Dystonia in an Animal Model of Kernicterus

脑损伤和由此导致的肌张力障碍运动障碍仍然是 胆红素毒性，尽管新生儿高胆红素血症(黄疸)的治疗取得了进展。对PA-02-156号方案公告的回应： 我们将使用一个经典的动物模型--黄褐斑Gunn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新生儿高胆红素血症继发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形式的脑瘫。典型的核黄体炎伴肌张力障碍、手足徐动性脑瘫、眼球运动和听力障碍，以及更轻微的胆红素诱导的神经发育障碍，最近重新出现，部分原因是新生儿较早出院。在先前重点研究了胆红素对Gunn大鼠胆红素脑病模型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、肌电图和来自脑深部核的颅内微电极记录来表征该模型中核黄体肌张力障碍的运动障碍。我们将把我们对肌张力障碍的研究与胆红素的测量和脑干联系起来。 听觉诱发电位--胆红素毒性的灵敏、非侵入性电生理指标。我们将使用损伤和细胞死亡的标准组织学技术，包括TUNEL和caspase3染色的细胞凋亡，以及无偏见的体视学来确定神经元细胞的丢失，并在基底节进行微电极记录，以探索我们关于该模型肌张力障碍的神经生理学基础的假说。最后，我们将研究立体定向和微电极引导的基底节区靶向消融手术治疗。这项拟议研究的发现应该会为人类继发性核黄体性肌张力障碍和其他继发性肌张力障碍的病理生理学和治疗带来新的见解。

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.