This proposal requests support for a combined neurochemical and histochemical study of normally innervated forebrain structures and those from a neurological mutant mouse which suffers severe depletion of dopamine. The mutant mouse to be examined is Weaver, an autosomal recessive mutation in which certain of the brain's dopamine-containing projections are altered. Preliminary work for this project suggests that the ventral and dorsal striatum of Weaver are affected differentially by this gene. The caudoputamen contains about 30% of normal dopamine content, whereas the nucleus accumbens retains normal dopamine concentrations. The first objectives of the proposed work are a) to determine by further mapping which dopamine systems in brain are affected, with special attention being paid to the nigrostriatal and mesolimbic systems, b) to establish when the targeted dopamine systems are affected and whether they die or fail to develop; and c) to examine features which distinguish the specifically targeted dopamine cells from the unaffected population. In parallel with these survey studies, an analysis will be carried out to determine the consequences of the loss of dopamine for the final organization of striatum. In particular, it is known that the striatum has a precise mosaic organization. Individual elements of the mosaic are formed by, for example, patches of low acetylcholinesterase and high opiate peptide and receptor concentrations. These mosaics are coextensive with patterns formed by other transmitter-related substances and input-output connections. The Weaver animal provides the opportunity to examine a striatum in which one component of the mosaics (that formed by the so-called dopamine islands) either never fully appears or largely disappears. The development of dopamine systems in normal and mutant mice will be followed to assess whether other neurotransmitter mosaic organizations depend upon the early-arriving dopamine fibers. These projects will involve making correlated biochemical and histochemical studies of regions of brain normally rich in dopamine, and comparing Weaver mice to controls. Some of the work will also require retrograde tracer studies and 3H-thymidine mapping. These studies should contribute to an understanding of the genetic control of the dopamine innervation of dorsal and ventral striatum and should also contribute to the understanding of the development of the patchy geometry of the striatum. The work described here has direct relevance to human diseases of the basal ganglia both acquired and genetically determined.
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