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

Abstract

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 orexinpositive 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.

Disintegration of the Sleep-Wake Cycle and Circadian Timing in Huntington's Disease

“…One important circadian output pathway from the SCN is to the dorsomedial hypothalamus, which contains orexinergic neurons that maintain arousal (Pace-Schott and Hobson, 2002;Chou et al, 2003). Sleep disturbances have been reported in rats expressing a polyglutamine repeat transgene in these neurons (Beuckmann et al, 2004). Interestingly, progressive death of orexin-containing neurons with the gradual development of narcoleptic-like behavior in R6/2 mice as well as loss of orexin neurons in HD patients have recently been found (Petersén et al, 2004).…”

Epigenetic Modulation of Seizure-Induced Neurogenesis and Cognitive Decline

“…EEG/EMG recordings were performed as described previously (Beuckmann et al, 2004). Female Fisher 344 rats (180 -200 g; n ϭ 3 per group) were anesthetized (50 mg/kg ketamine, 5 mg/kg xylazine, and 1 mg/kg acepromazine, i.p.…”

Orexin Neurons Function in an Efferent Pathway of a Food-Entrainable Circadian Oscillator in Eliciting Food-Anticipatory Activity and Wakefulness

“…For tissue collection from mice under ALF, mice continued to be fed ad libitum from day 0 to day 10. Double staining for orexin and Fos was performed as described (Beuckmann et al, 2004), using anti-orexin (Chemelli et al, 1999) and anti-Fos (Ab-5; 1:50,000 dilution) (Oncogene Research Products, Cambridge, MA) antibodies. Numbers of stained cells in the perifornical area, LC (bilateral counting from one section per sample), and the tuberomammillary nucleus (TMN) (bilateral counting from three sections 90 m apart per sample) were counted using a Bioquant (Nashville, TN) Nova system.…”