The neurons of the substantia nigra-ventral tegmental area sustain a major dopamine-containing projection to the striatum, or caudate-putamen, in the rat and other animals. A number of markers have recently been shown to be distributed non-homogeneously in the striatum. A complex patch-matrix organization has been revealed. How this organization develops and is maintained is not known. Many recent studies have begun to elucidate the importance of characterized factors which mediate cell growth, differentiation, response to injury and neuronal survival. Our recent experiments have shown that several well characterized growth factors, including epidermal growth factor, transforming growth factor, and fibroblast growth factor are localized to a number of discrete systems in the brains of both adult and developing rats. It has also been shown that certain brain chemicals thought to act as neurotransmitters, including dopamine and members of the opiate family, may have effects on basic growth processes. This proposal outlines experiments designed to further examine the localization of these neurochemicals and to elucidate the role they might play in such basic growth processes. These and experiments will be carried out in a model system with which we have considerable experience, the nigro-striatal system. Experiments will utilize three different culture systems, including intra-cerebral cell suspension transplants, organotypic tissue slice cultures, and dissociated cell cultures. All will be examined for expression of, and/or response to, these neurochemicals. In addition, brains of the mutant mouse weaver, which exhibit a postnatal decline in dopamine content, will be analyzed to determine the role of these growth factors in the neurological deficit expressed. These experiments will produce data relevant to the hypothesis that the organization of the nigro-striatal system is controlled by dynamic interactions between defined neurochemical systems.
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