The proposed research seeks to understand the mechanisms whereby estradiol induces female-typical aspects of neural differentiation in female mice. The classic dogma of sexual differentiation is that testosterone secreted by the testes promotes the development of a male brain whereas a female brain develops in the absence of any sex steroid action. However, in a recent study female aromatase knockout mice, which produce no estradiol due to a targeted mutation in the aromatase gene, showed little interest in approaching volatile odors derived from conspecifics of either sex and showed low levels of sexual receptivity after adult treatment with ovarian hormones. The central hypothesis to be tested is that estradiol makes an essential contribution to the differentiation of the neuroendocrine mechanisms controlling mate recognition and sexual behavior in female mice. An initial study will determine how much estradiol is actually formed in the female's hypothalamus during perinatal development. Additional studies will determine whether estradiol contributes to the development of female-typical aspects of function in the main olfactory system. Experiments will be conducted to determine whether the discriminative capacity of the main olfactory system is impaired in female aromatase knockout mice. First, the capacity of the main olfactory system to respond to volatile urinary odors from male and female mice will be assessed by mapping the spatial distribution of c-fos glomerular activation in the main olfactory bulb. Second, the ability of the main olfactory system to detect volatile urinary odors and to discriminate male and female odors will be assessed using habituation/dishabituation tests as well as a thirst-motivated olfactometer task. The contribution of the main olfactory system to odor preferences and female sexual behavior will be assessed by determining whether destruction of the main olfactory epithelium by zinc sulfate in wild-type females mimicks the syndrome of reduced olfactory investigation and deficient lordosis responsiveness characteristic of ArKO female mice. A final study will determine whether observed deficits in sexual receptivity and olfactory investigation reflect deficits in the capacity of ArKO females to find contacts with conspecifics rewarding as opposed to deficits in olfactory function per se. The proposed studies should provide new information about the contribution of estradiol to the development of essential aspects of female-typical neural and behavioral functions.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD044897-02
Application #
6777618
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
De Paolo, Louis V
Project Start
2003-07-16
Project End
2006-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
2
Fiscal Year
2004
Total Cost
$248,441
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; 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
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
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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