A rapid arousal brake on hunger neurons and its release in narcolepsy

Abstract

The brain must constantly integrate internal needs with external cues, requiring it to evaluate potential rewards and prioritize urgent environmental demands. How arousal systems control hunger to achieve this is a fundamental question. We targeted the functional connection from arousal hypocretin/orexin neurons (HONs) to hunger (AGRP) neurons and discovered that it operates through a local GABAergic relay, revealing a circuit for rapid, arousal-driven hunger suppression. We found this suppression deployed in several critical functions. In appetitive evaluation, it controls food value perception by suppressing AGRP based on a foods predicted caloric worth. In adaptive vigilance, it creates an opportunity to prioritize other needs, such as responding to novel, arousing stimuli. During spontaneous pupil dilations, it creates hunger-free windows for optimal assessment of the environment. These findings reveal a fundamental inhibitory circuit that allows pupil-linked arousal to dynamically gate hunger on a moment-to-moment basis, providing a new framework for how the brain balances competing internal and external demands.