The gut vagal sensory pathway drives postprandial sleep via activation of PVH-projecting GABAergic neurons in the NTS

Abstract

Feeding status bidirectionally modulates sleep; however, the neural circuitry that integrates the sensing of gastrointestinal (GI) state and sleep remains poorly understood. The afferent fibers of the vagus nerve extensively innervate the GI tract, transmitting postprandial satiety signals to the brain. This study investigates the key role of the upper gut-innervating vagal sensory neurons in modulating sleep-wake states and promoting postprandial sleep, uncovering the underlying circuit mechanisms. Both feeding and activation of stomach/duodenum-innervating vagal sensory neurons reduce wakefulness and increase NREM sleep in male mice. Conversely, chemogenetic inhibition abolished the sleep-promoting effects of feeding. Using anterograde transsynaptic tracing, single-nucleus RNA sequencing combined with optogenetic manipulation, we identified a vagal ascending pathway connecting the upper gut to the paraventricular nucleus of the hypothalamus (PVH) via GABAergic neurons in the nucleus of solitary tract (NTS). Stomach/duodenum-innervating vagal sensory neurons project directly to and functionally activate NTS GABAergic neurons. Activation of these neurons and their projections to the PVH suppressed wakefulness and prolonged NREM sleep. Overall, our study reveals a vagal sensory pathway that integrates satiety signals to modulate sleep. It reveals the direct neural circuitry mechanisms driving postprandial sleep and offers distinctive perspectives into the development of innovative interventions for sleep disorders.