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.

项目摘要/摘要：纹状体中的多巴胺 (DA) 信号传导，是基底层的主要输入。 神经节对于工具性学习至关重要，工具性学习是一个涉及刺激、反应和结果关联的过程。 DA 功能障碍会导致多种疾病症状，例如强迫症、帕金森症 疾病和成瘾通常归因于不同工具学习过程的不平衡。 纹状体在解剖学上分离的子区域被认为支持刺激结果（S-O）、刺激-结果 此外，背内侧纹状体（DMS）是反应（S-R）和反应结果（R-O）关联。 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、结果的 而多巴胺（DA）通常被认为编码了奖励预测错误。 （RPE），一种驱动联想学习的教学信号，研究表明 DA 释放动态各不相同 然而，自然时空 DA 释放动态如何支持尚不清楚。 学习刺激、反应和结果的关联性这些差距阻碍了有针对性的发展。 影响不同纹状体区域的多巴胺功能障碍的诊断和治疗。 这个拟议的项目将在理解功能和计算方面取得重大进展 空间变化的 DA 动态在不同的联想学习过程中的重要性。 这要求小鼠从依赖线索的 S-R 策略切换到基于最近的线索独立策略 行动和结果将使跨时间尺度的行为策略分类成为可能。 将与新的多光纤光度测量方法相结合，全程记录 DA 释放动态 当小鼠学习和更新不同的刺激、反应和意外结果时，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用于建立不同 DA 的空间图 RPE 关联并可用于记录任何大脑区域的分布式细胞类型特定动态 最后，该方法将通过数字镜装置（DMD）来实现目标。 光照射到纹状体的大区域，但在空间上是精确的，以进行光遗传学操作，模拟空间 自然 DA 释放动态的规模和分辨率。 该项目的完成将支持三个主要领域的实践和理论培训：行为 测试和分析、功能电路分析以及技术开发。 提供神经回路和动力学体内分析的指导和培训。 David Boas 博士（共同发起人）， 波士顿大学神经光子学中心主任将提供概念和技术方面的培训 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实习计划。神经科学研究生计划 (GPN) 波士顿大学将提供额外的培训，同时营造协作和跨学科的环境。