The globus pallidus (GP; external pallidum of primates) plays a key role in the circuitry of the basal ganglia. It receives synaptic input from all of the striatal spiny projection neurons and distributes axon collaterals to all structures of this circuit, including the striatum. Recent research highlights the diversity of its neurons, with many containing parvalbumin (PV) and others expressing preproenkephalin (PPE) mRNA. The dopaminergic innervation of the pallidum is functional, because intrapallidal infusions of dopamine (DA) or DA antagonists alter unit firing and affect GP immediate early gene expression. The influences of D2-class DA antagonists on immediate early gene expression occur predominantly within the PPE+/-/(PV-) pallidostriatal cells. The mRNA for the D2 dopamine receptor is expressed by many (48 percent) of the neurons in rodent GP, making this nucleus a likely target for actions of exogenously administered dopaminergic agents (e.g., L-dopa in Parkinson's disease).
Four specific aims will address the issues of neuronal heterogeneity in GP neuron populations and the actions of DA on pallidal neuron function.
These aims i nclude: (1) studying pallidal immediate early gene response to local infusions of D2-, D3-, and D4-preferring DA antagonists and characterizing D3 mRNA-expressing neurons according to their axonal projections, their PPE mRNA, and their immediate early gene response; (2) investigating interactions between subthalamic nucleus activation or inactivation and local pallidal effects of D2-class agonists or antagonists, (3) determining the expression of GAD67 mRNA within identified populations of GP neurons after DA cell injury or DA antagonist treatment to determine cell type-specific regulation of this transmitter-related late gene; and (4) testing the hypothesis that the pallidostriatal axon collaterals influence gene expression within striatal PV interneurons. This last aim uses a paradigm of cortically-driven c-fos induction in striatal PV and enkephalin neurons to investigate whether intrapallidal GABA-A or D2 receptor drug infusions can suppress or enhance c-fos induction within these striatal interneuron and projection neuron populations. These experiments should substantially advance our understanding of (1) the phenotypic diversity of GP neurons, and (2) the actions of DA in the globus pallidus. The proposed research focuses on the GP neurons that contain D2 or D3 mRNA and/or are altered by the administration of DA antagonists. The significance of this work derives both from its relevance to basal ganglia disorders such as Parkinson's disease and also because of its potential to elucidate the significance of the pallidostriatal circuitry.
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