ZFIN ID: ZDB-PERS-050502-7
Rihel, Jason
Email: j.rihel@ucl.ac.uk
URL: http://www.homepages.ucl.ac.uk/~ucbtjr3/index.html
Affiliation: Rihel Lab
Address: 1st Floor Department of Cell and Developmental Biology UCL Gower St. London WC1E 6BT, UK
Country: United Kingdom


In March 2012, Dr. Rihel joined the Department of Cell and Developmental Biology at UCL, where he is a Senior Research Fellow probing the mysteries of sleep in zebrafish. He started his career in behavioral genetics as an undergraduate in Dr. Jeff Price’s lab at West Virginia University (WVU) by investigating the fruit fly circadian clock mutant, double-time. After graduating from WVU summa cum laude with Honors, he joined Dr. Catherine Dulac’s lab for his PhD studies at Harvard University (1998-2004). In the Dulac lab on a Howard Hughes Medical Institute (HHMI) predoctoral fellowship, Dr. Rihel developed sensitive methods to observe gene expression in single cells, which he applied to studies on the molecular underpinnings of mouse pheromone detection. He cultivated his current research interests—understanding the genes and neurons that regulate sleep in zebrafish—while a Bristol-Myers Squibb Life Sciences Research Fellow in Dr. Alexander Schier’s lab, first at the Skirball Institute at the NYU School of Medicine and then at Harvard University.

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.

Suppermpool, A., Lyons, D.G., Broom, E., Rihel, J. (2024) Sleep pressure modulates single-neuron synapse number in zebrafish. Nature. 629(8012):639-645
Özcan, G.G., Lim, S., Canning, T., Tirathdas, L., Donnelly, J., Kundu, T., Rihel, J. (2024) Genetic and chemical disruption of amyloid precursor protein processing impairs zebrafish sleep maintenance. iScience. 27:108870108870
Barlow, I.L., Mackay, E., Wheater, E., Goel, A., Lim, S., Zimmerman, S., Woods, I., Prober, D.A., Rihel, J. (2023) The zebrafish mutant dreammist implicates sodium homeostasis in sleep regulation. eLIFE. 12:
Tornini, V.A., Miao, L., Lee, H.J., Gerson, T., Dube, S.E., Schmidt, V., Kroll, F., Tang, Y., Du, K., Kuchroo, M., Vejnar, C.E., Bazzini, A.A., Krishnaswamy, S., Rihel, J., Giraldez, A.J. (2023) linc-mipep and linc-wrb encode micropeptides that regulate chromatin accessibility in vertebrate-specific neural cells. eLIFE. 12:
Weinschutz Mendes, H., Neelakantan, U., Liu, Y., Fitzpatrick, S.E., Chen, T., Wu, W., Pruitt, A., Jin, D.S., Jamadagni, P., Carlson, M., Lacadie, C.M., Enriquez, K.D., Li, N., Zhao, D., Ijaz, S., Sakai, C., Szi, C., Rooney, B., Ghosh, M., Nwabudike, I., Gorodezky, A., Chowdhury, S., Zaheer, M., McLaughlin, S., Fernandez, J.M., Wu, J., Eilbott, J.A., Vander Wyk, B., Rihel, J., Papademetris, X., Wang, Z., Hoffman, E.J. (2023) High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways. Cell Reports. 42:112243112243
Tuschl, K., White, R.J., Trivedi, C., Valdivia, L.E., Niklaus, S., Bianco, I.H., Dadswell, C., González-Méndez, R., Sealy, I.M., Neuhauss, S.C.F., Houart, C., Rihel, J., Wilson, S.W., Busch-Nentwich, E.M. (2022) Loss of slc39a14 causes simultaneous manganese hypersensitivity and deficiency in zebrafish. Disease models & mechanisms. 15(6)
Kroll, F., Powell, G.T., Ghosh, M., Gestri, G., Antinucci, P., Hearn, T.J., Tunbak, H., Lim, S., Dennis, H.W., Fernandez, J.M., Whitmore, D., Dreosti, E., Wilson, S.W., Hoffman, E.J., Rihel, J. (2021) A simple and effective F0 knockout method for rapid screening of behaviour and other complex phenotypes. eLIFE. 10:
