Dystonia in an Animal Model of Kernicterus

脑损伤和由此产生的肌张力障碍性运动障碍仍然是 尽管新生儿高胆红素血症（黄疸）的治疗取得了进展，但胆红素毒性仍然存在。为响应PA-02-156号方案公告，“研究 肌张力障碍”，我们将使用经典的动物模型，黄疸古恩大鼠，系统地研究这种继发性肌张力障碍的病理生理学及其与发育的关系。目前项目的总体目标是了解继发于新生儿高胆红素血症的肌张力障碍的定位和病理生理学，以便更好地治疗这种严重的肌张力障碍型脑瘫。典型的核黄疸伴肌张力障碍、“手足徐动样脑瘫”、眼和听觉障碍，以及更微妙的胆红素诱导的神经发育障碍，最近重新出现，部分原因是新生儿提前出院。在关注胆红素对古恩大鼠胆红素脑病模型中听觉神经系统的影响后，我们现在建议使用行为分析、解剖学和免疫组织化学、肌电图和脑深部核团的颅内微电极记录来表征该模型中核黄疸的张力障碍性运动障碍。我们将把我们对肌张力障碍的研究与胆红素和脑干的测量联系起来， 听觉诱发电位，胆红素毒性的敏感，非侵入性电生理测量。我们将使用损伤和细胞死亡的标准组织学技术，包括凋亡的TUNEL和半胱天冬酶3染色，以及无偏体视学来确定神经元细胞损失，以及基底神经节中的微电极记录来探索我们关于该模型中肌张力障碍的神经生理学基础的假设。最后，我们将研究立体定向和微电极引导靶向基底神经节区域的消融手术治疗。从拟议的研究结果应导致新的见解的病理生理学和治疗继发性核肌张力障碍和其他继发性肌张力障碍的人类。

Brain damage and resultant dystonic movement disorders continue to be major complications of bilirubin toxicity despite advances in the treatment of hyperbilirubinemia (jaundice) in newborns. In response to Program Announcement PA-02-156, "Studies into the causes and mechanisms of dystonia," we will use a classic animal model, the jaundiced Gunn rat, to systematically investigate the pathophysiology of this secondary dystonia and its relationship with development. The overall goal of the current project is to understand the localization and pathophysiology of dystonia secondary to neonatal hyperbilirubinemia in order to better treat this severe dystonic form of cerebral palsy. Classic kernicterus with dystonia, "athetoid cerebral palsy," oculomotor and auditory impairments, as well as more subtle bilirubin-induced neurodevelopmental disabilities, have recently re-emerged due in part to the earlier discharge of newborns from hospitals. After focusing previously on the effect of bilirubin on the auditory nervous system in the Gunn rat model of bilirubin encephalopathy, we now propose to characterize the dystonic movement disorder of kernicterus in this model using behavioral analyses, anatomy and immunohistochemistry, electromyography, and intracranial microelectrode recordings from deep brain nuclei. We will relate our studies of dystonia to measures of bilirubin and to brainstem auditory evoked potentials, a sensitive, noninvasive electrophysiological measure of bilirubin toxicity. We will use standard histological techniques of injury and cell death including TUNEL and caspase 3 staining for apoptosis, and unbiased stereology to determine neuronal cell loss, and microelectrode recordings in the basal ganglia to explore our hypotheses regarding the neurophysiological basis of dystonia in this model. Finally, we will investigate stereotactic and microelectrode guided targeting of basal ganglia areas for ablative surgical treatment. The findings from the proposed research should lead to new insights into the pathophysiology and treatment of secondary kernicteric dystonia and other secondary dystonias in humans.