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.
View: Text | PDF
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

×

Figure 4

Restoration of orexin receptors in the DR or LC of Ox1r–/–Ox2r–/– mice using neuron type-selective promoters.

Options: View larger image (or click on image) Download as PowerPoint
Restoration of orexin receptors in the DR or LC of Ox1r–/–Ox2r–/– mice u...
(A–C) Coronal brain sections from Ox1r–/–Ox2r–/–+5HT-OX2R mice (with targeted injection of AAV-Pet1/OX2R::EYFP) were double-stained with anti-GFP antibody (red) and either anti-TPH (A and B) or anti-TH (C, for dopaminergic neurons in the DR) antibody (green). (D–G) Sections from Ox1r–/–Ox2r–/–+NA-OX1R mice (with AAV-PRSx8/OX1R::EYFP injection) were double-stained with anti-GFP (red) and anti-TH (green) antibodies. Leaked expression of OX1R::EYFP in regions lateral (E, including PB), medial (F), and ventral (G, including SubC) to the LC (D) is shown. Regions denoted by white arrowheads are shown at higher magnification. Schematics show the spread of OX1R::EYFP or OX2R::EYFP expression. Mean numbers of EGFP+ cells are shown by green or red circles, indicative of the absence or presence, respectively, of the neuronal type–specific marker. For LC, only 1 side was shown. LPB, lateral PB; MPB, medial PB. Scale bars: 100 μm.