Rules of disengagement: orexin-arousal and dopamine-utility as separable axes

Abstract

Staying on task, leaving it, and coming back to it are processes we experience daily. They depend on task utility and arousal, but the neurochemical processes behind this interplay are unknown. In mice performing a decision-making task with shifting reward size, we identified latent engagement states and the transitions between them. Pupil-linked arousal and dopaminergic utility coding predicted these transitions along separable axes. Orexin antagonism with almorexant disengaged mice at low reward, an effect mediated by pupil-linked arousal and not by dopamine. GLP-1 receptor agonism with semaglutide reduced the gain with which accumbal dopamine integrates reward history, which predicted the progressive disengagement it caused, with no detectable contribution from arousal or orexin. Fast striatal and slow accumbal dopamine codes predicted engagement on their own timescales. These results decouple orexin-driven arousal from dopamine-mediated utility coding in task engagement, with implications for two widely used drug classes and for disorders of motivation.