The role of direct and indirect pathway activity in striatal learning

J. David Gladstone Institutes, San Francisco CA

Investigators

Abstract

DESCRIPTION (provided by applicant): The basal ganglia are a set of brain structures that contribute to many functions, including associative and reward learning. Unfortunately, this brain system is susceptible to many diseases. One example is Parkinson's Disease (PD), characterized by debilitating motor and cognitive dysfunction. This disease affects approximately 1.5 million Americans, and this number is projected to increase as our elderly population grows. Despite decades of research, there are no effective long term treatments or cures for any of these major diseases of the basal ganglia. In addition, many treatments targeted at improving motor deficits do not address the deficits in what are called executive function: difficulties with multitasking, experience-dependent decision-making and behavioral flexibility. In order to treat the broad spectrum of symptoms associated with PD, understanding the role of basal ganglia circuitry in learning and behavioral flexibility is important. We propose to combine novel optogenetic tools with chronic electrophysiology to interrogate basal ganglia circuitry in awake mice with unprecedented access and control. Our overarching goal is to better understand the basal ganglia and its role in learning and behavioral flexibility. Although the basal ganglia consist of many brain structures, this proposal focuses on the striatum, the major input nuclei of the basal ganglia. The striatum has two major populations of output neurons: the direct and indirect pathway neurons. The direct pathway neurons facilitate movement, while the indirect pathway neurons inhibit movement. In addition, new research indicates that the direct pathway is involved in the formation of rewarding associations, while the indirect pathway is involved in aversive associations. Despite knowledge of the function of these two neural populations, the role of these separate populations of cells in associative and reward learning is not well understood. In this proposal, we will use novel techniques to record from striatal neurons in awake mice, characterize the activity of each population during associative and reward learning, and manipulate the firing of these neurons to study the role of neuronal activity in learning. With this knowledge, we hope to better understand how dysfunction of the circuit can lead to cognitive problems associated with diseases of the basal ganglia.