The present proposal will use a multidisciplinary approach to further elucidate the physiological events leading to the proestrus surge of prolactin (PRL) and the mechanism by which the PRL surge is coupled to the proestrus surge of luteinizing hormone (LH). Findings from ongoing experiments suggest that the suprachiasmatic nucleus (SCN) and the medial preoptic nucleus (MPN) are both responsible for the PRL and LH surge. It is also apparent that interactions between the two structures generate a signal which directly or indirectly regulates the luteinizing hormone releasing hormone (LHRH) neurons. Initial experiments are designed to explore the effects of SCN or MPN lesions on the ability of progesterone to induce the preovulatory LH and PRL surge. Secondly, we will elucidate the effects of the lesions on the hypothalamic content of LHRH and preproLHRH. We will also explore through Northern blot (RNA) and in situ hybridization the synthetic activity of the LHRH neurons during proestrus as compared to estrus, and evaluate the effects of SCN or MPN lesions on the LHRH synthetic activity. Thereafter we will initiate in vivo studies to explore the sensitivity of the hypothalamic-pituitary axis to estrogen following MPN/SCN lesions. In vitro slice preparation experiments will continue to study the electrophysiological properties of the SCN/MPN neurons. We will use intracellular and patch-clamp recording techniques to determine the synaptic input, the chemosensitivity to the neurotransmitters/neuromodulators (serotonin 5HT), norepinephrine/epinephrine (NE/E), acetylcholine (Ach), dopamine and Beta-endorphin (Beta-end)), and the effects of estrogen on membrane excitability of SCN/MPN neurons. Intracellular staining with procion yellow (PY) will be done in conjunction with immunocyto-chemistry to identify the morphology and cytochemistry of these neurons. Finally, we will use the sagittal slice preparation to study the electrophysiological interaction between the MPN and the SCN to elucidate the basic mechanism by which the two structures initiate the signal leading to the proestrus surge of LH and PRL.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD016793-07
Application #
3313946
Study Section
Reproductive Biology Study Section (REB)
Project Start
1982-09-01
Project End
1990-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
7
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Type
Schools of Dentistry
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Lagrange, A H; Ronnekleiv, O K; Kelly, M J (1995) Estradiol-17 beta and mu-opioid peptides rapidly hyperpolarize GnRH neurons: a cellular mechanism of negative feedback? Endocrinology 136:2341-4
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Lagrange, A H; Ronnekleiv, O K; Kelly, M J (1994) The potency of mu-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17 beta-estradiol. J Neurosci 14:6196-204
Loose, M D; Ronnekleiv, O K; Kelly, M J (1991) Neurons in the rat arcuate nucleus are hyperpolarized by GABAB and mu-opioid receptor agonists: evidence for convergence at a ligand-gated potassium conductance. Neuroendocrinology 54:537-44
Ronnekleiv, O K; Resko, J A (1990) Ontogeny of gonadotropin-releasing hormone-containing neurons in early fetal development of rhesus macaques. Endocrinology 126:498-511
Ma, Y J; Kelly, M J; Ronnekleiv, O K (1990) Pro-gonadotropin-releasing hormone (ProGnRH) and GnRH content in the preoptic area and the basal hypothalamus of anterior medial preoptic nucleus/suprachiasmatic nucleus-lesioned persistent estrous rats. Endocrinology 127:2654-64
Roselli, C E; Kelly, M J; Ronnekleiv, O K (1990) Testosterone regulates progonadotropin-releasing hormone levels in the preoptic area and basal hypothalamus of the male rat. Endocrinology 126:1080-6
Ronnekleiv, O K; Loose, M D; Erickson, K R et al. (1990) A method for immunocytochemical identification of biocytin-labeled neurons following intracellular recording. Biotechniques 9:432-8
Ronnekleiv, O K; Naylor, B R; Bond, C T et al. (1989) Combined immunohistochemistry for gonadotropin-releasing hormone (GnRH) and pro-GnRH, and in situ hybridization for GnRH messenger ribonucleic acid in rat brain. Mol Endocrinol 3:363-71

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