Female receptivity including the immobile hormone-dependent lordosis posture is essential for successful reproduction in rodents. It is well documented that lordosis is organized during the perinatal period when the actions of androgens decrease the males' ability to display this behavior in adulthood. Conversely the absence of androgens, and the presence of low levels of prepubertal estrogens, preserve circuitry that regulates this behavior in females. The current study set out to determine whether sex chromosomal genes are involved in the differentiation of this behavior. An agonadal mouse model was used to test this hypothesis. The SF-1 gene (Nr5a1) is required for development of gonads and adrenal glands, and knockout mice are consequently not exposed to endogenous gonadal steroids. Thus contributions of sex chromosome genes can be disassociated from the actions of estrogens. Use of this model reveals a direct genetic contribution from sex chromosomes in the display of lordosis and other female-typical sexual behavior patterns. It is likely that the concentrations of gonadal steroids present during normal male development modify the actions of sex chromosome genes on the potential to display female sexual behavior.
Female sexual behaviors facilitate and enable copulation and therefore ensure successful mating and consequently reproductive success. One of the best documented indicators of receptivity in rodents is lordosis, an arched back immobile reflex posture exhibited when males attempt to mount and mate. This posture has been used to map the reflexive circuits in the central nervous system that are regulated by the steroid hormones required for its expression (Kow and Pfaff, 1977 and Pfaff and Sakuma, 1979). The lordosis reflex is sexually differentiated and is displayed to a much greater extent by females as the male brain is normally defeminized (Blaustein and Erskine, 2002). The sex differences in circulating androgens during the perinatal period mold brain sex differences via a number of factors, including steroidogenic enzymes, receptors and neurotransmitters including but not limited to: testosterone, aromatase enzyme, estradiol, estrogen receptors, and glutamate receptors (Kudwa et al., 2006 and Schwarz et al., 2008). The ability of neonatal testosterone to block adult expression of these “female-typical” behavior patterns in rodents is one of the cornerstone arguments for the primary role that gonadal steroids play in brain sexual differentiation (Phoenix et al., 1959).
In addition to the organizing roles that steroid hormones play, sex differences can also be influenced in the brain by genes on the sex chromosomes that are expressed at different levels in male and female brains. For example, genes on the Y-chromosome that are not represented on X-chromosome, and/or X-chromosome genes that escape X-inactivation might favor differentiation in male or female directions (De Vries et al., 2002). There are several mouse models currently available that can be used to test this hypothesis (Majdic and Tobet, 2011).
Steroidogenic factor 1 (SF-1) is a transcription factor that regulates the expression of many genes involved in development and function of the reproductive axis (Parker and Schimmer, 1997). Mice lacking the Nr5a1 gene (SF-1 KO) are born without gonads and adrenal glands and are therefore not exposed to endogenous sex steroid hormones ( Ingraham et al., 1994). As such, sex differences between chromosomal males (XY) and females (XX) may be caused by genes located on sex chromosomes in contrast to differences in gonadal steroid hormones during development ( Budefeld et al., 2008). In addition to gonadal and adrenal agenesis, these mice have a disorganized ventromedial hypothalamus (VMH) and the male knockouts have feminine external genitalia ( Dellovade et al., 2000 and Parker and Schimmer, 1997). The SF-1 KO model has provided evidence that developmental exposure to gonadal steroids is not required for adult display of aggression ( Grgurevic et al., 2008) while brain specific female knockout mice have reduced levels of lordosis ( Kim et al., 2010).
The aim of the present study was therefore to examine female-typical sexual behaviors and immunoreactive progesterone receptors in SF-1 KO mice to determine a contribution from sex chromosomal genes to the development of female biased brain circuitry and behavior. It is well established that progesterone, acting through the estrogen-induced receptors in the VMH area are an important component of the functional circuitry needed for the appropriate display of female sex behavior (Rubin and Barfield, 1983). In the current study, immunoreactive progesterone receptors were examined to assess the functional capacity of this component of the behavioral circuitry.
