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The identification of an inheritable narcolepsy phenotype in dogs in the 1970s allowed the establishment of a breeding colony at Stanford University, resulting in studies that provided the first insights into the genetics and neurotransmitter systems that underlie cataplexy and rapid-eye movement sleep atonia. Although the discovery of the hypocretin\/orexin neuropeptides in 1998 initially seemed unrelated to sleep\/wake control, the description of the phenotype of the prepro-orexin knockout (KO) mouse as strongly resembling cataplexy, the pathognomonic symptom of narcolepsy, along with identification of a mutation in hypocretin receptor-2 gene as the source of canine narcolepsy, unequivocally established the relationship between this system and narcolepsy. The subsequent discovery of hypocretin neuron degeneration in human narcolepsy demystified a disorder whose etiology had been unknown since its initial description 120 years earlier. These breakthroughs prompted the development of numerous other animal models that have allowed manipulation of the hypocretin\/orexin system, thereby advancing our understanding of sleep\/wake circuitry. While animal models have greatly informed understanding of this fascinating disorder and the role of the hypocretin\/orexin system in sleep\/wake control, the question of why these neurons degenerate in human narcolepsy is only beginning to be understood. The development of new immune-mediated narcolepsy models are likely to further inform the etiology of this sleep disorder and animal models will undoubtedly play a critical role in the development of novel narcolepsy therapeutics.<\/jats:p>","DOI":"10.1093\/sleep\/zsaa278","type":"journal-article","created":{"date-parts":[[2020,12,12]],"date-time":"2020-12-12T08:14:53Z","timestamp":1607760893000},"source":"Crossref","is-referenced-by-count":22,"title":["Animal models of narcolepsy and the hypocretin\/orexin system: Past, present, and future"],"prefix":"10.1093","volume":"44","author":[{"given":"Ryan K","family":"Tisdale","sequence":"first","affiliation":[{"name":"Center for Neuroscience, Biosciences Division, SRI International"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6099-7306","authenticated-orcid":false,"given":"Akihiro","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Neuroscience II, Research Institute of Environmental Medicine, Nagoya University, Japan"},{"name":"Department of Neural Regulation, Nagoya University Graduate School of Medicine, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6823-0094","authenticated-orcid":false,"given":"Thomas S","family":"Kilduff","sequence":"additional","affiliation":[{"name":"Center for Neuroscience, Biosciences Division, SRI International"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,12]]},"reference":[{"key":"2021061108584016100_CIT0001","first-page":"631","article-title":"Eigenh\u00fcmliche mit Einschl\u00e4fen verbundene Anf\u00e4lle","volume":"7","author":"Westphal","year":"1877","journal-title":"Arch Psychiatry."},{"key":"2021061108584016100_CIT0002","first-page":"535","article-title":"De la Narcolepsie","volume":"53","author":"G\u00e9lineau","year":"1880","journal-title":"Gaz Hop (Paris)"},{"issue":"3","key":"2021061108584016100_CIT0003","doi-asserted-by":"crossref","first-page":"301","DOI":"10.5664\/jcsm.26804","article-title":"English translations of the first clinical reports on narcolepsy and cataplexy by Westphal and G\u00e9lineau in the late 19th century, with commentary","volume":"3","author":"Schenck","year":"2007","journal-title":"J Clin Sleep Med."},{"key":"2021061108584016100_CIT0004","first-page":"320","article-title":"Criteria for diagnosis of the narcoleptic syndrome","volume":"32","author":"Yoss","year":"1957","journal-title":"Mayo Clin Proc."},{"issue":"9","key":"2021061108584016100_CIT0005","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/s41582-019-0226-9","article-title":"Narcolepsy\u2014clinical spectrum, aetiopathophysiology, diagnosis and treatment","volume":"15","author":"Bassetti","year":"2019","journal-title":"Nat Rev Neurol."},{"issue":"3062","key":"2021061108584016100_CIT0006","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1126\/science.118.3062.273","article-title":"Regularly occurring periods of eye motility, and concomitant phenomena, during sleep","volume":"118","author":"Aserinsky","year":"1953","journal-title":"Science."},{"issue":"4","key":"2021061108584016100_CIT0007","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/0013-4694(57)90088-3","article-title":"Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming","volume":"9","author":"Dement","year":"1957","journal-title":"Electroencephalogr Clin Neurophysiol."},{"key":"2021061108584016100_CIT0008","first-page":"1024","article-title":"On a stage of rapid cerebral electrical activity in the course of physiological sleep","volume":"153","author":"Jouvet","year":"1959","journal-title":"C R Seances Soc Biol Fil."},{"issue":"3","key":"2021061108584016100_CIT0009","first-page":"195","article-title":"A two process model of sleep regulation","volume":"1","author":"Borb\u00e9ly","year":"1982","journal-title":"Hum Neurobiol."},{"key":"2021061108584016100_CIT0010","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1001\/archpsyc.1960.01710040091011","article-title":"Studies in psychophysiology of dreams. 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