Physiology and function of basal ganglia subcircuits in sequence learning

描述（由申请人提供）：生物体的行为通常被组织为动作序列。序列学习和执行是生物体生存和繁殖的广泛能力，从捕食，交配到交流。基底神经节被认为是关键参与学习和执行的行动序列。然而，这些过程背后的分子和电路机制仍然在很大程度上未被发现。目前关于基底神经节功能的理论表明，有两个主要的神经通路，纹状体黑质（直接）与纹状体苍白（间接）通路，以拮抗的方式分别促进和抑制运动。虽然这一工作假设已被应用于基底神经节功能和相关疾病多年，但这一经典模型尚未通过实验直接评估，因此尚不清楚它是否正确。本研究将系统地探讨纹状体黑质与纹状体苍白球在动作序列学习与执行过程中的生理与功能。不同技术的组合，包括操作性条件反射，行为微观结构分析，体内电生理学，遗传和光遗传学工具将被用来解剖行为小鼠的基底神经节亚回路。将在小鼠中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。基于行为微结构的分析，将建立基底神经节回路不同核团中的序列相关神经元活动， 比较了将通过光遗传学激活在体内鉴定细胞类型，然后进行光遗传学操作实验以确定序列行为中纹状体黑质与纹状体苍白球子回路的细胞类型和途径特异性功能。该项目旨在 生理和功能上重新审视基底神经节通路的经典工作模型。

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.