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Sleep and Biological Rhythms

開催日 2014/9/12
時間 11:00 - 12:00
会場 Poster / Exhibition(Event Hall B)

Orexin neurons suppress narcolepsy via two distinct efferent pathways

  • P2-213
  • 長谷川 恵美 / Emi Hasegawa:1 柳沢 正史 / Masashi Yanagisawa:2,3 櫻井 武 / Takeshi Sakurai:1 三枝 理博 / Michihiro Mieda:1 
  • 1:金沢大学院・医・分子神経科学/統合生理学 / Dept of Molecular Neuroscience and Integrative Physiology, Grad Sch of Medical Science, Kanazawa Univ. 2:筑波大学 国際統合睡眠医科学研究機構 / International Institute for Integrative Sleep Medicine, University of Tsukuba 3:筑波大学 分子行動科学研究コア / Center for Behavioral Molecular Genetics, University of Tsukuba 

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

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