The Aromatase Knock-Out Mouse Provides New Evidence That Estradiol Is Required during Development in the Female for the Expression of Sociosexual Behaviors in Adulthood

Abstract

We used estrogen-deficient aromatase knock-out (ArKO) mice to determine whether estrogens contribute to the development of the brain and behavior in females. Female mice of three different genotypes [i.e., wild type (WT), heterozygous (HET), and homozygous (ArKO)] were ovariectomized in adulthood and subsequently tested for odor preferences (choice: intact male vs estrous female) in a Y-maze. When treated with testosterone, ArKO females spent significantly less time sniffing odors (both volatile and nonvolatile) from either male or female stimuli compared with WT and HET females. When given direct access to anesthetized stimulus animals or when given a choice between odor and visual cues from both stimulus animals, ArKO females continued to spend less time investigating the stimuli compared with WT and HET females. These defects in olfactory investigation of ArKO females were partially corrected with estradiol treatment in adulthood. Estradiol-treated ArKO females no longer differed from WT and HET females in the time spent investigating either nonvolatile odors or the anogenital region of anesthetized animals. However, ArKO females still investigated volatile odors and/or visual cues less than WT and HET females. Sexual receptivity was severely impaired in ArKO females after treatments with estradiol and progesterone that successfully induced receptivity in WT and HET females. Furthermore, ArKO females showed diminished levels of male sexual behaviors, whereas WT and HET females readily mounted an estrous female. Together, these findings demonstrate that estrogen is required for normal female development. The concept that the female brain develops in the absence of any hormonal stimulation should therefore be reconsidered.

Potential contribution of progesterone receptors to the development of sexual behavior in male and female mice

“…In contrast with earlier studies on lordosis behavior (Bakker et al, 2002;2006;Brock et al, 2011), we did not observe the typical increase in lordosis behavior in the OIL-treated females during repeated testing. Actually, quite surprisingly, lordosis quotients were quite similar between OIL-and ZKtreated females in the first test, i.e.…”

“…By using female mice carrying a targeted mutation of the aromatase gene (aromatase knockout or ArKO), we provided more robust evidence for a role of estradiol in the development of lordosis behavior (Bakker et al, 2002). Female ArKO mice showed significantly lower levels of lordosis behavior than wild type (WT) controls following adult ovariectomy and treatment with ovarian hormones.…”

“…The male and female C57Bl/6j mice used for the pilot experiment Bakker et al, 2002). Females were allowed to recover for two weeks before the onset of the behavioral tests.…”

The main and the accessory olfactory systems interact in the control of mate recognition and sexual behavior

“…Indeed, male odors still induced significant Fos expression in the medial amygdala of ArKO females, although this increase was clearly reduced in comparison with WT female mice, and failed to activate the VMH, a brain region critical for the expression of reproductive behavior in female mice. This result suggests that, in ArKO females, olfactory cues from a potential mate are correctly detected at the level of the olfactory bulb but that the integration of their reproductive value at the level of the amygdala and VMH is reduced, which may explain their deficits in the expression of sexual behavior [5]. Different patterns of Fos expression following exposure to urinary odors from conspecifics of both sexes were also observed in the amygdala of WT and ArKO males, a region that seems to be essential for the integration of olfactory stimuli in mice [20], suggesting that perinatal estrogens may be involved in the development of this brain area in both males and females.…”

Reconsidering Prenatal Hormonal Influences on Human Sexual Orientation: Lessons from Animal Research

“…Thus, feminine receptivebehavior(lordosis)was severely reduced in female ArKO mice when tested in adulthood following ovariectomy and treatment with estradiol and progesterone (Bakker, Honda, Harada, & Balthazart, 2002). Interestingly, administration of estradiol benzoate during a specific prepubertal period (between postnatal Days 15 and 25, but not between postnatal Days 5 and 15) almost completely restored lordosis performance in femaleArKOmiceandaugmentedtheirmale-directedpheromonal preference (Brock, Baum, & Bakker, 2011).…”