The long term objective of this research is to determine the physiological changes in the hypothalamo-hypophysial unit that are responsible for the reversible suppression of reproductive function. Based on previous work, we have proposed that seasonal alterations of fertility in the ewe result from a photoperiod-induced shift in the neural systems controlling LH secretion. During the breeding season when normal ovarian cycles occur, progesterone appears to inhibit LH pulse frequency via the endogenous opiates (EOP), while estradiol decreases LH pulse amplitude via mechanisms involving both EOP and alpha-adrenergic (NA) neurons. During anestrus, when ovarian cycles cease, these systems are still present, but their effects are superseded by two additional inhibitory neural systems activated by the long-day photoperiod: an estradiol-sensitive catecholaminergic system that accounts for the seasonal variation in estradiol negative feedback and a serotonergic (5HT) system that is responsible for the steroid-independent inhibition of LH secretion in anestrous ewes. The experiments in this proposal will further test this hypothesis by identifying the neural systems involved and begin to explore the neuroendocrine control of these systems. The first specific aim focuses on the catecholaminergic systems activated in anestrus. Previous data suggests that this system involves dopaminergic (DA) cell bodies in the lateral retrochiasmatic area (Al5) that are stimulated by NA input and project to the medial basal hypothalamus (MBH) where they act to inhibit LH release. These experiments will: 1) further test this hypothesis, using radiofrequency lesions in the AI 5, 2) determine where these cell bodies project using anterograde tracing, 3) examine the effects of estradiol and NA tone on release of DA from this system using in vivo microdialysis, and 4) use retrograde tracing techniques to locate the source of the NA input. Experiments in Specific Aim 2 will first use local administration of 5HT agonists and antagonists to determine where in the ovine hypothalamus the steroid-independent inhibition occurs. They will then determine which 5HT perikarya project to this area and if there is a seasonal variation in endogenous release of 5HT in this area.
Specific Aim 3 examines the neural systems active in the breeding season. We will first test if estradiol acts via EOP neurons to inhibit GnRH pulse amplitude in the breeding season. The next study uses immunocytochemical and in situ hybridization techniques to determine if different beta-endorphin neurons mediate the negative feedback actions of progesterone and estradiol. A final study examines the possible interactions of EOP and NA neurons in the control of LH pulse amplitude. These studies will provide basic information on the mechanism controlling reproductive function. They will thus broaden our understanding of the physiology (and ultimately the pathology) of normal alterations in reproductive activity, including puberty and the suppression of reproductive function during lactation.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
2R01HD017864-07A1
Application #
3314874
Study Section
Reproductive Biology Study Section (REB)
Project Start
1983-09-01
Project End
1996-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
7
Fiscal Year
1991
Total Cost
Indirect Cost
Name
West Virginia University
Department
Type
Schools of Dentistry
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Nestor, Casey C; Bedenbaugh, Michelle N; Hileman, Stanley M et al. (2018) Regulation of GnRH pulsatility in ewes. Reproduction 156:R83-R99
Weems, Peyton; Smith, Jeremy; Clarke, Iain J et al. (2017) Effects of Season and Estradiol on KNDy Neuron Peptides, Colocalization With D2 Dopamine Receptors, and Dopaminergic Inputs in the Ewe. Endocrinology 158:831-841
Grachev, P; Porter, K L; Coolen, L M et al. (2016) Surge-Like Luteinising Hormone Secretion Induced by Retrochiasmatic Area NK3R Activation is Mediated Primarily by Arcuate Kisspeptin Neurones in the Ewe. J Neuroendocrinol 28:
Fergani, Chrysanthi; Mazzella, Leanne; Coolen, Lique M et al. (2016) Do Substance P and Neurokinin A Play Important Roles in the Control of LH Secretion in Ewes? Endocrinology 157:4829-4841
Weems, Peyton W; Goodman, Robert L; Lehman, Michael N (2015) Neural mechanisms controlling seasonal reproduction: principles derived from the sheep model and its comparison with hamsters. Front Neuroendocrinol 37:43-51
Goodman, Robert L; Coolen, Lique M; Lehman, Michael N (2014) A role for neurokinin B in pulsatile GnRH secretion in the ewe. Neuroendocrinology 99:18-32
Porter, K L; Hileman, S M; Hardy, S L et al. (2014) Neurokinin-3 receptor activation in the retrochiasmatic area is essential for the full pre-ovulatory luteinising hormone surge in ewes. J Neuroendocrinol 26:776-84
Goodman, Robert L; Hileman, Stanley M; Nestor, Casey C et al. (2013) Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology 154:4259-69
Nestor, Casey C; Coolen, Lique M; Nesselrod, Gail L et al. (2013) Evidence that orphanin FQ mediates progesterone negative feedback in the ewe. Endocrinology 154:4249-58
Merkley, Christina M; Porter, Katrina L; Coolen, Lique M et al. (2012) KNDy (kisspeptin/neurokinin B/dynorphin) neurons are activated during both pulsatile and surge secretion of LH in the ewe. Endocrinology 153:5406-14

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