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

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 wake-promoting effects of orexins, but orexins must stabilize sleep through other targets.

Pubmed ID: 21368172


  • Mochizuki T
  • Arrigoni E
  • Marcus JN
  • Clark EL
  • Yamamoto M
  • Honer M
  • Borroni E
  • Lowell BB
  • Elmquist JK
  • Scammell TE


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 15, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK081185
  • Agency: NHLBI NIH HHS, Id: HL095491
  • Agency: NINDS NIH HHS, Id: NS055367
  • Agency: NHLBI NIH HHS, Id: P01 HL095491
  • Agency: NINDS NIH HHS, Id: R01 NS055367

Mesh Terms

  • Animals
  • Antigens, Surface
  • Dependovirus
  • Electrophysiological Phenomena
  • Female
  • Hypothalamic Area, Lateral
  • Hypothalamus
  • Integrases
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Transgenic
  • Microinjections
  • Narcolepsy
  • Neuropeptides
  • Orexin Receptors
  • Orexins
  • Receptors, Cell Surface
  • Signal Transduction
  • Sleep
  • Transcription, Genetic
  • Wakefulness