LHRH PULSE GENERATION AND STEROID FEEDBACK

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Objective: To understand the mechanism of LHRH pulse generation and the mechanism of steroid action on LHRH neurons. DESCRIPTION: Pulsatile release of LHRH from the hypothalamus is essential for normal reproductive function, yet the mechanism of GnRH pulse generation is unclear. We cultured GnRH neurons originating from the olfactory pit/placode region and characterized the cellular mechanism of GnRH pulse generation. The periodicity of peptide release and bursting activity of GnRH neurons were much slower than mouse GnRH neurons, although many characteristics in monkey GnRH neurons are similar to those described for mice. The aim of this study is to understand the mechanism of GnRH pulse generation and the mechanism of steroid action on GnRH neurons. PROGRESS: We have made three important discoveries. First, primate GnRH neuronal maturation is characterized by age-dependent development of spontaneous synchronizing [Ca2+]i oscillations, pulsatile peptide release, increased GnRH gene expression and demethylation of a 5' CpG rich region of the GnRH gene. Second, rapid action of estradiol inducing intracellular calcium oscillations and GnRH release is mediated by neither estrogen receptor alpha nor beta. Rather, it appears to be, in part, mediated by the 7-transmembrane G-protein coupled receptor, GPR30 as well as a STX- sensitive receptor. Third, GnRH neurons releases the decapeptide from the cell body and neuroprocesses. These exciting findings are extremely important for the development of contraceptive tools and treatment of infertility. This research used WNPRC Animal Services and Assay Services. PUBLICATIONS: Terasawa, E., Kurian, J.R., Guerriero, K.A., Kenealy, B.P., Hutz, E.D., and Keen, K.L. Recent discoveries on the control of GnRH neurons in nonhuman primates. J. Neuroendocrinol. 22:630-638, 2010. PMID: 20456608, PMCID: PMC2908205. Kurian J.R., Keen, K.L., and Terasawa, E. 2010 Epigenetic changes coincide with in vitro primate GnRH neuronal maturation. Endocrinology 151:5359-5368. PMID: 20861233, PMCID: PMC2954729.