Dissecting basal ganglia circuit mechanisms underlying instrumental learning

摘要 基底节(BG)对运动控制和工具性学习至关重要。尤其是经典病变 研究表明，纹状体的不同区域，即主要的BG输入核，是 与动作选择和学习的不同方面有关：背内侧纹状体负责 对于行动-结果学习和基于结果预期的行动选择，而背外侧 纹状体负责习惯和行为自律性的发展。也有越来越多的 一致认为，适应不良的工具性学习和表现会导致许多障碍 比如上瘾和精神分裂症也牵涉到BG。尽管最近的研究已经开始 显示皮质纹状体可塑性在仪器学习和习惯形成中的关键作用，详细电路 机制仍不清楚。本提案的总体目标是确定下列电路机制 BG是器乐学习和表演的基础。我们将使用综合方法，结合 以确定的神经元群体和通路以及精确的行为为目标的交叉策略 量化学习和行为的分析。监测和操纵已定义细胞的神经活动 ，我们将使用体内钙成像、光遗传学和转基因小鼠品系 有可能针对BG中的关键神经元群体和通路。评估…的内容 不断学习和量化行为，我们将使用来自工具的已建立的行为分析 条件化与3D运动捕捉相结合。提出了四个目标。目标1和目标2将决定 纹状体直接通路和间接通路在不同纹状体中的作用 各地区的乐器学习和表演。目标3-4将决定DISTINCT的贡献 皮质纹状体通路(脑内束和锥体束)通向工具性学习和 性能。拟议研究的结果可以揭示目标背后的神经机制-- 定向动作和习惯养成，以及BG回路机制的功能障碍如何导致 多种精神和神经疾病的主要症状。

SUMMARY The basal ganglia (BG) are critical for motor control and instrumental learning. In particular, classic lesion studies have demonstrated that different regions of the striatum, the major BG input nucleus, are associated with distinct aspects of action selection and learning: the dorsomedial striatum is responsible for action-outcome learning and action selection based on outcome expectancy, whereas the dorsolateral striatum is responsible for the development of habits and behavioral automaticity. There is also growing consensus that maladaptive instrumental learning and performance contribute to numerous disorders such as addiction and schizophrenia that also implicate the BG. Although recent studies have begun to show a key role for corticostriatal plasticity in instrumental learning and habit formation, the detailed circuit mechanisms remain unclear. The overall aim of this proposal is to determine the circuit mechanisms in the BG underlying instrumental learning and performance. We will use a integrative approach, combining intersectional strategies to target defined neuronal populations and pathways and precise behavioral assays to quantify learning and behavior. To monitor and manipulate neural activity of defined cell populations, we will use in vivo calcium imaging, optogenetics, and transgenic mouse lines that make it possible to target the key neuronal populations and pathways in the BG. To assess the content of learning and quantify behavior continuously, we will use established behavioral assays from instrumental conditioning combined with 3D motion capture. Four aims are proposed. Aims 1 and 2 will determine the contribution of the direct (striatonigral) pathway and indirect (striatopallidal) pathways in different striatal regions to instrumental learning and performance. Aims 3-4 will determine the contributions of distinct corticostriatal pathways (intratelencephalic and pyramidal tract) to instrumental learning and performance. Results from proposed research can shed light on the neural mechanisms underlying goal- directed actions and habit formation, and how dysfunctions in the BG circuit mechanisms can result in key symptoms of multiple psychiatric and neurological disorders.