The hypogonadal (hpg) mouse has infantile gonads due to a genetic inability to produce GnRH. Implantation of normal fetal preoptic area (POA), containing GnRH neurons, into the third ventricle of the mutant mouse (hpg/POA) corrects many aspects of reproductive function. The most physiologically important function subserved by the brain grafts is ovulation, which may occur in the female hpg/POA either reflexively after mating or as positive feedback to a steroid challenge. There is evidence in the normal animal that the ovulatory LH surge follows increased GnRH neuronal activity. As GnRH neurons do not concentrate steroids it is widely accepted that some neuromodulator(s) convey(s) information regarding the steroid milieu. It is not known whether these are identical to or different from the mediator(s) of the sensory input that results in reflex ovulation. As individual mice may show one but not-another reproductive capacity, the hpg/POA model provides the opportunity to study separate components of neuroendocrine function, and to relate specific capabilities in individuals to the degree/characterization of host modulation of the grafted GnRH neurons. Proposed studies will determine whether hpg/POA mice that (1) do/do not show capacity for positive feedback (2) and/or reflex ovulation differ in their LH secretion to challenge by putative neuromodulators of GnRH secretion. Results should (1) define afferents to GnRH neurons necessary to support the ovulatory surge and (2) determine whether specific neurotransmitter systems may be involved in mediating sensory information to the GnRH neuron. Related anatomical studies will corroborate appropriate connectivity. These studies should clarify whether the two types of ovulatory surge involve similar mechanisms. Using measures, of neuronal activity such as fluorogold uptake and expression of the protooncogene c-fos by GnRH cells in grafts in hpg/POA. mice, we will determine the extent of GnRH neuronal activity in the steroid-induced vs the sensory-induced LH surge. Expression of cfos and appropriate immunocytochemistry in association with reflex ovulation will also be used to attempt to determine afferent pathways mediating this neuroendocrine reflex. The hpg/POA mouse provides a unique model in which a discrete population of GnRH neurons with physiological activity may be studied in regard to neural afferents and other factors modulating their activity.
