[ { "id": "authors:n1za8-wn592", "collection": "authors", "collection_id": "n1za8-wn592", "cite_using_url": "https://authors.library.caltech.edu/records/n1za8-wn592", "type": "article", "title": "Melatonin promotes sleep by suppressing responses to visual stimuli via MT1 receptors", "author": [ { "family_name": "Hill", "given_name": "Andrew J.", "orcid": "0000-0002-4621-0500", "clpid": "Hill-Andrew-James" }, { "family_name": "Eliopoulos", "given_name": "Olivia", "orcid": "0000-0002-8887-9456" }, { "family_name": "Emtage", "given_name": "Jasmine", "orcid": "0000-0002-6748-4172" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "

Sleep is regulated by a homeostatic process that increases sleep propensity with time spent awake and a circadian process that determines when most sleep occurs during the 24-h circadian cycle. While several factors mediate homeostatic regulation of sleep in a partially redundant manner, circadian regulation of sleep is abolished in zebrafish that lack melatonin, indicating that melatonin is indispensable for circadian regulation of sleep in this diurnal species. However, the mechanisms through which melatonin promotes sleep are unclear. Here, we show that melatonin is both necessary and sufficient for sleep in zebrafish due to signaling via melatonin receptor 1a paralogs. We found that these receptors are highly expressed in neurons that receive and process visual information and that melatonin suppresses behavioral responses to visual stimuli. These results indicate that circadian regulation of sleep is implemented, at least in part, by the suppression of responses to environmental stimuli, which is an essential feature of sleep.

", "doi": "10.1016/j.cub.2026.03.059", "issn": "0960-9822", "publisher": "Elsevier", "publication": "Current Biology", "publication_date": "2026-05-04", "series_number": "9", "volume": "36", "issue": "9", "pages": "1-15" }, { "id": "authors:skrdt-ewv72", "collection": "authors", "collection_id": "skrdt-ewv72", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20220421-752293600", "type": "article", "title": "Large-scale Analysis of Sleep in Zebrafish", "author": [ { "family_name": "Lee", "given_name": "Daniel A.", "orcid": "0000-0001-7411-2740", "clpid": "Lee-Daniel-A" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "Over the past decade, zebrafish have emerged as a powerful model for the study of vertebrate sleep and wake behaviors. Experimental evidence has demonstrated behavioral, anatomical, genetic, and pharmacological conservation of sleep between zebrafish and mammals, suggesting that discoveries in zebrafish can inform our understanding of mammalian sleep. Here, we describe a protocol for performing sleep behavioral experiments in larval zebrafish, using a high-throughput video tracking system. We explain how to set up a sleep behavioral experiment and provide guidelines on how to analyze the data. Using this protocol, a typical experiment can be completed in less than five days, and this method provides a scalable platform to perform genetic and pharmacological screens in a simple and cost-effective vertebrate model. By combining high-throughput behavioral assays with several advantageous features of zebrafish, this model system provides new opportunities to make discoveries that clarify the genetic and neurological mechanisms that regulate sleep.", "doi": "10.21769/bioprotoc.4313", "issn": "2331-8325", "publisher": "Bio-Protocol", "publication": "Bio-protocol", "publication_date": "2022-02-05", "series_number": "3", "volume": "12", "issue": "3", "pages": "Art. No. e4313" }, { "id": "authors:e6w2s-sht53", "collection": "authors", "collection_id": "e6w2s-sht53", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20200102-084029093", "type": "article", "title": "Neuropeptide VF neurons promote sleep via the serotonergic raphe", "author": [ { "family_name": "Lee", "given_name": "Daniel