UC San Diego

Action sequences form the functional basis of animal and human behavior and are compromised in disorders of movement control such as Parkinson’s and Huntington’s disease. While ongoing research implicates basal ganglia circuitry as critical for action selection, little is known about how the modulation and refinement of cortico-basal ganglia circuits through synaptic plasticity contributes to sequence learning; furthermore, we still do not fully understand how the direct and indirect pathways of the basal ganglia function together to control the execution of well-learned sequences. Finally, the way in which actions are behaviorally organized into robust movement repertoires remains poorly understood. A debate regarding whether action sequences are arranged in a chain, activated in series by stimulus-response events or instead in a hierarchy containing different levels of control remains unresolved. In this dissertation, I begin by reviewing the literature pertaining to molecular and circuit mechanisms underlying sequence learning and performance as well as the different theories pertaining to sequence organization. Using a combination of genetic, electrophysiological, and optogenetic tools in a novel heterogeneous action sequence task, I demonstrate that the basal ganglia direct and indirect pathways mediate the initiation of the sequence and the switch between distinct actions of the sequence, respectively. Rather than working in opposition as classically thought, these findings indicate that basal ganglia pathways work cooperatively to control the execution of a well-learned sequence. Furthermore, I use these manipulations to demonstrate support for a hierarchical, rather than serial, organization of action sequences. I then use the same action sequence paradigm to investigate the molecular mechanisms underlying sequence learning. Corticostriatal plasticity has been shown to rely on a whole host of striatal receptors; yet, the necessity of these different receptor types for sequence learning has not been causally tested. Taking advantage of mouse genetics, I developed many different mouse lines lacking particular receptors within well-defined basal ganglia populations and assessed these animals’ ability to learn our heterogeneous action sequence. I demonstrate that striatal output as well as the expression of dopamine D1 and D2 receptors on striatal neurons are the key mediators of sequence learning. Together, this work provides a comprehensive evaluation of how basal ganglia circuits contribute to the learning and execution of an complex action sequence and new insight into the behavioral organization of action repertoires.