The genetic defect in the hypogonadal mutant mouse (hpg) is a lack in the neurohormone, GnRH which results in an infantile reproductive tract. We have been able to correct this defect by implanting normal fetal or neonatal CNS tissue containing GnRH neurons into the third ventricle of adult hpg hosts. Complete endocrine recovery is evident in both males and females. Questions regarding the physiological regulation and function of the graft, the anatomical connectivity between the graft and host brain, and factors guiding or promoting axonal outgrowth from the graft to its target will be further studied. Normal CNS regulation of gonadotropin secretion is based on the activity of a central """"""""LH pulse generator"""""""" - a neural mechanism that drives the circhoral release of LH, regulated in the normal animal by gonadal steroids as well as various neurotransmitter systems. We shall evaluate the release pattern of gonadotropins in the hpg mice with implants for pulsatility and attempt to correlate the presence of this mode of release with the interaction of GnRH neurons with the appropriate neuronal systems. We shall also explore the modifiability of gonadotropin release by gonadal steroids and endogenous opioids. Such regulation implies synaptic connectivity between host and graft and so determination of the afferent and efferent connections of the graft using light and electron microscopic immunocytochemistry and anterograde and retrograde tracing techniques will be made. Finally, GnRH axons leave the graft following specific routes to their target. The nature of the exit zone that permits or promotes neurite outgrowth will be investigated by examining the relationship between GnRH axons with tanycytes and reactive astroglia. Additionally, the region of the arcuate nucleus will be perturbed either by destroying intrinsic neurons using neonatal MSG treatment or by neurotoxin lesions of specific inputs. This will be followed by an evaluation of the success of the implants in innervating the target as well as promoting gonadal recovery. Methods used in this project are light and EM immunocytochemistry, RIA of pituitary and plasma LH and FSH concentrations. These studies should produce further information as to factors involved in neural outgrowth as well as providing a unique model for studying the nature of the CNS regulation of gonadotropin secretion.
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