A.", "orcid": "0000-0001-7411-2740", "clpid": "Lee-Daniel-A" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Cammidge", "given_name": "Tasha", "clpid": "Cammidge-Tasha" }, { "family_name": "Andreev", "given_name": "Andrey", "orcid": "0000-0002-7833-1390", "clpid": "Andreev-Andrey" }, { "family_name": "Hong", "given_name": "Young", "orcid": "0000-0001-9548-5511", "clpid": "Hong-Young" }, { "family_name": "Hurley", "given_name": "Hannah", "clpid": "Hurley-Hannah" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "Although several sleep-regulating neuronal populations have been identified, little is known about how they interact with each other to control sleep/wake states. We previously identified neuropeptide VF (NPVF) and the hypothalamic neurons that produce it as a sleep-promoting system (Lee et al., 2017). Here we show using zebrafish that npvf-expressing neurons control sleep via the serotonergic raphe nuclei (RN), a hindbrain structure that is critical for sleep in both diurnal zebrafish and nocturnal mice. Using genetic labeling and calcium imaging, we show that npvf-expressing neurons innervate and can activate serotonergic RN neurons. We also demonstrate that chemogenetic or optogenetic stimulation of npvf-expressing neurons induces sleep in a manner that requires NPVF and serotonin in the RN. Finally, we provide genetic evidence that NPVF acts upstream of serotonin in the RN to maintain normal sleep levels. These findings reveal a novel hypothalamic-hindbrain neuronal circuit for sleep/wake control.", "doi": "10.7554/eLife.54491", "pmcid": "PMC7748413", "issn": "2050-084X", "publisher": "eLife Sciences Publications", "publication": "eLife", "publication_date": "2020-12-18", "volume": "9", "pages": "Art. No. e54491" }, { "id": "authors:z0ajw-09t69", "collection": "authors", "collection_id": "z0ajw-09t69", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20191115-152248915", "type": "article", "title": "Evolutionarily conserved regulation of sleep by epidermal growth factor receptor signaling", "author": [ { "family_name": "Lee", "given_name": "Daniel A.", "orcid": "0000-0001-7411-2740", "clpid": "Lee-Daniel-A" }, { "family_name": "Liu", "given_name": "Justin", "orcid": "0000-0002-5338-6491", "clpid": "Liu-Justin" }, { "family_name": "Hong", "given_name": "Young", "orcid": "0000-0001-9548-5511", "clpid": "Hong-Young" }, { "family_name": "Lane", "given_name": "Jacqueline M.", "orcid": "0000-0001-6101-2855", "clpid": "Lane-Jacqueline-M" }, { "family_name": "Hill", "given_name": "Andrew J.", "clpid": "Hill-Andrew-J" }, { "family_name": "Hou", "given_name": "Sarah L.", "clpid": "Hou-Sarah-L" }, { "family_name": "Wang", "given_name": "Heming", "orcid": "0000-0002-1486-7495", "clpid": "Wang-Heming-MED" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Pham", "given_name": "Uyen", "clpid": "Pham-Uyen" }, { "family_name": "Engle", "given_name": "Jae", "clpid": "Engle-Jae" }, { "family_name": "Saxena", "given_name": "Richa", "orcid": "0000-0003-2233-1065", "clpid": "Saxena-Richa" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "The genetic bases for most human sleep disorders and for variation in human sleep quantity and quality are largely unknown. Using the zebrafish, a diurnal vertebrate, to investigate the genetic regulation of sleep, we found that epidermal growth factor receptor (EGFR) signaling is necessary and sufficient for normal sleep levels and is required for the normal homeostatic response to sleep deprivation. We observed that EGFR signaling promotes sleep via mitogen-activated protein kinase/extracellular signal\u2013regulated kinase and RFamide neuropeptide signaling and that it regulates RFamide neuropeptide expression and neuronal activity. Consistent with these findings, analysis of a large cohort of human genetic data from participants of European ancestry revealed that common variants in genes within the EGFR signaling pathway are associated with variation in human sleep quantity and quality. These results indicate that EGFR signaling and its downstream pathways play a central and ancient role in regulating sleep and provide new therapeutic targets for sleep disorders.", "doi": "10.1126/sciadv.aax4249", "pmcid": "PMC6853770", "issn": "2375-2548", "publisher": "American Association for the Advancement of Science", "publication": "Science