Improved strategies are needed to treat movement disorders, such as Parkinson?s disease (PD), which debilitates more than 10 million people worldwide. PD, in addition to many other neurological disorders, centrally involve dopamine neurochemical dysregulation. Current treatment for PD involves replenishing dopamine through systemic L-Dopa administration. These treatments, however, display limited efficacy and can have detrimental side-effects. The neurochemical pathophysiology is not well understood in these disorders. This limited understanding hinders development of better therapies. It has been shown that dopamine is dysregulated in a spatially heterogeneous pattern in PD, and the site-specific dopamine operations have specific roles in the generation of pathology. The goal of this proposal is to dynamically map the dopamine signals that mediate specific PD-implicated motor and mood behaviors in nonhuman primates. New arrayed neurochemical probes have been developed to permit dopamine mapping in rodents. We have recently confirmed our ability to measure multi-site dopamine neurochemicals, chronically, in the nonhuman primate, using fast scan cyclic voltammetry (FSCV) electrochemical recording to measure dopamine at sub-second timescales.
Aim 1 of this proposal is to chart the spatially-distributed dopamine signaling in the striatum of rats with receptor-selective pharmacological modulation and post-hoc chemically labeled co- localization of measured sites. An expected outcome of this aim is a classification of dopamine dynamics in terms of regional and structural striatal domains.
Aim 2 of this proposal is to measure dopamine across striatal sites in the task performing nonhuman primate to correlate site-specific dopamine with metrics of behaviors implicated in PD. The results from this aim will elucidate how dopamine signals mediate key movement and mood behavioral processes that are degraded in PD, and how these signals are distributed across the striatum. A functional map of dopamine could help inform better treatment strategies based on current symptomatic diagnostic criteria.
Aim 3 involves measuring and mapping the interaction between two hallmarks of PD, dopamine and beta-band local field potential (LFP), using acute and chronic models of PD in rodents and nonhuman primates. The concurrent dopamine and LFP measurements will provide more quantitative markers of pathology and enable improved strategies for diagnosing and treating PD. The proposed work for Aims 1 and 2 will be performed during the K99 mentored stage, during which I will continue my training in primate neurophysiology, surgery, and immunohistochemistry. These trainings will be pivotal in transitioning to independence in the R00 independent investigator stage, during which Aim 3 will be executed.
Numerous debilitating neurological disorders, such as Parkinson?s disease and many other movement and mood disorders, are rooted in the dysregulation of dopamine neurochemicals, for which there is insufficient understanding and limitation in investigative techniques. Improved diagnostics and therapies are urgently needed for treating patients afflicted by these disorders. We propose dynamic neurochemical mapping strategies to elucidate the site-specific dopamine operations of the striatum and basal ganglia networks, as implicated in pathology.
