TABLE 4.

Summary of studies that investigated the role of orexin system in sleep-wake regulation.

Experiment		Species	Effect on arousal	References
Acute ICV infusion of orexins	Orexin-A	Wild type mice (C57BL/6J), Rats (Sprague-Dawley and hooded lister)	Increased in wake amounts Decreased in NREM and REM amounts cycle Increased in locomotor activity	Hagan et al., 1999; Piper et al., 2000; Espana et al., 2002; Mieda et al., 2011
Orexin gene knockout		Transgenic mice (orexin -/- with C57BL/6J-129/SvEv mixed background)	Increased in the number of NREM and REM bouts during the dark phase Decreased in the duration of NREM and REM bouts during the dark phase Decreased in REM latency during the dark phase Decreased in the duration of wake bouts during the dark phase Alterations in the circadian frequencies of REM episodes Increased fragmentation of the sleep-wake cycle Hypersomnia	Chemelli et al., 1999; Willie et al., 2003; Mochizuki et al., 2004
Orexin neurons ablation		Transgenic mice (orexin/ataxin-3)	Increased in REM amount during the dark phase Increased in the duration of REM bouts during the dark phase Decreased in the duration of wake bouts during the dark phase Increased fragmentation of the sleep-wake cycle	Hara et al., 2001; Zhang et al., 2007
OX2-receptor deletion		Transgenic mice (OX2R–/–) OX2R Transcription-Disrupted mice	Increased fragmentation of the sleep-wake cycle Decreased in the duration of wake during the dark phase Decreased in the duration of NREM during the dark phase Decreased in REM latency during the dark phase	Willie et al., 2003; Mochizuki et al., 2011
Optogenetic stimulation of orexin neurons		Transgenic mice (Hcrt:EGFP) injected with lentivirus Hcrt:ChR2-mCherry	Increased the transition to wake from NREM or REM 5–30 Hz light pulse trains decreased wake latency Strong reduction of REM duration	Adamantidis et al., 2007
Chemoactivation of orexin neurons		Transgenic mice (orexin-Cre)	Increased in wake amounts during the light phase Decreased in NREM amounts during the light phase Decreased in REM amounts during the light phase Modest increase in wake amounts during the dark phase Increased in the latency from wake to REM during the dark phase	Sasaki et al., 2011