Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice

Takatoshi Mochizuki, Elda Arrigoni, Jacob N. Marcus, Erika L. Clark, Mihoko Yamamoto, Michael Honer, Edilio Borroni, Bradford B. Lowell, Joel K. Elmquist, Thomas E. Scammell

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

Narcolepsy is caused by a loss of orexin/hypocretin signaling, resulting in chronic sleepiness, fragmented non-rapid eye movement sleep, and cataplexy. To identify the neuronal circuits underlying narcolepsy, we produced a mouse model in which a loxP-flanked gene cassette disrupts production of the orexin receptor type 2 (OX2R; also known as HCRTR2), but normal OX2R expression can be restored by Cre recombinase. Mice lacking OX2R signaling had poor maintenance of wakefulness indicative of sleepiness and fragmented sleep and lacked any electrophysiological response to orexin-A in the wake-promoting neurons of the tuberomammillary nucleus. These defects were completely recovered by crossing them with mice that express Cre in the female germline, thus globally deleting the transcription-disrupter cassette. Then, by using an adeno-associated viral vector coding for Cre recombinase, we found that focal restoration of OX2R in neurons of the tuberomammillary nucleus and adjacent parts of the posterior hypothalamus completely rescued the sleepiness of these mice, but their fragmented sleep was unimproved. These observations demonstrate that the tuberomammillary region plays an essential role in the wakepromoting effects of orexins, but orexins must stabilize sleep through other targets.

Original languageEnglish (US)
Pages (from-to)4471-4476
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number11
DOIs
StatePublished - Mar 15 2011

    Fingerprint

Keywords

  • Arousal
  • Cre-loxP
  • G protein-coupled receptors
  • Histamine

ASJC Scopus subject areas

  • General

Cite this

Mochizuki, T., Arrigoni, E., Marcus, J. N., Clark, E. L., Yamamoto, M., Honer, M., Borroni, E., Lowell, B. B., Elmquist, J. K., & Scammell, T. E. (2011). Orexin receptor 2 expression in the posterior hypothalamus rescues sleepiness in narcoleptic mice. Proceedings of the National Academy of Sciences of the United States of America, 108(11), 4471-4476. https://doi.org/10.1073/pnas.1012456108