Rationale: There is no cure for Parkinson's disease (PD). Available data show that service in active theater may place military personnel at a high risk for PD. In fact, post 9/11 Veterans face a disproportionate risk for developing PD in their lifetime. Gold standard medications for PD increase dopamine levels and are prescribed to alleviate motor impairments (the hallmark characteristic of PD). The problem with PD medications is that over time, they often become less effective and produce an increased number of adverse side-effects making them intolerable for many patients. Clinical data suggest that patients with PD may receive benefit with non-medication treatments such as exercise to improve motor functioning without unwanted medication side-effects. However, neural mechanisms (brain chemicals, effects on brain tissue, and transmission of chemicals via pathways) associated with exercise-related motor functioning and improvement remain uncertain and are critically important to investigate.

Here, our objective is to identify the impact that exercise has on mechanisms involved in modulating dopamine as well as dopamine synthesis by investigating the role of the substantia nigra (brain area), its neurons and pathways (nigrostriatal), and the brain protein that synthesizes dopamine (tyrosine hydroxylase) as well as modulates dopamine release (glutamate and growth factor). We believe that protecting levels of tyrosine hydroxylase in the substantia nigra is a critical component of preserving whatever remaining capabilities of locomotor function PD patients may have. This project will rigorously evaluate this hypothesis and aligns with the DoD's award focus area of investigating the "Biological mechanisms of impact from exercise on neurodegeneration in Parkinson's disease."

The primary aim is to investigate neural mechanisms impacted by exercise-induced motor recovery after the onset of motor impairment. Using rat models well-established in the Salvatore lab, we will demonstrate that the substantia nigra, nigrostriatal neurons and pathways, tyrosine hydroxylase, dopamine, and glutamate are synergistic in mediating exercise effects to reverse motor decline and increase exercise-mediated recovery in both a toxin and a rat PD genetic model.

The clinical application is to use the results of this study to help researchers better understand how these mechanisms are involved in exercise-induced recovery of motor functioning in PD rat models that will be translatable to PD patients at all disease stages.

The impact of this scientific inquiry will broaden the knowledge base with clinically relevant insights on the trajectory of motor functioning in PD animal models, and increase our understanding about the molecular basis of exercise as a mitigating factor to prevent motor decline prophylactically and/or reverse existing motor impairment in Veterans and civilian patients with PD. With exercise as a treatment modality, the timeline of application of our results is an immediate patient-related outcome as exercise is a holistic therapeutic strategy available to treating clinicians that avoids the decades-old burden of waiting for FDA approval for a new investigational drug. However, the identification of the neurobiological mechanism associated with exercise-related motor improvements will also allow us to use a targeted approach toward developing genetic models of motor recovery or function. The genetic model results will inform researchers concerning the development of precision medicine without the adverse side-effects for PD patients who are unable to exercise. In this case, the timeline of applying these results translated into clinical trials is expected to be roughly 9 to 10 years.