QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, May 5, 2004, 24(18):4469-4477; doi:10.1523/JNEUROSCI.5560-03.2004

This Article Full Text Full Text (PDF) Supplementary Movies Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (36) Citing Articles via Google Scholar Google Scholar Articles by Beuckmann, C. T. Articles by Yanagisawa, M. Search for Related Content PubMed PubMed Citation Articles by Beuckmann, C. T. Articles by Yanagisawa, M.

 Previous Article  |  Next Article 

Neurobiology of Disease
Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy–Cataplexy in the Rat

Carsten T. Beuckmann,^1,2 * Christopher M. Sinton,^3 * S. Clay Williams,^1,2 James A. Richardson,⁴ Robert E. Hammer,^1,5 Takeshi Sakurai,^6,7 and Masashi Yanagisawa^1,2,7

¹Howard Hughes Medical Institute, ²Department of Molecular Genetics, ³Department of Internal Medicine, ⁴Department of Pathology, ⁵Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ⁶Department of Pharmacology, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575, Japan, and ⁷ Exploratory Research for Advanced Technology Yanagisawa Orphan Receptor Project, Japan Science and Technology Agency, Tokyo 135-0064, Japan

The sleep disorder narcolepsy has been linked to loss of hypothalamic neurons producing the orexin (hypocretin) neuropeptides. Here, we report the generation of transgenic rats expressing a human ataxin-3 fragment with an elongated polyglutamyl stretch under control of the human prepro-orexin promoter (orexin/ataxin-3 rats). At 17 weeks of age, the transgenic rats exhibited postnatal loss of orexin-positive neurons in the lateral hypothalamus, and orexin-containing projections were essentially undetectable. The loss of orexin production resulted in the expression of a phenotype with fragmented vigilance states, a decreased latency to rapid eye movement (REM) sleep and increased REM sleep time during the dark active phase. Wakefulness time was also reduced during the dark phase, and this effect was concentrated at the photoperiod boundaries. Direct transitions from wakefulness to REM sleep, a defining characteristic of narcolepsy, occurred frequently. Brief episodes of muscle atonia and postural collapse resembling cataplexy were also noted while rats maintained the electroencephalographic characteristics of wakefulness. These findings indicate that the orexin/ataxin-3 transgenic rat could provide a useful model of human narcolepsy.

Key words: cataplexy; electroencephalography; electromyography; sleep; REM; lateral hypothalamus

---

Received Dec 17, 2003; revised March 26, 2004; accepted March 28, 2004.

This article has been cited by other articles:

				B. M. Kublaoui, T. Gemelli, K. P. Tolson, Y. Wang, and A. R. Zinn Oxytocin Deficiency Mediates Hyperphagic Obesity of Sim1 Haploinsufficient Mice Mol. Endocrinol., July 1, 2008; 22(7): 1723 - 1734. [Abstract] [Full Text] [PDF]

				C. G. Diniz Behn, N. Kopell, E. N. Brown, T. Mochizuki, and T. E. Scammell Delayed Orexin Signaling Consolidates Wakefulness and Sleep: Physiology and Modeling J Neurophysiol, June 1, 2008; 99(6): 3090 - 3103. [Abstract] [Full Text] [PDF]

				C. Blanco-Centurion, D. Gerashchenko, and P. J. Shiromani Effects of Saporin-Induced Lesions of Three Arousal Populations on Daily Levels of Sleep and Wake J. Neurosci., December 19, 2007; 27(51): 14041 - 14048. [Abstract] [Full Text] [PDF]

				G. J. Landry and R. E. Mistlberger Food Entrainment: Methodological Issues J Biol Rhythms, December 1, 2007; 22(6): 484 - 487. [PDF]

				S. Zhang, J. M. Zeitzer, T. Sakurai, S. Nishino, and E. Mignot Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy J. Physiol., June 1, 2007; 581(2): 649 - 663. [Abstract] [Full Text] [PDF]

				S. Jessberger, K. Nakashima, G. D. Clemenson Jr, E. Mejia, E. Mathews, K. Ure, S. Ogawa, C. M. Sinton, F. H. Gage, and J. Hsieh Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline J. Neurosci., May 30, 2007; 27(22): 5967 - 5975. [Abstract] [Full Text] [PDF]

				B. M. Kublaoui, J. L. Holder Jr., T. Gemelli, and A. R. Zinn Sim1 Haploinsufficiency Impairs Melanocortin-Mediated Anorexia and Activation of Paraventricular Nucleus Neurons Mol. Endocrinol., October 1, 2006; 20(10): 2483 - 2492. [Abstract] [Full Text] [PDF]

				A. J. Morton, N. I. Wood, M. H. Hastings, C. Hurelbrink, R. A. Barker, and E. S. Maywood Disintegration of the Sleep-Wake Cycle and Circadian Timing in Huntington's Disease J. Neurosci., January 5, 2005; 25(1): 157 - 163. [Abstract] [Full Text] [PDF]

				A. Petersen, J. Gil, M. L.C. Maat-Schieman, M. Bjorkqvist, H. Tanila, I. M. Araujo, R. Smith, N. Popovic, N. Wierup, P. Norlen, et al. Orexin loss in Huntington's disease Hum. Mol. Genet., January 1, 2005; 14(1): 39 - 47. [Abstract] [Full Text] [PDF]

				M. Mieda, S. C. Williams, C. M. Sinton, J. A. Richardson, T. Sakurai, and M. Yanagisawa Orexin Neurons Function in an Efferent Pathway of a Food-Entrainable Circadian Oscillator in Eliciting Food-Anticipatory Activity and Wakefulness J. Neurosci., November 17, 2004; 24(46): 10493 - 10501. [Abstract] [Full Text] [PDF]

				J. John, M.-F. Wu, N. T Maidment, H. A Lam, L. N Boehmer, M. Patton, and J. M Siegel Developmental changes in CSF hypocretin-1 (orexin-A) levels in normal and genetically narcoleptic Doberman pinschers J. Physiol., October 15, 2004; 560(2): 587 - 592. [Abstract] [Full Text] [PDF]

				G. B. Lundkvist, K. Kristensson, and M. Bentivoglio Why Trypanosomes Cause Sleeping Sickness Physiology, August 1, 2004; 19(4): 198 - 206. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help