The overall goal of this proposal is to investigate the cellular and molecular mechanisms underlying pulsatile gonadotropin-releasing hormone (GnRH) secretion. GnRH neurons provide the final common pathway for the central neural control of reproduction in all vertebrate species. Release of GnRH in a rhythmic manner is absolutely indispensable for reproductive function. Understanding this biological phenomenon is not only of basic interest, but also has broad application to both the enhancement and the reversible suppression of fertility. This problem will be studied in three Specific Aims, using electrophysiological, cellular and molecular techniques to investigate GnRH neurons identified by expression of green fluorescent protein.
In Specific Aim I, isolated GnRH neurons will be compared with those in networks to determine possible sources of rhythmicity for episodic GnRH release. The hypotheses that individual GnRH neurons are intrinsically rhythmic but need to be organized into a network in order to generate pulsatile release at a frequency appropriate for pituitary control will be tested. The role of subcellular oscillations in generating rhythmic GnRH release and the currents underlying these oscillations will be determined.
In Specific Aim II, the mechanisms coordinating GnRH neurons will be examined. The hypotheses that GnRH serves as an inhibitory neuromediator of its own release, that nitric oxide originating outside the GnRH neurosecretory network affects subthreshold activity and thereby helps coordinate GnRH neurons and that the median eminence is required for synchronization of this system will be tested. We will also conduct pilot studies to test if GnRH neurons produce traditional neurotransmitters to coordinate release by fast synaptic transmission.
In Specific Aim III, the role of calcium currents in GnRH neuronal rhythmicity will be examined. The types of cell membrane calcium channels will first be determined. Then the hypothesis that these channels undergo changes in activity and/or voltage dependence due to post-translational modifications will be tested. The proposed experiments will greatly enhance our understanding of the cellular aspects of the operation of an important neuroendocrine oscillator.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD034860-08
Application #
6753644
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
De Paolo, Louis V
Project Start
1997-04-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
8
Fiscal Year
2004
Total Cost
$265,363
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Vanacker, Charlotte; Moya, Manuel Ricu; DeFazio, R Anthony et al. (2017) Long-Term Recordings of Arcuate Nucleus Kisspeptin Neurons Reveal Patterned Activity That Is Modulated by Gonadal Steroids in Male Mice. Endocrinology 158:3553-3564
Ruka, Kristen A; Burger, Laura L; Moenter, Suzanne M (2016) Both Estrogen and Androgen Modify the Response to Activation of Neurokinin-3 and ?-Opioid Receptors in Arcuate Kisspeptin Neurons From Male Mice. Endocrinology 157:752-63
Moran, Spencer; Moenter, Suzanne M; Khadra, Anmar (2016) A unified model for two modes of bursting in GnRH neurons. J Comput Neurosci 40:297-315
Moenter, Suzanne M (2015) Leap of Faith: Does Serum Luteinizing Hormone Always Accurately Reflect Central Reproductive Neuroendocrine Activity? Neuroendocrinology 102:256-266
Glanowska, Katarzyna M; Moenter, Suzanne M (2015) Differential regulation of GnRH secretion in the preoptic area (POA) and the median eminence (ME) in male mice. Endocrinology 156:231-41
Glanowska, Katarzyna M; Burger, Laura L; Moenter, Suzanne M (2014) Development of gonadotropin-releasing hormone secretion and pituitary response. J Neurosci 34:15060-9
Gaskins, Garrett T; Glanowska, Katarzyna M; Moenter, Suzanne M (2013) Activation of neurokinin 3 receptors stimulates GnRH release in a location-dependent but kisspeptin-independent manner in adult mice. Endocrinology 154:3984-9
Ruka, Kristen A; Burger, Laura L; Moenter, Suzanne M (2013) Regulation of arcuate neurons coexpressing kisspeptin, neurokinin B, and dynorphin by modulators of neurokinin 3 and ?-opioid receptors in adult male mice. Endocrinology 154:2761-71
Glanowska, Katarzyna M; Venton, B Jill; Moenter, Suzanne M (2012) Fast scan cyclic voltammetry as a novel method for detection of real-time gonadotropin-releasing hormone release in mouse brain slices. J Neurosci 32:14664-9
Chu, Z; Tomaiuolo, M; Bertram, R et al. (2012) Two types of burst firing in gonadotrophin-releasing hormone neurones. J Neuroendocrinol 24:1065-77

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