Effect of Orexin-A on Discharge Rate of Rat Suprachiasmatic Nucleus Neurons In Vitro

Abstract

The suprachiasmatic nuclei (SCN) constitute the principal pacemaker of the circadian timing system in mammals. The generated rhythm is forwarded mostly through projections to various hypothalamic nuclei. On the other hand, the regulated processes feedback to the SCN. One of the possible feedback pathways is the orexinergic projection from the lateral hypothalamus. Orexins are recently identified neuropeptides with an overall facilitatory effect on waking behaviors. Orexinergic fibers are widely distributed throughout the brain and are also present in the SCN. In this study we examined the effect of orexin-A on the spontaneous activity of rat SCN cell in vitro. Neurons showed 2 different firing pattern (continuous-regular, intermittent-irregular). Orexin-A increased firing rate in both cell types at 10−8 M concentration, but caused a clear supression of neuronal activity at 10−7 M. Continuously firing neurons were less responsive than those firing intermittently. These results show that orexin-A may play a role in the modulation of the circadian pacemaker function. The neuropeptide might exert both direct, postsynaptic effects on SCN neurons and indirect, presynaptic effects on excitatory and inhibitory terminals. The dose-dependent modification of the firing rate indicate that the weight of these factors changes with the concentration of orexin-A.

References

  1. 1.

    Abrahamson, E. E., Leak, R. K., Moore, R. Y. (2001) The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12, 435–440.

    CAS  Article  Google Scholar 

  2. 2.

    Bouskila, Y., Dudek, F. E. (1995) Can a population of suprachiasmatic nucleus neurons with different period lengths produce a stable circadian rhythm? Brain Res. 670, 333–336.

    CAS  Article  Google Scholar 

  3. 3.

    Coogan, A. N., Rawlings, N., Luckman, S. M., Piggins, H. D. (2001) Effects of neurotensin on discharge rates of rat suprachiasmatic nucleus neurons in vitro. Neuroscience 103, 663–672.

    CAS  Article  Google Scholar 

  4. 4.

    Cutler, D. J., Piggins, H. D., Selbie, L. A., Mason, R. (1998) Responses to neuropeptide Y in adult hamster suprachiasmatic nucleus neurones in vitro. Eur. J. Pharmacol. 345, 155–162.

    CAS  Article  Google Scholar 

  5. 5.

    Date, Y., Ueta, Y., Yamashita, H., Yamaguchi, H., Matsukura, S., Kangawa, K., Sakurai, T., Yanagisawa, M., Nakazato, M. (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc. Natl. Acad. Sci. U.S.A. 96, 748–753.

    CAS  Article  Google Scholar 

  6. 6.

    De Lecea, L., Kilduff, T. S., Peyron, C., Gao, X., Foye, P. E., Danielson, P. E., Fukuhara, C., Battenberg, E. L., Gautvik, V. T., Bartlett, F. S., Frankel, W. N., van den Pol, A. N., Bloom, F. E., Gautvik, K. M., Sutcliffe, J. G. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A. 95, 322–327.

    Article  Google Scholar 

  7. 7.

    Dube, M. G., Kalra, S. P., Kalra, P. S. (1999) Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res. 842, 473–477.

    CAS  Article  Google Scholar 

  8. 8.

    Glass, J. D., DiNardo, L. A., Ehlen, J. C. (2000) Dorsal raphe nuclear stimulation of SCN serotonin release and circadian phase-resetting. Brain Res. 859, 224–232.

    CAS  Article  Google Scholar 

  9. 9.

    Harrington, M. E., Nance, D. M., Rusak, B. (1985) Neuropeptide Y immunoreactivity in the hamster geniculo-suprachiasmatic tract. Brain Res. Bull. 15, 465–472.

    Article  Google Scholar 

  10. 10.

    Ida, T., Nakahara, K., Katayama, T., Murakami, N., Nakazato, M. (1999) Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res. 821, 526–529.

    CAS  Article  Google Scholar 

  11. 11.

    Jiang, Z. G., Teshima, K., Yang, Y., Yoshioka, T., Allen, C. N. (2000) Pre- and postsynaptic actions of serotonin on rat suprachiasmatic nucleus neurons. Brain Res. 866, 247–256.

    CAS  Article  Google Scholar 

  12. 12.

    Kilduff, T. S., Peyron, C. (2000) The hypocretin/orexin ligand-receptor system: implications for sleep and sleep disorders. Trends Neurosci. 23, 359–365.

    CAS  Article  Google Scholar 

  13. 13.

    Korotkova, T. M., Eriksson, K. S., Haas, H. L., Brown, R. E. (2002) Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul. Pept. 104, 83–89.

    CAS  Article  Google Scholar 

  14. 14.

