Pubertal activation of estrogen receptor α in the medial amygdala is essential for the full expression of male social behavior in mice

Abstract

Testosterone plays a central role in the facilitation of male-type social behaviors, such as sexual and aggressive behaviors, and the development of their neural bases in male mice. The action of testosterone via estrogen receptor (ER) α, after being aromatized to estradiol, has been suggested to be crucial for the full expression of these behaviors. We previously reported that silencing of ERα in adult male mice with the use of a virally mediated RNAi method in the medial preoptic area (MPOA) greatly reduced sexual behaviors without affecting aggressive behaviors whereas that in the medial amygdala (MeA) had no effect on either behavior. It is well accepted that testosterone stimulation during the pubertal period is necessary for the full expression of male-type social behaviors. However, it is still not known whether, and in which brain region, ERα is involved in this developmental effect of testosterone. In this study, we knocked down ERα in the MeA or MPOA in gonadally intact male mice at the age of 21 d and examined its effects on the sexual and aggressive behaviors later in adulthood. We found that the prepubertal knockdown of ERα in the MeA reduced both sexual and aggressive behaviors whereas that in the MPOA reduced only sexual, but not aggressive, behavior. Furthermore, the number of MeA neurons was reduced by prepubertal knockdown of ERα. These results indicate that ERα activation in the MeA during the pubertal period is crucial for male mice to fully express their male-type social behaviors in adulthood.T estosterone plays a central role in the regulation of male-type social behaviors in many mammalian species. It is known that testosterone facilitates the expression of sexual and aggressive behaviors through two kinds of actions. During the developmental period, testosterone exerts its "organizational action" to irreversibly masculinize the sexually undifferentiated brain and build the male-type neural network. In adulthood, testosterone exerts "activational action" to regulate the function of the fully masculinized neural network. As well as acting through androgen receptors (ARs), testosterone also acts through estrogen receptor (ER) α or ERβ, after being aromatized to estradiol (E2). Because the expression of sexual and aggressive behaviors is greatly reduced in aromatase knockout (ArKO) and ERα knockout (αERKO) male mice, aromatization of testosterone and its action via ERα have been suggested to be crucial for the facilitation of male-type social behaviors in mice (1-8). However, the exact timing and brain site(s) of ERα activation crucial for the expression of sexual and aggressive behaviors remain undetermined.In our previous study, we demonstrated site-specific involvement of ERα in the activational action of testosterone by using a virally mediated RNAi method. In this study, knocking down of ERα in the medial preoptic area (MPOA) of gonadally intact adult male mice suppressed sexual behavior while in the ventromedial nucleus (VMN) of hypothalamus reduced both sexual and aggressive behaviors...

Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats

“…Of these, the POA and BnST have larger roles in social preference, mating and territorial aggression, while the MePD is linked to social recognition (Ervin et al, 2015, Russell et al, 2012, Sano et al, 2013). Other studies have linked the MePD with aggressive behaviors (Sano et al, 2016, Unger et al, 2015). …”

Neurotransmitters and neuropeptides in gonadal steroid receptor-expressing cells in medial preoptic area subregions of the male mouse

“…For single immunostaining for ERα or AR, brain sections were washed and incubated with rabbit anti-ERα (1:5000, C1355, Millipore) or anti-AR (1:500, sc-816, Santa Cruz biotechnology) antibodies, of which the specificities were verified using gene-deficient mice, shRNA-based gene knockdown or preabsorption with antigen 12 , 13 , 55 , 56 . The sections were washed and immersed in Alexa568-conjugated donkey anti-rabbit IgG antibody (1:250, A10037, Thermo scientific) and Hoechst 33342 (1 μg/ml).…”

Estrogenic regulation of social behavior and sexually dimorphic brain formation

“…So far, these studies manipulated site-specific activation of ER by 17β-E only in adulthood. A recent study has reported that site-specific manipulation of ERα expression in sexually immature male mice has different effects (Sano et al, 2016) than in adult mice. Pre-pubertal (21days old) silencing of ERα in the MeA significantly reduces both sexual and aggressive behavior in adulthood.…”

“…Therefore, it is concluded that ER activation in the MeA during pubertal period is crucial for male mice to fully express their male-type social behaviors in adulthood. Furthermore, pre-pubertal knockdown of ERα in male mice reduces the number of neurons in the MeA to the levels of female mice (Sano et al, 2016). It is expected that future studies will elucidate the exact mechanisms of ERα action that results in full masculinization of neural networks for male-type social behavior, during the pubertal period.…”