Neuronal Vulnerability in Experimental Epilepsy

描述(由申请人提供)：本申请概述了实验室癫痫研究领域的5年学术研究生涯发展计划。申请者是一名内科医生，同时拥有神经科学博士学位。他已经完成了神经学住院医师学位，目前正在亚利桑那大学完成临床和癫痫研究奖学金。在奠定了学术生涯的基础后，申请人将在Robert Sloviter博士的指导下专注于开发癫痫的实验模型。这位导师开发了颞叶癫痫的动物模型，并拥有20多年在这一领域进行和监督研究的经验。他将继续在其实验室为申请人提供监督和不受限制的资源。海马区硬化症是一种常见的与颞叶癫痫相关的病变，通常是单侧或不对称的，通常发生在对大脑的相对无害的侮辱之后，不会导致广泛的脑损伤，就像目前的颞叶癫痫动物模型中所看到的那样。新的人类数据表明，海马区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侮辱对颞叶结构的影响。利用对清醒、长期植入的大鼠的持续电生理和行为监测，实验将首先确定穿孔路径刺激诱导癫痫持续状态后正常大鼠的损伤和癫痫发生阈值。在确定损伤阈值后，申请者将利用新开发的高度特异的方法选择性地局部破坏海马区抑制性中间神经元。癫痫发作后的损伤和癫痫发生的阈值将在单侧和双侧缺陷的动物身上确定。局灶性去抑制将降低损伤和癫痫发生的阈值，并将在相对保留其他脑区的情况下导致不对称的海马区损害，这将有助于开发合理的模型来理解和开发治疗颞叶癫痫的方法。

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.