Dissecting basal ganglia circuit mechanisms underlying instrumental learning

总结 基底神经节（BG）对运动控制和工具性学习至关重要。特别是，典型病变 研究表明，纹状体的不同区域，主要的BG输入核， 与动作选择和学习的不同方面相关：背内侧纹状体负责 对于基于结果预期的动作-结果学习和动作选择，而背外侧 纹状体负责习惯和行为自动性的发展。也有越来越多 一致认为，适应不良的工具性学习和表现有助于许多疾病 比如成瘾和精神分裂症，这些都与BG有关尽管最近的研究已经开始 显示了皮质纹状体可塑性在工具性学习和习惯形成中的关键作用，详细的电路 机制尚不清楚。本建议的总体目标是确定电路机制， 工具性学习和绩效的基础。我们将采用综合方法， 交叉策略，以确定的神经元群体和通路为目标， 用于量化学习和行为的分析。监控和操纵特定细胞的神经活动 人口，我们将使用体内钙成像，光遗传学，和转基因小鼠品系，使它 可能靶向BG中的关键神经元群体和通路。评估的内容 学习和量化行为不断，我们将使用建立的行为分析，从仪器 条件反射结合3D动作捕捉。提出了四个目标。目标1和2将决定 直接（纹状体黑质）通路和间接（纹状体苍白球）通路在不同纹状体中的作用 区域工具学习和性能。目标3-4将决定不同组织的贡献， 皮质纹状体通路（端脑内和锥体束）到工具性学习， 性能拟议研究的结果可以揭示目标背后的神经机制- 定向行为和习惯的形成，以及BG电路机制的功能障碍如何导致 多种精神和神经疾病的关键症状。

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.