Establishing a spatial map of dopamine reward prediction error computations and their function in distinct associative learning processes across the striatum: a methodological framework

建立多巴胺奖励预测误差计算的空间图及其在纹状体不同联想学习过程中的功能：方法框架

• 批准号: 10725129
• 负责人: Eleanor Brown
• 金额: $ 3.17万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725129
• 关键词: 3-Dimensional; Affect; Anatomy; Animals; Area; Association Learning; Basal Ganglia; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Boston; Brain region; Characteristics; Choice Behavior; Chronic; Classification; Complex; Corpus striatum structure; Cues; Development; Devices; Diagnostic; Disease; Dopamine; Educational process of instructing; Etiology; Fiber; Fiber Optics; Fostering; Functional disorder; Future; Goals; Heterogeneity; Impairment; Investigation; Learning; Light; Location; Maps; Mental disorders; Mentorship; Methodology; Methods; Modeling; Mus; Neurosciences; Obsessive-Compulsive Disorder; Operant Conditioning; Optics; Outcome; Parkinson Disease; Pattern; Photometry; Process; Recording of previous events; Research; Resolution; Response to stimulus physiology; Rewards; Schizophrenia; Shapes; Signal Transduction; Site; Stimulus; Symptoms; Techniques; Testing; Traineeship; Training; Training Support; Universities; Update; Variant; addiction; behavior test; cell type; collaborative environment; design; digital; dopaminergic neuron; effective therapy; experience; flexibility; improved; in vivo; nervous system disorder; neural circuit; optical fiber; optogenetics; postsynaptic; programs; response; segregation; spatiotemporal; technology development; tool

PROJECT SUMMARY/ABSTRACT. Dopamine (DA) signaling in the striatum, the main input to the basal ganglia, is critical for instrumental learning, a process involving associations of stimuli, responses, and outcomes. DA dysfunction results in diverse symptoms in disorders such as obsessive-compulsive disorder, Parkinson’s Disease, and addiction, which are often attributed to an imbalance in distinct instrumental learning processes. Anatomically segregated subregions of the striatum are thought to support stimulus-outcome (S-O), stimulus- response (S-R), and response-outcome (R-O) associations. Further, while the dorsomedial striatum (DMS) is necessary for flexible goal-directed behavior, the dorsolateral striatum (DLS) supports automatic, outcome- independent habitual behavior. While dopamine (DA) is typically thought to encode a reward prediction error (RPE), a teaching signal which drives associative learning, studies suggest that DA release dynamics vary depending on the target region. However, it is unknown how natural spatiotemporal DA release dynamics support learning distinct stimulus, response, and outcome associations. These gaps hinder the development of targeted diagnostics and treatments for dopamine-dysfunction affecting distinct striatum regions. This proposed project will make strides toward understanding the functional and computational significance of spatially varying DA dynamics in distinct associative learning processes. A behavioral paradigm which requires mice to switch from a cue-dependent S-R strategy to a cue-independent strategy based on recent actions and outcomes will enable classification of behavior strategy across timescales. This behavioral paradigm will be combined with a new multi optical fiber photometry method to record DA release dynamics throughout the volume of the striatum as mice learn and update distinct stimulus, response and outcome contingencies. This new large-scale, cell-type specific recording method will be applied to establish a spatial map of distinct DA RPE correlates and can be adapted to record distributed cell-type specific dynamics of any brain region with high spatiotemporal resolution. Finally, this method will be advanced with a digital mirror device (DMD) to target light to large, yet spatially precise, regions of the striatum for optogenetic manipulation which mimics the spatial scale and resolution of natural DA release dynamics. Completion of this project will support practical and theoretical training in three main areas: behavioral testing and analysis, functional circuit analysis, and technology development. Dr. Mark Howe (sponsor) will provide mentorship and training in in vivo analysis of neural circuits and dynamics. Dr. David Boas (co-sponsor), the director of the Neurophotonics Center at Boston University, will provide training in the concepts and techniques used for optical neuro-engineering, which will augment training supported by the NSF Neurophotonics National Research Traineeship Program. The Graduate Program for Neuroscience (GPN) at Boston University will provide additional training while fostering a collaborative and interdisciplinary environment.

项目总结/抽象。多巴胺（DA）信号在纹状体中，主要输入基底