    Kow, L. M., Pfaff, D. W. (1984) Suprachiasmatic neurons in tissue slices from ovariectomized rats: electrophysiological and neuropharmacological characterization and the effects of estrogen treatment. Brain Res. 297, 275–286.

    CAS  Article  Google Scholar 

  15. 15.

    Krout, K. E., Kawano, J., Mettenleiter, T. C., Loewy, A. D. (2002) CNS inputs to the suprachiasmatic nucleus of the rat. Neuroscience 110, 73–92.

    CAS  Article  Google Scholar 

  16. 16.

    Kunii, K., Yamanaka, A., Nambu, T., Matsuzaki, I., Goto, K., Sakurai, T. (1999) Orexins/hypocretins regulate drinking behaviour. Brain Res. 842, 256–261.

    CAS  Article  Google Scholar 

  17. 17.

    Liou, S. Y., Shibata, S., Albers, H. E., Ueki, S. (1990) Effects of GABA and anxiolytics on the single unit discharge of suprachiasmatic neurons in rat hypothalamic slices. Brain Res. Bull. 25, 103–107.

    CAS  Article  Google Scholar 

  18. 18.

    Meijer, J. H., van der Zee, E. A., Dietz, M. (1988) Glutamate phase shifts circadian activity rhythms in hamsters. Neurosci. Lett. 86, 177–183.

    CAS  Article  Google Scholar 

  19. 19.

    Meijer, J. H., Rietveld, W. J. (1989) Neurophysiology of the suprachiasmatic circadian pacemaker in rodents. Physiol. Rev. 69, 671–707.

    CAS  Article  Google Scholar 

  20. 20.

    Miller, J. D. (1993) On the nature of the circadian clock in mammals. Am. J. Physiol. 264, R821–R832.

    CAS  PubMed  Google Scholar 

  21. 21.

    Moga, M. M., Moore, R. Y. (1997) Organization of neural inputs to the suprachiasmatic nucleus in the rat. J. Comp. Neurol. 389, 508–534.

    CAS  Article  Google Scholar 

  22. 22.

    Piper, D. C., Upton, N., Smith, M. I., Hunter, A. J. (2000) The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur. J. Neurosci. 12, 726–730.

    CAS  Article  Google Scholar 

  23. 23.

    Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., Arch, J. R., Buckingham, R. E., Haynes, A. C., Carr, S. A., Annan, R. S., McNulty, D. E., Liu, W. S., Terrett, J. A., Elshourbagy, N. A., Bergsma, D. J., Yanagisawa, M. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585.

    CAS  Article  Google Scholar 

  24. 24.

    Starkey, S. J., Walker, M. P., Beresford, I. J., Hagan, R. M. (1995) Modulation of the rat suprachiasmatic circadian clock by melatonin in vitro. Neuroreport 6, 1947–1951.

    CAS  Article  Google Scholar 

  25. 25.

    Sutcliffe, J. G., De Lecea, L. (2002) The hypocretins: setting the arousal threshold. Nat. Rev. Neurosci. 3, 339–349.

    CAS  Article  Google Scholar 

  26. 26.

    Thomson, A. M., West, D. C., Vlachonikolis, I. G. (1984) Regular firing patterns of suprachiasmatic neurons maintained in vitro. Neurosci. Lett. 52, 329–334.

    CAS  Article  Google Scholar 

  27. 27.

    van den Pol, A. N., Gao, X. B., Obrietan, K., Kilduff, T. S., Belousov, A. B. (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J. Neurosci. 18, 7962–7971.

    Article  Google Scholar 

  28. 28.

    Vibert, J. F., Costa, J. (1979) Spike separation in multiunit records: a multivariate analysis of spike descriptive parameters. Electroencephalogr. Clin. Neurophysiol. 47, 172–182.

    CAS  Article  Google Scholar 

  29. 29.

    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.

    CAS  Article  Google Scholar 

  30. 30.

    Yu, G. D., Liu, Y. L., Jiang, X. H., Guo, S. Y., Zhang, H. Q., Yin, Q. Z., Hisamitsu, T. (2001) The inhibitory effect of serotonin on the spontaneous discharge of suprachiasmatic neurons in hypothalamic slice is mediated by 5-HT(7) receptor. Brain Res. Bull. 54, 395–398.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ildikó Világi.

Additional information

Dedicated to Professor György Ádám on the occasion of his 80th birthday.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Cite this article

Farkas, B., Világi, I. & Détári, L. Effect of Orexin-A on Discharge Rate of Rat Suprachiasmatic Nucleus Neurons In Vitro. BIOLOGIA FUTURA 53, 435–443 (2002). https://doi.org/10.1556/ABiol.53.2002.4.5

Download citation

Keywords

  • Circadian rhythms
  • cortical slices
  • orexin-A
  • SCN
  • single unit activity