Narcolepsy in orexin Knockout Mice
Open accessAbstract
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.
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Orexin neurons are both necessary and sufficient for wakefulness.
“Orexin neurons are both necessary and sufficient for wakefulness.”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [40]
The Results (page unavailable) report that orexin knockout mice still spent time awake, although their awake time and episode duration decreased during the dark period. This contradicts the claim that orexin is necessary for wakefulness. The paper also does not establish that activating orexin neurons is sufficient to produce wakefulness; it concludes that orexin helps regulate sleep–wake states. (LLM, conf=0.87)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredOrexin knockout animals demonstrate the same amount of sleep overall compared to normal animals but have shorter bouts of sleep with more transitions between behavioral states.
“Orexin knockout animals demonstrate the same amount of sleep overall compared to normal animals but have shorter bouts of sleep with more transitions between behavioral states.39–41”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [40]
The Results (page unavailable) describe more fragmented non-REM sleep and more rapid cycling between sleep and wakefulness in knockout mice during the dark phase. They do not establish equal overall sleep: knockout mice spent more time in REM sleep during the dark phase, and their REM episodes were longer, not shorter. The reported shorter episodes were episodes of wakefulness. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIdentical symptoms occur in mice genetically lacking hypocretins.
“and identical symptoms occur in mice genetically lacking hypocretins.10”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [10]
The Discussion reports that mice lacking orexin (hypocretin) have narcoleptic attacks and sleep dysregulation remarkably similar to human narcolepsy. It does not establish that the symptoms are identical: the authors say they cannot clearly distinguish the mice’s narcoleptic from cataplectic episodes and note an EEG feature not reported in humans or dogs. (LLM, conf=0.82)
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- 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)
- 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
- bronze
- doi.org
- 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
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