Skip to main content
SpringerLink
Log in

Robust Synchrony and Rhythmogenesis in Endocrine Neurons via Autocrine Regulations In Vitro and In Vivo

  • Original Article
  • Published:
Bulletin of Mathematical Biology Aims and scope Submit manuscript

Abstract

Episodic pulses of gonadotropin-releasing hormone (GnRH) are essential for maintaining reproductive functions in mammals. An explanation for the origin of this rhythm remains an ultimate goal for researchers in this field. Some plausible mechanisms have been proposed among which the autocrine-regulation mechanism has been implicated by numerous experiments. GnRH binding to its receptors in cultured GnRH neurons activates three types of G-proteins that selectively promote or inhibit GnRH secretion (Krsmanovic et al. in Proc. Natl. Acad. Sci. 100:2969–974, 2003). This mechanism appears to be consistent with most data collected so far from both in vitro and in vivo experiments. Based on this mechanism, a mathematical model has been developed (Khadra and Li in Biophys. J. 91:74–3, 2006) in which GnRH in the extracellular space plays the roles of a feedback regulator and a synchronizing agent. In the present study, we show that synchrony between different neurons through sharing a common pool of GnRH is extremely robust. In a diversely heterogeneous population of neurons, the pulsatile rhythm is often maintained when only a small fraction of the neurons are active oscillators (AOs). These AOs are capable of recruiting nonoscillatory neurons into a group of recruited oscillators while forcing the nonrecruitable neurons to oscillate along. By pointing out the existence of the key elements of this model in vivo, we predict that the same mechanism revealed by experiments in vitro may also operate in vivo. This model provides one plausible explanation for the apparently controversial conclusions based on experiments on the effects of the ultra-short feedback loop of GnRH on its own release in vivo.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Blake, C.A., Sawyer, C.H., 1974. Effects of hypothalamic deafferentation on the pulsatile rhythm in plasma concentrations of luteinizing hormone in ovariectomized rats. Endocrinology 94, 730–36.

    Article  Google Scholar 

  • Caraty, A., Locatelli, A., Delaleu, B., Spitz, I.M., Schatz, B., Bouchard, P., 1990. Gonadotropin-releasing hormone (GnRH) agonists and GnRH antagonists do not alter endogenous GnRH secretion in short-term castrated rams. Endocrinology 127, 2523–529.

    Article  Google Scholar 

  • Cartwright, J.H.E., 2000. Emergent global oscillations in heterogeneous excitable media: The example of pancreatic β cells. Phys. Rev. E 62, 1149–154.

    Article  Google Scholar 

  • Corbin, A., Beattie, C.W., 1976. Effect of luteinizing hormone releasing hormone (LHRH) and an LHRH antagonist on hypothalamic and plasma LHRH of hypophysectomized rats. Endocrinology 98, 247–50.

    Article  Google Scholar 

  • de la Escalera, G.M., Choi, A.L.H., Weiner, R.I., 1992. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: Intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc. Natl. Acad. Sci. 89, 1852–855.

    Article  Google Scholar 

  • DePaolo, L.V., King, R.A., Carrillo, A.J., 1987. In vivo and in vitro examination of an autoregulatory mechanism for luteinizing hormone releasing hormone. Endocrinology 120, 272–79.

    Article  Google Scholar 

  • Goldsmith, P.C., Lamberts, R., Brezina, L.R., 1983. Gonadotropin-releasing hormone neurons and pathways in the primate hypothalamus and forebrain. In: Norman, R.L. (Ed.), Aspects of Reproduction, pp. 7–5. Academic, New York

    Google Scholar 

  • Grzegorzewski, W.J., Skipor, J., Wasowska, B., Krzymowski, T., 1997. Countercurrent transfer of 125I-LHRH in the perihypophyseal cavernous sinus-carotid rete vascular complex, demonstrated on isolated pig heads perfused with autologous blood. Domest. Anim. Endocrinol. 14, 149–60.

    Article  Google Scholar 

  • Hyyppa, M., Motta, M., Martini, L., 1971. ‘Ultrashort’ feedback control of follicle-stimulating hormone-releasing factor secretion. Neuroendocrinology 7, 227–35.

