Investigation of Pallidal Neurons in Motor Inhibition

The long-term goal of this project is to deepen our understanding of how the external globus pallidus (GPe) within the basal ganglia controls movement and how it goes awry in Parkinson’s disease (PD). Despite compelling evidence that the GPe plays a critical role in regulating motor activity, its neuronal composition has been poorly defined. As the neurons that encompass the GPe are heterogeneous, understanding how the activity of the GPe is regulated in behavioral and disease contexts has posed a challenge. Through a series of investigations during the last funding cycle, we surveyed the molecular landscape of the mouse GPe. By characterizing a number of driver and reporter lines, we have now established a near-complete neuron taxonomy of the GPe. Using these newly available genetic tools in conjunction with cell- and circuit-specific approaches, we began to understand how GPe neuron subtypes control full-body movements. Through a combination of in vivo and ex vivo approaches, we will examine the activity dynamics of GPe neuron subtypes and their regulation of their synaptic partners to clarify the mechanisms involved. These experiments will provide new information about how motor inhibition is executed by the GPe and the basal ganglia as a whole. Using a well-established chronic model of PD, we will provide unprecedented insights into how alterations in these processes underlie hypokinetic symptoms of PD. The yielded knowledge will not only inform the processes underlying motor (dys)function but will also help develop circuit interventions that target the hypokinetic symptoms of PD.