Hypocretin-2-Saporin Lesions of the Lateral Hypothalamus Produce Narcoleptic-Like Sleep Behavior in the Rat
Open accessAbstract
Hypocretins (Hcrts) are recently discovered peptides linked to the human sleep disorder narcolepsy. Humans with narcolepsy have decreased numbers of Hcrt neurons and Hcrt-null mice also have narcoleptic symptoms. Hcrt neurons are located only in the lateral hypothalamus (LH) but neither electrolytic nor pharmacological lesions of this or any other brain region have produced narcoleptic-like sleep, suggesting that specific neurons need to be destroyed. Hcrt neurons express the Hcrt receptor, and to facilitate lesioning these neurons, the endogenous ligand hypocretin-2/orexin B (Hcrt2) was conjugated to the ribosome-inactivating protein saporin (SAP). In vitro binding studies indicated specificity of the Hcrt2-SAP because it preferentially bound to Chinese hamster ovary cells containing the Hcrt/orexin receptor 2 (HcrtR2/OX(2)R) or the Hcrt/orexin receptor 1 (HcrtR1/OX(1)R) but not to Kirsten murine sarcoma virus transformed rat kidney epithelial (KNRK) cells stably transfected with the substance P (neurokinin-1) receptor. Administration of the toxin to the LH, in which the receptor is known to be present, eliminated some neurons (Hcrt, melanin-concentrating hormone, and adenosine deaminase-containing neurons) but not others (a-melanocyte-stimulating hormone), indicating specificity of the toxin in vivo. When the toxin was administered to the LH, rats had increased slow-wave sleep, rapid-eye movement (REM) sleep, and sleep-onset REM sleep periods. These behavioral changes were negatively correlated with the loss of Hcrt-containing neurons but not with the loss of adenosine deaminase-immunoreactive neurons. These findings indicate that damage to the LH that also causes a substantial loss of Hcrt neurons is likely to produce the multiple sleep disturbances that occur in narcolepsy.
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Several genes showed enrichment in developing human but not mouse SP, including HCRTR2.
“Several genes showed enrichment in developing human but not mouse SP, including the hypocretin (orexin) receptor HCRTR2 (Fig. 4c; Extended Data Fig. 8a), which is thought to regulate sleep-wakefulness and is highly expressed in mouse hypothalamus45.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [45]
HCRTR2 is thought to regulate sleep-wakefulness and is highly expressed in mouse hypothalamus.
“Several genes showed enrichment in developing human but not mouse SP, including the hypocretin (orexin) receptor HCRTR2 (Fig. 4c; Extended Data Fig. 8a), which is thought to regulate sleep-wakefulness and is highly expressed in mouse hypothalamus45.”
From Transcriptional landscape of the prenatal human brain (2014) · cites this paper as [45]
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- Authors
- Gerashchenko, D., Kohls, M. D., Greco, M., Waleh, N. S., Salin-Pascual, R., Kilduff, T. S., Lappi, D. A., & Shiromani, P. J.
- Affiliations
- Harvard University (US)
- Advanced Targeting Systems (United States) (US)
- SRI International (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2001-09-15
- Volume
- 21
- Issue
- 18
- Pages
- 7273-7283
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6762996
- OpenAlex
- W2102884007
- Cited by
- 272
- References
- 58
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 9 · 2023: 4 · 2022: 7 · 2021: 3 · 2020: 4 · 2019: 10 · 2018: 21 · 2017: 6 · 2016: 8 · 2015: 10 · 2014: 16 · 2013: 11 · 2012: 10
- FWCI
- 10.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute on Aging (AG09975, AG-15853, P01AG009975, R01AG015853)
- National Institute of Mental Health (MH-55772, MH61755, R01MH055772, R01MH061755)
- National Institute of Neurological Disorders and Stroke (NS30140, R01NS030140)
- 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 › Regulation of Appetite and Obesity
- Keywords
- hypocretin-2, saporin, lateral hypothalamus, narcolepsy, orexin, slow-wave sleep, REM sleep, melanin-concentrating hormone neurons, sleep disorders
- MeSH terms
- Orexins, Saporins, Adenosine Deaminase, Animals, Immunotoxins, Behavior, Animal, Cell Line, Circadian Rhythm, Electroencephalography, Flow Cytometry, Cricetinae, Disorders of Excessive Somnolence, Hypothalamus, Male, Microinjections, Narcolepsy, Nerve Tissue Proteins, Neurons, Neuropeptides, N-Glycosyl Hydrolases, Plant Proteins, Sleep, Toxins, Biological, Transfection, Video Recording, Rats, Sprague-Dawley, Receptors, Neuropeptide, Receptors, Neurokinin-1, Receptors, G-Protein-Coupled, Intracellular Signaling Peptides and Proteins, Mice, Rats, Ribosome Inactivating Proteins, Type 1, Orexin Receptors
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