Distinct Narcolepsy Syndromes in Orexin Receptor-2 and Orexin Null Mice
Open accessAbstract
Narcolepsy-cataplexy, a neurological disorder associated with the absence of hypothalamic orexin (hypocretin) neuropeptides, consists of two underlying problems: inability to maintain wakefulness and intrusion of rapid eye movement (REM) sleep into wakefulness. Here we document, using behavioral, electrophysiological, and pharmacological criteria, two distinct classes of behavioral arrests exhibited by mice deficient in orexin-mediated signaling. Both OX2R(-/-) and orexin(-/-) mice are similarly affected with behaviorally abnormal attacks of non-REM sleep ("sleep attacks") and show similar degrees of disrupted wakefulness. In contrast, OX2R(-/-) mice are only mildly affected with cataplexy-like attacks of REM sleep, whereas orexin(-/-) mice are severely affected. Absence of OX2Rs eliminates orexin-evoked excitation of histaminergic neurons in the hypothalamus, which gate non-REM sleep onset. While normal regulation of wake/non-REM sleep transitions depends critically upon OX2R activation, the profound dysregulation of REM sleep control unique to the narcolepsy-cataplexy syndrome emerges from loss of signaling through both OX2R-dependent and OX2R-independent pathways.
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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 [39]
The sleep/wake findings report awake episodes in orexin-null mice, so orexin is not necessary for wakefulness itself. The Conclusions say orexin helps maintain wakefulness through OX2R signaling, a narrower point. The paper also does not establish that orexin neurons are sufficient for wakefulness. (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 [39]
The sleep/wake analysis (indexed as Abstract; page unavailable) reports shorter non-REM sleep bouts and more frequent waking and non-REM episodes in orexin-null mice than in wild-type controls. It does not establish that their total sleep time was the same; it reports only nonsignificant changes in dark-phase non-REM sleep and a significant increase in dark-phase REM sleep. (LLM, conf=0.86)
Experimental — accuracy not yet measuredWithout orexin or with altered orexin receptors, humans and animals experience narcolepsy.
“Without orexin or with altered orexin receptors, humans and animals experience narcolepsy,34–39”
From Effects of Traumatic Brain Injury on the Orexin/Hypocretin System (2025) · cites this paper as [39]
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Cites
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- Authors
- Willie, J. T., Chemelli, R. M., Sinton, C. M., Tokita, S., Williams, S. C., Kisanuki, Y. Y., Marcus, J. N., Lee, C., Elmquist, J. K., Kohlmeier, K. A., Leonard, C. S., Richardson, J. A., Hammer, R. E., & Yanagisawa, M.
- Affiliations
- Howard Hughes Medical Institute (US)
- The University of Texas Southwestern Medical Center (US)
- Beth Israel Deaconess Medical Center (US)
- New York Medical College (US)
- Corresponding author
- Yanagisawa, Masashi
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2003-06
- Volume
- 38
- Issue
- 5
- Pages
- 715-730
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W1977320288
- Cited by
- 645
- References
- 3
- Citations by year
- 2026: 6 · 2025: 28 · 2024: 20 · 2023: 25 · 2022: 18 · 2021: 22 · 2020: 24 · 2019: 18 · 2018: 26 · 2017: 28 · 2016: 31 · 2015: 26 · 2014: 38 · 2013: 56 · 2012: 39
- FWCI
- 14.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 3699 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Science and Technology Corporation
- National Institutes of Health (NS27881, HL64150, MH61583, DK56116)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Keywords
- narcolepsy type 1, orexin receptor 2, orexin knockout mice, REM sleep, NREM sleep, sleep attacks, wakefulness, histaminergic neurons, hypothalamus, sleep-wake regulation, cataplexy
- MeSH terms
- Orexins, Animals, Arousal, Carrier Proteins, Cells, Cultured, Clomipramine, Disease Models, Animal, Efferent Pathways, Electroencephalography, Electromyography, Histamine, Hypothalamic Area, Lateral, Hypothalamus, Male, Narcolepsy, Synaptic Transmission, Neuropeptides, Sleep, Sleep, REM, Receptors, Neuropeptide, Mice, Knockout, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Orexin Receptors
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