Christopher H. Donahue, Ph.D - US grants

? DESCRIPTION (provided by applicant): Dysfunction of the basal ganglia has been associated with motor and cognitive deficits across a wide range of neurological and psychiatric disorders, including Parkinson's disease, obsessive compulsive disorder, and attention deficit disorder. The basal ganglia comprise two major circuits, the direct and indirect pathways, which are thought to have opposing effects on movement. While many previous studies examined how the balance of activity in these circuits shapes motor control, relatively little is known about their contributions to higher cognitive function. Recent work highlighted the basal ganglia's central role in reinforcement learning and decision-making and suggested that dysfunction in the decision process may underlie some of the cognitive deficits that are observed in basal ganglia disorders. One of the greatest barriers to progress is the fact that the direct and indirect pathwa projection neurons are intermingled and electrophysiologically indistinguishable, making it extremely difficult to study the functional role of these circuits in behaving animals. With the development of optogenetics, light-activated ion channels can be targeted to genetically defined neuronal populations, making it feasible to dissect the function of these circuits in behaving animals. Our goal is to define the pathway-specific mechanisms of decision making and reinforcement learning in the basal ganglia by applying advanced optical and electrophysiological methods. Recent studies using these tools revealed that the direct pathway plays a selective role in learning from reinforcement, and the indirect pathway plays a role in learning from punishment. This may have profound implications for drug addiction and depression, since selective deficits in learning from positive and negative outcomes may underlie some of the symptoms associated with these disorders. We will build on this work by investigating how pathway-specific neuronal activity and plasticity plays a role in learning in a dynamic decision-making task. With our findings we hope to further understand the basic circuit mechanisms underlying reinforcement learning, and to shed light on the higher cognitive deficits observed in basal ganglia disorders.

PROJECT SUMMARY ABSTRACT Motivational deficits accompany a wide range of neurological and psychiatric disorders including Parkinson's Disease, Depression, and Schizophrenia. To gain a more complete understanding of these motivational deficits, it is necessary to the study brain circuitry that stands at the interface of motivation and action. Motivation and movement are intimately linked. In healthy animals, decision costs and benefits have been shown to decrease or increase the speed or vigor of action execution. The basal ganglia and dopaminergic neurons in the midbrain have been implicated in this process, but their precise roles are still unclear. The goal of this study is to examine how costs and benefits are integrated in subcortical dopamine and basal ganglia circuitry, and to understand how integration of these motivational variables shape motor responses. The basal ganglia is comprised of two major circuits, the direct and indirect pathways, which are thought to have opposing effects on movement. However, it is still not well known how these circuits encode positive and negative motivational information and how this may modulate motor responses. In addition, we know little about how dopaminergic innervation in different regions of the basal ganglia contribute to this process. To gain a better understanding of the circuit mechanisms underlying motivated behavior, we developed a novel set of tasks for mice that allows for quantitative dissection of the effects of effort and reward magnitude on response vigor. We will employ the use of the latest cutting-edge techniques for recording single-cell activity from identified cell types and for recording the activity of anatomically-defined projection targets to determine how dopaminergic and basal ganglia circuits transform motivational variables into action. My long-term career goal is to study the computational role of circuits involved in learning and decision making, with a specific interest in how information processing is impaired in psychiatric disorders. The Gladstone Institutes and broader environment at UCSF provide a unique emphasis on both translational and basic science approaches to understanding psychiatric disease. I plan to take advantage of the full range of career development opportunities that are offered for young investigators. These include speaking opportunities at internal retreats, taking scientific leadership and management courses, and attending seminars related to grant writing and mentoring that are specifically tailored for postdoctoral scholars seeking research independence.