UCL Research Department of Cell and Developmental Biology

Research Summary

The Rihel lab studies the genes and neuronal circuits that regulate sleep in zebrafish. Sleep has fascinated poets, playwrights, philosophers, and scientists at least since Aristotle wrote “On Sleep and Sleeplessness” around 350 B.C. More recently, increased public and clinical attention has been paid to the negative health consequences of the lack of adequate sleep. Despite this scrutiny, the mysteries of sleep’s function and regulation endue. Why is sleep essential for animals as diverse as flies and humans? And what are the regulatory genes and neuronal circuits that control the timing, amount, and duration of sleep? Recent advances, including the discovery that narcolepsy is caused by dysfunction of the Hypocretin/Orexin (Hcrt) signaling system, the behavioral characterization of sleep-like states in non-mammalian species, and the identification of short-sleeping mutants in Drosophila, have provided the first genetic entry points into sleep research. Inspired by this work, we use zebrafish as a genetically tractable vertebrate model system to investigate sleep. Zebrafish are an attractive model system for sleep studies because, unlike invertebrates, they possess the Hcrt system and other conserved brain structures thought to regulate mammalian sleep. Moreover, zebrafish are also the only vertebrate model system easily amenable to large-scale genetic and pharmacologic screens. Zebrafish larvae are optically transparent, facilitating the direct study of neural circuits. They also have a complex behavioral repertoire, including circadian rhythms, feeding, and sleep by the fifth day of development. Thus, the zebrafish model is uniquely suited for sleep studies, as it combines the genetic tractability of invertebrate models with the sleep-relevant neural anatomy and physiology of mammals. Using automated video-tracking software, we watch the sleep/wake behavior of hundreds of zebrafish larvae simultaneously over several days and nights. From the analysis of these large datasets, we search for genetic and chemical manipulations that alter the timing and duration of sleep episodes. For example, we tested the effects of thousands of small molecules in our assay and identified hundreds of pharmacological agents that robustly altered zebrafish sleep, including not only known sedatives and psychotropic compounds but also novel molecules not previously implicated in sleep/wake regulation. A major focus of the lab is now to combine molecular biology, genetics, and neural imaging techniques to identify the underlying neuronal circuits that are modulated by these sleep-altering compounds. We also study several sleep-altering neuropeptides that were identified as sleep/wake regulators in a genetic over-expression screen. In particular, we would like to know how these neuropeptide systems functionally interact with the hypocretin and other sleep-regulating neural circuits to orchestrate the observed behavioral dynamics of zebrafish sleep/wake cycles.