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.
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