Regulation of arousability by signaling from the gut

Project Summary Sensory information is always present in the environment but animals can flexibly filter much of it out. During sleep, the threshold for sensory arousal is increased so that only stimuli of sufficient magnitude can cross it. In fact, elevating arousal threshold is essential for being able to sleep deeply, which is essential for the normal restorative function of sleep. The mechanisms that control arousability are largely mysterious, but they must integrate sensory information with information about internal physiology. Nutritional status is a major determinant of arousability – hungry animals often stay awake and forage; if asleep, they are easily arousable. While some progress has been made in understanding how nutrients regulate sleep duration (quantity), there is almost no understanding when it comes to their influence on sleep depth (quality). We discovered a gut-to-brain signaling pathway that uses information about ingested nutrients to control arousability from sleep, and consequently sleep depth, without affecting sleep duration. Protein ingestion causes endocrine cells in the Drosophila gut to produce more CCHa1, a peptide that decreases sensory responsiveness. CCHa1 is received by a small group of brain dopaminergic neurons whose activity gates behavioral responsiveness to mechanical stimulation. These dopaminergic neurons innervate the mushroom body, a brain structure that is also involved in determining sleep duration – at a compact point in the brain, the streams of information relevant for sleep quantity and quality converge. This affords an opportunity to study the regulation of sleep quantity and quality separately, but also to understand how these parameters are integrated. Here we propose to characterize the CCHa1 pathway in more detail. We will ask how, on a molecular level, dietary proteins are sensed in the gut and how this information is converted into changed activity of dopamine neurons in the brain. We will also investigate the impact of sleep quality on health and longevity across lifetime.