An important organizational role for E
2 in male-typical differentiation of rodent sexual behavior is widely accepted and indeed, was confirmed in the present experiments. However, until now it has not been clear whether E
2 contributes to the female-typical development of sexual behaviors. The present study provides new evidence for such an active role of prepubertal E
2 in female-typical differentiation of brain mechanisms controlling both appetitive and consummatory aspects of female sexual behavior. Thus the ability of ArKO female mice to show WT-like levels of lordosis behavior in response to adult ovarian hormones was almost completely rescued by daily treatment with EB over a specific prepubertal period, P15–P25, whereas EB given over an earlier postnatal period (P5–P15) had no such effect in ArKO females and actually abolished lordosis behavior in WT females. In addition, prepubertal EB treatment restored the motivation of ArKO females to prefer to approach distal cues from a stimulus male as opposed to another female. These findings suggest that the classic view of a default organization of female typical neural and behavioral characteristics must be revised. Evidence from a previous retrospective interview study (
Downey et al., 1989) of Turner Syndrome (45, XO) women in whom the ovaries failed to develop are also consistent with, though not definitive proof of, an active role of E
2 in the development of female sexual behavior. The Turner sample, who (29 of 31 subjects) received exogenous ovarian hormones as young adults, was significantly less likely than a control group of ovary intact (46, XX) women with constitutional short stature to have ever had a boyfriend or to have engaged in sexual activity with a man. Even though the Turner syndrome and control subjects were matched for short stature, there were additional cognitive and/or physical attributes of Turner Syndrome women (in addition to the absence of ovarian E
2) that could have contributed to observed group differences in psychosexual function. Further studies are needed in women and in other mammalian species to test the generality of our conclusion that prepubertal E
2 is normally required for the development of female sexual behavior.
The classic view of the sexual differentiation of brain and behavior in male rodents holds that perinatal T exerts strong defeminizing effects on the neural mechanisms mediating sexual behavior, with these effects of T being mediated by E
2 derived from local aromatization of T. The present results confirm the defeminizing effects of neonatal E
2 on the brain since lordosis behavior was completely suppressed in WT females given EB between P5 and P15. They also corroborate an early study showing that neonatal T and E
2 were equally effective in suppressing sexual receptivity in female mice (
Edwards and Thompson, 1970), and are in line with many additional studies conducted in additional rodent species (reviewed in
Wallen and Baum, 2002).
The classic view of brain sexual differentiation also holds that female-typical brain and behavior develop in the absence of any active hormone signaling. This conclusion was primarily based on the finding that male rodents neonatally deprived of T or E
2 showed lordosis behavior when primed with E
2 and P
4 in adulthood (reviewed in
Baum, 1979). Along with the seminal work of
Toran-Allerand (1976), the possible importance of E
2 in female-typical differentiation of sexual behavior was suggested by early behavioral studies (
Lisk, 1969;
Gerall et al., 1973) showing that female rats ovariectomized on the day of birth had lower lordosis quotients following adult treatment with E
2 and P
4 than females that either kept their ovaries (
Lisk, 1969) or were implanted with ovaries from birth until postnatal day 60 (
Gerall et al., 1973). These various behavioral results thus suggested that exposure to E
2 over a postnatal interval between birth and the age of puberty facilitated the later capacity to display female sexual behavior; however, they did not provide incontrovertible evidence that E
2 normally contributes to the development of female sexual behavior in female mammals. For instance, the effects of neonatal ovariectomy on the potential to show lordosis behavior later in life were only transient (
Gerall et al., 1973). However, our observation (
Bakker et al., 2002) of reduced lordosis behavior and lack of a male-directed mate preference in female ArKO mice resurrected the question of whether E
2 actively contributes to the development of the female brain. The present results specify a specific prepubertal period during which E
2 exerts a feminizing action on both appetitive and consummatory aspects of female sexual behavior in mice. Finally, prepubertal (P15–P25) EB treatment had no detrimental effect on the expression of lordosis behavior by WT females whereas earlier neonatal (P5–P15) EB treatment strongly defeminized WT females. These results suggest that the defeminization of sexual behavior capacity that normally occurs in male mice is completed by the actions of E
2 prior to P15.
Our finding in both experiments that WT control females showed more mounting behavior (after T treatment) than ArKO control females provide an endocrine explanation for why female mice normally show male-typical mating behavior and argue against a previous proposal (
Kimchi et al., 2007) that female mice will only display male-like mounting behavior when adult function of vomeronasal sensory neurons is disrupted. Our observation that early postnatal (P5–P15) EB treatment strongly masculinized both WT and ArKO females confirms the classic view that neonatal E
2, formed via the neural aromatization of circulating T, masculinizes aspects of brain and behavior in male mice. The neural substrate that controls mounting behavior in adulthood could normally be masculinized in fetal females by the local aromatization of T derived either from fetal males lying adjacent to the developing female fetuses (
vom Saal and Bronson, 1980) or from the placenta which could also be a significant source of T, as was observed in fetal rats (
Gibori and Sridaran, 1981;
Vreeburg et al., 1983;
Baum et al., 1991). In contrast with lordosis capacity and male-oriented mate preferences, prepubertal (P15–P25) EB treatment did not rescue mounting capacity in ArKO females nor did it masculinize this behavior in WT females. These results suggest that by P15 the critical period for the development of the mounting behavior neural substrate is completed; they also provide further evidence that the neural substrate for female- and male-typical sexual behaviors in mice have different responses to E
2 across the first 4 weeks of life (for review, see
Baum, 1979). The neural substrate for female-typical sexual behavior is defeminized by early postnatal E
2 actions (P5–P15) and actively feminized by the same sex hormone acting prepubertally over P15–P25. By contrast, E
2 acts solely over the early postnatal period (P0–P15) to masculinize the substrate for male sex behavior. After P15, this male behavior substrate is impervious to E
2 manipulation until adulthood, when this hormone, perhaps acting with T, activates this behavior. Indeed, the high level of mounting shown in EB-treated ArKO females (P5–P15) confirms the ability of adult T to activate this behavior, even in the absence of its conversion to E
2. It should be noted that, in male mice, organization of mounting behavior capacity is mediated, at least in part, by an androgen receptor mediated process (
Raskin et al., 2009). To date, no data are available on the effects of knocking out the androgen receptor on the adult expression of mounting behavior by female mice so it is unknown whether different hormonal mechanisms underlie the organization of the neural circuitry regulating mounting behavior in the 2 sexes.
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