The role of the centromedian and pedunculopontine nuclei in motor function during naïve, parkinsonian and DBS conditions

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ABSTRACT Parkinson's Disease (PD) is the second most common neurodegenerative disease and affects up to 3% of the population in industrialized countries. Patients in the advanced stages of the disease can partake in different therapies, including deep brain stimulation (DBS). This particular therapy can ameliorate symptoms of tremor, bradykinesia, akinesia and rigidity of the limbs, however, there is an unmet need to increase the effectiveness of this therapy on gait dysfunction, a symptom of the disease that can drastically reduce the quality-of-life of patients. Recently, there has been interest in novel targets for deep brain stimulation in order to address this deficit. Two brain areas, the mesencephalic locomotor region (MLR) and the centromedian- parafascicular nucleus of the thalamus (CM-Pf) have been identified as involved in initiation, halting or modulating locomotion and selecting new motor actions in the context of changing sensory environments, respectively, and clinical trials have been conducted with mixed results. While the roles of these nuclei in motor function have been illustrated in the literature, it is unknown how the signaling of these nuclei change from a naïve to parkinsonian state and how DBS in the basal ganglia further perturbs their firing. The overall goal of this project is to understand the firing changes in these structures after parkinsonian onset in a non- human primate MPTP-model of PD and how DBS targeting traditional DBS targets, such as the subthalamic nucleus and globus pallidus internus, exacerbates or facilitates their signaling. Aim 1 of this proposal will be to record from the MLR during naturalistic gait and characterize firing changes and behavioral changes seen with parkinsonism and different DBS stimulation. Aim 2 will include the same methods, but in CM, and furthermore, it will include studying the circuit dynamics of MLR-CM through simultaneous recording in these structures. Preliminary data has validated the behavioral paradigm and changes in gait variables can be seen after DBS application. The results of this proposal will elucidate the mechanisms of the MLR and CM in normal gait function and the electrophysiological changes that occur after parkinsonism and DBS onset. This will provide much-needed information in these structures that cannot be gleaned from PD patients in the clinic and, furthermore, it will provide clues on how to improve current DBS therapy.