Approximately 16% of US couples remain involuntarily childless or experience major fertility problems. Although amenorrhea appears to be one of the principal causes of human infertility, the underlying neuroendocrine pathways responsible for its occurrence are poorly understood. On the other hand, it is already well established that luteinizing hormone-releasing hormone (LHRH) acts as the primary neuroendocrine link between the central nervous system and the rest of the reproductive axis. Consequently, a deeper understanding of the neural circuitry that controls the pulsatile and surge patterns of LHRH secretion should help to elucidate the underlying causes of centrally- originating reproductive disorders. In the proposed study, a series of non-invasive experiments will be performed to provide evidence that excitatory amino acid (EAA) receptors play a major role in the control of LHRH neuronal function. The results are expected to demonstrate the EAA receptors are critically involved in the generation and modulation of pulsatile LHRH secretion (Specific Aim #1) and that EAA receptors of both the N-methyl-D-aspartate (NMDA) and kainate sub-types are critically involved in the generation of the preovulatory LH surge (Specific Aim #2). Furthermore, the results are expected to demonstrate that at the time of puberty the LHRH neurons of the preoptic area primarily express EAA receptor of the NMDA sub-type while those of the arcuate nuclei primarily express EAA receptors of the kainate sub-type (Specific Aim #3). It is predicted that expression of these receptors in LHRH neurons first occurs during the peripubertal period and plays a pivotal role in triggering sexual maturation. The involvement of EAA receptors in regulating the pattern of LHRH secretion (Specific Aims #1 & 2) will be examined in vivo by administering various EAA agonists and antagonists and monitoring alterations in the pulsatile or surge patterns of LH and/or LHRH secretion. Elucidation of the neural circuits through which EAAs influence the activity of LHRH neurons (Specific Aims #3) will be investigated in vitro using combined immunocytochemistry and in situ hybridization to demonstrate co-localization of either NMDA or kainate receptor MRNAS within LHRH neurons. It is envisioned that the results will significantly further our understanding of the neuroendocrine control of puberty and reproductive function. In a broader context, they should also help to lay the foundation for the development of novel approaches to contraception and the treatment of human infertility.
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