Dissecting basal ganglia circuit mechanisms underlying instrumental learning

剖析工具学习背后的基底神经节回路机制

• 批准号: 10444477
• 负责人: Henry Yin
• 金额: $ 36.23万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10444477
• 关键词: 3-Dimensional; Anatomy; Basal Ganglia; Behavior; Behavioral; Behavioral Assay; Bilateral; Brain Stem; Brain region; Cell Nucleus; Cells; Cerebral cortex; Collection; Consensus; Corpus striatum structure; Development; Disease; Dopamine Receptor; Expectancy; Feedback; Functional disorder; Goals; Habits; Impairment; Learning; Lesion; Light; Medial; Mental disorders; Monitor; Motion; Motor Cortex; Movement; Mus; Neurons; Obsessive-Compulsive Disorder; Operant Conditioning; Outcome; Pathway interactions; Pattern; Performance; Play; Population; Prefrontal Cortex; Process; Psychological reinforcement; Pyramidal Tracts; Research; Rewards; Role; Schizophrenia; Shapes; Signal Pathway; Signal Transduction; Spinal Cord; Symptoms; Testing; Transgenic Mice; Work; addiction; base; experimental study; flexibility; hippocampal pyramidal neuron; in vivo calcium imaging; learned behavior; learning outcome; motor control; nervous system disorder; neural circuit; neuromechanism; optogenetics; receptor; recruit; relating to nervous system

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.

概括 基底神经节 (BG) 对于运动控制和乐器学习至关重要。特别是经典病变 研究表明，纹状体（主要 BG 输入核）的不同区域 与动作选择和学习的不同方面相关：背内侧纹状体负责 用于基于结果预期的行动结果学习和行动选择，而背外侧 纹状体负责习惯和行为自动化的发展。也有不断增长的 一致认为，工具性学习和表现的适应不良会导致多种疾病 例如成瘾和精神分裂症也与 BG 有关。尽管最近的研究已经开始 显示皮质纹状体可塑性在乐器学习和习惯形成中的关键作用，详细电路 机制仍不清楚。该提案的总体目标是确定电路机制 BG 是器乐学习和表演的基础。我们将采用综合方法，结合 针对特定神经元群和通路以及精确行为的交叉策略 量化学习和行为的分析。监测和操纵特定细胞的神经活动 人群，我们将使用体内钙成像、光遗传学和转基因小鼠品系，使其成为可能 可能针对 BG 中的关键神经元群和通路。评估内容 不断学习和量化行为，我们将使用仪器中既定的行为分析 调节与 3D 动作捕捉相结合。提出了四个目标。目标 1 和 2 将决定 不同纹状体中直接（纹状体黑质）途径和间接（纹状体苍白）途径的贡献 乐器学习和表演的区域。目标 3-4 将确定不同的贡献 皮质纹状体通路（端脑内和锥体束）到工具学习和 表现。拟议研究的结果可以揭示目标背后的神经机制 定向行为和习惯形成，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关键症状。