Advances", "publication_date": "2019-11", "series_number": "11", "volume": "5", "issue": "11", "pages": "Art. No. eaax4249" }, { "id": "authors:tvp5y-12b43", "collection": "authors", "collection_id": "tvp5y-12b43", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20190624-113552525", "type": "article", "title": "The Serotonergic Raphe Promote Sleep in Zebrafish and Mice", "author": [ { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Altermatt", "given_name": "Michael", "orcid": "0000-0003-2841-5374", "clpid": "Altermatt-Michael" }, { "family_name": "Zhang", "given_name": "Rong-wei", "orcid": "0000-0003-1145-8589", "clpid": "Zhang-Rong-wei" }, { "family_name": "Coughlin", "given_name": "Gerard M.", "clpid": "Coughlin-Gerard-M" }, { "family_name": "Montz", "given_name": "Christin", "clpid": "Montz-Christin" }, { "family_name": "Gradinaru", "given_name": "Viviana", "orcid": "0000-0001-5868-348X", "clpid": "Gradinaru-V" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "The role of serotonin (5-HT) in sleep is controversial: early studies suggested a sleep-promoting role, but eventually the paradigm shifted toward a wake-promoting function for the serotonergic raphe. Here, we provide evidence from zebrafish and mice that the raphe are critical for the initiation and maintenance of sleep. In zebrafish, genetic ablation of 5-HT production by the raphe reduces sleep, sleep depth, and the homeostatic response to sleep deprivation. Pharmacological inhibition or ablation of the raphe reduces sleep, while optogenetic stimulation increases sleep. Similarly, in mice, ablation of the raphe increases wakefulness and impairs the homeostatic response to sleep deprivation, whereas tonic optogenetic stimulation at a rate similar to baseline activity induces sleep. Interestingly, burst optogenetic stimulation induces wakefulness in accordance with previously described burst activity of the raphe during arousing stimuli. These results indicate that the serotonergic system promotes sleep in both diurnal zebrafish and nocturnal rodents.", "doi": "10.1016/j.neuron.2019.05.038", "pmcid": "PMC6706304", "issn": "0896-6273", "publisher": "Cell Press", "publication": "Neuron", "publication_date": "2019-08-21", "series_number": "4", "volume": "103", "issue": "4", "pages": "686-701" }, { "id": "authors:j3w9p-mpa87", "collection": "authors", "collection_id": "j3w9p-mpa87", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170623-125222628", "type": "article", "title": "Light-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish", "author": [ { "family_name": "Chen", "given_name": "Shijia", "clpid": "Chen-Shijia" }, { "family_name": "Reichert", "given_name": "Sabine", "clpid": "Reichert-Sabine" }, { "family_name": "Singh", "given_name": "Chanpreet", "orcid": "0000-0002-2697-3033", "clpid": "Singh-Chanpreet" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Rihel", "given_name": "Jason", "orcid": "0000-0003-4067-2066", "clpid": "Rihel-Jason" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "Light affects sleep and wake behaviors by providing an indirect cue that entrains circadian rhythms and also by inducing a direct and rapid regulation of behavior. While circadian entrainment by light is well characterized at the molecular level, mechanisms that underlie the direct effect of light on behavior are largely unknown. In zebrafish, a diurnal vertebrate, we found that both overexpression and mutation of the neuropeptide prokineticin 2 (Prok2) affect sleep and wake behaviors in a light-dependent but circadian-independent manner. In light, Prok2 overexpression increases sleep and induces expression of galanin (galn), a hypothalamic sleep-inducing peptide. We also found that light-dependent, Prok2-induced sedation requires prokineticin receptor 2 (prokr2) and is strongly suppressed in galn mutants. These results suggest that Prok2 antagonizes the direct wake-promoting effect of light in zebrafish, in part through the induction of galn expression in the hypothalamus.", "doi": "10.1016/j.neuron.2017.06.001", "pmcid": "PMC5653285", "issn": "0896-6273", "publisher": "Cell