PT  - JOURNAL ARTICLE
AU  - Tabuchi, Sawako
AU  - Tsunematsu, Tomomi
AU  - Black, Sarah W.
AU  - Tominaga, Makoto
AU  - Maruyama, Megumi
AU  - Takagi, Kazuyo
AU  - Minokoshi, Yasuhiko
AU  - Sakurai, Takeshi
AU  - Kilduff, Thomas S.
AU  - Yamanaka, Akihiro
TI  - Conditional Ablation of Orexin/Hypocretin Neurons: A New Mouse Model for the Study of Narcolepsy and Orexin System Function
AID  - 10.1523/JNEUROSCI.0073-14.2014
DP  - 2014 May 07
TA  - The Journal of Neuroscience
PG  - 6495--6509
VI  - 34
IP  - 19
4099  - http://www.jneurosci.org/content/34/19/6495.short
4100  - http://www.jneurosci.org/content/34/19/6495.full
SO  - J. Neurosci.2014 May 07; 34
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.