Brain masculinization requires androgen receptor function

Abstract

Testicular testosterone produced during a critical perinatal period is thought to masculinize and defeminize the male brain from the inherent feminization program and induce male-typical behaviors in the adult. These actions of testosterone appear to be exerted not through its androgenic activity, but rather through its conversion by brain aromatase into estrogen, with the consequent activation of estrogen receptor (ER)-mediated signaling. Thus, the role of androgen receptor (AR) in perinatal brain masculinization underlying the expression of male-typical behaviors remains unclear because of the conversion of testosterone into estrogen in the brain. Here, we report a null AR mutation in mice generated by the Cre-loxP system. The AR-null mutation in males (AR L؊/Y ) resulted in the ablation of male-typical sexual and aggressive behaviors, whereas female AR-null homozygote (AR L؊/L؊ ) mice exhibited normal female sexual behaviors. Treatment with nonaromatizable androgen (5␣-dihydrotestosterone, DHT) was ineffective in restoring the impaired male sexual behaviors, but it partially rescued impaired male aggressive behaviors in AR L؊/Y mice. Impaired maletypical behaviors in ER␣ ؊/؊ mice were restored on DHT treatment. The role of AR function in brain masculinization at a limited perinatal stage was studied in AR L؊/L؊ mice. Perinatal DHT treatment of females led to adult females sensitive to both 17␤-estradiol and DHT in the induction of male-typical behaviors. However, this female brain masculinization was abolished by AR inactivation. Our results suggested that perinatal brain masculinization requires AR function and that expression of male-typical behaviors in adults is mediated by both AR-dependent and -independent androgen signaling.

Enhanced urinary odor discrimination in female aromatase knockout (ArKO) mice

“…In this respect, it is interesting to note that our work in male ArKO mice (Bakker et al, 2002a(Bakker et al, , 2004a and the work of Sato et al (2004) using mice with a null mutation in the androgen receptor clearly show that the masculinization of the mouse brain requires the presence of androgens as well as a functional androgen receptor. Sato et al (2004) showed that WT females which were treated pre-and postnatally (from embryonic day 14 until postnatal day 8) with dihydrotestosterone (DHT) showed higher levels of mounting and intromissive behaviors, and at times even ejaculatory patterns, than untreated controls. This masculinization of the brain by perinatal DHT treatment was absent in male and female mice carrying a null mutation of the androgen receptor (Sato et al, 2004).…”

“…Sato et al (2004) showed that WT females which were treated pre-and postnatally (from embryonic day 14 until postnatal day 8) with dihydrotestosterone (DHT) showed higher levels of mounting and intromissive behaviors, and at times even ejaculatory patterns, than untreated controls. This masculinization of the brain by perinatal DHT treatment was absent in male and female mice carrying a null mutation of the androgen receptor (Sato et al, 2004). These results also show that the critical period for brain masculinization does not extend beyond the early neonatal period (i.e., day 8 after birth) which is well before the time that mouse ovaries start to produce androgenic precursor.…”

Evidence for the existence of an estrogen-responsive sexually dimorphic group of cells in the medial preoptic area of the 129SvEv mouse strain

“…In addition, using the androgen receptor knockout mouse, it was demonstrated that the development of male sexual behaviors in mice requires androgen receptor function. 36 Further studies using prepubertal and adult gonadectomized mice followed by placebo, estradiol or testosterone replacement, would enable us to decipher the exact role of steroid hormones in the development of sexually dimorphic cell groups in the MPO and the regulation of male sexual behaviors in mice.…”

The role of androgen receptors in the masculinization of brain and behavior: What we've learned from the testicular feminization mutation

“…However, newborn male rats administered an aromatase inhibitor retain masculine sexual behaviors (Dominguez-Salazar et al, 2002), while genetically produced AR knockout mice (ARKO) show less masculine sexual behavior (Sato et al, 2004), suggesting that ARs are also involved in male sexual behavior. Tfm male mice, similar to ARKO mice, also display impaired male sexual behavior (Ohno et al, 1974), but this impairment in coital behavior (mounts and thrusts), is not observed after E2 replacement in adulthood (Bodo and Rissman, 2007).…”