Press", "publication": "Neuron", "publication_date": "2017-07-05", "series_number": "1", "volume": "95", "issue": "1", "pages": "153-168" }, { "id": "authors:bn0pt-9aq07", "collection": "authors", "collection_id": "bn0pt-9aq07", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170410-104149609", "type": "article", "title": "Attacking sleep from a new angle: contributions from zebrafish", "author": [ { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "Sleep consumes a third of our lifespan, but we are far from understanding how it is initiated, maintained and terminated, or what purposes it serves. To address these questions, alternative model systems have recently been recruited. The diurnal zebrafish holds the promise of bridging the gap between simple invertebrate systems, which show little neuroanatomical conservation with mammals, and well-established, but complex and nocturnal, murine systems. Zebrafish larvae can be monitored in a high-throughput fashion, pharmacologically tested by adding compounds into the water, genetically screened using transient transgenesis, and optogenetically manipulated in a non-invasive manner. Here we discuss work that has established the zebrafish as a powerful system for the study of sleep, as well as novel insights gained by exploiting its particular advantages.", "doi": "10.1016/j.conb.2017.03.009", "pmcid": "PMC5659277", "issn": "0959-4388", "publisher": "Elsevier", "publication": "Current Opinion in Neurobiology", "publication_date": "2017-06", "volume": "44", "pages": "80-88" }, { "id": "authors:1eymx-4xn31", "collection": "authors", "collection_id": "1eymx-4xn31", "cite_using_url": "https://resolver.caltech.edu/CaltechAUTHORS:20170313-124518512", "type": "article", "title": "Genetic Analysis of Histamine Signaling in Larval Zebrafish Sleep", "author": [ { "family_name": "Chen", "given_name": "Audrey", "orcid": "0000-0003-2139-9535", "clpid": "Chen-Audrey" }, { "family_name": "Singh", "given_name": "Chanpreet", "orcid": "0000-0002-2697-3033", "clpid": "Singh-Chanpreet" }, { "family_name": "Oikonomou", "given_name": "Grigorios", "orcid": "0000-0001-6797-7375", "clpid": "Oikonomou-Grigorios" }, { "family_name": "Prober", "given_name": "David A.", "orcid": "0000-0002-7371-4675", "clpid": "Prober-D-A" } ], "abstract": "Pharmacological studies in mammals and zebrafish suggest that histamine plays an important role in promoting arousal. However, genetic studies using rodents with disrupted histamine synthesis or signaling have revealed only subtle or no sleep/wake phenotypes. Studies of histamine function in mammalian arousal are complicated by its production in cells of the immune system and its roles in humoral and cellular immunity, which can have profound effects on sleep/wake states. To avoid this potential confound, we used genetics to explore the role of histamine in regulating sleep in zebrafish, a diurnal vertebrate in which histamine production is restricted to neurons in the brain. Similar to rodent genetic studies, we found that zebrafish that lack histamine due to mutation of histidine decarboxylase (hdc) exhibit largely normal sleep/wake behaviors. Zebrafish containing predicted null mutations in several histamine receptors also lack robust sleep/wake phenotypes, although we are unable to verify that these mutants are completely nonfunctional. Consistent with some rodent studies, we found that arousal induced by overexpression of the neuropeptide hypocretin (Hcrt) or by stimulation of hcrt-expressing neurons is not blocked in hdc or hrh1 mutants. We also found that the number of hcrt-expressing or histaminergic neurons is unaffected in animals that lack histamine or Hcrt signaling, respectively. Thus, while acute pharmacological manipulation of histamine signaling has been shown to have profound effects on zebrafish and mammalian sleep, our results suggest that chronic loss of histamine signaling due to genetic mutations has only subtle effects on sleep in zebrafish, similar to rodents.", "doi": "10.1523/ENEURO.0286-16.2017", "pmcid": "PMC5334454", "issn": "2373-2822", "publisher": "Society for Neuroscience", "publication": "eNeuro", "publication_date": "2017-01", "series_number": "1", "volume": "4", "issue": "1", "pages": "Art. No. e0286-16.2017" } ]