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: 10537425
• 负责人: Eleanor Brown
• 金额: $ 4.68万
• 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/10537425
• 关键词: 3-Dimensional; Affect; Anatomy; Animals; Area; Basal Ganglia; Behavior; Behavioral; Behavioral Model; Behavioral Paradigm; Boa; Boston; Brain region; Characteristics; Choice Behavior; Chronic; Classification; Complex; Conflict (Psychology); Corpus striatum structure; Cues; Development; Devices; Diagnostic; Disease; Dopamine; Educational process of instructing; Engineering; Etiology; Fiber; 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; Synapses; Techniques; Testing; Traineeship; Training; Training Support; Universities; Update; Variant; addiction; base; behavior test; cell type; classical conditioning; collaborative environment; design; digital; dopaminergic neuron; effective therapy; experience; flexibility; improved; in vivo; nervous system disorder; neural circuit; optical fiber; optogenetics; programs; response; 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/摘要。纹状体中的多巴胺（DA）信号传导，主要输入到基底神经元， 神经节是工具性学习的关键，工具性学习是一个涉及刺激、反应和结果的关联的过程。 DA功能障碍导致各种疾病的症状，如强迫症，帕金森氏症， 疾病和成瘾，这往往归因于不同的工具性学习过程的不平衡。 纹状体的解剖学上分离的亚区被认为支持刺激-结果（S-O），刺激-结果（S-O），刺激-结果（S-O），刺激-结果（S-O），刺激-结果（S-O）和刺激-结果（S-O）。 反应（S-R）和反应-结果（R-O）关联。此外，虽然背内侧纹状体（DMS）是 背外侧纹状体（DLS）是灵活的目标导向行为所必需的，它支持自动的、结果性的， 独立的习惯性行为。虽然多巴胺（DA）通常被认为是编码奖励预测错误， (RPE)，一个驱动联想学习的教学信号，研究表明，DA释放动力学不同， 取决于目标区域。然而，自然时空DA释放动力学如何支持 学习不同的刺激、反应和结果关联。这些差距阻碍了有针对性的发展 用于影响不同纹状体区域的多巴胺功能障碍的诊断和治疗。 该项目将在理解功能和计算方面取得进展。 空间变化的DA动力学在不同的联想学习过程中的意义。一种行为范式 这需要小鼠从线索依赖的S-R策略转换到线索独立的策略， 行动和结果将使跨时间尺度的行为策略分类成为可能。这种行为模式 将与一种新的多光纤光度法相结合，记录整个过程中DA的释放动态 当小鼠学习和更新不同的刺激、反应和结果偶然性时，纹状体的体积。 这种新的大规模，细胞类型特异性记录方法将被应用于建立不同DA的空间图 RPE与任何脑区域的分布的细胞类型特异性动力学相关，并且可以适于记录任何脑区域的分布的细胞类型特异性动力学， 高时空分辨率。最后，将这种方法与数字反射镜器件（DMD）进行了对比 用于光遗传学操作的纹状体的大的但空间精确的区域，其模拟了空间的光遗传学操作。 自然DA释放动力学的规模和分辨率。 该项目的完成将支持三个主要领域的实践和理论培训： 测试与分析、功能电路分析和技术开发。Mark Howe博士（申办者）将 提供神经回路和动力学的体内分析方面的指导和培训。大卫博厄斯博士（共同申办者）， 波士顿大学神经光子学中心主任，将提供概念培训， 用于光学神经工程的技术，这将增强NSF支持的培训 神经光子学国家研究培训计划。神经科学研究生课程（GPN） 波士顿大学将提供额外的培训，同时培养协作和跨学科的环境。