Tryptamine from wake-active monoaminergic neurons regulates sleep homeostasis

Wakefulness produces sleep-promoting substances and the cerebrospinal fluid contains substances that reflect homeostatic sleep pressure. However, identities of such molecules, and the neural mechanisms for producing and sensing them, remain mysterious. Here we show that cerebrospinal fluid levels of tryptamine (TrpA) track homeostatic sleep pressure in nocturnal mice and diurnal pigs, reflecting physical activity history independently of light-dark cycles. We developed a ratiometric fluorescent sensor for TrpA and showed that TrpA is produced by wake-active monoaminergic nuclei in the diencephalon and brainstem and is secreted in an activity-dependent manner. We showed that released TrpA binds to G-protein-coupled receptor 139 (GPR139) and enhances neuronal excitability in the hypothalamic preoptic area to promote sleep. TrpA-GPR139 signaling was necessary for homeostatic sleep rebound and small-molecule GPR139 agonists promoted sleep duration and quality. Together, our study reveals TrpA as a signal related to sleep homeostasis and GPR139 as a druggable target against its disruption.