Genetic and physiological dissection of the circuit mechanisms in the striatum

描述(申请人提供)：基底节在行为中起着重要的作用，包括运动控制和学习。纹状体是基底神经节的主要输入站，在那里它处理和分类来自皮质区域和丘脑的信息，进入下游通路。纹状体功能缺陷是在神经精神障碍中观察到的认知和行为缺陷的原因，包括帕金森氏症、强迫症和药物成瘾。在两个水平上对纹状体功能的理解已经取得了长足的进步。首先，在行为水平上，人们已经了解了纹状体在动作选择和执行中的关键作用。其次，在单细胞水平上，对单个纹状体神经元的分子和生理特性以及它们在行为中的总体作用进行了广泛的研究。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了解还处于起步阶段。我经常围绕功能分区(例如，皮质柱)和细胞类型(例如，层)组织其他大脑区域的神经元电路 5A和5B皮质锥体神经元)。虽然纹状体根据其功能大致分为三个亚型，并且已知至少由五个主要神经元亚型组成，但其功能依赖于细分和细胞类型特异性的微电路尚不完全清楚。在这里，我们建议通过检查小鼠的纹状体细分依赖和细胞类型特异的微电路来填补这一空白，这是明确定义细胞类型所需的一个遗传上容易处理的系统。我们将通过研究丘脑纹状体投射的组织来做到这一点，丘脑纹状体投射由纹状体的两个主要兴奋性输入之一组成，在解剖和功能水平上都是如此。我们将使用解剖示踪、成像、遗传学、光遗传学和生理学方法的创新组合。我们期望我们的研究将提供一个完整的丘脑-纹状体功能配置图，并揭示丘脑信息如何被分离到下游特定细胞类型和特定功能细分电路背后的原理。我们所获得的知识将与目前关于纹状体的行为和单个神经元属性的知识协同作用，以促进我们对纹状体如何发挥作用以及丘脑如何促进作为上游输入来源的基底神经节的功能的理解。这一知识还将为未来纹状体功能和病理学的研究铺平道路，为正常情况下的电路连接提供一个基准。

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.