Dynamic Dopamine Modulation of Striato-Cortical Circuits in Cognition: Converging Neuropsychological, Psychopharmacological and Computational Studies

Date The final copy of this thesis has been examined by the signatories, and we find that both the content and the form meet acceptable presentation standards of scholarly work in the above mentioned discipline. How do we produce complex motor sequences? To what extent do we learn from the positive versus negative consequences of our decisions? How do we maintain task-relevant information in working memory while ignoring distracting information? This dissertation provides a mechanistic framework that explores how these seemingly unrelated processes recruit remarkably similar neural circuits linking the basal ganglia (BG) with frontal cortex. Drawing from neuroanatomical and biochemical considerations, this framework suggests that the BG facilitate or suppress cortical " actions " (e.g., motor responses and working memory updating) via separate Go and NoGo pathways projecting to frontal cortex, and that the relative balance of these pathways is dynamically modulated by dopamine (DA). Transient DA bursts and dips during positive and negative reinforcement support Go and NoGo learning via D1 and D2 receptors, respectively. Computational neural network models instantiate key biological properties and provide insight into the underlying role of BG/DA interactions during the learning and execution of cognitive tasks. These models account for complex medication-dependent cognitive deficits in Parkinson's disease, and make simple predictions for the underlying source of these deficits, emphasizing the importance of the dynamic range of DA signals. These predictions have been subsequently confirmed in medicated and non-medicated Parkinson's patients and in healthy individuals under pharmacologically-induced DA manipulation. In all of these studies, elevated levels of phasic DA release led to greater Go learning from positive outcomes of decisions, whereas diminished DA levels led to better NoGo learning to avoid negative outcomes. Tonic DA stimulation led to more overall Go responding. These effects extended to higher level cognitive function: tonic DA stimulation led to more overall working memory updating and concomitant distractibility, whereas enhanced phasic DA release led to greater selective updating for task-relevant (i.e., " positively-valenced ") information, but difficulty in ignoring this information in a subsequent set-shift. Drug effects also interacted with baseline working memory span. Taken together, these results provide substantial support for a unified account of the role of DA in modulating cognitive processes that depend on the basal ganglia. iv Acknowledgements This dissertation would have not been possible without the support of many people and institutions throughout the last several years. First and foremost, I want to thank …