The Androgen Receptor Governs the Execution, but Not Programming, of Male Sexual and Territorial Behaviors

Abstract

SUMMARY Testosterone and estrogen are essential for male behaviors in vertebrates. How these two signaling pathways interact to control masculinization of the brain and behavior remains to be established. Circulating testosterone activates the androgen receptor (AR) and also serves as the source of estrogen in the brain. We have used a genetic strategy to delete AR specifically in the mouse nervous system. This approach permits us to determine the function of AR in sexually dimorphic behaviors in males while maintaining circulating testosterone levels within the normal range. We find that AR mutant males exhibit masculine sexual and territorial displays, but they have striking deficits in specific components of these behaviors. Taken together with the surprisingly limited expression of AR in the developing brain, our findings indicate that testosterone acts as a precursor to estrogen to masculinize the brain and behavior, and signals via AR to control the levels of male behavioral displays.

Sex differences in spatiotemporal expression of AR, ERα, and ERβ mRNA in the perinatal mouse brain

“…The transient increase of AR mRNA levels in the hypo may reflect the existence of similar regulation by testosterone in mice. It was reported that mutant male mice with a deletion of AR specifically in the central nervous system displayed a reduced masculinized repertoire of mating and territorial fighting and marking behaviors [8,22]. In these mutant males, a dramatic decrease in AR expression in the brain at PD1 was also observed, compared to control littermates.…”

Species differences in the winner effect disappear in response to post-victory testosterone manipulations

“…Recent work in California mice shows that males respond to social victories in the home territory by increasing androgen receptor (AR) expression in select areas of the mesolimbic system and that these changes in neural androgen sensitivity are positively associated with winning [17]. Although the persistence and functionality of this newly expressed AR are not yet clear, heightened androgen sensitivity throughout the mesolimbic system may help intensify the output and motivational elements of future aggression [41,42]. Given this, white-footed mice may naturally sustain levels of mesolimbic AR that are sufficient for postvictory T to enhance the reinforcing elements of aggression that compel mice to fight [43].…”

Modular genetic control of innate behaviors

“…Similarly, male mice lacking ERa also fail to exhibit any sexual behavior. In contrast, animals with a brain-specific deletion of AR retain low levels of sexual behavior, but mount and intromit at a much lower frequency than controls [14]. These steroid hormone receptors are cognate nuclear receptors, which upon ligand binding translocate to the nucleus to regulate expression of target genes.…”