title: Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function.
abstract: The sleep disorder narcolepsy results from loss of hypothalamic orexin/hypocretin neurons. Although narcolepsy onset is usually postpubertal, current mouse models involve loss of either orexin peptides or orexin neurons from birth. To create a model of orexin/hypocretin deficiency with closer fidelity to human narcolepsy, diphtheria toxin A (DTA) was expressed in orexin neurons under control of the Tet-off system. Upon doxycycline removal from the diet of postpubertal orexin-tTA;TetO DTA mice, orexin neurodegeneration was rapid, with 80% cell loss within 7 d, and resulted in disrupted sleep architecture. Cataplexy, the pathognomic symptom of narcolepsy, occurred by 14 d when ∼5% of the orexin neurons remained. Cataplexy frequency increased for at least 11 weeks after doxycycline. Temporary doxycycline removal followed by reintroduction after several days enabled partial lesion of orexin neurons. DTA-induced orexin neurodegeneration caused a body weight increase without a change in food consumption, mimicking metabolic aspects of human narcolepsy. Because the orexin/hypocretin system has been implicated in the control of metabolism and addiction as well as sleep/wake regulation, orexin-tTA; TetO DTA mice are a novel model in which to study these functions, for pharmacological studies of cataplexy, and to study network reorganization as orexin input is lost.
authors.affiliation: Research Institute of Environmental Medicine, Nagoya University, Nagoya, 464-8601, Japan, Department of Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8585, Japan, Japan Society for the Promotion of Science, Tokyo 102-8472, Japan, Center for Neuroscience, Biosciences Division, SRI International, Menlo Park, California 94025, Division of Cell Signaling, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8787, Japan, Center for Multidisciplinary Brain Research, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, Division of Endocrinology and Metabolism, National Institute for Physiological Sciences, National Institute of Natural Sciences, Okazaki 444-8585, Japan, and Department of Molecular Neuroscience and Integrative Physiology, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Sawako
authors.initials: S
authors.lastname: Tabuchi
authors.forename: Tomomi
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Sarah W
authors.initials: SW
authors.lastname: Black
authors.forename: Makoto
authors.initials: M
authors.lastname: Tominaga
authors.forename: Megumi
authors.initials: M
authors.lastname: Maruyama
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takagi
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sakurai
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Kilduff
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yamanaka
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002385:Cataplexy / Q000503:physiopathology; D004167:Diphtheria Toxin / Q000235:genetics; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004326:Drinking / Q000187:drug effects / Q000502:physiology; D004435:Eating / Q000187:drug effects / Q000502:physiology; D004569:Electroencephalography; D004576:Electromyography; D005260:Female; D005502:Food; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009290:Narcolepsy / Q000188:drug therapy* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects*; D009479:Neuropeptides / Q000037:antagonists & inhibitors*; D000068797:Orexins; D012890:Sleep / Q000502:physiology; D014851:Wakefulness / Q000502:physiology
chemical_list: D004167:Diphtheria Toxin; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D004318:Doxycycline
keywords: diphtheria toxin A fragment; hypocretin; model mice; narcolepsy; orexin; transgenic