The nigrostriatal dopamine system is one important brain pathway involved in the coordination of movement control. For reasons that remain unknown, that system degenerates in Parkinson's disease. In the proposed studies, neural grafting techniques are adopted in an attempt to compensate for a genetically-determined nigrostriatal dopamine deficiency that is found in weaver mulani mice. The abnormality of the nigrostriatal dopamine projection, which is caused by a recessive mutant gene, renders the homozygous weaver mouse a parlicularly valuable model in understanding pathogenetic mechanisms of dopamine neuron degeneration and in designing and testing transplantation methodologies for the correction of the neurological deficit by replacing missing cells with homologous donor tissue. In particular, the issues addressed include the ability of the grafts to sustain an anatomical and functional innervation of the host for the longest possible survival-time; the specifically of the reconstructed neuronal circuit that is formed by graft-derived afferents in the recipient brain; the mechanisms of neurotransmitter function in the graft-induced anatomical condition; and the potential of the grafts for the correction of specific behaviors at the organism level, which require a precise rewiring of the neuronal network. The proposed goals will be achieved by combining a mullitude of neurobiological techniques, including neural grafting, histology, optical and ultrastructural immunocytochemisiry, neurochemistry, neuropharmacology, and behavioral analysis. Particular reference is made to the integration of healthy donor cells with the pathologic nervous system of the genetically-mutant host. The experiments proposed will provide fundamental information pertinent to the design of strategies and to the effects of therapeutic intervention in degenerative brain disorders.
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