BRAIN EAGER: Integrated Measurement of Dopamine Release and Large-Scale Ensemble Activity in Behaving Animals

该奖项由两个项目联合颁发：生物研究仪器开发项目（IDBR）和生物科学理事会（BIO）的新兴前沿项目（EF）。神经递质多巴胺在学习、决策、动机和运动控制中起着核心作用。据推测，多巴胺通过调节单个神经元与其他神经元形成短暂或持久连接的能力来影响这些功能。然而，这一假设尚未得到验证，因为目前还没有仪器可以实时测量自由运动动物的多巴胺释放和个体神经元群的活动。为了构建这样一个设备，将结合以下技术：快速扫描循环伏安法，当前最先进的测量多巴胺释放的技术，以及用于实时测量大量单个神经元的高密度细胞外电极阵列。该仪器将被设计用于记录自由行为的动物，为科学家提供前所未有的机会来解决诸如：多巴胺释放是否增强了大脑远端神经元之间的交流？这种增强的沟通是否与学习、决策或运动控制的改善相一致？睡眠中多巴胺的释放是否与近期学习经历中神经元的重新激活有关？这种再激活对长期记忆的形成很重要吗？解决这些问题的社会影响将是根本性的进步，答案将带来对大脑作为一个综合系统的理解，这个系统在学习和决策过程中是如何工作的，当这个系统的组成部分因神经系统疾病或损伤而崩溃时，会出现什么问题。目前还没有一种工具能让研究人员调查大群单个神经元的活动与自由行为动物的多巴胺释放之间的联系。这个项目的目标是建立一种仪器，能够测量多巴胺的释放和100个同时活跃的神经元在清醒和行为的动物的活动。该仪器集成了测量多巴胺（快速扫描循环伏安法）和神经活动（高密度集合记录）的最先进技术。由于技术限制，这些技术尚未集成。例如，伏安法产生的电脉冲会干扰神经记录。我们的方法是1)将最近开发的多通道前置放大器应用到我们的记录系统中，该系统可以快速适应电子伪影；2)开发一种新型的金属电极碳膜涂层，允许从电极阵列中记录多巴胺。我们的方法是通过排除故障和收集系统中麻醉和自由行为的大鼠的科学数据来确定技术障碍。这项为期两年的研究范围是收集和发布功能齐全的原型的科学和技术数据。这些数据将为开发和销售商业产品提供资金支持。启发这项工作的理论基础是，多巴胺通过持续调节神经元群的可塑性和神经活动来调节决策、学习和运动控制。根据多巴胺功能的强化学习理论，意外奖励后多巴胺的释放触发了神经元网络的联想学习和可塑性。在行为动物中，多巴胺如何调节活动和连通性的问题尚未得到解答，而提出的工具将有助于填补这一理解上的空白。

This award is jointly made by two programs: the Instrument Development for Biological Research program (IDBR) and Emerging Frontiers (EF) in the Directorate of Biological Sciences (BIO).The neurotransmitter dopamine plays a central role in learning, decision making, motivation, and the control of movement. It is assumed that dopamine influences these functions by modulating the capacity of individual neurons to form brief or lasting connections with other neurons. This assumption, however, has not been tested as no instrument exists for the real-time measurement of both dopamine release and the activities of groups of individual neurons in freely-moving animals. To build such a device the following will be combined: fast-scan cyclic voltammetry, the current state-of-the-art technology for measuring dopamine release, and high-density extracellular electrode arrays for the real-time measurement of large groups of individual neurons. The instrument will be designed for recording in freely-behaving animals, giving scientists the unprecedented opportunity to address questions such as: Is communication between neurons in distant brain regions enhanced by dopamine release? Does such enhanced communication correspond with improvements in learning, decision making, or motor control? Does dopamine release during sleep coordinate the reactivation of neurons involved in a recent learning experience? Is such reactivation important for the formation of long-term memories? The societal impact of addressing questions such as these would be in the fundamental advances answers would bring to the understanding of the brain as an integrated system, how this system works during learning and decision making, and what goes wrong when components of this system break down due to neurological disease or injury.No tool exists that enables researchers to investigate the link between the activities of large groups of individual neurons and dopamine release in freely-behaving animals. The goal of this project is to build an instrument capable of measuring dopamine release and the activity of 100s of simultaneously active neurons in awake and behaving animals. The instrument integrates state-of-the-art technologies for measuring dopamine (fast-scan cyclic voltammetry) and neural activity (high-density ensemble recording). These technologies have not been integrated due to technical limitations. For example, electrical pulses created during voltammetry interfere with neural recording. Our methods are 1) adapt a recently-developed multi-channel headstage amplifier into our recording system that rapidly adapts to electrical artifacts, and 2) develop a novel carbon-film coating for metal electrodes, permitting dopamine recordings from electrode arrays. Our approach is to identify technical hurdles by troubleshooting and collecting scientific data from the system in anesthetized and freely-behaving rats. The two-year scope of this study is to collect and publish scientific and technical data from fully functional prototypes. These data will support funding efforts to build and distribute a commercial product. The theoretical foundation inspiring this work is that dopamine modulates decision making, learning, and motor control through its ongoing regulation of plasticity and neural activity in neuronal groups. According to the reinforcement-learning theory of dopamine function, dopamine release following unexpected rewards triggers associative learning and plasticity in networks of neurons. The question of how activity and connectivity are regulated by dopamine in behaving animals is unanswered and the proposed instrument will help fill this gap in understanding.