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

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.