Abstract
Orexins (also called hypocretins), which are neuropeptides exclusively expressed by a population of neurons specifically localized in the lateral hypothalamic area, are critically implicated in the regulation of sleep/wake states. Orexin deficiency results in narcoleptic phenotype in rodents, dogs, and humans, suggesting that orexins are important for maintaining consolidated wakefulness states. However, the physiological effect of constitutive increased orexinergic transmission tone, which might be important for understanding the effects of orexin agonists that are promising candidates for therapeutic agents of narcolepsy, has not been fully characterized. We report here the sleep/wakefulness abnormalities in transgenic mice that exhibit widespread overexpression of a rat prepro-orexin transgene driven by a β-actin/cytomegalovirus hybrid promoter (CAG/orexin transgenic mice). CAG/orexin mice exhibit sleep abnormalities with fragmentation of non-rapid eye movement (REM) sleep episode and a reduction in REM sleep. Non-REM sleep was frequently disturbed by short episodes of wakefulness. EEG/EMG studies also reveal incomplete REM sleep atonia with abnormal myoclonic activity during this sleep stage. These results suggest that endogenous orexinergic activity should be appropriately regulated for normal maintenance of sleep states. Orexinergic transmission should be activated during wakefulness, while it should be inactivated or decreased during sleep state to maintain appropriate vigilance states.
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References
Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ (2002) Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome. Neurology 59:639–641
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell TE et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451
Funato H, Tsai A, Willie JT, Kisanuki Y, Williams SC et al (2009) Enhanced orexin signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 9:64–76
Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM et al (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30:345–354
Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N et al (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 98:9965–9970
Lee MG, Hassani OK, Jones BE (2005) Discharge of identified orexin/hypocretin neurons across the sleep–waking cycle. J Neurosci 25:6716–6720
Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M (2004) Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 101:4649–4654
Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2002) Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla. J Neurophysiol 87:2480–2489
Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46:787–798
Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827:243–260
Niwa H, Yamamura K, Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199
Piper DC, Upton N, Smith MI, Hunter AJ (2000) The novel brain neuropeptide, orexin-A, modulates the sleep–wake cycle of rats. Eur J Neurosci 12:726–730
Sakurai T (2007) The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 8:171–181
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92:573–585
Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N et al (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46:297–308
Schenck CH, Mahowald MW (2002) REM sleep behavior disorder: clinical, developmental, and neuroscience perspectives 16 years after its formal identification in SLEEP. Sleep 25:120–138
Takakusaki K, Takahashi K, Saitoh K, Harada H, Okumura T et al (2005) Orexinergic projections to the midbrain mediate alternation of emotional behavioral states from locomotion to cataplexy. J Physiol 568(Pt 3):1003–1020
Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K (1999) Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849:248–252
Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494:845–861
Acknowledgements
This study was supported in part by a grant-in-aid for scientific research from the 21st Century COE Program from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, a grant for anorexia nervosa research from the Japanese Ministry of Health, Labour and Welfare, Uehara Memorial Foundation and research grants from the ERATO/JST. M.Y. is an investigator of the Howard Hughes Medical Institute. J.T.W. is a joint fellow of the DCMB and MST programs of University of Texas Southwestern Medical Center at Dallas.
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This manuscript is related to the GPCR2010 symposium.
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Supplementary Figure 1
Orexinergic fibers make appositions to the choline acetyltransferase (ChAT)-positive neurons in the laterodorsal tegmental nucleus (LDT). Upper panel, a low-power view of a brain slice of approximately −4.8 mm bregma. Middle panel, a higher-power view of rectangle region shown in upper panel. Lower panel, a higher-power view of rectangle region shown in middle panel. ChAT-immunoreactive neurons were found in the LDT in the C57BL/6 mouse brain (Alexa Fluor 594, red). A lot of terminals of the orexin-producing neurons exist in the same area (Alexa Fluor 488, green). Scale bar indicates 20 μm. (JPEG 475 kb)
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Willie, J.T., Takahira, H., Shibahara, M. et al. Ectopic Overexpression of Orexin Alters Sleep/Wakefulness States and Muscle Tone Regulation during REM Sleep in Mice. J Mol Neurosci 43, 155–161 (2011). https://doi.org/10.1007/s12031-010-9437-7
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DOI: https://doi.org/10.1007/s12031-010-9437-7