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

Human sleep-wake disorders are often accompanied by eating disorders; the reasons for this apparent interplay between hunger and arousal remain unclear. Pupil-linked arousal fluctuates second-by-second, closely correlating with dynamics of hypocretin/orexin (H/O) neurons, whose malfunctions are linked to multiple pathologies. It is currently thought that H/O neurons activate hunger-causing agouti-related peptide (AGRP) neurons, thus creating concurrent arousal and hunger. Here, we directly measure pupil-linked arousal dynamics and concurrent AGRP neuron activity and find that, instead, pupil dilations correlate with reductions in AGRP neuron activity. Direct H/O neuron stimulation reproduced this inhibitory effect, while H/O neuron ablation attenuated it. Furthermore, in a mouse model of human type 1 (i.e. O/H deficient) narcolepsy, which involves unexplained overeating, we detected abnormal AGRP neuron hyperactivation during specific brain states, including the symptomatic shut-downs of arousal (cataplexy). Finally, we show that intact H/O neurons are required for normal food value perception by AGRP neurons, and for eating and AGRP neuron suppression by unexpected non-food stimuli. By demonstrating a rapid inhibitory H/O→AGRP influence and multiple pathophysiological consequences of its loss, these findings reveal a rapid functional link between arousal and hunger that is impaired by a neural defect associated with human disorders.