Physiology and function of basal ganglia subcircuits in sequence learning

描述(申请人提供)：生物体的行为通常被组织成动作序列。序列学习和执行为生物体的生存和繁殖提供了广泛的能力，从捕食、交配到交流。基底节被认为与动作序列的学习和执行密切相关。然而，这些过程背后的分子和电路机制在很大程度上仍然不为人知。目前关于基底节功能的理论认为，有两条主要的神经通路，纹状体黑质(直接)和纹状体苍白质(间接)通路，分别以拮抗的方式促进和抑制运动。虽然这一工作假说已经应用于基底节功能和相关疾病多年，但这一经典模型还没有通过实验直接评估，因此它是否正确仍不清楚。本项目将系统地研究在动作序列的学习和执行过程中纹状体黑质与纹状体苍白质亚回路的生理和功能。不同的技术组合，包括操作条件反射、行为微结构分析、活体电生理学、遗传学和光遗传学工具，将被用来解剖行为小鼠的基底节子回路。将在小鼠身上开发一种新的动作序列训练范例，并在任务执行期间进行体内多电极神经元记录。在行为微结构分析的基础上，将建立与序列相关的神经元在不同基底节回路核团中的活动，并 比较一下。细胞类型将在体内通过光基因激活来鉴定，随后将通过光基因操作实验来确定纹状体黑质与纹状体苍白质亚回路在序列行为中的细胞类型和路径特定功能。该项目旨在共同努力 从生理和功能上重温基底节通路的经典工作模式。

DESCRIPTION (provided by applicant): The organism's behaviors are usually organized as action sequences. Sequence learning and execution serve as a wide range of abilities for the organism's survival and reproduction, from predating, mating to communicating. The basal ganglia have been suggested to be critically involved in learning and performance of action sequences. However, the molecular and circuit mechanisms underlying these processes remain largely uncovered. The current theory about basal ganglia function suggests that there are two major neural pathways, the striatonigral (direct) vs. striatopallidal (indirect) pathway, that workin an antagonistic manner to facilitate and inhibit movements respectively. Although this working hypothesis has been applied to basal ganglia function and related diseases for many years, this classic model has not been directly evaluated through experiments and thus it remains unclear if it's correct. The present project will systemically investigate the physiology and function of te striatonigral vs. striatopallidal subcircuit during learning and execution of action sequences. A combination of different techniques including operant conditioning, behavioral microstructure analysis, in vivo electrophysiology, genetic and optogenetic tools will be utilized to dissect the basal ganglia subcircuits in behaving mice. A novel action sequence training paradigm will be developed in mice and in vivo multiple-electrode neuronal recording will be performed during the performance of the task. Based on the analysis of behavioral microstructure, the sequence-related neuronal activity in the different nuclei of basal ganglia circuits will be established and compared. Cell types will be identified in vivo through optogenetic activation, followed by optogenetic manipulation experiments to define the cell-type and pathway- specific function of the striatonigral vs. striatopallidal subcircuit in sequence behavior. Together the project aims to physiologically and functionally revisit the classic working model of basal ganglia pathways.