Brain control of reproductive aging : GnRH neuroterminal, glia and portal capillary interactions



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Reproductive function is essential to the survival of all species. In mammals and other vertebrates, the control of reproduction relies on the hypothalamic-pituitary-gonadal axis, with the primary driving force provided by hypothalamic GnRH neurons. In the median eminence, the decapeptide GnRH are released in a unique pattern from GnRH neuroterminals into the portal capillary system as part of reproductive cycle. During aging, the biological rhythms of GnRH release are altered in a species-specific manner, with a reduction of GnRH pulsatility and surge in aging female rats resulting in reproductive senescence, which happens much earlier than gonadal failure in rats. Relatively few studies have focused on regulation of GnRH release at the neuroterminal level in the median eminence during reproductive aging. Therefore, the aims of this dissertation are to 1) Study the regulation of GnRH secretion at the neuroterminal level, focusing on glutamate transmission; 2) Ascertain the interaction between GnRH neuroterminals and their surrounding microenvironment focused on glial cells and the portal capillary system in the median eminence; and 3) Analyze age and hormone effects on GnRH neuroterminals and their microenvironment. An aging ovariectomized female rat model was used to study the effects of age and hormones on GnRH neuroterminal system. Fluorescence microscopy, confocal microscopy and transmission electron microscopy were used in conjunction with several imaging analysis tools. I mastered the use of cryo-embedding multi-probe immunogold labeling electron microscopy, which was essential to visualize and quantify the ultrastructral changes in GnRH neuroterminals. I combined the serial electron microscopy with cryo-embedding immunogold electron microscopy preparation and developed a new technique to examine biological markers with a three-dimensional perspective at the cellular level. Results from a series of four research projects showed: 1) There is a novel glutermatergic pathway in GnRH neuroterminals, which may regulate GnRH secretion; 2) There are dramatic age related morphological changes in the GnRH neuroterminal /glia/ portal capillary system of the median eminence that may be involved in reproductive senescence and other neuroendocrine system impairments with age; 3) Serial electron microscopy combined with immunogold labeling technique is a useful method to study the regulation of neuronal signaling pathway. Although my studies were performed on a rat model, it seems reasonable to predict that some of these changes in the median eminence with age may apply to other species, including humans, relevant to some of the menopausal symptoms in women.