The hypogonadism and infertility of the adult hypogonadal (hpg) mouse is correctable by intracerebral implantation of perinatal normal brain tissue that contains gonadotropin-releasing hormone (GnRH) neurons. This phenomonon depends upon the capacity of these implanted neurons to send axons to the median eminence and on their integration into appropriate host neural circuits. We have undertaken several in vivo studies to address these issues and now propose to combine these with in vitro methods in a concerted program to elucidate the factors underlying both pathfinding of GnRH axons and steroid regulation of their connectivity. We will first carry out a detailed analysis of GnRH axonal development from early embryonic to late postnatal stages. In parallel, we shall employ an insert chamber culture system to determine whether the mediobasal hypothalamus (MBH) provides chemotaxic or chemotropic signal(s) for GnRH axons. For continued in vivo analysis in the adult hpg we shall use purified olfactory epithelial-derived (OE) cells as a source of embryonic GnRH neuroblasts. Prior data from our laboratory suggest that it is likely that these cells can differentiate into 'adult' GnRH neurons and send axons to the median eminence. We shall now test whether the site of implantation of the OE cells is critical to their overall differentiation, axonal targeting, and capacity to support reproductive function. As a second focus we shall pursue our observation that estrogen (E2) has a neuromodulatory action on GnRH secretion in hpg male mice with grafts (hpg/POA). Studies will evaluate aromatizable vs. nonaromatizable steroids in sensitizing hpg/POA males to respond to neuromodulatory challenges such as nMDA. We will determine whether E2 treatment affects NMDARI receptor expression in GnRH cells, and evaluate the relevance of these findings to normal development. The possibility that E2 treatment induces opioid modulation of nMDA- stimulated LH release in these mice or alters the connectivity between host MBH and graft-derived GnRH cells will also be assessed . Immunocytochemical and ultrastructural studies will examine E2-induced alterations in GAP-43 expression in the vicinity of grafted GnRH cells and fibers, changes in the beta-endorphin input to GnRH neuronal elements and the relationship of tanycytes to GnRH terminals in the median eminence. These two interrelated lines of research should provide important new information not only regarding critical conditions for successful neuronal transplantation, but insights into how GnRH neurons target during development and are modulated by the hormonal milieu.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS020335-13
Application #
2668960
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Chiu, Arlene Y
Project Start
1983-07-01
Project End
2000-02-29
Budget Start
1998-03-01
Budget End
1999-02-28
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Drapkin, Paola T; Monard, Denis; Silverman, Ann-Judith (2002) The role of serine proteases and serine protease inhibitors in the migration of gonadotropin-releasing hormone neurons. BMC Dev Biol 2:1
Gibson, M J; Ingraham, L; Dobrjansky, A (2000) Soluble factors guide gonadotropin-releasing hormone axonal targeting to the median eminence. Endocrinology 141:3065-71
Rajendren, G; Levenkova, N; Gibson, M J (2000) Galanin immunoreactivity in mouse basal forebrain: sex differences and discrete projections of galanin-containing cells beyond the blood-brain barrier. Neuroendocrinology 71:27-33
Wu, T J; Gibson, M J; Roberts, J L (2000) Effect of N-methyl-D,L-aspartate (NMA) on gonadotropin-releasing hormone (GnRH) gene expression in male mice. Brain Res 862:238-41
Apostolinas, S; Rajendren, G; Dobrjansky, A et al. (1999) Androgen receptor immunoreactivity in specific neural regions in normal and hypogonadal male mice: effect of androgens. Brain Res 817:19-24
Rajendren, G; Gibson, M J (1999) Expression of galanin immunoreactivity in gonadotropin-releasing hormone neurons in mice: a confocal microscopic study. Brain Res 821:270-6
Rogers, M C; Silverman, A J; Gibson, M J (1998) Preoptic area grafts implanted in mammillary bodies of hypogonadal mice: patterns of GnRH neuronal projections. Exp Neurol 151:265-72
Wu, T J; Gibson, M J; Rogers, M C et al. (1997) New observations on the development of the gonadotropin-releasing hormone system in the mouse. J Neurobiol 33:983-98
Rogers, M C; Silverman, A J; Gibson, M J (1997) Gonadotropin-releasing hormone axons target the median eminence: in vitro evidence for diffusible chemoattractive signals from the mediobasal hypothalamus. Endocrinology 138:3956-66
Gibson, M J; Wu, T J; Miller, G M et al. (1997) What nature's knockout teaches us about GnRH activity: hypogonadal mice and neuronal grafts. Horm Behav 31:212-20

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