The adult hypogonadal (hpg) mouse, genetically lacking the brain peptide gonatropin hormone releasing hormone (GnRH) is infertile and possesses infantile reproductive organs. In normal mouse, many GnRH cells found in the preoptic area (POA) of the brain project to the median eminence, where GnRH has capillary access to the pituitary. Grafts of POA tissue derived from normal fetal or neonatal mouse, when placed in the third ventricle of the brains of adult hpg mice stimulate pituitary gonadotropin (LH and FSH) production and gonadal development. GnRH cells present within the grafts send axonal projections to the median eminence of the host brain, where terminals are found in close apposition to capillaries of the portal plexus. Male hpg hosts respond with testicular growth and spermatogenesis. HpG FEMALES WITH poa grafts show vaginal opening (signalling the onset of puberty in rodents) and enter persistent vaginal estrus, not showing the spontaneous ovulatory cyclicity seen in normal mice. Many hpgs in persistent estrus do, however, respond with a plasma LH surge and ovulation in response t mating with a normal male, or to the challenge of progesterone administration. An LH surge in response to mating has the exciting implication that the grafted GnRH cells are regulated by the host brain since reflex ovulation is a neurally mediated event. The proposed studies will examine some of the questions raised by the above findings. These include: determination of the degree to which the grafts respond to ovarian steroid feedback; evaluation of the sensory stimuli involved in the mating-induced LH surge; evaluation of the afferent regulation of the graft through both physiological and anatomical studies; and determination of the effect of sexually differentiated graft tissue on reproductive function in hpg hosts. Methods will include sterotaxic surgery, behavior studies, neuroanatomical tracing, RIA of gonadotropins. It is rare that brain grafts respond to input from the host. The hpg mouse with POA graft, therefore, provides a unique model in which a discrete population of GnRH cells with physiological activity may be studied in regard to neural afferents and other factors modulating their activity. New information regarding the LH surge-generating mechanism should emerge from these studies.
