Skip to main content
SpringerLink
Log in

Hypocretin/Orexin Receptor Functions in Mesopontine Systems Regulating Sleep, Arousal, and Cataplexy

  • Chapter
  • First Online:
Narcolepsy

Abstract

It is eminently clear from numerous chapters in this volume that the orexin (hypocretin) neuropeptides are necessary for the normal expression of waking and sleep. However, it remains fundamentally unclear how the absence of signaling by these peptides results in the symptoms of narcolepsy. Which of the many neurons bearing orexin receptors are necessary to sustain normal waking and sleep, and which of the numerous orexin actions are required for these processes? Does the simple loss of orexin’s excitatory actions produce narcolepsy, or are there more subtle aspects to the loss of orexin signaling that result in plastic or trophic changes that give rise to the symptoms of narcolepsy and cataplexy?

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 149.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 199.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Peyron C, Tighe DK, van den Pol AN, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci. 1998;18(23):9996–10015.

    PubMed  CAS  Google Scholar 

  2. Marcus JN, Aschkenasi CJ, Lee CE, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol. 2001;435(1):6–25.

    Article  PubMed  CAS  Google Scholar 

  3. Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 2000;23(8):359–65.

    Article  PubMed  CAS  Google Scholar 

  4. Hagan JJ, Leslie RA, Patel S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA. 1999;96(19):10911–6.

    Article  PubMed  CAS  Google Scholar 

  5. Piper DC, Upton N, Smith MI, Hunter AJ. The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci. 2000;12(2):726–30.

    Article  PubMed  CAS  Google Scholar 

  6. Bourgin P, Huitron-Resendiz S, Spier AD, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci. 2000;20(20):7760–5.

    PubMed  CAS  Google Scholar 

  7. Xi M, Morales FR, Chase MH. Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res. 2001;901(1–2):259–64.

    Article  PubMed  CAS  Google Scholar 

  8. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98(4):437–51.

    Article  PubMed  CAS  Google Scholar 

  9. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98(3):365–76.

    Article  PubMed  CAS  Google Scholar 

  10. Burlet S, Tyler CJ, Leonard CS. Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy. J Neurosci. 2002;22(7):2862–72.

    PubMed  CAS  Google Scholar 

  11. Kohlmeier KA, Watanabe S, Tyler CJ, Burlet S, Leonard CS. Dual orexin actions on dorsal raphe and laterodorsal tegmentum neurons: noisy cation current activation and selective enhancement of Ca transients mediated by L-type calcium channels. J Neurophysiol. 2008;100:2265–81.

    Article  PubMed  CAS  Google Scholar 

  12. Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K. Electrophysiological effects of orexins/hypocretins on pedunculopontine tegmental neurons in rats: an in vitro study. Peptides. 2009;30(2):191–209.

    Article  PubMed  CAS  Google Scholar 

  13. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92(4):573–85.

    Article  PubMed  CAS  Google Scholar 

  14. Larsson KP, Peltonen HM, Bart G, et al. Orexin-A-induced Ca2+ entry: evidence for involvement of TRPC channels and protein kinase C regulation. J Biol Chem. 2005;280(3):1771–81.

    Article  PubMed  CAS  Google Scholar 

  15. van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci. 1998;18(19):7962–71.

    PubMed  Google Scholar 

  16. Kohlmeier KA, Inoue T, Leonard CS. Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol. 2004;92(1):221–35.

    Article  PubMed  CAS  Google Scholar 

  17. Leonard CS, Tyler CJ, Burlet S, Watanabe S, Kohlmeier KA. Hypocretin/Orexin actions on mesopontine cholinergic systems controling behavioral state. In: de Lecea L, Sutcliffe JG, editors. Hypocretins: integrators of physiological functions. New York: Springer; 2005. p. 153–68.

    Chapter  Google Scholar 

  18. West AE, Chen WG, Dalva MB, et al. Calcium regulation of neuronal gene expression. Proc Natl Acad Sci USA. 2001;98(20):11024–31.

    Article  PubMed  CAS  Google Scholar 

  19. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci. 2002;22(21):9453–64.

    PubMed  CAS  Google Scholar 

  20. Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci. 2002;22(20):8850–9.

    PubMed  CAS  Google Scholar 

  21. Haj-Dahmane S, Shen RY. The wake-promoting peptide orexin-B inhibits glutamatergic transmission to dorsal raphe nucleus serotonin neurons through retrograde endocannabinoid signaling. J Neurosci. 2005;25(4):896–905.

    Article  PubMed  CAS  Google Scholar 

  22. Horvath TL, Peyron C, Diano S, et al. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol. 1999;415(2):145–59.

    Article  PubMed  CAS  Google Scholar 

  23. Murai Y, Akaike T. Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res. 2005;51(1):55–65.

    Article  PubMed  CAS  Google Scholar 

  24. Van Den Pol AN, Ghosh PK, Liu RJ, Li Y, Aghajanian GK, Gao XB. Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol. 2002;541(Pt 1):169–85.

    PubMed  Google Scholar 

  25. Chen XW, Mu Y, Huang HP, et al. Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus ceruleus neurons. J Neurosci. 2008;28(12):3202–8.

    Article  PubMed  CAS  Google Scholar 

  26. Korotkova TM, Sergeeva OA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci. 2003;23(1):7–11.

    PubMed  CAS  Google Scholar 

  27. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci. 2001;21(23):9273–9.

