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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044897-06
Application #
7618189
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Lamar, Charisee A
Project Start
2003-07-16
Project End
2011-04-30
Budget Start
2009-05-01
Budget End
2011-04-30
Support Year
6
Fiscal Year
2009
Total Cost
$251,677
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Szymanski, L; Bakker, J (2012) Aromatase knockout mice show normal steroid-induced activation of gonadotrophin-releasing hormone neurones and luteinising hormone surges with a reduced population of kisspeptin neurones in the rostral hypothalamus. J Neuroendocrinol 24:1222-33
Brock, Olivier; Keller, Matthieu; Douhard, Quentin et al. (2012) Female mice deficient in alpha-fetoprotein show female-typical neural responses to conspecific-derived pheromones. PLoS One 7:e39204
Veyrac, Alexandra; Bakker, Julie (2011) Postnatal and adult exposure to estradiol differentially influences adult neurogenesis in the main and accessory olfactory bulb of female mice. FASEB J 25:1048-57
Brock, Olivier; Bakker, Julie (2011) Potential contribution of prenatal estrogens to the sexual differentiation of mate preferences in mice. Horm Behav 59:83-9
Brock, Olivier; Baum, Michael J; Bakker, Julie (2011) The development of female sexual behavior requires prepubertal estradiol. J Neurosci 31:5574-8
Taziaux, Melanie; Keller, Matthieu; Balthazart, Jacques et al. (2011) Rapid activation of phosphorylated mitogen-activated protein kinase after sexual stimulation in male mice. Neuroreport 22:294-8
Veyrac, Alexandra; Wang, Guan; Baum, Michael J et al. (2011) The main and accessory olfactory systems of female mice are activated differentially by dominant versus subordinate male urinary odors. Brain Res 1402:20-9
Brock, Olivier; Douhard, Quentin; Baum, Michael J et al. (2010) Reduced prepubertal expression of progesterone receptor in the hypothalamus of female aromatase knockout mice. Endocrinology 151:1814-21
Bakker, J; Brock, O (2010) Early oestrogens in shaping reproductive networks: evidence for a potential organisational role of oestradiol in female brain development. J Neuroendocrinol 22:728-35
Brock, O; Keller, M; Veyrac, A et al. (2010) Short term treatment with estradiol decreases the rate of newly generated cells in the subventricular zone and main olfactory bulb of adult female mice. Neuroscience 166:368-76

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