CoChat
Sign Up
Cited by 3,095Sleep and Wakefulness ResearchNeuroscience of respiration and sleepCircadian rhythm and melatonin

The DOI matches its Crossref record; 2 of the 2 references it cites were found in a registry or an index.

Narcolepsy in orexin Knockout Mice

Open access
Chemelli, Richard M., Willie, Jon T., Sinton, Christopher M., Elmquist, Joel K., Scammell, Thomas, Lee, Charlotte, Richardson, James A., Williams, S.Clay, Xiong, Yumei, Kisanuki, Yaz, Fitch, Thomas E., Nakazato, Masamitsu, Hammer, Robert E., Saper, Clifford B., Yanagisawa, Masashi·1999·Cell
DOI 10.1016/s0092-8674(00)81973-x
Open this paper in CoChat — free accountOpen PDF

Abstract

Neurons containing the neuropeptide orexin (hypocretin) are located exclusively in the lateral hypothalamus and send axons to numerous regions throughout the central nervous system, including the major nuclei implicated in sleep regulation. Here, we report that, by behavioral and electroencephalographic criteria, orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, as well as canarc-1 mutant dogs, the only known monogenic model of narcolepsy. Moreover, modafinil, an anti-narcoleptic drug with ill-defined mechanisms of action, activates orexin-containing neurons. We propose that orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1016/s0092-8674(00)81973-x

