Orexin neurons suppress narcolepsy via 2 distinct efferent pathways
Emi Hasegawa, … , Takeshi Sakurai, Michihiro Mieda
Emi Hasegawa, … , Takeshi Sakurai, Michihiro Mieda
Published January 2, 2014
Citation Information: J Clin Invest. 2014;124(2):604-616. https://doi.org/10.1172/JCI71017.
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Research Article Neuroscience

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways

Abstract

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron–dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

Authors

Emi Hasegawa, Masashi Yanagisawa, Takeshi Sakurai, Michihiro Mieda

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Figure 2

Restoration of orexin receptor expression in the DR and LC inhibits cataplexy-like episodes and consolidates wakefulness, respectively.

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Restoration of orexin receptor expression in the DR and LC inhibits cata...
Control Ox1r–/–Ox2r–/– (n = 16), Ox1r–/–Ox2r–/–+DR-OX2R (n = 7), Ox1r–/–Ox2r–/–+LC-OX1R (n = 8), Ox1r–/–Ox2r–/–+TMN-OX2R (n = 4), Ox1r–/–Ox2r–/–+PPT-OX1R (n = 4), and WT (n = 4) mice were recorded. Mean values of 3 nights’ recordings are shown. Ox1r–/–Ox2r–/– controls were injected with AAV-CAG/EGFP into the DR or LC, AAV-Pet1/ChR2::EYFP into the DR, or AAV-PRSx8/ChR2::EYFP into the LC. (A) Number of and time spent in cataplexy-like episodes. (B) REM sleep latency and time spent in REM sleep. (C) Duration and number of wakefulness episodes during the dark phase. *P < 0.05, **P < 0.01 vs. Ox1r–/–Ox2r–/– control; #P < 0.05, ##P < 0.01 vs. WT. Values are mean ± SEM.