Current dogma states that testosterone secreted perinatally by the testes promotes male brain sexual differentiation in mammals whereas the female brain develops in the absence of any sex hormone action. We challenge this dogma by hypothesizing that estradiol makes an essential contribution to the differentiation of neuroendocrine mechanisms controlling female-typical olfactory mate recognition and sexual behavior. First we will compare the number of progesterone receptor immunoreactive cells in hypothalamic nuclei of perinatal female mice with a null mutation either of the estrogen biosynthetic enzyme, aromatase (ArKO) or of the plasma estradiol binding protein, alpha feto protein (AFP-KO) and of wild type controls to determine whether there is a critical early postnatal period when estradiol normally acts in the female hypothalamus. Next, we will determine whether treatment of ArKO female mice with estradiol at early postnatal times specified by the outcome of Aim 1 will reverse adult deficits (previously seen in ArKO females) in the investigation of urinary odors and in sexual behavior. We will also determine whether treatment of wild type females with an aromatase inhibitor, ATD, over this same early period disrupts later female-typical behaviors. We recently showed that the discrimination of closely related urinary odors was significantly better in ArKO than in wild type female mice. Others had previously shown that forebrain estradiol receptor expression is upregulated in ArKO mice. We will test the hypothesis that adult treatment with estradiol more effectively enhances the discrimination of urinary odors needed for sex discrimination and/or individual mate recognition in ArKO than in wild type females. Finally, we will compare the ability of estradiol vs no steroid treatments of adult ovariectomized ArKO and wild type female mice to stimulate the birth and/or survival of neurons in the anterior portion of the subventricular zone which are destined to migrate along the rostral migratory stream into the main olfactory bulb where they may enhance olfactory discrimination. These studies should provide new information about the contribution of estradiol to the development of essential aspects of female-typical neural and behavioral functions. Affirmation of a perinatal role for estradiol in brain sexual differentiation in female mice would raise the question of whether estradiol plays a similar role in female-typical psychosexual differentiation in women.
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