Neuronal Vulnerability in Experimental Epilepsy

描述（由申请人提供）：本申请概述了一个5年的学术研究职业发展计划，在实验室为基础的癫痫研究。申请人是一名医生，同时拥有神经科学博士学位。他已经完成了神经病学的住院医师培训，目前正在亚利桑那大学完成临床和研究癫痫学的奖学金。在奠定了学术生涯的基础后，申请人将专注于在Robert Sloviter博士的指导下开发癫痫的实验模型。导师开发了颞叶癫痫的动物模型，并在该领域拥有二十多年的执行和监督研究经验。他将继续在实验室为申请人提供监督和不受限制的资源。海马硬化是与颞叶癫痫相关的常见病变，通常是单侧或不对称的，并且通常发生在对大脑相对无害的损伤之后，不会引起广泛的脑损伤，如在目前的颞叶癫痫动物模型中所见。新的人类数据表明，海马结构和功能中预先存在的局灶性缺陷可能会放大癫痫发作或其他损伤对颞叶结构的影响。在清醒的慢性植入大鼠中使用连续电生理和行为监测，实验将首先确定正常大鼠在穿通路径刺激诱导的癫痫持续状态后的损伤和癫痫发生阈值。在确定损伤阈值后，申请人将利用新开发的高度特异性方法选择性和局灶性破坏海马抑制性中间神经元。然后将在单侧和双侧缺陷的动物中确定癫痫发作后损伤和癫痫发生的阈值。预测局灶性去抑制将降低诱导损伤和癫痫发生的阈值，并将诱导不对称的海马损伤与其他脑区的相对保护，将促进合理的模型的发展，了解和发展颞叶癫痫的治疗。

DESCRIPTION (provided by applicant): This application outlines a 5-year academic research career development plan in laboratory based epilepsy research. The applicant is a physician who also holds a Ph.D in Neuroscience. He has completed a residency in neurology and is currently completing a fellowship in clinical and research epileptology, all at the University of Arizona. Having laid the foundations for an academic career, the applicant will focus on developing experimental models of epilepsy under the mentorship of Robert Sloviter, Ph.D. The mentor has developed animal models of temporal lobe epilepsy and has over twenty years of experience performing and supervising research in this area. He will continue to provide the applicant with supervision and unrestricted resources in his laboratory. Hippocampal sclerosis, a common lesion associated with temporal lobe epilepsy, is often unilateral or asymmetric, and often occurs after relatively innocuous insults to the brain that do not cause widespread brain injury, as seen in current animal models of temporal lobe epilepsy. Novel human data suggest that pre-existing focal defects in hippocampal structure and function might amplify the effects of seizures or other insults on temporal lobe structures. Using continuous electrophysiological and behavioral monitoring in awake, chronically implanted rats, experiments will first determine the threshold for injury and epileptogenesis in normal rats following perforant path stimulation-induced status epilepticus. Following determination of the threshold for injury, the applicant will utilize newly developed and highly specific methods to selectively and focally destroy hippocampal inhibitory interneurons. The threshold for injury and epileptogenesis following seizures will then be determined in animals with unilateral and bilateral defects. The predictions that focal disinhibition will lower the threshold for inducing injury and epileptogenesis, and will induce asymmetric hippocampal damage with relative preservation of other brain regions, will facilitate development of rational models for understanding and developing treatments for temporal lobe epilepsy.