Dissecting basal ganglia circuit mechanisms underlying instrumental learning

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SUMMARY The basal ganglia (BG) are critical for motor control and instrumental learning. In particular, classic lesion studies have demonstrated that different regions of the striatum, the major BG input nucleus, are associated with distinct aspects of action selection and learning: the dorsomedial striatum is responsible for action-outcome learning and action selection based on outcome expectancy, whereas the dorsolateral striatum is responsible for the development of habits and behavioral automaticity. There is also growing consensus that maladaptive instrumental learning and performance contribute to numerous disorders such as addiction and schizophrenia that also implicate the BG. Although recent studies have begun to show a key role for corticostriatal plasticity in instrumental learning and habit formation, the detailed circuit mechanisms remain unclear. The overall aim of this proposal is to determine the circuit mechanisms in the BG underlying instrumental learning and performance. We will use a integrative approach, combining intersectional strategies to target defined neuronal populations and pathways and precise behavioral assays to quantify learning and behavior. To monitor and manipulate neural activity of defined cell populations, we will use in vivo calcium imaging, optogenetics, and transgenic mouse lines that make it possible to target the key neuronal populations and pathways in the BG. To assess the content of learning and quantify behavior continuously, we will use established behavioral assays from instrumental conditioning combined with 3D motion capture. Four aims are proposed. Aims 1 and 2 will determine the contribution of the direct (striatonigral) pathway and indirect (striatopallidal) pathways in different striatal regions to instrumental learning and performance. Aims 3-4 will determine the contributions of distinct corticostriatal pathways (intratelencephalic and pyramidal tract) to instrumental learning and performance. Results from proposed research can shed light on the neural mechanisms underlying goal- directed actions and habit formation, and how dysfunctions in the BG circuit mechanisms can result in key symptoms of multiple psychiatric and neurological disorders.