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: Sawako Tabuchi, Tomomi Tsunematsu, Sarah W Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi, Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S Kilduff, Akihiro Yamanaka
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 34 Issue 19 Pg. 6495-509 (May 07 2014) ISSN: 1529-2401 [Electronic] United States
• PMID: 24806676 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Diphtheria Toxin
• Intracellular Signaling Peptides and Proteins
• Neuropeptides
• Orexins
• Doxycycline

Topics

• Animals
• Body Weight (drug effects, physiology)
• Cataplexy (physiopathology)
• Diphtheria Toxin (genetics)
• Disease Models, Animal
• Doxycycline (pharmacology)
• Drinking (drug effects, physiology)
• Eating (drug effects, physiology)
• Electroencephalography
• Electromyography
• Female
• Food
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Male
• Mice
• Mice, Transgenic
• Motor Activity (drug effects, physiology)
• Narcolepsy (drug therapy, physiopathology)
• Neurons (drug effects)
• Neuropeptides (antagonists & inhibitors)
• Orexins
• Sleep (physiology)
• Wakefulness (physiology)