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 2 references

Research works printed but not linked: 48

  1. Aldrich, 1998, Diagnostic aspects of narcolepsy, Neurology, 50, S2, 10.1212/WNL.50.2_Suppl_1.S2 · DOI
  2. Aston-Jones, 1981, Activity of norepinephrine containing locus coeruleus neurons in behaving rats anticipates fluctuations in the sleep-waking cycle, J. Neurosci, 1, 876, 10.1523/JNEUROSCI.01-08-00876.1981 · DOI · Paper page
  3. Baker, 1982, Canine model of narcolepsy, Exp. Neurol, 75, 729, 10.1016/0014-4886(82)90038-3 · DOI
  4. Baker, 1986, Comparative polysomnographic study of narcolepsy and idiopathic central nervous system hypersomnia, Sleep, 9, 232, 10.1093/sleep/9.1.232 · DOI
  5. Barone, 1981, Afferent connections to the lateral hypothalamus, Brain Res. Bull, 7, 75, 10.1016/0361-9230(81)90101-5 · DOI
  6. Bassetti, 1996, Narcolepsy, Neurol. Clinics, 14, 545, 10.1016/S0733-8619(05)70273-5 · DOI
  7. Bernardis, 1996, The lateral hypothalamic area revisited, Neurosci. Biobehav. Rev, 20, 189, 10.1016/0149-7634(95)00015-1 · DOI
  8. Date, 1999, Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems, Proc. Natl. Acad. Sci. USA, 96, 748, 10.1073/pnas.96.2.748 · DOI
  9. Elias, 1998, Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area, J. Comp. Neurol, 402, 442, 10.1002/(SICI)1096-9861(19981228)402:4<442::AID-CNE2>3.0.CO;2-R · DOI
  10. Elias, 1998, Leptin activates hypothalamic CART neurons projecting to the spinal cord, Neuron, 21, 1375, 10.1016/S0896-6273(00)80656-X · DOI
  11. Ellis, 1998, Proton spectroscopy in the narcoleptic syndrome, Neurology, 50, S23, 10.1212/WNL.50.2_Suppl_1.S23 · DOI
  12. Elmquist, 1998, Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei, Proc. Natl. Acad. Sci. USA, 95, 741, 10.1073/pnas.95.2.741 · DOI
  13. Glin, 1991, The intermediate stage of sleep in mice, Physiol. Behav, 50, 951, 10.1016/0031-9384(91)90420-S · DOI
  14. Gottesmann, 1996, The transition from slow-wave sleep to paradoxical sleep, Neurosci. Biobehav. Rev, 20, 367, 10.1016/0149-7634(95)00055-0 · DOI
  15. Guilleminault, 1998, Investigations into the neurologic basis of narcolepsy, Neurology, 50, S8, 10.1212/WNL.50.2_Suppl_1.S8 · DOI
  16. Hishikawa, 1976, Sleep satiation in narcoleptic patients, Electroencephalogr. Clin. Neurophysiol, 41, 1, 10.1016/0013-4694(76)90210-8 · DOI
  17. Jones, 1998, The neural basis of consciousness across the sleep-waking cycle, Adv. Neurol, 77, 75
  18. Kadotani, 1998, Genetic studies in the sleep disorder narcolepsy, Genome Res, 8, 427, 10.1101/gr.8.5.427 · DOI
  19. Koizumi, 1976, Circadian and other rhythmic activity of neurons in the ventromedial nuclei and lateral hypothalamus area, J. Physiol, 263, 331, 10.1113/jphysiol.1976.sp011634 · DOI
  20. Kushida, 1985, Electroencephalographic correlates of cataplectic attacks in narcoleptic canines, Electroencephalogr. Clin. Neurophysiol, 61, 61, 10.1016/0013-4694(85)91073-9 · DOI
  21. Lin, 1996, Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat, Proc. Natl. Acad. Sci. USA, 93, 14128, 10.1073/pnas.93.24.14128 · DOI
  22. Lin, 1999, The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene, Cell, 98, 365, 10.1016/S0092-8674(00)81965-0 · DOI · Paper page
  23. Lucas, 1979, Sleep cycle organization in narcoleptic and normal dogs, Brain Res, 23, 737
  24. McGinty, 1976, Dorsal raphe neurons, Brain Res, 101, 569, 10.1016/0006-8993(76)90480-7 · DOI
  25. Mignot, 1998, Genetic and familial aspects of narcolepsy, Neurology, 50, S16, 10.1212/WNL.50.2_Suppl_1.S16 · DOI
  26. Mikkelsen, 1990, A neuronal projection from the lateral geniculate nucleus to the lateral hypothalamus of the rat demonstrated with Phaseolus vulgaris leucoagglutinin tracing, Neurosci. Lett, 116, 58, 10.1016/0304-3940(90)90386-N · DOI
  27. Mitler, 1977, Sleep studies on canine narcolepsy, Electroencephalogr. Clin. Neurophysiol, 43, 691, 10.1016/0013-4694(77)90084-0 · DOI
  28. Mondal, 1999, Widespread distribution of orexin in rat brain and its regulation upon fasting, Biochem. Biophys. Res. Commun, 256, 495, 10.1006/bbrc.1999.0362 · DOI
  29. Montplaisir, 1978, Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption, Biol. Psychiatr, 13, 73
  30. Nambu, 1999, Distribution of orexin neurons in the adult rat Brain, Brain Res, 827, 243, 10.1016/S0006-8993(99)01336-0 · DOI
  31. Nishino, 1997, Pharmacological aspects of human and canine narcolepsy, Prog. Neurobiol, 52, 27, 10.1016/S0301-0082(96)00070-6 · DOI
  32. Nishino, 1995, Muscle atonia is triggered by cholinergic stimulation of the basal forebrain, J. Neurosci, 15, 4806, 10.1523/JNEUROSCI.15-07-04806.1995 · DOI
  33. Radulovacki, 1984, Adenosine analogs and sleep in rats, J. Pharmacol. Exp. Ther, 228, 268, 10.1016/S0022-3565(25)21636-6 · DOI
  34. Riehl, 1998, Development of cataplexy in genetically narcoleptic dobermans, Exp. Neurol, 152, 292, 10.1006/exnr.1998.6847 · DOI
  35. Risold, 1999, Preprohypocretin (orexin) and prolactin-like immunoreactivity are coexpressed by neurons of the rat lateral hypothalamic area, Neurosci. Lett, 259, 153, 10.1016/S0304-3940(98)00906-9 · DOI
  36. Rye, 1997, Contributions of the pedunculopontine region to normal and altered REM sleep, Sleep, 20, 757, 10.1093/sleep/20.9.757 · DOI
  37. Sakurai, 1998, Orexins and orexin receptors, Cell, 92, 573, 10.1016/S0092-8674(00)80949-6 · DOI · Paper page
  38. Sakurai, 1999, Structure and function of human prepro-orexin gene, J. Biol. Chem, 274, 17771, 10.1074/jbc.274.25.17771 · DOI
  39. Sherin, 1996, Activation of ventrolateral proptic neurons during sleep, Science, 271, 216, 10.1126/science.271.5246.216 · DOI · Paper page
  40. Sherin, 1998, Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat, J. Neurosci, 18, 4705, 10.1523/JNEUROSCI.18-12-04705.1998 · DOI
  41. Steriade, 1990, Neuronal activities in brain-stem cholinergic nuclei related to tonic activation processes in thalamocortical systems, J. Neurosci, 10, 2541, 10.1523/JNEUROSCI.10-08-02541.1990 · DOI
  42. Tafti, 1997, Localization of candidate genomic regions influencing paradoxical sleep in mice, Neuroreport, 8, 3755, 10.1097/00001756-199712010-00019 · DOI
  43. Trivedi, 1999, Distribution of orexin receptor mRNA in the rat brain, FEBS Lett, 438, 71, 10.1016/S0014-5793(98)01266-6 · DOI
  44. van den Pol, 1999, Hypothalamic hypocretin (orexin), J. Neurosci, 19, 3171, 10.1523/JNEUROSCI.19-08-03171.1999 · DOI
  45. van den Pol, 1998, Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, Hypocretin/Orexin, J. Neurosci, 18, 7962, 10.1523/JNEUROSCI.18-19-07962.1998 · DOI
  46. Vanni-Mercier, 1984, “Waking-state specific” neurons in the caudal hypothalamus of the cat, C. R. Acad. Sci. III, 298, 195
  47. Yanagiawa, 1998, Dual genetic pathways of endothelin-mediated intercellular signaling revealed by targeted disruption of endothelin converting enzyme-1 gene, Development, 125, 825, 10.1242/dev.125.5.825 · DOI
  48. Zorick, 1982, Patterns of sleepiness in various disorders of excessive daytime somnolence, Sleep, 5, S165, 10.1093/sleep/5.S2.S165 · DOI

