The objectives of this research are to better understand the neural mechanisms that regulate the age-related deterioration of the female reproductive system. Cyclic reproductive function in rodents depends upon the integrity of the """"""""biological clock"""""""" and normal circadian rhythms. The rhythmic occurrence of several neurochemical events regulates the release of LHRH and gonadotropins. Experiments have been designed to test the hypothesis that the ability of the biological clock to maintain the circadian rhythmicity of several neurochemical and neuroendocrine events, which are critical to cyclic LH release, deteriorates during middle-age. This causes the gradual disappearance of regular estrous cycles and the transition to age-related infertility. The significance of the working hypothesis is that the experimental results will be the first evidence to document that changes in the biological clock, or its ability to entrain rhythms, occur early during the aging process. They will be the first data to suggest that changes in the biological clock may cause, and not merely be the result of age-related deterioration.
The specific aims of this proposal are to answer the following questions: 1. Do norepinephrine and serotonin activities exhibit circadian rhythms? 2. Do the receptors which bind to norepinephrine (alpha1-, alpha2-, Beta1- and Beta2-adrenergic) and serotonin (5HT1 and 5HT2) exhibit circadian rhythms? 3. Do pharmacological manipulations which alter neurotransmitter activity rhythms to mimic those of middle-aged rats cause aging-like LH surges? The following methods will be used: (1) A microdissection technique will discriminate nuclei, fiber pathways and terminal projection fields from the rat brain. (2) Norepinephrine and serotonin turnover rates will be determined using high pressure liquid chromatograhic methods. (3) Neurotransmitter receptors will be localized and quantitated using topical quantitative autoradiography. Thus, we will monitor the rhythmicity of two neurotransmitters and their receptors under controlled endocrine conditions to determine the relationship between these and the endocrine milieu and the time of day. We will compare these rhythms with those in aging rats under similar conditions and correlate age-related changes with the disappearance of regular LH surges.
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