This project will investigate the contribution of aberrant motor learning to the motor deficits associated with Parkinson's disease (PD) and the role that correcting aberrant learning plays in treatment efficacy. Though human studies have demonstrated motor learning impairments in PD, the extent and nature of learning impairments and their relationship to disease progression and treatment have been controversial. This project proposes the hypothesis that dopamine denervation induces abnormal corticostriatal plasticity, as has been observed in animal models, that results in aberrant, inappropriate inhibitory learning in the dorsolateral striatum that impedes rather than optimizes motor performance. As a consequence, under decreased dopamine, aberrant motor learning will gradually replace the established learning (encoded as synaptic strengths) that enables effective movement with learning and synaptic weights that disable movement. In contrast, dopamine replacement therapy corrects this aberrant learning and re-enables the optimization function associated with the dorsolateral striatum and facilitates movement. The human studies in this project will utilize a strategy of testing subjects at home using two novel iPad based task in order to conduct extended testing across time and to test subjects during different phases in the daily pharmacokinetic fluctuations in their daily medication regimen (i.e., peak vs. trough medication). The intent is to clearly distinguish the effects of these fluctuations on motor learning and performance and to assess the contribution of the motor learning component, independent of the direct performance effects of medication. Knowledge gained from these studies will contribute to greater understanding of (a) the role of learning mechanisms in the core symptoms and progression of PD and (b) the contribution of learning to the therapeutic efficacy of current treatments. Establishing a role for aberrant learning in the pathophysiology and treatment of PD will open new avenues for the development novel pharmaceuticals targeting signaling pathways that underlie aberrant learning. Finally, as rehabilitative therapies are ultimately based on practice, they are fundamentally based on learning. Understanding how practice-based learning may be optimized could potentially provide insight to enhance strategies for rehabilitation treatments.
The primary goal of this project is to assess the role of abnormal motor learning in Parkinson's disease and its contribution to motor performance deficits associated with PD. Understanding the role of aberrant learning in clinical symptoms may offer alternative targets for drug development and provide insight to improve therapeutic strategies with existing medications.
|Xia, Jianxun; Meyers, Allison M; Beeler, Jeff A (2017) Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses. Neuropsychopharmacology 42:2314-2324|