Cited by

Sorted by citations

Metadata

Authors
Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., Richardson, J. A., Williams, S. C., Xiong, Y., Kisanuki, Y., Fitch, T. E., Nakazato, M., Hammer, R. E., Saper, C. B., & Yanagisawa, M.
Affiliations
  • Howard Hughes Medical Institute (US)
  • The University of Texas Southwestern Medical Center (US)
  • Beth Israel Deaconess Medical Center (US)
  • University of Miyazaki (JP)
Corresponding author
Yanagisawa, Masashi
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
1999-08
Volume
98
Issue
4
Pages
437-451
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/s0092-8674(00)81973-x
OpenAlex
W2072154498
Cited by
3,095
References
2
Citations by year
2026: 46 · 2025: 73 · 2024: 75 · 2023: 82 · 2022: 89 · 2021: 83 · 2020: 86 · 2019: 110 · 2018: 111 · 2017: 106 · 2016: 126 · 2015: 124 · 2014: 125 · 2013: 152 · 2012: 141
FWCI
67.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Diabetes and Digestive and Kidney Diseases (DK53301)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Keywords
narcolepsy, orexin, orexin knockout mice, sleep regulation, REM sleep, sleep-wake behavior, modafinil, lateral hypothalamus
MeSH terms
Orexins, Modafinil, Animals, Benzhydryl Compounds, Carrier Proteins, Disease Models, Animal, Dog Diseases, Dogs, Electroencephalography, Electromyography, Humans, Hypothalamus, Male, Mice, Inbred C57BL, Narcolepsy, Neurons, Neuropeptides, Phenotype, Posture, Protein Precursors, Sleep, Sleep, REM, Species Specificity, Stereotyped Behavior, Age of Onset, Receptors, Neuropeptide, Mice, Knockout, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review