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Resolving the Neuropharmacology and Genetics of Zebrafish Sleep

Final Report Summary - ZFISHSLEEP (Resolving the Neuropharmacology and Genetics of Zebrafish Sleep)

The regulation and function of sleep remains a fundamental mystery. Where in the brain is sleep regulated, what are the cues that modulate sleep, and how does sleep contribute to health and disease? In this project, we tackled these questions using the zebrafish as a model system for investigating sleep. Zebrafish are an excellent model to study sleep because they share most, if not all, of the signaling systems that are known to be at play in humans, they are optically transparent, which allows us to visualize the function of the brain during behavior, and they are amenable to genetic screening, which lets us identify novel regulators of sleep in an unbiased way. Importantly, they are awake during the day and asleep at night, like humans and unlike mice, which we believe may be important as we seek to understand how sleep is regulated in humans.

We took several approaches in this project to uncover the regulation of sleep. First, we made mutants in various genes that encode proteins involved in brain development and neuronal signaling, and then we observed the affect this had on sleep. This let us uncover animals that had specific defects in sleep, which told us something about how sleep is regulated. For example, we uncovered mutants that had normal activity during the day but hyperactivity at night. This tells us that the mechanisms that regulate activity during the day and the night may not be identical. Second, we found mutants that can initiate sleep but, once asleep, cannot maintain sleep, and vice versa. This suggests that the initiation and maintenance of sleep are differently regulated, a point that may be have clinical importance, as insomnia can be divided into problems falling asleep and difficulty maintaining sleep. Third, we found mutants that have altered responses to light, which usually wake up fish and humans, and darkness, which usually puts us to sleep. This gave us new clues about the mechanisms by which our brain responds to day and night. Fourth, we found that animals with changes in autism risk genes-- that is, humans with similar mutations have a high rate of autism spectrum disorder-- also have sleep defects. In one demonstration of how useful the zebrafish model may be for the discovery of new drugs, we were able to identify small molecules that brought the autism mutants' sleep back into the normal range. Finally, we used various imaging tool to map where in the brain changes had occurred in the mutants to affect sleep and other behaviors. This allowed us to map the functional circuits that are altered in sleep mutants and suggest pathways in the brain that are responsible for regulating sleep and arousal.

Together, these advances develop zebrafish as a useful tool to study sleep, one that we believe complements traditional mouse models. Using genetics, chemistry, and behavioral neuroscience, we have identified new pathways involved in regulating sleep. We hope that this knowledge will inform on new sleep treatments and will highlight the impact of sleep on the development and progress of disease.