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: 10165838
• 负责人: KATHRYN E SAATMAN
• 金额: --
• 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 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165838
• 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.

项目摘要 每年在美国接受大脑后，每年有超过一百万的人受到医学治疗 损伤和创伤性脑损伤（TBI）通常伴随着创伤后的延迟发展 癫痫（PTE），几乎没有有效的疗法。尽管TBI和 癫痫病有充分的文献记载，旨在防止PTE的治疗方法在很大程度上没有成功。在 据报道，最有前途的抗癫痫治疗据报道是抑制哺乳动物的日期中心 （机械）雷帕霉素（MTOR）途径的靶标。 MTOR在TBI和癫痫发作后被激活，并且是活动 调节各种细胞活性，包括生长和增殖，尤其是在发育中的神经元中。 抑制MTOR活性已显示出改变在啮齿动物模型中改变癫痫发生进展的希望 癫痫病，包括PTE，但也有几个警告，特别是：抑制 已经提出了TBI MTOR后用于预防癫痫发生，而MTOR激活已提出 作为改善患者TBI后认知恢复的一种手段。 mtor的机制 调节发挥其抗癫痫作用的作用尚不清楚，新生儿神经元和 齿状回的突触重组与癫痫发生和认知是有争议的。预防 这些基本知识差距阻碍了PTE。该建议将使用受控的皮质影响 （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（即癫痫发生）的延迟发展，以研究 关于突触兴奋性的新生神经元在齿状回的变化。负面和 MTOR对癫痫发生和认知恢复的正调节也将在 脑损伤后神经发生。总体假设是成年出生的神经元有助于突触 TBI和MTOR活性依赖性调节神经发生后的重组会改变癫痫发生 和TBI后认知恢复。电生理，组织学和行为技术的结合 利用成年出生神经元的光遗传学和化学修饰将用于解决三个目标： 1）确定TBI之后成年出生DGC的功能突触组织； 2）确定MTOR的影响 TBI后齿状回的神经发生和突触连通性的调节； 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。对如何的机械理解 成人出生的神经元有助于DGC电路，MTOR调节如何改变这些神经元的电路 在CCI之后，将在TBI后的认知恢复和PTE发展后开发。一个 更好地理解成年出生神经元对TBI后恢复和癫痫发生的贡献 促进治疗的发展以防止PTE。