Neural mechanisms of performance evaluation during motor sequence learning

 描述(由申请人提供)：NINDS的一个主要目标是确定神经系统如何构建运动序列。多巴胺(DA)-基底节(BG)回路是运动序列学习所必需的，但这些回路如何指导试错式学习过程仍不清楚。值得注意的是，我们目前对这些途径的理解主要来自对动物学习简单动作以换取外部奖励的研究，比如食物或果汁。然而，帕金森氏症、亨廷顿氏症和肌张力障碍等BG疾病的症状包括与寻求奖励无关的运动行为退化。而大多数人类行为，如学习一项运动或一种乐器，并不是追求外部奖励的简单行为，而是通过将表现与内部目标相匹配而获得的复杂运动序列。鸣禽模型系统为研究内部引导的运动序列是如何构建的提供了一个独特的机会。斑马雀通过将复杂的声音序列与对辅导歌曲的听觉记忆相匹配来学习它们的歌曲。这种感觉运动学习需要一个DA-BG回路，而这个回路是一个容易驯服的“歌曲系统”的一部分。我们将把我们在唤醒行为电生理学方面的核心优势应用到易驯服的鸣禽模型系统中，以破译如何在练习中评估运动性能。首先，为了测试DA神经元是否评估运动表现(学习中的“错误”部分)，我们将首次对BG投射的DA神经元进行录音，同时用扭曲的听觉反馈控制歌曲的“错误”(目标1)。初步的录音支持这样一种假设，即DA神经元在歌唱过程中编码“演奏预测误差”信号。为了确定上游感觉运动信号是如何计算“错误”的，我们将记录在错误反馈任务中从听觉皮质和BG投射到鸣禽的DA神经元(目标2)。最后，斑马雀在两种依赖DA的运动状态下唱歌：一种是独处时的可变练习模式，另一种是雌性指导的刻板印象的表演模式。为了测试DA是否既可以评估性能又可以控制其变异性，我们将在无定向到定向歌曲状态转换的错误反馈任务中记录DA神经元(目标3)。总之，这些研究将确定构成运动序列的内部评估系统的神经关联。理解BG相关疾病中观察到的病理活动模式的一个主要障碍是对通过健康回路的信号传播的有限理解。拟议的工作旨在了解DA-BG信号的功能以及它们在电路的连续阶段是如何处理的。这个问题关系到基于正常大脑生理学的详细知识量身定做治疗方法的可能性，例如神经回路重新编程和针对运动障碍的脑深部刺激。

 DESCRIPTION (provided by applicant): A principle aim of the NINDS is to determine how motor sequences are constructed by the nervous system. Dopamine (DA)-basal ganglia (BG) circuits are required for motor sequence learning, but it remains unclear how these circuits guide the trial-and-error learning process. Remarkably, our current understanding of these pathways comes largely from studies of animals learning simple actions for external rewards such as food or juice. Yet symptoms of BG diseases such as Parkinson's, Huntington's and dystonia include degradation of motor behaviors unrelated to reward seeking. And most human behaviors, such as learning a sport or an instrument, are not simple actions in pursuit of external rewards but are instead complex motor sequences learned by matching performance to internal goals. The songbird model system offers a unique opportunity to study how internally guided motor sequences are constructed. Zebra finches learn their song by matching a complex vocal sequence to an auditory memory of a tutor song. This sensorimotor learning requires a DA-BG circuit that is part of a tractable 'song system.' We will apply our core strengths in awake- behaving electrophysiology to the tractable songbird model system to decipher how motor performance is evaluated during practice. First, to test if DA neurons evaluate motor performance (the 'error' part of learning) we will conduct the first-ever recordings of BG-projecting DA neurons while controlling song 'error' with distorted auditory feedback (Aim 1). Preliminary recordings support the hypothesis that DA neurons encode 'performance prediction error' signals during singing. To determine how upstream sensorimotor signals compute 'error,' we will record from auditory cortical and BG projections to DA neurons in singing birds during the error-feedback task (Aim 2). Finally, zebra finches sing in two DA-dependent motor states: a variable practice mode when alone and a female-directed, stereotyped performance mode. To test if DA can both evaluate performance and also control its variability, we will record DA neurons during the error feedback task during undirected-to-directed song state transitions (Aim 3). Altogether, these studies will identify the neural correlates of the internal evaluation system that construct motor sequences. A major impediment to understanding pathological activity patterns observed in BG-related diseases is a limited understanding of signal propagation through the healthy circuit. The proposed work aims to understand the functions of DA-BG signals and how they are processed at successive stages of the circuit. At stake in this issue is the potential to tailor therapies, such as neural circuit re-programming and deep brain stimulation for movement disorders, based on detailed knowledge of normal brain physiology.