Effects of Ketamine on Neural Signatures of Parkinson's Disease and a Novel String-Pulling Behavior Quantification System

Abstract

The first part of the thesis reviews my investigations into the neural mechanisms underlying Parkinson’s disease (PD) and levodopa-induced dyskinesia (LID) and their treatment with levodopa and ketamine. The second part of the thesis summarizes our group’s development of a novel string-pulling behavior for assessing motor function in rodents.Part 1: Parkinson’s disease (PD) is a debilitating neurodegenerative disorder with motor and cognitive deficits. While levodopa is the leading treatment for PD, in many individuals long-term administration leads to Levodopa-Induced Dyskinesias (LID), which are uncontrollable involuntary movements. These side-effects are as debilitating as PD. A common neurophysiological feature of LID is the emergence of 80-Hz brain oscillations in the motor cortex. Ketamine, an FDA approved drug used in treating depression among other disorders and has been shown to alleviate LID symptoms in an animal model of LID. We used a unilateral 6-hydroxydopamine-lesion PD rat model to investigate the neural systems-level mechanisms of the effects of ketamine on LID. We found that ketamine administration was followed by reduced 80-Hz LID oscillations, increased gamma oscillations (~50 Hz), and reduced burst firing in individual neurons. One interpretation of these results is that ketamine triggers gamma activity that competes with and consequently reduces 80 Hz activity. Part 2: The development of complex motor tasks and behavioral analysis is crucial for understanding the workings of motor neurons and study motor deficits. We developed a novel behavior quantification system for a bi-manual string-pulling task. The system has a unique “infinite loop” and the capacity to simultaneous record neural activity. This integrated string-pulling system allows for investigation into the neural systems of motor behavior in healthy and disease populations.