TY - JOUR
T1 - Expression of a Poly-Glutamine-Ataxin-3 Transgene in Orexin Neurons Induces Narcolepsy-Cataplexy in the Rat
AU - Beuckmann, Carsten T.
AU - Sinton, Christopher M.
AU - Williams, S. Clay
AU - Richardson, James A
AU - Hammer, Robert E
AU - Sakurai, Takeshi
AU - Yanagisawa, Masashi
PY - 2004/5/5
Y1 - 2004/5/5
N2 - 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.
AB - 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.
KW - Cataplexy
KW - Electroencephalography
KW - Electromyography
KW - Lateral hypothalamus
KW - REM
KW - Sleep
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UR - http://www.scopus.com/inward/citedby.url?scp=2342602218&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.5560-03.2004
DO - 10.1523/JNEUROSCI.5560-03.2004
M3 - Article
C2 - 15128861
AN - SCOPUS:2342602218
SN - 0270-6474
VL - 24
SP - 4469
EP - 4477
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 18
ER -