The overall goal of this research is to elucidate the mechanisms underlying the impact of testosterone on the developing mammalian nervous system. Testosterone sculpts the developing nervous system, insuring that the sexual phenotype of the brain matches that of the gonads. In rodents, testosterone exposure during the perinatal period permanently masculinizes not only the morphology, connectivity, and chemistry of the central nervous system but also behavioral and neuroendocrine functions. The prominent role of both estrogenic metabolites of testosterone and estrogen receptors in the process of forebrain masculinization is undisputed. Compelling accumulated data, however, have led us to hypothesize that androgen receptors are an integral component of the organizational effects of testosterone on the nervous system, and that spatial and temporal shifts in androgen receptor expression and regulation contribute to specific actions of androgens in modulation of brain development. An integrated molecular and anatomical approach will be used to examine the development and hormonal regulation of androgen receptor expression in seven functionally relevant regions of the rat brain. These studies will form the basis for behavioral experiments that will test whether androgen receptor activation during development modifies the development of sexually differentiated behaviors. Four specific hypotheses will be tested: I. The anatomical substrate for testosterone action via androgen receptors exists prenatally in the forebrain; II. Prenatal testosterone masculinizes androgen receptor mRNA and protein levels during later development; III. Hormonal regulation of androgen receptor expression is specific to the developmental stage; IV. Androgen exposure masculinizes behaviors via androgen receptor dependent mechanisms. Rats will be treated with specific steroid receptor ligands or antagonists, and androgen receptor mRNA and protein expression will be assessed using in situ hybridization, immunocytochemistry and western blots, or behaviors will be analyzed using standard measures of adult behavioral responses to hormones. These studies will determine when androgen receptor mRNA and protein expression begins, the cellular phenotype of androgen receptor protein expressing cells through development, whether pre or postnatal androgen modifies subsequent androgen receptor expression, and when adult patterns of androgen receptor regulation arise, and finally, whether alterations in androgen receptor expression and regulation affect sensitivity to subsequent hormone exposure and play a role in maturation of adult sexual behaviors. The studies proposed will provide data essential to dissecting the complex mechanisms underlying the process of sexual differentiation of the brain, and contribute to an understanding of developmental stage-specific responses to hormones. Further, these studies will shed light on the etiology of neurologic and mental disorders that are more prevalent in men vs. women.
| DonCarlos, Lydia L; Azcoitia, Iñigo; Garcia-Segura, Luis M (2009) Neuroprotective actions of selective estrogen receptor modulators. Psychoneuroendocrinology 34 Suppl 1:S113-22 |
| Ahmed, Eman I; Zehr, Julia L; Schulz, Kalynn M et al. (2008) Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat Neurosci 11:995-7 |
| Garcia-Segura, Luis Miguel; Lorenz, Betty; DonCarlos, Lydia L (2008) The role of glia in the hypothalamus: implications for gonadal steroid feedback and reproductive neuroendocrine output. Reproduction 135:419-29 |
| Sarkey, Sara; Azcoitia, Inigo; Garcia-Segura, Luis Miguel et al. (2008) Classical androgen receptors in non-classical sites in the brain. Horm Behav 53:753-64 |
| DonCarlos, L L; Sarkey, S; Lorenz, B et al. (2006) Novel cellular phenotypes and subcellular sites for androgen action in the forebrain. Neuroscience 138:801-7 |
| Huppenbauer, Christopher B; Tanzer, Lisa; DonCarlos, Lydia L et al. (2005) Gonadal steroid attenuation of developing hamster facial motoneuron loss by axotomy: equal efficacy of testosterone, dihydrotestosterone, and 17-beta estradiol. J Neurosci 25:4004-13 |
| Lorenz, Betty; Garcia-Segura, Luis Miguel; DonCarlos, Lydia L (2005) Cellular phenotype of androgen receptor-immunoreactive nuclei in the developing and adult rat brain. J Comp Neurol 492:456-68 |
| Garcia-Ovejero, Daniel; Azcoitia, Inigo; Doncarlos, Lydia L et al. (2005) Glia-neuron crosstalk in the neuroprotective mechanisms of sex steroid hormones. Brain Res Brain Res Rev 48:273-86 |
| Veiga, Sergio; Melcangi, Roberto C; Doncarlos, Lydia L et al. (2004) Sex hormones and brain aging. Exp Gerontol 39:1623-31 |
| Azcoitia, Inigo; DonCarlos, Lydia L; Garcia-Segura, Luis M (2003) Are gonadal steroid hormones involved in disorders of brain aging? Aging Cell 2:31-7 |
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