RT Journal Article SR Electronic T1 Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 6495 OP 6509 DO 10.1523/JNEUROSCI.0073-14.2014 VO 34 IS 19 A1 Sawako Tabuchi A1 Tomomi Tsunematsu A1 Sarah W. Black A1 Makoto Tominaga A1 Megumi Maruyama A1 Kazuyo Takagi A1 Yasuhiko Minokoshi A1 Takeshi Sakurai A1 Thomas S. Kilduff A1 Akihiro Yamanaka YR 2014 UL http://www.jneurosci.org/content/34/19/6495.abstract AB 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.