Gonadotropin-releasing hormone (GnRH), the brain peptide that drives the reproductive system, is not produced in the mutant hypogonadal (hpg) mouse due to a truncated GnRH gene. Thus the adult hpg mouse is infertile with infantile gonads. Implants of fetal normal mouse preoptic area (POA), containing GnRH cells, into the third ventricle of hpg mice result in pituitary gonadotropin production and gonadal development when GnRH fibers grow into the host median eminence (ME). Proposed studies will further evaluate the degree of physiological function supported by grafts, and the anatomical connectivity underlying specific neuroendocrine responses. For example, a majority of hpg males with grafts show pulsatile LH secretion, but the classical feedback response of increased LH after castration is largely undetectable. We will now evaluate the role of specific putative neuromodulators in regulating LH secretion in hpg mice with POA grafts, and then determine the anatomical connectivity in representative responding and nonresponding mice in comparison to normal mice. Similarly, behavioral studies will assess ability of hpg males with grafts to show a neuroendocrine response to female olfactory/sensory stimuli and associated anatomical studies using immunocytochemistry and anterograde tract-tracing methods will determine the presence or absence of specific connectivity. The power of these studies lies in the ability to study a discrete population of GnRH cells and correlate specific connectivity with the ability of the host animal to show a given neuroendocrine response. Other pulsatility experiments will clarify whether hpg male mice with grafts respond to changes on the hormonal milieu. Since very few GnRH cells support many near-normal reproductive responses in hpg hosts, activity of cells will be determined by: evaluating GnRH message production in grafted and normal GnRH cells in various hormonal states, and indirectly by measuring neuronal activity with cytochrome oxidase histochemistry and expression of cfos oncogene. The proposed studies will contribute to an understanding of the neuroendocrine mechanisms underlying reproduction in the male, and elucidate the extent of anatomical integration of the physiologically successful brain grafts.
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