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

项目摘要/摘要。纹状体中的多巴胺 (DA) 信号传导是基底细胞的主要输入 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 反应（S-R）和反应-结果（R-O）关联。此外，虽然背内侧纹状体（DMS） 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 独立的习惯行为。虽然多巴胺 (DA) 通常被认为编码奖励预测错误 （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 取决于目标区域。然而，尚不清楚自然时空 DA 释放动态如何支持 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 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。行为范式 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。这种行为范式 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 高时空分辨率。最后，该方法将通过数字镜装置（DMD）来推进以瞄准 光到纹状体的大但空间精确的区域，用于模拟空间的光遗传学操作 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 测试与分析、功能电路分析、技术开发。马克·豪博士（赞助商）将 提供神经回路和动力学体内分析的指导和培训。大卫·博阿斯博士（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。神经科学研究生项目 (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。

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.