Genetic and physiological dissection of the circuit mechanisms in the striatum

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DESCRIPTION (provided by applicant): The basal ganglia play essential roles in behavior, including movement control and learning. The striatum is the primary input station of the basal ganglia where it processes and sorts information from the cortical areas and the thalamus into downstream pathways. Defects in striatal function are responsible for the cognitive and behavioral deficits observed in neuropsychiatric disorders, including Parkinson's disease, obsessive-compulsive disorder, and drug addiction. Great strides have been made toward understanding striatal function at two levels. First, at the behavioral level, much has been learned about the crucial roles of the striatum in action selection and execution. Second, at the single cell level, the molecular and physiological properties of individual striatal neurons as wel as their overall roles in behaviors have been examined extensively. However, our understanding of the circuit mechanisms that bridge striatal behavioral functions and the cellular properties of individual striatal neurons remains in its infancy. The neuronal circuitry in other brain regions i often organized around functional subdivisions (e.g., cortical columns) and cell types (e.g., layer 5A and 5B cortical pyramidal neurons). Although the striatum has been grossly divided into three divisions according to their functions and it is known to consist of at least five major neuronal subtypes, its functional subdivision-dependent and cell-type- specific microcircuits are not fully understood. Herein, we propose to fill this gap by examining the striatal subdivision-dependent and cell-type-specific microcircuits in mice, a genetically tractable system required for unambiguously defining cell types. We will do so by investigating the organization of the thalamostriatal projections, which consist of one of the two major excitatory inputs to the striatum, at both anatomical and functional levels. We will use an innovative combination of anatomical tracing, imaging, genetic, optogenetic, and physiological approaches. We expect that our study will provide a complete functional thalamostriatal wiring diagram and uncover the principles behind how information from the thalamus is segregated into the downstream cell-type-specific and functional subdivision-specific circuits. Our acquired knowledge will synergize with current knowledge regarding the striatum at the levels of behavior and single-neuron properties to advance our understanding of how the striatum functions and how the thalamus contributes to the function of the basal ganglia as a source of upstream input. This knowledge will also pave the way for future studies of striatal function and pathology by providing a benchmark for circuit connectivity under normal conditions.