WHAT NATURES KNOCKOUT TEACHES US ABOUT GNRH ACTIVITY - HYPOGONADAL MICE AND NEURONAL GRAFTS

The hypogonadal mouse is one of ''nature's knockouts,'' bearing a spec ific deletion in the gene for gonadotropin-releasing hormone (GnRH), w ith the result that no GnRH peptide is detectable in the brain. The la ck of reproductive development after birth provides an animal model th at has proved fruitful in clarifying the role of GnRH in reproductive behavior and physiology. Behavioral studies with hypogonadal mice conv incingly demonstrate that although GnRH may facilitate the appearance of sexual behavior, this peptide is not essential for either male or f emale sexual behavior in the mouse. Administration of GnRH to hypogona dal mice with regimens mimicking GnRH pulsatility initiates reproducti ve development. Surprisingly, continuous exposure to GnRH stimulates r emarkable ovarian and uterine growth and increased FSH release, althou gh pituitary content of LH and FSH remains unchanged. In contrast, whe n brain grafts of normal fetal preoptic area (POA), containing GnRH ce lls, are implanted in the third ventricle of adult hypogonadal mice, b oth pituitary and plasma gonadotropin levels increase. Grafted GnRH ne urons innervate the median eminence of the host and support pulsatile LH secretion in the majority of animals with graft-associated gonadal development. Studies of hypogonadal mice with POA grafts demonstrate t hat distinct components of reproductive function are dissociable: host s may demonstrate reflex but not spontaneous ovulation; others may sho w positive but not negative feedback. Activation of grafted GnRH cells in response to sensory input to the host, as revealed in Fos expressi on studies, is an example of the integration of the graft with the hos t brain that underlies such capabilities. A goal of these studies is t o elucidate the specific connectivity underlying discrete aspects of r eproductive function. (C) 1997 Academic Press.