The proposal describes a combined neurochemical and histochemical approach to the study of the genetic regulation of the mesolimbic and nigrostriatal dopamine-containing systems. The work is focused on a mutant allele that discriminates in its action among the brain's dopaminergic neurons resulting in a striking regional specificity. The genetic mutation to be examined is weaver, an autosomal recessive mutation in mouse in which the ventral and dorsal striatum are affected according to recognized functional subdivisions. Specifically, the nucleus accumbens retains entirely normal concentrations of dopamine whereas the dopamine content of the caudoputamen is reduced by 70%. Other striatal and non-striatal targets of the dopamine-containing cell bodies in midbrain are affected or not in a remarkable pattern with its strict boundaries entirely reproducible in homozygous weaver animals and in a less severe way but with exactly the same pattern in the heterozygous weavers. The pattern strongly suggests separable genetic control of the mesolimbic and nigrostriatal systems. Our preliminary developmental studies show that this control is exerted during early postnatal life. It has its developmental timing and many other features in common with the defect that this gene exerts on a completely unrelated (anatomically) population of cells, the cerebellar granule cells.
The aims have four long-term targets. One is to define the spared and affected populations of dopamine cells and to examine the features which distinguish them. The second is to make an analysis of the consequences of the loss of dopamine for the final organization of the striatum.
The third aim i s to examine how the genetic control of these subsets of dopamine neurons is regulated.
The fourth aim i s to define features in common between the action of the gene in the cerebellum and in the dopamine system in an effort to reveal a common molecular mechanism. These studies will require measurements of and anatomical distribution of dopamine and tyrosine hydroxylase (TH) as well as measurements of the messenger RNA which encodes for TH. There will be retrograde tracer studies, 3H-thymidine mapping, and examination of migration of dopamine neurons and their relationships to glial cells. This work has the eventual aim of uncovering the orderly sequence of genetic information which governs the development of dopamine-containing neurons.
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