Bryant, D., Seda, M., Peskett, E., Maurer, C., Pomeranz, G., Ghosh, M., Hawkins, T.A., Cleak, J., Datta, S., Hariri, H., Eckert, K.M., Jafree, D.J., Walsh, C., Demetriou, C., Ishida, M., Alemán-Charlet, C., Vestito, L., Seselgyte, R., McDonald, J.G., Bitner-Glindzicz, M., Hemberger, M., Rihel, J., Teboul, L., Henne, W.M., Jenkins, D., Moore, G.E., Stanier, P. (2020) Diverse species-specific phenotypic consequences of loss of function sorting nexin 14 mutations. Scientific Reports. 10:13763
Özcan, G.G., Lim, S., Leighton, P., Allison, W.T., Rihel, J. (2020) Sleep is bi-directionally modified by amyloid beta oligomers. eLIFE. 9:
Lyons, D.G., Rihel, J. (2020) Sleep Circuits and Physiology in Non-Mammalian Systems. Current opinion in physiology. 15:245-255
Ghosh, M., Rihel, J. (2020) Hierarchical Compression Reveals Sub-Second to Day-Long Structure in Larval Zebrafish Behavior. eNeuro. 7(4):
Shibata-Germanos, S., Goodman, J.R., Grieg, A., Trivedi, C.A., Benson, B.C., Foti, S.C., Faro, A., Castellan, R.F.P., Correra, R.M., Barber, M., Ruhrberg, C., Weller, R.O., Lashley, T., Iliff, J.J., Hawkins, T.A., Rihel, J. (2019) Structural and functional conservation of non-lumenized lymphatic endothelial cells in the mammalian leptomeninges. Acta Neuropathologica. 139(2):383-401
Reichert, S., Pavón Arocas, O., Rihel, J. (2019) The Neuropeptide Galanin Is Required for Homeostatic Rebound Sleep following Increased Neuronal Activity. Neuron. 104(2):370-384.e5
Ashlin, T.G., Blunsom, N.J., Ghosh, M., Cockcroft, S., Rihel, J. (2018) Pitpnc1a Regulates Zebrafish Sleep and Wake Behavior through Modulation of Insulin-like Growth Factor Signaling. Cell Reports. 24:1389-1396
Rihel, J. (2018) Copper on the brain. Nature Chemical Biology. 14:638-639
Singh, C., Rihel, J., Prober, D.A. (2017) Neuropeptide Y Regulates Sleep by Modulating Noradrenergic Signaling. Current biology : CB. 27(24):3796-3811.e5
Shams, S., Rihel, J., Ortiz, J.G., Gerlai, R. (2017) The zebrafish as a promising tool for modeling human brain disorders: A review based upon an IBNS Symposium. Neuroscience and biobehavioral reviews. 85:176-190
Chen, S., Reichert, S., Singh, C., Oikonomou, G., Rihel, J., Prober, D.A. (2017) Light-Dependent Regulation of Sleep and Wake States by Prokineticin 2 in Zebrafish. Neuron. 95(1):153-168.e6
Barlow, I.L., Rihel, J. (2017) Zebrafish sleep: from geneZZZ to neuronZZZ. Current opinion in neurobiology. 44:65-71
van Lessen, M., Shibata-Germanos, S., van Impel, A., Hawkins, T.A., Rihel, J., Schulte-Merker, S. (2017) Intracellular uptake of macromolecules by brain lymphatic endothelial cells during zebrafish embryonic development. eLIFE. 6
Naumann, E.A., Fitzgerald, J.E., Dunn, T.W., Rihel, J., Sompolinsky, H., Engert, F. (2016) From Whole-Brain Data to Functional Circuit Models: The Zebrafish Optomotor Response. Cell. 167:947-960.e20
Tuschl, K., Meyer, E., Valdivia, L.E., Zhao, N., Dadswell, C., Abdul-Sada, A., Hung, C.Y., Simpson, M.A., Chong, W.K., Jacques, T.S., Woltjer, R.L., Eaton, S., Gregory, A., Sanford, L., Kara, E., Houlden, H., Cuno, S.M., Prokisch, H., Valletta, L., Tiranti, V., Younis, R., Maher, E.R., Spencer, J., Straatman-Iwanowska, A., Gissen, P., Selim, L.A., Pintos-Morell, G., Coroleu-Lletget, W., Mohammad, S.S., Yoganathan, S., Dale, R.C., Thomas, M., Rihel, J., Bodamer, O.A., Enns, C.A., Hayflick, S.J., Clayton, P.T., Mills, P.B., Kurian, M.A., Wilson, S.W. (2016) Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia. Nature communications. 7:11601
