Neural Mechanisms of Performance Evaluation During Motor Sequence Learning

项目摘要 赛点上的两次失误令人非常失望。然而，这也是一个性能错误， 提高你未来发球能力。“边缘”结构，如外侧缰核（LHb）、腹侧苍白球（VP）和 腹侧被盖区（VTA）与享乐功能有关。但这种强调可能 行为主义者用奖励和惩罚来训练实验动物的传统。更一般的功能 边缘系统的作用可能是对任何预测错误施加效价，包括在预测过程中发生的错误。 电机性能如果是这样的话，那么几十年来关于大脑如何处理奖励的研究进展， 概括为运动序列任务，如演讲，运动和音乐表演。在过去的工作中，我们 研究发现，当一只雄性鸣禽出人意料地唱出正确的音符时，它的腹侧被盖区多巴胺（DA）神经元会 就像一只口渴的灵长类动物意外地喝到果汁一样。在歌曲错误之后， DA神经元被抑制，就像灵长类动物经历令人失望的奖励遗漏一样。我们还发现 当雄性对雌性唱歌时，这些表现评估信号被关闭，DA神经元取而代之， 被女性的呼唤所激活这些发现对运动学习回路具有重要意义， 建议的工作。首先，为了确定如何评估VTA上游电路的性能质量，我们将 解剖学上识别VTA的输入，进行损伤以测试歌曲学习所必需的，记录VTA 对不同输入的微刺激的反应，并进行神经记录以识别听觉错误和/或 定时信号对误差计算很重要（目标1）。第二，在过去的工作中，我们将VP确定为 听觉、运动和错误处理。在初步实验中，我们正在鉴定LHb和丘脑底核 核（nucleus，NTA）作为VP的新靶点，也投射到VTA。剖析副总裁在绩效评估中的作用， 我们将从解剖学上定义VP的输入和输出，并记录投射到丘脑、LHb和运动皮质的VP 唱歌时的神经元（Aim 2）。最后，我们过去的发现，当雄性唱歌时，DA错误信号被关闭， 女性是前所未有的。为了确定DA信号门控是否与行为相关，我们首先测试男性是否可以 从有女性在场的实验控制错误中学习（目标3.1）。测试错误信号是否被关闭 在全局范围内，我们将记录腹侧被盖区投射区（听觉皮层、VP、LHb）的神经元，因为我们同时控制 感知错误和女性在场（目标3.2）。总之，这些研究将确定神经相关的 构建运动序列的内部评估系统。理解病理学的主要障碍 在BG相关疾病中观察到的活动模式是对信号传播的有限理解， 健康的电路拟议的工作旨在了解DA-BG信号的功能，以及它们是如何 在电路的连续阶段处理。这个问题的关键是定制疗法的潜力，例如 基于详细的知识，神经回路重新编程和深部脑刺激治疗运动障碍 正常的大脑生理学。

PROJECT SUMMARY Double faulting on match point is intensely disappointing. Yet it is also a performance error that could help improve your future serve. ‘Limbic’ structures such as the lateral habenula (LHb), ventral pallidum (VP) and ventral tegmental area (VTA) have classically been associated with hedonic functions. But this emphasis might result from behaviorist traditions that train lab animals with rewards and punishments. A more general function of the limbic system may be to impose valence on any prediction error, including mistakes that occur during motor performance. If this is the case, then decades of progress on how the brain processes reward can generalize to motor sequence tasks such as speech, sport, and musical performance. In past work, we discovered that when a male songbird unexpectedly sings the right note, its VTA dopamine (DA) neurons are activated in the same way as when a thirsty primate unexpectedly receives juice. And following song errors, its DA neurons are suppressed as when a primate experiences disappointing reward omission. We also found that when males sing to females, these performance evaluation signals are turned off and DA neurons are instead activated by female calls. These discoveries have important implications for motor learning circuits that motivate the proposed work. Frist, to determine how performance quality is evaluated in circuits upstream of VTA, we will anatomically identify inputs to VTA, perform lesions to test which are necessary for song learning, record VTA responses to microstimulation of distinct inputs, and conduct neural recordings to identify auditory error and/or timing signals important for error computation (Aim 1). Second, in past work we identified the VP as a hub for auditory, motor, and error processing during singing. In pilot experiments we are identifying LHb and subthalamic nucleus (STN) as novel targets of VP that also project to VTA. To dissect VP’s role in performance evaluation, we will anatomically define VP inputs and outputs, and will record STN-, LHb-, and motor cortex-projecting VP neurons during singing (Aim 2). Finally, our past discovery that DA error signals are turned off when males sing to females is unprecedented. To determine if DA signal gating is behaviorally relevant, we first test if males can learn from experimentally controlled errors with females present (Aim 3.1). To test if error signals are gated off globally, we will record neurons in VTA-projecting areas (auditory cortex, VP, STN, LHb) as we control both perceived error and female presence (Aim 3.2). Altogether, these studies will identify the neural correlates of the internal evaluation systems 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.