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Sleep. 2016 Feb 1;39(2):369-77. doi: 10.5665/sleep.5446.

Progressive Loss of the Orexin Neurons Reveals Dual Effects on Wakefulness.

Author information

1
Department of Applied Mathematics & Statistics, Colorado School of Mines, Golden, CO.
2
Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
3
Department of Biology, Tokai University, Sapporo, Japan.
4
Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA.
5
Division of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO.

Abstract

STUDY OBJECTIVES:

Narcolepsy is caused by loss of the orexin (also known as hypocretin) neurons. In addition to the orexin peptides, these neurons release additional neurotransmitters, which may produce complex effects on sleep/wake behavior. Currently, it remains unknown whether the orexin neurons promote the initiation as well as the maintenance of wakefulness, and whether the orexin neurons influence initiation or maintenance of sleep. To determine the effects of the orexin neurons on the dynamics of sleep/wake behavior, we analyzed sleep/wake architecture in a novel mouse model of acute orexin neuron loss.

METHODS:

We used survival analysis and other statistical methods to analyze sleep/wake architecture in orexin-tTA ; TetO diphtheria toxin A mice at different stages of orexin neuron degeneration.

RESULTS:

Progressive loss of the orexin neurons dramatically reduced survival of long wake bouts, but it also improved survival of brief wake bouts. In addition, with loss of the orexin neurons, mice were more likely to wake during the first 30 sec of nonrapid eye movement sleep and then less likely to return to sleep during the first 60 sec of wakefulness.

CONCLUSIONS:

These findings help explain the sleepiness and fragmented sleep that are characteristic of narcolepsy. Orexin neuron loss impairs survival of long wake bouts resulting in poor maintenance of wakefulness, but this neuronal loss also fragments sleep by increasing the risk of awakening at the beginning of sleep and then reducing the likelihood of quickly returning to sleep.

KEYWORDS:

hypocretin; narcolepsy; orexin; sleep; survival analysis

PMID:
26446125
PMCID:
PMC4712398
DOI:
10.5665/sleep.5446
[Indexed for MEDLINE]
Free PMC Article

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