Hoffman, E.J., Turner, K.J., Fernandez, J.M., Cifuentes, D., Ghosh, M., Ijaz, S., Jain, R.A., Kubo, F., Bill, B.R., Baier, H., Granato, M., Barresi, M.J., Wilson, S.W., Rihel, J., State, M.W., Giraldez, A.J. (2016) Estrogens Suppress a Behavioral Phenotype in Zebrafish Mutants of the Autism Risk Gene, CNTNAP2. Neuron. 89(4):725-33
Chiu, C.N., Rihel, J., Lee, D.A., Singh, C., Mosser, E.A., Chen, S., Sapin, V., Pham, U., Engle, J., Niles, B.J., Montz, C.J., Chakravarthy, S., Zimmerman, S., Salehi-Ashtiani, K., Vidal, M., Schier, A.F., Prober, D.A. (2016) A Zebrafish Genetic Screen Identifies Neuromedin U as a Regulator of Sleep/Wake States. Neuron. 89:842-856
Davies, W.I., Tamai, T.K., Zheng, L., Fu, J.K., Rihel, J., Foster, R.G., Whitmore, D., Hankins, M.W. (2015) An extended family of novel vertebrate photopigments is widely expressed and displays a diversity of function. Genome research. 25(11):1666-79
Rihel, J., and Schier, A.F. (2013) Sites of action of sleep and wake drugs: insights from model organisms. Current opinion in neurobiology. 23(5):831-40
Rihel, J., and Schier, A.F. (2012) Behavioral screening for neuroactive drugs in zebrafish. Developmental Neurobiology. 72(3):373-385
Emran, F., Rihel, J., Adolph, A.R., and Dowling, J.E. (2010) Zebrafish larvae lose vision at night. Proceedings of the National Academy of Sciences of the United States of America. 107(13):6034-6039
Rihel, J., Prober, D.A., Arvanites, A., Lam, K., Zimmerman, S., Jang, S., Haggarty, S.J., Kokel, D., Rubin, L.L., Peterson, R.T., and Schier, A.F. (2010) Zebrafish behavioral profiling links drugs to biological targets and rest/wake regulation. Science (New York, N.Y.). 327(5963):348-351
Rihel, J., Prober, D.A., and Schier, A.F. (2010) Chapter 11 - Monitoring sleep and arousal in zebrafish. Methods in cell biology. 100:281-294
Emran, F., Rihel, J., and Dowling, J.E. (2008) A behavioral assay to measure responsiveness of zebrafish to changes in light intensities. Journal of visualized experiments : JoVE. (20)
Prober, D.A., Zimmerman, S., Myers, B.R., McDermott, B.M. Jr, Kim, S.H., Caron, S., Rihel, J., Solnica-Krezel, L., Julius, D., Hudspeth, A.J., and Schier, A.F. (2008) Zebrafish TRPA1 channels are required for chemosensation but not for thermosensation or mechanosensory hair cell function. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28(40):10102-10110
Emran, F., Rihel, J., Adolph, A.R., Wong, K.Y., Kraves, S., and Dowling, J.E. (2007) OFF ganglion cells cannot drive the optokinetic reflex in zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 104(48):19126-19131
Prober, D.A., Rihel, J., Onah, A.A., Sung, R.J., and Schier, A.F. (2006) Hypocretin/orexin overexpression induces an insomnia-like phenotype in zebrafish. The Journal of neuroscience : the official journal of the Society for Neuroscience. 26(51):13400-13410
Giraldez, A.J., Mishima, Y., Rihel, J., Grocock, R.J., Van Dongen, S., Inoue, K., Enright, A.J., and Schier, A.F. (2006) Zebrafish MiR-430 Promotes Deadenylation and Clearance of Maternal mRNAs. Science (New York, N.Y.). 312(5770):75-79