UCSF

The basal ganglia are a group of interconnected, subcortical nuclei that mediate a wide array of behavioral functions. The primary input nucleus of the basal ganglia, the striatum, is a region implicated in behaviors ranging from motor control, reward learning, decision making, habit formation, to social interaction. How these diverse behavioral functions map onto various striatal cell types and circuit connections remains a major question within the basal ganglia field. Classical models of striatal circuitry that divide output neurons into populations called the direct and indirect pathways have proven extremely useful in understanding how the striatum mediates function such as movement initiation and behavioral reinforcement. Furthermore, such models have played a foundational role in understanding the pathophysiology of disorders linked to the basal ganglia, such as Parkinson’s disease and Huntington’s disease. These models, however, struggle to explain how the striatum mediates other well-established functions, and can even lead to contradictory predictions of behavior in other types of disease. To explore how alternative models of striatal circuitry might be used to fill in these gaps, we took two parallel approaches. First, we investigated whether striosome and matrix neurons—an alternative model for dividing striatal neurons—differ in the electrophysiological properties and synaptic connectivity. Early anatomical work suggested that striosome and matrix may represent two parallel circuits, relaying limbic and motor information to downstream nuclei, respectively. However, recent attempts to genetically isolate these population cast doubt upon these earlier findings. Using a developmental approach to isolate striosome and matrix neurons, we found that these population receive differing cortical input consistent with early anatomical studies. Furthermore, we determined that striosome and matrix differ in how they process cortical input and where they project information within the midbrain. Next, we investigated how changes in striatal activity relate to a disorder called tardive dyskinesia. Resulting from chronic administration of antipsychotic medications, tardive dyskinesia is characterized by involuntary movements of the face, mouth, and tongue that can be irreversible once developed. Several lines of evidence implicate a causal role for the striatum in tardive dyskinesia, and classical models predict that excessive involuntary movements may be driven by hypoactivity of indirect pathway neurons. Unfortunately, little is known about how striatal activity changes over the course of the disease. To address this gap in knowledge, we used a combination of genetic manipulations, in vivo recordings, and slice electrophysiology to determine how striatal activity changes of the development of TD. Currently in progress, our findings indicate that alternative changes outside that predicted by classical models of basal ganglia function likely underlie TD. Mainly, we find that tardive dyskinesia may arise as the result of changes in dopaminergic signaling that affect both direct and indirect pathway neurons. In combination, the results of these projects demonstrate that additional models of striatal circuitry are necessary to describe its function, and additionally identify new cellular populations on which to build such models.