Physiology and function of basal ganglia subcircuits in sequence learning

项目摘要： 对生物体来说，把一系列的行为按顺序组合起来，并获得一个大的 为了生存和繁衍而采取的行动将行为组织成动作序列，以及如何 在神经系统中的实现一直是神经科学的中心问题。皮质功能障碍- 基底神经节回路与许多神经和精神疾病中受损的顺序行为有关。 包括帕金森病、亨廷顿病和强迫症（OCD）的疾病。 纹状体是基底神经节的主要输入核团，负责接收感觉、运动和认知信号 大脑皮层的信息。目前的基底神经节模型表明，有两个主要的神经 子回路，称为“直接”和“间接”途径，分别用于选择和抑制行动。 然而，这种过于简单化的对立观点受到了最近研究的挑战。此外，除了 直接和间接途径，很长一段时间以来，人们都知道，有两个隔室在 纹状体，称为补丁（纹状体）和基质，这可以通过表达免疫- 组织化学标记如μ阿片受体。重要的功能差异已经提出 之间的补丁和基质室的基础上观察人类基底神经节疾病。 然而，对贴剂与基质隔室的功能理解及其在控制中的作用还有待进一步研究。 目前基本上没有采取行动。传统的解剖学和电生理学方法是病态的- 适合于解决这些问题，因为这些隔室形状不规则，细胞类型不同 在分布上是混合的，使得精确的病变或生理研究相当困难，如果不是不可能的话。 该项目将利用一系列尖端的神经技术，包括在体内记录细胞 类型鉴定，光遗传学，快速扫描循环伏安法，病毒追踪和微型镜成像，结合 定量行为和计算模型，解剖特定的纹状体区室的作用， 动作序列学习和执行，与纹状体通路的功能相比。而且 目的是系统地研究不同类型的纹状体细胞的生理和功能及其相互作用 在行为过程中有特定的皮层输入。首先，在小鼠中进行了一种新的动作序列任务， 行为将被开发，以确定纹状体参与分子和细胞的作用序列， 程度.然后进行体内电化学、电生理学和光遗传学实验， 定义各种纹状体细胞类型对序列执行的活性和贡献。最终改良狂犬病 病毒将被用来定义细胞类型特异性皮质-纹状体通路，并解剖生理学和 这些途径在行为过程中的功能与先进的成像和光遗传学。该项目将 促进对这两个动作序列的特定皮质纹状体回路的功能和逻辑的理解 学习和执行。

Project Summary: It is a fundamental challenge for organisms to chunk a series of actions into sequence and acquire a large action repertoire for survival and reproduction. The organization of behavior into action sequences, and how it is realized in the nervous system has been a central question in neuroscience. Dysfunctions of the cortico- basal ganglia circuits are associated with impaired sequential behavior in many neurological and psychiatric diseases including Parkinson's disease, Huntington's disease and Obsessive-Compulsive Disorder (OCD). The striatum is the major input nuclei of the basal ganglia, which receive sensory, motor and cognitive information across cerebral cortex. Current model of basal ganglia suggested that there are two major neural subcircuits, called the “direct” and “indirect” pathways, for selecting and inhibiting actions respectively. Nevertheless, this over-simplified opponent view has been challenged by recent work. In addition, besides the direct and indirect pathways, it has been known for a long time that there are two compartments in the striatum, termed the patch (striosome) and matrix, which can be defined by the expression of immune- histochemical markers like mu-opioid receptors. Important functional differences have been suggested between the patch and matrix compartments based on the observations in human basal ganglia disorders. However, the functional understanding of the patch vs. matrix compartment and their roles in controlling actions are largely missing at this moment. Conventional anatomical and electrophysiological methods are ill- suited to address these questions because these compartments are irregular in shape and different cell types are mixed in distribution, making the precise lesion or physiological studies rather difficult if not impossible. This project will take advantage of a series of cutting-edge neurotechniques including in vivo recording with cell type identification, optogenetics, fast-scan cyclic voltammetry, viral tracing and miniscope imaging, combined with quantitative behavior and computational modeling, to dissect the role of specific striatal compartments in action sequence learning and execution, in comparison with the function of striatal pathways. Furthermore, it aims to systemically investigate the physiology and function of different striatal cell types and their interaction with specific cortical inputs during behavior. Firstly, a novel action sequence task in mice with quantitative behavior will be developed to determine the striatal involvement in action sequences at molecular and cellular levels. It is then followed by in vivo electro-chemical, electrophysiological and optogenetic experiments to define the activity and contribution of various striatal cell types to sequence execution. Finally modified rabies virus will be utilized to define cell-type-specific cortico-striatal pathways, and dissect the physiology and function of these pathways during behavior with advanced imaging and optogenetics. Together this project will advance the understanding of the function and logic of specific corticostriatal circuitry for both action sequence learning and execution.