The neurons that contain gonadotropin-releasing hormone (GnRH), the neurohormone essential for development and function of the reproductive system, are widely scattered in the rostral forebrain. Thus, despite intense study, important gaps remain in our understanding of the essential regulation of GnRH neurons involved in either the steroid hormone- induced or sensory-induced ovulatory LH surge. In the former case, characteristic of spontaneous ovulation during reproductive cycles in vertebrates such as rat, mouse and human, the virtual absence of steroid receptors on GnRH neurons has led to the implication of numerous intermediate neuromodulators as transmitter of information regarding the hormonal milieu. As for the latter, little is known of the final pathway to GnRH neurons from the sensory input involved in reflex or sensory-induced ovulation. We used expression of Fos, the protein product of the immediate-early gene cfos, to demonstrate activation of GnRH neurons in normal female mice and in preoptic area grafts in the brains of hypogonadal (hpg) mice. The use of two different steroid-priming regimens now permits clear discrimination between the two types of stimuli in normal mice. With the surge-priming protocol, normal mice have a steroid-induced LH surge and Fos expression in GnRH neurons. With the behavior- priming protocol, normal female mice have a significant LH surge and robust Fos expression in GnRH neurons in response to mating, but not to the steroid regimen alone. The goal of the proposed studies is to identify essential afferents to GnRH cells that transmit information regarding circulating gonadal steroid and/or sensory stimuli that are involved in initiating an ovulatory LH surge.
Specific Aim I will test the hypothesis that there is a difference in the extent and phenotype of connectivity of GnRH neurons that are steroid- or sensory-activated in normal mice.
Aim II will test the hypothesis that neuromodulators that are implicated in transmitting sensory information to GnRH neurons in normal mice are afferent to activated grafted GnRH neurons within the brains of hpg mice.
Aim III will test the hypothesis that those brain regions that show high numbers of neurons expressing Fos in response to mating stimuli contain neurons that are afferent to activated GnRH neurons. The unique hpg model provides a discrete population of GnRH neurons whose support of distinct aspects of physiological activity such as reflex ovulation permits testing function in relation to specific connectivity, permitting new insights into the regulation of these crucial neurons.
