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24 - Hypocretinergic system: role in REM-sleep regulation

from Section IV - Neuroanatomy and neurochemistry

Published online by Cambridge University Press:  07 September 2011

By
Ronald Szymusiak ,
Md. Noor Alam  and
Dennis McGinty
Edited by
Birendra N. Mallick ,
S. R. Pandi-Perumal ,
Robert W. McCarley  and
Adrian R. Morrison
Ronald Szymusiak
Affiliation:
University of California, Los Angeles
Md. Noor Alam
Affiliation:
University of California, Los Angeles
Dennis McGinty
Affiliation:
University of California, Los Angeles
Birendra N. Mallick
Affiliation:
Jawaharlal Nehru University
S. R. Pandi-Perumal
Affiliation:
Somnogen Canada Inc, Toronto
Robert W. McCarley
Affiliation:
Harvard University, Massachusetts
Adrian R. Morrison
Affiliation:
University of Pennsylvania
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Summary

Summary

The hypocretins (HCRTs) are two hypothalamic peptides that have been implicated in a variety of functions including the regulation of behavioral arousal. In the brain, HCRT-expressing neurons are localized within the perifornical-lateral hypothalamic area, where they are intermingled with various other neuronal groups, including GABAergic, glutamatergic, and melanin-concentrating hormone containing neurons. Hypocretin neurons are active during behavioral arousal and are quiet during non-REM and REM sleep. Deficiency of HCRTergic signaling is linked to the symptoms of narcolepsy in humans, dogs, and rodents. Narcolepsy is a debilitating sleep disorder characterized by excessive daytime sleepiness, disrupted nighttime sleep, sleep-onset REM sleep, and sudden loss of muscle tone during waking (cataplexy). Hypocretin neurons project extensively to brain structures, especially to those that are involved in arousal and motor control as well as receive extensive inputs from areas regulating emotions, autonomic tone, appetite, circadian rhythms, and sleep–wake behavior. Therefore, HCRT neurons are well positioned to integrate a variety of interoceptive and homeostatic signals to increase behavioral arousal and suppress REM sleep and its atonia. This chapter provides a brief review of the HCRTergic system, its interactions with other neuronal systems involved in sleep–wake regulation, and the neuronal circuitry and the potential mechanism(s) by which the HCRTergic system promotes behavioral arousal and suppresses REM sleep and its muscle atonia.

Type
Chapter
Information
Rapid Eye Movement Sleep
Regulation and Function
 , pp. 234 - 246
Publisher: Cambridge University Press
Print publication year: 2011

