We propose to study the relative loss or preservation of subpopulations of striatal neurons in Huntington's disease (HD) and the quinolinic acid (QA) model of HD. Recent research has shown that some striatal neurons are preferentially affected and others relatively spared in HD. These findings give clues to the pathogenesis of cell death in HD. An understanding of pathogenesis will be necessary for the development of a therapy for HD and may aid in the understanding of other degenerative disorders of the nervous system. Knowledge of changes in striatal neuron subpopulations also provide a tool with which to evaluate and develops models of HD pathogenesis. An accurate model would greatly facilitate the understanding of HD pathogenesis and pathophysiology.
Our specific aims are: 1) To continue present research on changes in striatal efferent peptidergic neurons in HD. Using immunocytochemistry, we have been able to correlate these changes with some of the clinical and pharmacological features of HD. 2) To apply a set of criteria derived from studies of striatal neuron sub-populations in HD to the established QA model of HD. Utilizing an acute QA striatal lesion paradigm in rats, we will examine the effects of QA on both striatal interneurons and identify NADPH-diaphorase containing and cholinergic interneurons. The latter will be examined using immunocytochemistry to identify striatal efferent peptidergic neurons and quantitative autoradiography to assess receptor changes in striatal target areas. 3) To develop a model of HD that more closely approximates the characteristics of the disease. The striatum of the rat is substantially different from that of primates. We will evaluate acute QA striatal lesions in cats, whose striatum appears to be quite similar to that of primates. Finally, we will develop a new paradigm of chronic subthreshold intoxication and evaluate it in both rats and cats.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Clinical Investigator Award (CIA) (K08)
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Neurological Disorders Program Project Review A Committee (NSPA)
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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