The overall goal of this program project is to continue our investigation of the function of the basal ganglia using a variety of techniques and preparations by a closely linked team of principal investigators (working together for more than 10 years) representing the fields of morphology, electrophysiology, pharmacology, and molecular biology. Human and animal studies have shown that parkinsonism (PK) results from degeneration of the nigrostriatal dopaminergic neurons. In PK patients and in primate models of PK, electrical activity of globus pallidus and sub-thalamic neurons is abnormal. They exhibit synchronous, rhythmic oscillations in spiking. It has been hypothesized that his abnormal activity is responsible for the motor symptoms in Parkinson's disease (PD) and serve as the rational for surgical intervention as a treatment for elimination of the motor symptoms. In this renewal application, we have reduced our projects to four from the original six to dedicate our effort to understand the underlying mechanisms for the changes in neuronal activities in the basal ganglia brought about by dopamine denervation. Two cores (administrative and central facilities) will be cooperatively shared by investigators for the effective and efficient use of administrative staff, space and equipment. We plan to investigate the emergence of oscillatory and synchronous activity in the dopamine denervated brain in: Project (Cellular and Molecular Determinants of Neuronal Rhythmicity and Synchrony)- to characterize the cellular/molecular determinants responsible in GP/EP neurons in acutely isolated preparation; Project (The Synchronized Rhythmic Activity of the Pallidum)-electrical membrane, synaptic and morphological determinants responsible in GP/EP in slice and in vivo preparation; Project (Rhythmogenesis in the Subthalamic Nucleus)- electrical membrane and morphological determinants responsible in STN neurons in slice preparation; and Project (Rhythmicity and Synchrony in the Pallido-Subthalamic Recurrent Feedback Loop)-to characterize the synaptic interactive determinants between GP and STN neurons responsible for rhythmic oscillation and the role of dopamine for this phenomena in organotypic cultured preparation.
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