理学、组织学和行为学技术的结合 利用成年出生神经元的光遗传和化学遗传修饰将用于解决三个目标： 1)检测脑损伤后成年DGCs的功能性突触组织；2)检测mTOR的作用 脑损伤后对海马齿状回神经发生和突触连接的调节；以及3)决定如何 成年出生的DGC有助于脑损伤后的功能恢复和癫痫发作。机械地理解如何 成年出生的神经元参与DGC回路，以及mTOR调制如何改变这些神经元的回路 CCI后将在脑创伤后认知恢复和PTE发展的背景下发展。一个 更好地了解成年新生神经元在脑外伤后恢复和癫痫发生中的作用 促进制定预防PTE的治疗方法。

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.