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The Genetic and Neuronal Substrates of Melatonin Signaling in Zebrafish Sleep


Hill, Andrew James (2024) The Genetic and Neuronal Substrates of Melatonin Signaling in Zebrafish Sleep. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/4sba-6h56.


Sleep is hypothesized to be regulated by two processes: a circadian drive, which communicates time of day to ensure that sleep is timed to the appropriate day/night phase, and a homeostatic drive, by which the propensity for sleep becomes stronger over the course of prolonged wakefulness. While studies suggest that adenosine and serotonin signaling in part mediate the homeostatic sleep drive, factors that act downstream of the circadian clock to promote sleep were unidentified until recently. Previous work in the Prober lab has shown that the nocturnal hormone melatonin acts downstream of the circadian rhythm to promote sleep in zebrafish. The downstream processes by which melatonin promotes sleep is poorly understood across all animal models. This is likely because melatonin research has been primarily conducted using nocturnal laboratory rodent models, in whom melatonin does not seem to play a role in sleep, and because of the widely held view that melatonin informs the circadian clock and does not promote sleep directly. In Chapter 1 of this thesis, I review some of the research conducted over the last 50 years that has informed our current understanding of melatonin and its role in sleep. In Chapter 2, I describe our efforts to use the zebrafish, in which melatonin is both potently sedating and essential for nightly sleep, to uncover some of the mechanisms by which melatonin might promote sleep. We found that melatonin acts through a particular melatonin receptor family called MT1, whereas melatonin receptors belonging to other families were dispensable for sleep. We show that MT1 receptors are expressed broadly throughout the zebrafish brain and are enriched in brain regions involved in sensory processing, particularly in those related to vision. We tested the hypothesis that melatonin promotes sleep, at least in part, by dampening visual responsiveness at night. We show that, separable from sleep, exogenous melatonin suppresses behavioral responses to light stimuli, and loss of endogenous melatonin results in day-like behavioral responses to light stimuli during the night. We are using whole brain imaging in live zebrafish to corroborate our behavioral results with neuronal GCaMP recordings. We hope that the findings presented here contribute to a greater understanding of melatonin’s role in sleep, which may help enhance its value as a natural therapeutic aid.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:melatonin, sleep, zebrafish
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Biology
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Prober, David A.
Thesis Committee:
  • Gradinaru, Viviana (chair)
  • Hong, Elizabeth J.
  • Sternberg, Paul W.
  • Prober, David A.
Defense Date:15 September 2023
Funding AgencyGrant Number
National Institute of Neurological Disorders and Stroke1F31NS105487
Record Number:CaltechTHESIS:09282023-003458037
Persistent URL:
Hill, Andrew James0000-0002-4621-0500
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:16194
Deposited By: Andrew Hill
Deposited On:04 Oct 2023 17:04
Last Modified:12 Oct 2023 21:19

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