    Article  Google Scholar 

  • Khadra, A., Li, Y.X., 2006. A model for the pulsatile secretion of gonadotropin-releasing hormone from synchronized hypothalamic neurons. Biophys. J. 91, 74–3.

    Article  Google Scholar 

  • Knobil, E., 1980. On the control of gonadotropin in the rhesus monkey. Recent Prog. Horm. Res. 36, 53–8.

    Google Scholar 

  • Krey, L.C., Butler, W.R., Knobil, E., 1975. Surgical disconnection of the medial basal hypothalamus and pituitary function in the rhesus monkey. I. Gonadotropin secretion. Endocrinology 96, 1073–087.

    Article  Google Scholar 

  • Krsmanovic, L.Z., Stojilković, S.S., Balla, T., Al-Damluji, S., Weiner, R.I., Catt, K.J., 1991. Receptors and neurosecretory actions of endothelin in hypothalamic neurons. Proc. Natl. Acad. Sci. 88, 11124–1128.

    Article  Google Scholar 

  • Krsmanovic, L.Z., Stojilković, S.S., Mertz, L.M., Tomic, M., Catt, K.J., 1993. Expression of gonadotropin-releasing hormone receptors and autocrine regulation of neuropeptide release in immortalized hypothalamic neurons. Proc. Natl. Acad. Sci. 90, 3908–912.

    Article  Google Scholar 

  • Krsmanovic, L.Z., Martinez-Fuentes, A.J., Arora, K.K., Mores, N., Navarro, C.E., Chen, H.C., Stojilković, S.S., Catt, K.J., 1999. Autocrine regulation of gonadotropin-releasing hormone secretion in cultured hypothalamic neurons. Endocrinology 140, 1423–431.

    Article  Google Scholar 

  • Krsmanovic, L.Z., Mores, N., Navarro, C.E., Arora, K.K., Catt, K.J., 2003. An agonist-induced switch in G protein coupling of the gonadotropin-releasing hormone receptor regulates pulsatile neuropeptide secretion. Proc. Natl. Acad. Sci. 100, 2969–974.

    Article  Google Scholar 

  • Kuramoto, Y., 1984. Chemical Oscillations, Waves and Turbulence. Springer, Berlin.

    MATH  Google Scholar 

  • LeBeau, A.P., Van Goor, F., Stojilković, S.S., Sherman, A., 2000. Modeling of membrane excitability in gonadotropin-releasing hormone-secreting hypothalamic neurons regulated by Ca2+-mobilizing and adenylyl cyclase-coupled receptors. J. Neurosci. 20, 9290–297.

    Google Scholar 

  • Li, Y.X., Goldbeter, A., 1989. Frequency specificity in intercellular communication. Influence of patterns of periodic signaling on target cell responsiveness. Biophys. J. 55, 125–45.

    Article  Google Scholar 

  • Li, Y.X., Halloy, J., Martiel, J.L., Goldbeter, A., 1992. Suppression of chaos and other dynamical transitions induced by intercellular coupling in a model for cyclic AMP signaling in Dictyostelium cells. Chaos 2, 501–12.

    Article  Google Scholar 

  • Manor, Y., Rinzel, J., Segev, I., Yarom, Y., 1997. Low amplitude oscillations in the inferior olive: A model based on electrical coupling of neurons with heterogeneous channel density. J. Neurophys. 77, 2736–752.

    Google Scholar 

  • Moenter, S.M., DeFazio, R.A., Pitts, G.R., Nunemaker, C.S., 2003. Mechanisms underlying episodic gonadotropin-releasing hormone secretion. Front. Neuroendocrinol. 24, 79–3.

    Article  Google Scholar 

  • Nunemaker, C.S., DeFazio, R.A., Geusz, M.E., Herzog, E.D., Pitts, G.R., Moenter, S.M., 2001. Long-term recordings of networks of immortalized GnRH neurons reveal episodic patterns of electrical activity. J. Neurophys. 86, 86–3.

    Google Scholar 

  • Nunemaker, C.S., Straume, M., DeFazio, R.A., Moenter, S.M., 2003. Gonadotropin-releasing hormone neurons generate interacting rhythms in multiple time domains. Endocrinology 144, 823–31.