    PubMed  CAS  Google Scholar 

  28. Kohlmeier KA, Tyler CJ, Kalogiannis M, et al. Genetic dissection of orexin receptor functions in brainstem cholinergic and monoaminergic neurons: implications for orexinergic signaling in arousal and narcolepsy. (Submitted)

    Google Scholar 

  29. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null Mice. Molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron. 2003;38(5):715–30.

    Article  PubMed  CAS  Google Scholar 

  30. Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci. 2004;24(28):6291–300.

    Article  PubMed  CAS  Google Scholar 

  31. Kisanuki YY, Chemelli RM, Tokita S, Willie JT, Sinton CM, Yanagisawa M. Behavioral and polysomnographic characterization of orexin-1 receptor and orexin-2 receptor double knockout mice. Sleep. 2001;24(Abstract Supplement):A22.

    Google Scholar 

  32. Kisanuki YY, Chemelli RM, Sinton CM, Williams SCR, Richardson JA, Hammer RE, et al. The role of orexin receptor type-1 (OX1R) in the regulation of sleep. Sleep. 2000;23 Suppl 2:A91.

    Google Scholar 

  33. Nishino S, Mignot E. Pharmacological aspects of human and canine narcolepsy. Prog Neurobiol. 1997;52(1):27–78.

    Article  PubMed  CAS  Google Scholar 

  34. Kalogiannis M, Grupke SL, Potter PE, et al. Narcoleptic orexin receptor knockout mice express enhanced cholinergic properties in laterodorsal tegmental neurons. Eur J Neurosci. 2010;32(1):130–42.

    Article  PubMed  CAS  Google Scholar 

  35. Spitzer NC, Root CM, Borodinsky LN. Orchestrating neuronal differentiation: patterns of Ca2+ spikes specify transmitter choice. Trends Neurosci. 2004;27(7):415–21.

    Article  PubMed  CAS  Google Scholar 

  36. Belousov AB, O’Hara BF, Denisova JV. Acetylcholine becomes the major excitatory neurotransmitter in the hypothalamus in vitro in the absence of glutamate excitation. J Neurosci. 2001;21(6):2015–27.

    PubMed  CAS  Google Scholar 

  37. Belousov AB, Hunt ND, Raju RP, Denisova JV. Calcium-dependent regulation of cholinergic cell phenotype in the hypothalamus in vitro. J Neurophysiol. 2002;88:1352–62.

    PubMed  CAS  Google Scholar 

  38. Tafti M, Nishino S, Liao W, Dement WC, Mignot E. Mesopontine organization of cholinergic and catecholaminergic cell groups in the normal and narcoleptic dog. J Comp Neurol. 1997;379(2):185–97.

    Article  PubMed  CAS  Google Scholar 

  39. Reid MS, Siegel JM, Dement WC, Mignot E. Cholinergic mechanisms in canine narcolepsy-II. Acetylcholine release in the pontine reticular formation is enhanced during cataplexy. Neuroscience. 1994;59(3):523–30.

    Article  PubMed  CAS  Google Scholar 

  40. Semba K. Aminergic and cholinergic afferents to REM sleep induction regions of the pontine reticular formation in the rat. J Comp Neurol. 1993;330:543–56.

    Article  PubMed  CAS  Google Scholar 

  41. Nitz D, Andersen A, Fahringer H, Nienhuis R, Mignot E, Siegel J. Altered distribution of cholinergic cells in the narcoleptic dog. Neuroreport. 1995;6(11): 1521–4.

    Article  PubMed  CAS  Google Scholar 

  42. Kalogiannis M, Hsu E, Willie JT, et al. Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS One. 2011;6(4):e18697. doi:10.1371/journal.pone.0018697.

    Google Scholar 

  43. Lydic R, Douglas CL, Baghdoyan HA. Microinjection of neostigmine into the pontine reticular formation of C57BL/6J mouse enhances rapid eye movement sleep and depresses breathing. Sleep. 2002;25(8): 835–41.

    PubMed  Google Scholar 

  44. Lydic R, Baghdoyan HA. Pedunculopontine stimulation alters respiration and increases ACh release in the pontine reticular formation. Am J Physiol. 1993;264(3):R544–54.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by National Institutes of Health Grants HL64150 and NS27881. We would like to thank Drs. John Edwards, Iryna Gumenchuk, Masaru Ishibashi, Morten Kristensen, and Christopher Tyler along with Ms. Emily Hsu for their contributions to the experiments described in this chapter. We would also like to thank Dr. Masashi Yanagisawa and his colleagues for their contributions to this work, including engineering the knockout mouse lines.

Author information

Authors and Affiliations

  1. Department of Physiology, New York Medical College, Basic Sciences Building, Valhalla, NY, 10595, USA

    Christopher S. Leonard

Authors
  1. Christopher S. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mike Kalogiannis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristi A. Kohlmeier
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher S. Leonard .

Editor information

Editors and Affiliations

  1. , Department of Neurology, University Hospital of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland

    Christian R. Baumann

  2. Neurocenter EOC of Southern Switzerland, Department of Neurology, University Hospital Zurich, Via Tesserete 46, Lugano, 6903, Switzerland

    Claudio L. Bassetti

  3. and Harvard Medical School, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, 02215, Massachusetts, USA

    Thomas E. Scammell

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Leonard, C.S., Kalogiannis, M., Kohlmeier, K.A. (2011). Hypocretin/Orexin Receptor Functions in Mesopontine Systems Regulating Sleep, Arousal, and Cataplexy. In: Baumann, C., Bassetti, C., Scammell, T. (eds) Narcolepsy. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-8390-9_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-8390-9_13

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-8389-3

  • Online ISBN: 978-1-4419-8390-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation