Neural mechanisms of performance evaluation during motor sequence learning

 描述（由申请人提供）：NINDS的主要目的是确定神经系统如何构建运动序列。多巴胺（DA）-基底神经节（BG）回路是运动序列学习所必需的，但目前还不清楚这些回路如何指导试错学习过程。值得注意的是，我们目前对这些途径的理解主要来自于对动物学习简单动作以获得食物或果汁等外部奖励的研究。然而，BG疾病的症状，如帕金森氏症、亨廷顿氏症和肌张力障碍，包括与奖赏寻求无关的运动行为的退化。大多数人类行为，比如学习一项运动或一种乐器，并不是为了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学习到的复杂运动序列。鸣禽模型系统提供了一个独特的机会，研究如何内部指导运动序列的建设。斑胸草雀通过将复杂的声音序列与导师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，这是一个易驾驭的歌曲系统的一部分。“我们将把我们在清醒行为电生理学方面的核心优势应用于易于处理的鸣禽模型系统，以破译在实践中如何评估运动表现。首先，为了测试DA神经元是否评估运动表现（学习的“错误”部分），我们将进行BG投射DA神经元的首次记录，同时用扭曲的听觉反馈控制歌曲“错误”（目标1）。初步录音支持这一假设，即DA神经元编码的“性能预测错误”的信号在唱歌。为了确定上游感觉运动信号如何计算“错误”，我们将记录在错误反馈任务（目标2）期间从听觉皮层和BG投射到歌唱鸟类的DA神经元。最后，斑胸草雀在两个DA依赖的运动状态下唱歌：一个单独的可变练习模式和一个女性导向的刻板表演模式。为了测试DA是否既可以评估性能，也可以控制其变异性，我们将记录DA神经元在错误反馈任务期间，在无定向到定向的歌曲状态转换（目标3）。总之，这些研究将确定神经相关的内部评价系统，构建运动序列。理解BG相关疾病中观察到的病理活动模式的主要障碍是对通过健康电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，以及它们如何在电路的连续阶段进行处理。在这个问题上，关键是有可能根据对正常大脑生理学的详细了解，定制治疗方法，如神经回路重新编程和运动障碍的深部脑刺激。

 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.