GROWTH AND AGING--ANATOMY OF SUBSTANTIA NIGRA

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The objective of the proposed research is the systematic study of morphologic and immunocytochemical changes which occur during growth, development and aging in primate brain. The model chosen for study is the substantia nigra (SN) of rhesus monkeys. The specific aims of the project are (1) to determine the qualitative changes which are apparent in the morphology of substantia nigra neurons from birth to senescence, (2) to quantify the number of nigral neurons present in this nucleus and the volume of the nucleus at each stage of life, (3) to characterize the signal ultrastructural features of developmental, adult and aged monkey SN, (4) to quantify these ultrastructural changes using an appropriate statistico-mathematical analysis and (5) to localize, characterize and quantify the immunocytochemically- identified neurotransmitter endowment of neurons, dendrites and terminals at each stage of development and aging. These aims will be accomplished at the light (LM) and electron microscopic (EM) levels, using a wide range of techniques including the classic Golgi and Nissl methods for LM, Golgi-gold toning for LM-EM correlations, quantitative analysis including ultrastructural stereology, qualitative and quantitative post-embedding, as well as single and double label pre-embedding immunocytochemistry. All of these studies will be conducted separately on material from pars compacta (SNc) and pars reticulata (SNr). The proposed studies are designed to yield normative data on the morphologic natural history of the monkey substantia nigra. Nature and time provide a potent independent variable which may operate in such a fashion that aging represents a continuum, or a reversal, of the events which characterize development. This research constitutes a first step toward understanding the results of invasive experimental manipulations, as well as interferences with normal development and aging due to traumatic, environmental and metabolic disturbances. As such, the results of this investigation will provide a basis for the interpretation of behavioral and clinical studies of normal and experimentally- altered motor system development, studies of movement disorders and nigrostriatal pathways, deficits, brain transplant studies involving implants of fetal nigral tissue, and behavioral, clinical and pharmacologic studies of normal and abnormal aging processes. Parkinson's disease, Huntington's disease, schizophrenia, the Lesch-Nyhan syndrome, Gilles de la Tourette syndrome and tardive dyskinesia have all been suspected to encompass dysfunction of the substantia nigra.