Physiology and function of basal ganglia subcircuits in sequence learning

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Project Summary: It is a fundamental challenge for organisms to chunk a series of actions into sequence and acquire a large action repertoire for survival and reproduction. The organization of behavior into action sequences, and how it is realized in the nervous system has been a central question in neuroscience. Dysfunctions of the cortico- basal ganglia circuits are associated with impaired sequential behavior in many neurological and psychiatric diseases including Parkinson's disease, Huntington's disease and Obsessive-Compulsive Disorder (OCD). The striatum is the major input nuclei of the basal ganglia, which receive sensory, motor and cognitive information across cerebral cortex. Current model of basal ganglia suggested that there are two major neural subcircuits, called the “direct” and “indirect” pathways, for selecting and inhibiting actions respectively. Nevertheless, this over-simplified opponent view has been challenged by recent work. In addition, besides the direct and indirect pathways, it has been known for a long time that there are two compartments in the striatum, termed the patch (striosome) and matrix, which can be defined by the expression of immune- histochemical markers like mu-opioid receptors. Important functional differences have been suggested between the patch and matrix compartments based on the observations in human basal ganglia disorders. However, the functional understanding of the patch vs. matrix compartment and their roles in controlling actions are largely missing at this moment. Conventional anatomical and electrophysiological methods are ill- suited to address these questions because these compartments are irregular in shape and different cell types are mixed in distribution, making the precise lesion or physiological studies rather difficult if not impossible. This project will take advantage of a series of cutting-edge neurotechniques including in vivo recording with cell type identification, optogenetics, fast-scan cyclic voltammetry, viral tracing and miniscope imaging, combined with quantitative behavior and computational modeling, to dissect the role of specific striatal compartments in action sequence learning and execution, in comparison with the function of striatal pathways. Furthermore, it aims to systemically investigate the physiology and function of different striatal cell types and their interaction with specific cortical inputs during behavior. Firstly, a novel action sequence task in mice with quantitative behavior will be developed to determine the striatal involvement in action sequences at molecular and cellular levels. It is then followed by in vivo electro-chemical, electrophysiological and optogenetic experiments to define the activity and contribution of various striatal cell types to sequence execution. Finally modified rabies virus will be utilized to define cell-type-specific cortico-striatal pathways, and dissect the physiology and function of these pathways during behavior with advanced imaging and optogenetics. Together this project will advance the understanding of the function and logic of specific corticostriatal circuitry for both action sequence learning and execution.