PROJECT SUMMARY/ABSTRACT Nearly one million people in the USA are living with Parkinson’s disease (PD). It is a disabling neurodegenerative disease that causes progressive difficulty with movement, however equally debilitating is the progressive impairment of motivation that is experienced by most patients. Patients struggle to initiate things they want to do (apathy) and can also have difficulty suppressing things that they do not want to do (impulsivity) – symptoms that are defined here as impaired motivated behavior. There are no effective treatments for these symptoms and indeed, some PD medications can make them worse. It is urgent to understand how these symptoms originate in the brain in order develop new and effective treatments. The proposed research uses precise optogenetic and physiological tools available in mice to characterize the brain networks responsible for these symptoms of impaired motivation. These tools allow modulation and monitoring of brain activity at millisecond timescales at the level of specific cell-types (neurons) and groups of different neurons (circuits). This provides a powerful approach to determine how specific neurons and circuits in the brain cause changes in behavior. We know that patients living with PD have abnormal brain activity in an area deep in the brain known as the globus pallidus (GPe). Therefore, this research proposes to use a high temporal resolution behavior task to investigate the role of GPe in motivated behavior. In this task, normal mice quickly learn to lick a water spout on hearing a cue that signals water is about to be delivered (Go cue), and restrain licking after another cue signals that water is not forthcoming (NoGo cue). When the activity of neurons in the GPe is increased, mice become more impulsive - specifically, they have difficulty restraining themselves from licking the spout after the NoGo cue. This suggests that the GPe is a key brain region involved in motivated behavior. However, it is not known which cells or circuits in the GPe are responsible for driving this behavior, nor how they are disrupted in PD. The proposed research will manipulate specific neural populations (Specific Aim 1) and neural circuits (Specific Aim 2) in the GPe to determine how they contribute to motivated behavior in healthy mice. These findings will be translated to a mouse model of PD (Specific Aim 3) to enable the design of cell type- and circuit-specific interventions to rescue abnormal neural activity patterns and behaviors seen in the PD model (Specific Aim 3). The long-term objective of this work is to provide a framework to understand the neural circuit abnormalities underlying the diverse and challenging symptoms experienced by patients with PD and other neuropsychiatric disorders, to promote the development of more effective and specific pharmaceutical and surgical therapies.

PROJECT NARRATIVE Parkinson’s disease affects millions of individuals worldwide and causes progressive abnormalities in movement as well as changes in motivation such as apathy and impulsivity. The goal of this research is to understand the brain mechanisms underlying these impairments in motivation by probing brain networks at high resolution. This work may lead to new and precise strategies to treat these non-motor symptoms of Parkinson’s disease.