The overall goal of the proposal is to study the functional organization of the striatum. To do this, dopamine and acetylcholine muscarinic receptor mediated gene regulation of striatal neurons will be studied in rats. Administration of selective D1 and D2 dopamine and muscarinic receptor drugs will be used to examine specific receptor mediated gene regulation in connectionally and neurochemically characterized striatal neurons. Striatal neurons will be characterized by their connections using retrograde axonal tracing techniques and by the localization of D1 and D2 dopamine and m1 and m4 muscarinic receptor subtype mRNAs using in situ hybridization histochemical techniques. To assay changes in altered gene regulation, quantitative in situ hybridization histochemical techniques will be used to measure drug-induced changes in mRNAs encoding the transcription factor c-fos, and the neuropeptides enkephalin, substance P, and dynorphin, which serve as markers of specific striatal projection neurons. Results of these studies will provide insight into the molecular and cellular mechanisms through which dopamine and acetylcholine modulate gene regulation in connectionally defined subpopulations of striatal projection neurons. The segregation of the D1 and D2 dopamine receptor subtypes in striatal neurons projecting to the substantia nigra and the globus pallidus, respectively, results in opposite patterns of dopamine agonist-mediated gene regulation in these projection neurons. The goal of the proposed experiments is to study the interaction between dopamine and muscarinic receptor-mediated alterations in gene regulation. This research is relevant to understanding the cellular and molecular changes that occur in the striatum in Parkinson's disease and in helping to devise clinically relevant pharmacologic therapies for reversing these effects.
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