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.
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