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 During anestrus, when ovarian cycles cease, these systems are still present, but their effects are superseded by two additional inhibitory neural systems activated by the long-day photoperiod: an estradiol-sensitive catecholaminergic system that accounts for the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.
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