Conditional ablation of orexin/hypocretin neurons: A new mouse model for the study of narcolepsy and orexin system function

Sawako Tabuchi, Tomomi Tsunematsu, Sarah W. Black, Makoto Tominaga, Megumi Maruyama, Kazuyo Takagi, Yasuhiko Minokoshi, Takeshi Sakurai, Thomas S. Kilduff, Akihiro Yamanaka

研究成果: Article査読

127 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)6495-6509
ページ数15
ジャーナルJournal of Neuroscience
34
19
DOI
出版ステータスPublished - 2014

ASJC Scopus subject areas

  • 神経科学(全般)

フィンガープリント

「Conditional ablation of orexin/hypocretin neurons: A new mouse model for the study of narcolepsy and orexin system function」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル