Genetic and physiological dissection of the circuit mechanisms in the striatum

描述（申请人提供）：基底神经节在行为，包括运动控制和学习中起重要作用。纹状体是基底神经节的主要输入站，它处理和分类来自皮质区和丘脑的信息到下游通路。纹状体功能缺陷是神经精神疾病（包括帕金森病、强迫症和药物成瘾）中观察到的认知和行为缺陷的原因。在了解纹状体功能的两个层面上已经取得了巨大的进步。首先，在行为层面，我们已经了解到纹状体在行动选择和执行中的重要作用。其次，在单细胞水平上，纹状体神经元的分子和生理特性以及它们在行为中的整体作用已经得到了广泛的研究。然而，我们对连接纹状体行为功能和单个纹状体神经元细胞特性的电路机制的理解仍处于起步阶段。大脑其他区域的神经回路通常是围绕功能细分（如皮质柱）和细胞类型（如层）来组织的

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.