    Article  Google Scholar 

  • Plant, T.M., Nakai, Y., Belchetz, P., Keogh, E., Knobil, E., 1978. The sites of action of estradiol and phentolamine in the inhibition of the pulsatile, circhoral discharges of LH in the rhesus monkey (Macaca mulatta). Endocrinology 102, 1015–018.

    Article  Google Scholar 

  • Rubin, B.S., King, J.C., 1995. A relative depletion of LH-RH was observed in the median eminence of young but not middle-aged rats on the evening of proestrus. Neuroendocrinology 62, 259–69.

    Article  Google Scholar 

  • Silverman, A.J., Livne, I., Witkin, J.W., 1994. The gonadotropin-releasing hormone (GnRH) neuronal systems: Immunocytochemistry and in situ hybridization. In: Knobil, E., Neill, J.E. (Eds.), Physiology of Reproduction, 2nd edn., pp. 1683–709. Raven Press, New York

    Google Scholar 

  • Suter, K.J., Song, W.J., Sampson, T.L., Wuarin, J.P., Saunders, J.T., Dudek, F.E., Moenter, S.M., 2000a. Genetic targeting of green fluorescent protein to gonadotropin-releasing hormone neurons: characterization of whole-cell electrophysiological properties and morphology. Endocrinology 141, 412–19.

    Article  Google Scholar 

  • Suter, K.J., Wuarin, J.P., Smith, B.N., Dudek, F.E., Moenter, S.M., 2000b. Whole-cell recordings from preoptic/hypothalamic slices reveal burst firing in gonadotropin-releasing hormone neurons identified with green fluorescent protein in transgenic mice. Endocrinology 141, 3731–736.

    Article  Google Scholar 

  • Terasawa, E., 2001. Luteinizing hormone-releasing hormone (LHRH) neurons: mechanism of pulsatile LHRH release. Vit. Horm. 63, 91–29.

    Article  Google Scholar 

  • Terasawa, E., Keen, K.L., Mogi, K., Claude, P., 1999. Pulsatile release of luteinizing hormone-releasing hormone (LHRH) in cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. Endocrinology 140, 1432–441.

    Article  Google Scholar 

  • Todman, M.G., Han, S.K., Herbison, A.E., 2005. Profiling neurotransmitter receptor expression in mouse gonadotropin-releasing hormone neurons using green fluorescent protein-promoter transgenics and microarrays. Neuroscience 132, 703–12.

    Article  Google Scholar 

  • Valenca, M.M., Johnston, C.A., Ching, M., Negro-Villar, A., 1987. Evidence for a negative ultrashort loop feedback mechanism operating on the luteinizing hormone releasing hormone neuronal system. Endocrinology 121, 2256–259.

    Article  Google Scholar 

  • Witkin, J.W., Silverman, A.J., 1985. Synaptology of luteinizing hormone-releasing hormone neurons in rat preoptic area. Peptides 6, 263–71.

    Article  Google Scholar 

  • Woller, M.J., Nicholas, E., Herdendorf, T., Tutton, D., 1998. Release of luteinizing hormone releasing hormone from enzymatically disperse rat hypothalamic explants is pulsatile. Biol. Reprod. 59, 587–90.

    Article  Google Scholar 

  • Woller, M.J., Meyer, S., Ada-Nguema, A., Waechter-Brulla, D., 2003. Dissecting autocrine effects on pulsatile release of gonadotropin-releasing hormone in cultured rat hypothalamic tissue. Exp. Biol. Med. 229, 56–4.

    Google Scholar 

  • Xu, C., Xu, X.Z., Nunemaker, C.S., Moenter, S.M., 2004. Dose-dependent switch in response of gonadotropin-releasing hormone (GnRH) neurons to GnRH mediated through the type I GnRH receptor. Endocrinology 145, 728–35.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Mathematics, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada

    Yue-Xian Li

  2. Departments of Zoology, University of British Columbia, Vancouver, BC, V6T 1Z2, Canada

    Yue-Xian Li & Anmar Khadra

Authors
  1. Yue-Xian Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anmar Khadra
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yue-Xian Li.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, YX., Khadra, A. Robust Synchrony and Rhythmogenesis in Endocrine Neurons via Autocrine Regulations In Vitro and In Vivo. Bull. Math. Biol. 70, 2103–2125 (2008). https://doi.org/10.1007/s11538-008-9328-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11538-008-9328-z

Keywords

Search

Navigation