We have corrected a genetic defect in CNS GnRH production which leads to hypogonadism in male animals, by 3rd ventricular implantation of fetal preoptic area from unaffected animals. We now wish to study variables which may be involved in such successful transplantation. (A) In male animals we wish to study: (1) differences in responses to implants from male vs. female donors; (2) whether implants can be successful across strains and at different donor ages; (3) the effect of use of other GnRH-containing tissues and other host implantation sites; (4) graft responsiveness to gonadal hormone feedback; (5) the efficacy of such grafts in correcting abnormalities in sexual behavior of a GnRH-deficient animal (since such GnRH pathways are different from those which regulate gonadotropin release); (6) the nature of the host afferent connections to the grafts (their source and neurotransmitter and/or neuropeptide(s) content. (B) In female GnRH-deficient animals we wish to study (1) whether hypogonadism can be similarly corrected by fetal preoptic area grafts and whether ovulation will occur in such animals (this representing a more complex level of endocrine organization than that in the male); (2) their behavioral mating responses and, if positive, whether normal pregnancy can be maintained; (3) the responsiveness of such grafts to gonadal hormone feedback; (4) the similarity or dissimilarity of host afferent connections to those in the male. We will attempt to determine if host tissue contains a trophic factor(s) which influences graft outgrowth direction. Methods used are light and EM demonstration of GnRH, aminergic and peptidergic pathways, light and EM studies to assess gonadal functional capacity, measurement of graft and host immunoreactive GnRH content, cytochemical demonstration and immunoreactive measurement of pituitary LH, FSH and prolactin concentrations, measurements of pituitary GnRH and gonadal LH and FSH receptor activity, plasma gonadotropins, prolactin and gonadal hormone levels, co-culture of fetal preoptic area transplants with fetal median eminence. These studies should provide further information as to factors involved in neural outgrowth, as well as providing unique models for studying the nature of CNS sexual dimorphism and the role of various GnRH projection systems in the regulation of reproductive function. Studies in hosts of various ages should indicate the feasibility of correction of age-associated deficits.
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