Sleep-like states are conserved throughout evolution, and chronic sleep disorders affect over 10% of humans. However, the genetic and neural mechanisms that regulate sleep remain poorly understood. Most sleep studies have used nocturnal mammals such as mice and rats, but it is unclear whether circadian aspects of sleep regulation are conserved with diurnal mammals such as humans. I will exploit the relatively simple yet conserved neural circuits and optical transparency of the zebrafish, a diurnal vertebrate, to test several hypotheses regarding the role of Prokineticin 2 in regulating sleep and circadian behaviors. First, I will test the hypothesis that Prokineticin 2 acts as a circadian signal to inhibit locomotor activity by performing gain and loss of function genetic experiments using high throughput locomotor activity and arousal threshold assays. Second, I will test the hypothesis that Prokineticin 2 neurons are active at night in zebrafish larvae using a bioluminescence reporter that monitors the activities of genetically specified neurons in freely behaving zebrafish larvae. Third, I will test the hypothesis that Prokinectin 2 inhibits wake-promoting neurons and activates sleep-promoting neurons by monitoring the activities of these neural populations in response to Prokineticin 2 overexpression. These experiments have the potential to clarify the neural mechanisms that mediate circadian output and regulate sleep, which may lead to new therapies for sleep and circadian related disorders.

Public Health Relevance

Sleep is essential for survival and maintaining cognitive function, and chronic sleep disorders such as insomnia and narcolepsy affect over 10% of the population, but the mechanisms that regulate sleep are poorly understood. I will examine the roles of in Prokineticin 2 in regulating sleep and circadian behaviors in zebrafish, offering the potential to improve our understanding of how sleep is regulated by circadian cues and to lead to novel therapies for the treatment of sleep and circadian related disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-N (20))
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Gnadt, James W
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California Institute of Technology
Schools of Arts and Sciences
United States
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Chen, Shijia; Reichert, Sabine; Singh, Chanpreet et al. (2017) Light-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish. Neuron 95:153-168.e6
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