Reduced Number of Hypocretin Neurons in Human Narcolepsy
Open accessAbstract
Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin) precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy is not familial, is discordant in identical twins, and has not been linked to mutations of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons. The presence of gliosis in the hypocretin cell region is consistent with a degenerative process being the cause of the Hcrt cell loss in narcolepsy.
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Without 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 [38]
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 [38]
Selective loss of hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy.
“Selective loss of the hypocretin-producing neurons causes sleepiness and cataplexy in over 90% of patients with narcolepsy,5–9”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [8]
In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.
“In controls, the total number of hypocretin neurons and their distribution across the lateral and posterior hypothalamus were similar to prior reports.7,8,14,15”
From Loss of hypocretin (orexin) neurons with traumatic brain injury (2009) · cites this paper as [8]
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- Authors
- Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., Cornford, M., & Siegel, J. M.
- Affiliations
- University of California, Los Angeles (US)
- University of Pittsburgh (US)
- University of Michigan (US)
- Harbor–UCLA Medical Center (US)
- Corresponding author
- Siegel, Jerome M.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2000-09
- Volume
- 27
- Issue
- 3
- Pages
- 469-474
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC8760623
- OpenAlex
- W1983298714
- Cited by
- 2,089
- References
- 2
- Citations by year
- 2026: 45 · 2025: 72 · 2024: 64 · 2023: 68 · 2022: 64 · 2021: 72 · 2020: 67 · 2019: 58 · 2018: 85 · 2017: 84 · 2016: 75 · 2015: 82 · 2014: 94 · 2013: 115 · 2012: 87
- FWCI
- 42.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Michigan
- National Heart, Lung, and Blood Institute (R01HL041370, R37HL041370, HL 41370, HL6029C)
- National Institute of Mental Health (R01MH064109)
- National Institute of Neurological Disorders and Stroke (NS 14610, R01NS014610, R37NS014610)
- 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 related disorders
- Keywords
- narcolepsy, hypocretin neurons, orexin, neuronal loss, melanin-concentrating hormone neurons, gliosis, hypocretin receptor, neurodegeneration
- MeSH terms
- Orexins, Adult, Aged, Aged, 80 and over, Astrocytes, Brain, Carrier Proteins, Cell Count, Female, Glial Fibrillary Acidic Protein, Gliosis, Humans, Hypothalamic Hormones, Hypothalamus, Immunohistochemistry, Male, Melanins, Middle Aged, Narcolepsy, Neurons, Neuropeptides, Pituitary Hormones, Neurotransmitter Agents, Intracellular Signaling Peptides and Proteins
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