An optical-genetic toolbox for monitoring and controlling diverse neuromodulatory circuits governing complex behaviors in primates

摘要 感知引导的行为涉及外部输入和 例如，与警觉性、动机、期望和注意力相关的内部状态。广泛 有证据表明，灵长类动物大脑中感官信息的表达、处理和流动 受到几种神经调节系统的调节。然而，我们对生理和 在灵长类动物复杂行为中神经调节信号的行为影响是相当初级的， 落后于啮齿类动物。这种滞后的主要原因是缺乏先进的分子， 遗传和生理学工具，用于靶向神经调节回路并研究其在行为中的作用 非人灵长类动物，它们是人类感知、认知和运动控制的最佳动物模型。 目前提案的首要目标是开发和测试用于监测的光学遗传工具箱 以及控制清醒的、行为正常的非人类灵长类动物的多个相互作用的大脑区域。我们专注于 神经调节回路对皮层回路产生强大的影响，但人们对此知之甚少， 介导知觉决策。 为了实现这一目标，我们将使用先进的解剖学和转录组学工具来识别主要的 神经调节分子和回路可能在控制信息中发挥重要作用 在沿着感觉-决策-运动弧的几个关键皮层区域中进行处理和流动。然后我们将开发 基于病毒的遗传工具，将允许一个选择性地表达报告和执行器在这些关键 灵长类动物的神经调节回路。最后，我们将开发和优化光学和电生理学 这些工具将允许一个人监测和控制神经调节回路，同时测量 神经群体反应的关键皮质区，因为猴子执行复杂的知觉任务， 精确控制的行为需求。为了验证这些方法，我们将研究神经调质的作用 在灵长类动物的知觉决策过程中。这种光学遗传工具箱将广泛适用于 研究神经调节回路在调节灵长类动物适应行为中的作用。更一般地 这些工具将被开发用于监测和操纵多个相互作用的大脑区域， 行为将提高我们研究灵长类动物复杂行为过程中神经信息处理的能力。

ABSTRACT Perceptually guided behavior involves a complex and dynamic interplay between external inputs and internal states that are related, for example, to alertness, motivation, expectations and attention. A wide range of evidence suggests that the representation, processing, and flow of sensory information in the primate brain is regulated by several neuromodulatory systems. However, our understanding of the physiological and behavioral impact of neuromodulatory signals during complex behaviors in primates is quite rudimentary and is lagging behind what is known in rodents. The main reason for this lag is the lack of advanced molecular, genetic and physiological tools for targeting neuromodulatory circuits and for studying their role in behaving non-human primates, which are the best animal model for human perception, cognition and motor control. The overarching goal of the current proposal is to develop and test an optical-genetic toolbox for monitoring and controlling multiple interacting brain regions in awake, behaving non-human primates. We focus on neuromodulatory circuits that exert a powerful, yet poorly understood, impact on the cortical circuits that mediate perceptual decision-making. To achieve this goal, we will use advanced anatomical and transcriptomic tools to identify the main neuromodulatory molecules and circuits that are likely to play an important role in controlling information processing and flow in several key cortical regions along the sensory-decision-motor arc. We will then develop viral-based genetic tools that will allow one to selectively express reporters and actuators in these key neuromodulatory circuits in primates. Finally, we will develop and optimize optical and electrophysiological tools that will allow one to monitor and control neuromodulatory circuits while simultaneously measuring neural population responses in key cortical regions as monkeys perform complex perceptual tasks with precisely-controlled behavioral demands. To validate these methods, we will study the role of neuromodulators during perceptual decision-making in primates. This optical-genetic toolbox will be widely applicable for studying the role of neuromodulatory circuits in mediating adaptive behaviors in primates. More generally, the tools that will be developed for monitoring and manipulating multiple interacting brain regions during behavior will advance our ability to study neural information processing during complex behaviors in primates.