Contribution of adult neurogenesis to epileptogenesis and recovery after TBI

成人神经发生对 TBI 后癫痫发生和恢复的贡献

• 批准号: 9923738
• 负责人: KATHRYN E SAATMAN
• 金额: $ 42.37万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923738
• 关键词: Address; Adult; Affect; Antiepileptogenic; Behavior; Behavioral; Brain; Brain Injuries; Cells; Cessation of life; Clinical; Cognition; Coupled; Development; Disease; Disease Progression; Down-Regulation; Electrophysiology (science); Epilepsy; Epileptogenesis; FRAP1 gene; Growth; Hippocampus (Brain); Histologic; In Vitro; Injury; Knowledge; Medical; Modeling; Modification; Mus; Neurons; Newborn Infant; Outcome; Pathway interactions; Patients; Post-Traumatic Epilepsy; Recovery; Recovery of Function; Regulation; Reporting; Risk; Rodent Model; Role; Seizures; Sirolimus; Site; Structure; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Therapeutic; Time; Traumatic Brain Injury; Traumatic Brain Injury recovery; United States; Up-Regulation; adult neurogenesis; base; behavioral outcome; cognitive development; cognitive function; cognitive recovery; controlled cortical impact; dentate gyrus; effective therapy; experimental study; functional outcomes; granule cell; improved; injury recovery; mossy fiber; mouse model; neural network; neurogenesis; newborn neuron; optogenetics; prevent; therapeutic target; therapy design; therapy development

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.

项目概要 在美国，每年有超过一百万人在维持大脑功能后接受治疗 损伤和创伤性脑损伤（TBI）常常伴随着创伤后脑损伤的延迟发展。 癫痫（PTE），目前几乎没有有效的治疗方法。尽管 TBI 和 TBI 之间的临床关联 癫痫病已有充分记录，但旨在预防 PTE 的治疗基本上不成功。其中 迄今为止报道的最有希望的抗癫痫治疗方法集中在抑制哺乳动物 雷帕霉素 (mTOR) 途径的（机械）靶点。 mTOR 在 TBI 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，尤其是发育中的神经元。 在啮齿类动物模型中，抑制 mTOR 活性有望改变癫痫发生的进程 癫痫，包括 PTE，但也承认了一些警告，特别是： mTOR 已被提议用于预防 TBI 后癫痫发生，而 mTOR 激活已被提议 作为改善 TBI 后患者认知恢复的一种手段。 mTOR 的机制 调节发挥其抗癫痫作用尚不清楚，新生神经元和神经元的贡献 齿状回突触重组对癫痫发生和认知的影响存在争议。预防 PTE 受到这些基础知识差距的阻碍。该提案将使用受控皮质影响 (CCI) TBI 模型，导致细胞丢失、神经发生增加和突触重组 齿状回和自发性癫痫发作（即癫痫发生）的延迟发展来研究 新生神经元对齿状回突触兴奋性的变化。负面影响和负面影响 mTOR 对癫痫发生和认知恢复的正向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，成年神经元有助于突触 TBI 后的重组以及神经发生的 mTOR 活性依赖性调节改变了癫痫发生 以及 TBI 后的认知恢复。电生理学、组织学和行为技术的结合 利用成年神经元的光遗传学和化学遗传学修饰将用于实现三个目标： 1）确定TBI后成人出生的DGC的功能性突触组织； 2) 确定 mTOR 的效果 TBI 后齿状回神经发生和突触连接的调节； 3) 确定如何 成人出生的 DGC 有助于 TBI 后的功能恢复和癫痫发作。机械地理解如何 成年神经元对 DGC 电路有贡献，以及 mTOR 调制如何改变这些神经元的电路 CCI 后的发展将在 TBI 后认知恢复和 PTE 发展的背景下进行。一个 更好地了解成年神经元对 TBI 后恢复和癫痫发生的贡献将 促进预防 PTE 治疗方法的开发。