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References

Adamantidis, A. R., Zhang, F., Aravanis, A. M., Deisseroth, K. & de Lecea, L. (2007) Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450: –4.CrossRefGoogle Scholar
Alam, M. N., Gong, H., Alam, T., Jaganath, R., McGinty, D. & Szymusiak, R. (2002) Sleep–waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area. J Physiol 538: –31.CrossRefGoogle Scholar
Alam, M. N., Kumar, S., Bashir, T. . (2005) GABA-mediated control of hypocretin- but not melanin-concentrating hormone immunoreactive neurones during sleep in rats. J Physiol 563: –82.CrossRefGoogle Scholar
Chemelli, R. M., Willie, J. T., Sinton, C. M. . (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: –51.CrossRefGoogle Scholar
de Lecea, L., Kilduff, T. S., Peyron, C. . (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 95: –7.CrossRefGoogle Scholar
Eggermann, E., Bayer, L., Serafin, M. . (2003) The wake-promoting hypocretin-orexin neurons are in an intrinsic state of membrane depolarization. J Neurosci 23: –62.CrossRefGoogle Scholar
Eriksson, K. S., Sergeeva, O. A., Haas, H. L. & Selbach, O. (2010) Orexins/hypocretins and aminergic systems. Acta Physiol (Oxf) 198: 263–75.CrossRefGoogle ScholarPubMed
Fort, P., Bassetti, C. L. & Luppi, P. H. (2009) Alternating vigilance states: new insights regarding neuronal networks and mechanisms. Eur J Neurosci 29: –53.CrossRefGoogle Scholar
Gallopin, T., Fort, P., Eggermann, E., . (2000) Identification of sleep-promoting neurons in vitro. Nature 404: –5.CrossRefGoogle Scholar
Gong, H., McGinty, D., Guzman-Marin, R., . (2004) Activation of c-fos in GABAergic neurones in the preoptic area during sleep and in response to sleep deprivation. J Physiol 556: –46.CrossRefGoogle Scholar
Hassani, O. K., Lee, M. G. & Jones, B. E. (2009) Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep–wake cycle. Proc Natl Acad Sci U S A 106: –22.CrossRefGoogle Scholar
Henny, P. & Jones, B. E. (2006) Innervation of orexin/hypocretin neurons by GABAergic, glutamatergic or cholinergic basal forebrain terminals evidenced by immunostaining for presynaptic vesicular transporter and postsynaptic scaffolding proteins. J Comp Neurol 499: –61.CrossRefGoogle Scholar
Huang, Z. L., Qu, W. M., Li, W. D. . (2001) Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 98: –70.CrossRefGoogle Scholar
Jones, B. E. (2008) Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems. Ann N Y Acad Sci 1129: –34.CrossRefGoogle Scholar
Kukkonen, J. P., Holmqvist, T., Ammoun, S. & Akerman, K. E. (2002) Functions of the orexinergic/hypocretinergic system. Am J Physiol Cell Physiol 283: –91.CrossRefGoogle Scholar
Kumar, S., Szymusiak, R., Bashir, T. . (2008) Inactivation of median preoptic nucleus causes c-Fos expression in hypocretin- and serotonin-containing neurons in anesthetized rat. Brain Res 1234: –77.CrossRefGoogle Scholar
Kumar, S., Szymusiak, R., Methippara, M. M. . (2005) GABAergic and glutamatergic neurons in the perifornical lateral hypothalamic area exhibit differential Fos expression after sleep deprivation vs. recovery sleep. Sleep 29: .Google Scholar
Lee, M. G., Hassani, O. K. & Jones, B. E. (2005) Discharge of identified orexin/hypocretin neurons across the sleep–waking cycle. J Neurosci 25: –20.CrossRefGoogle Scholar
Li, Y., Gao, X. B., Sakurai, T. & van den Pol, A. N. (2002) Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron: a potential mechanism for orchestrating the hypothalamic arousal system. Neuron 36: –81.CrossRefGoogle Scholar
Lin, L., Faraco, J., Li, R. . (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98: –76.CrossRefGoogle Scholar
Liu, Z. W. & Gao, X. B. (2007) Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect. J Neurophysiol 97: –48.CrossRefGoogle Scholar
Lu, J., Sherman, D., Devor, M. & Saper, C. B. (2006) A putative flip-flop switch for control of REM sleep. Nature 441: –94.CrossRefGoogle Scholar
Marcus, J. N., Aschkenasi, C. J., Lee, C. E. . (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435: –25.CrossRefGoogle Scholar
Matsuki, T., Nomiyama, M., Takahira, H. . (2009) Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 106: –64.CrossRefGoogle Scholar
McCarley, R.W. (2007) Neurobiology of REM and NREM sleep. Sleep Med 8: –30.CrossRefGoogle Scholar
Mileykovskiy, B. Y., Kiyashchenko, L. I. & Siegel, J. M. (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46: –98.CrossRefGoogle Scholar
Modirrousta, M., Mainville, L. & Jones, B. E. (2005) Orexin and MCH neurons express c-Fos differently after sleep deprivation vs. recovery and bear different adrenergic receptors. Eur J Neurosci 21: –16.CrossRefGoogle Scholar
Mori, T., Ito, S., Kuwaki, T., Yanagisawa, M. & Sawaguchi, T. (2009)Monoaminergic neuronal changes in orexin deficient mice. Neuropharmacology.Google ScholarPubMed
Nishino, S., Okuro, M., Kotorii, N. . (2010)Hypocretin/orexin and narcolepsy: new basic and clinical insights, Acta Physiol (Oxf) 198: 209–22.CrossRefGoogle ScholarPubMed
Ohno, K. & Sakurai, T. (2008) Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 29: –87.CrossRefGoogle Scholar
Peyron, C., Faraco, J., Rogers, , . (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 6: –7.CrossRefGoogle Scholar
Peyron, C., Tighe, D. K., van den Pol, A. N., . (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: –10,015.CrossRefGoogle Scholar
Sakurai, T., Amemiya, A., Ishii, M. . (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: –85.CrossRefGoogle Scholar
Sakurai, T., Nagata, R., Yamanaka, A. . (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46: –308.CrossRefGoogle Scholar
Saper, C. B., Cano, G. & Scammell, T. E. (2005) Homeostatic, circadian, and emotional regulation of sleep. J Comp Neurol 493: –8.CrossRefGoogle Scholar
Siegel, J. M. (2004a) Hypocretin (orexin): role in normal behavior and neuropathology. Ann Rev Psychol 55: –48.CrossRefGoogle Scholar
Siegel, J.M. (2004b) The neurotransmitters of sleep, J Clin Psychiatry, 65 Suppl 16: –7.Google Scholar
Suntsova, N., Guzman-Marin, R., Kumar, S. . (2007) The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus. J Neurosci 27: –30.CrossRefGoogle Scholar
Suntsova, N., Szymusiak, R., Alam, M. N., Guzman-Marin, R. & McGinty, D. (2002) Sleep–waking discharge patterns of median preoptic nucleus neurons in rats. J Physiol 543: –77.CrossRefGoogle Scholar
Szymusiak, R. & McGinty, D. (2008) Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 1129: –86.CrossRefGoogle Scholar
Thakkar, M. M., Engemann, S. C., Walsh, K. M. & Sahota, P. K. (2008) Adenosine and the homeostatic control of sleep: effects of A1 receptor blockade in the perifornical lateral hypothalamus on sleep–wakefulness. Neuroscience 153: –80.CrossRefGoogle Scholar
Thakkar, M. M., Ramesh, V., Cape, E. G. . (1999) REM sleep enhancement and behavioral cataplexy following orexin (hypocretin)-II receptor antisense perfusion in the pontine reticular formation. Sleep Res Online 2: –20.Google Scholar
Thannickal, T. C., Moore, R. Y., Nienhuis, R. . (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27: –74.CrossRefGoogle Scholar
Torrealba, F., Yanagisawa, M. & Saper, C. B. (2003) Colocalization of orexin a and glutamate immunoreactivity in axon terminals in the tuberomammillary nucleus in rats. Neuroscience 119: –44.CrossRefGoogle Scholar
Trivedi, P., Yu, H., MacNeil, D. J., Van der Ploeg, L. H. & Guan, X. M. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438: –5.CrossRefGoogle Scholar
Uschakov, A., Gong, H., McGinty, D. & Szymusiak, R. (2006) Sleep-active neurons in the preoptic area project to the hypothalamic paraventricular nucleus and perifornical lateral hypothalamus. Eur J Neurosci 23: –96.CrossRefGoogle Scholar
Verret, L., Goutagny, R., Fort, P. . (2003) A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 4: .CrossRefGoogle Scholar
Yoshida, K., McCormack, S., Espana, R. A., Crocker, A. & Scammell, T. E. (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494: –61.CrossRefGoogle Scholar

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