Regulation of Estradiol-Induced Prolactin Secretion and Entrainment by the Suprachiasmatic Nucleus
Kennett, Jessica Elise (author)
Freeman, Marc E. (professor directing dissertation)
Gilmer, Penny J. (outside committee member)
Fadool, Debra A. (committee member)
Hull, Elaine (committee member)
Meredith, Michael (committee member)
Department of Biological Science (degree granting department)
Florida State University (degree granting institution)
In the female rat, secretion of prolactin is tightly controlled by a complex interplay of both stimulatory and inhibitory hypothalamic factors. In addition, the profile of prolactin release in the ovariectomized rat treated with estradiol exhibits circadian rhythmicity, which requires an intact suprachiasmatic nucleus (SCN). This suggests that photic cues influence the hypothalamic factors coordinating the release of prolactin, namely oxytocin (arising from the paraventricular and periventricular nucleus of the hypothalamus) and dopamine (arising from neuroendocrine dopaminergic neurons in the periventricular nucleus and the arcuate nucleus). How photic cues regulate the secretion of prolactin, however, has yet to be explicated in animals treated with estradiol. Recent research has determined that the SCN sends efferents of vasoactive intestinal polypeptide to neuroendocrine dopaminergic neurons as well as to the paraventricular and periventricular nuclei of the hypothalamus. The first purpose of this study was to elucidate the mechanism regulating the rhythmicity of prolactin release. To determine this, vasoactive intestinal polypeptide synthesis was disrupted using vasoactive intestinal polypeptide antisense deoxyoligonucleotides infused into the dorsal border of the SCN. This treatment caused a phase-advance in the pattern of prolactin secretion in estradiol-treated ovariectomized rats. Using immunohistochemistry, oxytocin and dopamine activity was established through double labeling with FOS-related antigens (a marker of neuronal activity). In both populations of neurons (oxytocin neurons and neuroendocrine dopaminergic neurons), a phase advance was also observed. In oxytocin neurons, disruption of vasoactive intestinal polypeptide phase-advanced the increase in activity that normally accompanies the prolactin surge. Whereas, in dopamine neurons, disruption of vasoactive intestinal polypeptide phase-advanced the decrease in activity that is required to allow for the prolactin surge. Furthermore, clock gene expression has been localized to neuroendocrine dopaminergic neurons. In all three populations of neuroendocrine dopaminergic neurons, the expression of the clock gene period 2 oscillates. Disruption of vasoactive intestinal polypeptide disrupted this pattern of activity. Thus, the SCN influences the precise timing of the estradiol-induced prolactin surge via vasoactive intestinal polypeptide projections to oxytocinergic and dopaminergic neurons, and possibly does so by entraining clock gene expression in these neurons. Once entrained, oxytocin exerts its stimulatory effects at a previously unknown site. Using a selective oxytocin antagonist that does not cross the blood brain barrier, the pituitary was determined to be the site of oxytocin stimulation. Interestingly, the oxytocin receptor density is upregulated in response to estradiol; therefore, suckling- and estradiol-induced prolactin surges require higher doses of oxytocin antagonist than cervically-stimulated ovariectomized animals. Furthermore, in the presence of progesterone, the oxytocin antagonist was incapable of blocking the estradiol-induced surge; raising the possibility that progesterone may act through mechanisms independent of oxytocin to stimulate prolactin secretion. Therefore, the work in this dissertation provides additional mechanisms involved in the temporal and physiological control of estradiol-induced prolactin secretion.
Endocrinology, Hypothalamus, Hormone
July 3, 2009.
A Dissertation submitted to the Department of Biological Science in partial fulfillment of the requirements for the degree of Doctor of Philosophy.
Includes bibliographical references.
Marc E. Freeman, Professor Directing Dissertation; Penny J. Gilmer, Outside Committee Member; Debra A. Fadool, Committee Member; Elaine Hull, Committee Member; Michael Meredith, Committee Member.
Florida State University
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