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：生物科学理事会(BIO)的生物研究仪器开发计划(IDBR)和新兴前沿(EF)。神经递质多巴胺在学习、决策、动机和运动控制方面发挥着核心作用。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联系的能力来影响这些功能。然而，这一假设还没有得到检验，因为没有仪器可以实时测量自由运动动物中的多巴胺释放和单个神经元组的活动。为了建造这样的设备，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组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行为自由的动物，为科学家提供了前所未有的机会来解决以下问题：远处大脑区域的神经元之间的沟通是否因多巴胺的释放而增强？这种加强的沟通是否与学习、决策或运动控制的改善相对应？睡眠中释放的多巴胺是否协调了最近学习经历中涉及的神经元的重新激活？这种重新激活对形成长期记忆很重要吗？解决此类问题的社会影响将体现在以下方面：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，以及当这个系统的组成部分因神经系统疾病或损伤而崩溃时，这个系统出了什么问题。目前还没有任何工具可以让研究人员调查大量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。该项目的目标是建立一种仪器，能够测量清醒和行为动物的多巴胺释放和100个同时活动的神经元的活动。该仪器集成了用于测量多巴胺(快速扫描循环伏安法)和神经活动(高密度整体记录)的最先进技术。由于技术限制，这些技术尚未整合。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台放大器应用到我们的记录系统中，以快速适应电子伪像；2)开发一种用于金属电极的新型碳膜涂层，允许从电极阵列记录多巴胺。我们的方法是通过对麻醉和行为自由的大鼠的系统进行故障排除和收集科学数据来确定技术障碍。这项研究的两年范围是收集和发布全功能原型的科学和技术数据。这些数据将支持为建造和分发商业产品提供资金的努力。激励这项工作的理论基础是，多巴胺通过对神经元组中的可塑性和神经活动的持续调节来调节决策、学习和运动控制。根据多巴胺功能的强化学习理论，意外奖励后的多巴胺释放触发了神经元网络中的联想学习和可塑性。多巴胺如何调节行为动物的活动和连通性的问题尚未得到回答，拟议中的工具将有助于填补这一理解空白。

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.