KINETICS OF CELL PROLIFERATION IN THE STRIATUM

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The long term goals of the research program are to characterize the mechanisms which regulate the generation of neurons destined for the corpus striatum (a component of the basal ganglia of the forebrain) during normal development or under pathological conditions. Those goals will be achieved in three stages: ontogenetic variation in the magnitudes of cytokinetic parameters (variables which regulate the process of cell generation) of striatal progenitors will be quantified and the variation will be related to the variation in the rate of generation and phenotypic diversity of the progeny; based on those data, an in vitro model of striatal cytogenesis will be developed; and using that in vitro model, the mechanisms by which intrinsic or extrinsic factors influence striatal cytogenesis under physiological or pathological conditions will be characterized. The data will be critically important for analyzing the effects of products of specific genes (e.g. Huntington's disease gene) or specific biochemical substances (e.g. growth factors, neurotransmitters or neuropeptides) on striatal development especially if transgenic animal models suitable for such analyses become available. Approaches such as those described above have been employed in research on non-neural systems with remarkable success, but not in research on cell generation in the corpus striatum. Experiments of this application will be the first of the three stages mentioned above. They will estimate for every day of the striatal neurogenetic period, the average values of the cytokinetic parameters of progenitors in the ganglionic eminence (embryonic source of striatal cells) in mice; quantify the rate of cellular Output from the ganglionic eminence, and determine the time of generation of two categories of striatal neurons. The Ontogenetic variation in the values of the cytokinetic parameters will be related to the variation in the rate of cellular output and phenotypic diversity of the progeny generated at the corresponding periods. Those data will serve as critical, baseline parameters for developing the in vitro model of cell generation in the corpus striatum. The principal technique to be used in the present experiments will be labeling cells in -phase of the mitotic cycle with bromodeoxyuridine and/or tritiated thymidine and identifying the labeled cells in tissue sections from the ganglionic eminence or the corpus striatum by immunocytochemical or autoradiographic methods. The number and spatial distribution of labeled cells at different developmental periods will be analyzed to estimate the cytokinetic parameters and the rate of cellular output. Those techniques will be combined with immunocytochemistry to determine the time of generation of striatal neurons containing substance P or enkephalin, the neuronal types selectively depleted in Huntington's disease.