Acute and Chronic Dopaminergic Modulation of Striatal Circuitry and Function in Health and Disease

The basal ganglia are an evolutionarily conserved set of nuclei that are crucial for context-dependent learning and selection of appropriate behavioral outputs. The striatum is considered the input nucleus of the basal ganglia because it not only receives the bulk of excitatory synaptic drive from sources outside the basal ganglia, but also contains two populations of medium spiny neurons that give rise to the direct and indirect basal ganglia pathways. The activity of direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) is sufficient to promote or suppress behavioral output, respectively. Changes in synaptic strength at excitatory inputs to MSNs are thought to underlie context-dependent learning, whereas the acute modulation of MSN intrinsic excitability affects motivation or vigor of an ongoing behavior. Previous research has revealed that the neuromodulator dopamine appears to be in a unique position to exert both acute and chronic modulatory effects over MSNs and their excitatory inputs. The differential expression of Gs-coupled D1 and Gi-coupled D2 receptors by dMSNs and iMSNs, respectively, results in opposing changes in direct and indirect pathway function with changes in striatal dopamine levels. However, previous technical limitations have restricted the study of dopamine's acute actions in the striatum and the long-term effects of dopamine on MSN subtypes and excitatory inputs of distinct origins. Here we use recently developed optogenetic and chemogenetic techniques combined with behavior and ex vivo brain slice electrophysiology to study the mechanisms of acute and chronic dopamine signaling in MSNs and their excitatory inputs. In Chapter One, we review the evidence for the dual-pathway model of basal ganglia function and its modulation by dopamine in the context of controlling behavioral output. In Chapter Two, we perform an electrophysiological comparison of common optogenetic proteins to determine the optimal tool for our experiments. We then use optogenetic control of dopamine release to show specific modulation of dMSN intrinsic excitability and D1-mediated invigoration of behavior in Chapter Three. In Chapter Four, we provide evidence that the chronic loss of dopamine in Parkinson's disease results in a reorganization of the thalamostriatal system that has negative outcomes on motor control. Finally, we discuss the overarching implications of these findings in the context of basal ganglia function in health and disease in Chapter Five. These findings not only represent a long overdue reevaluation of the assumptions surrounding the role of dopamine in striatal function, but also provide new testable hypotheses addressing the cellular and synaptic bases of an evolutionarily conserved system for the dynamic regulation of ethologically relevant behaviors