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

Abstract

Many studies demonstrate that exposure to testicular steroids such as testosterone early in life masculinizes the developing brain, leading to permanent changes in behavior. Traditionally, masculinization of the rodent brain is believed to depend on estrogen receptors (ERs) and not androgen receptors (ARs). According to the aromatization hypothesis, circulating testosterone from the testes is converted locally in the brain by aromatase to estrogens, which then activate ERs to masculinize the brain. However, an emerging body of evidence indicates that the aromatization hypothesis cannot fully account for sex differences in brain morphology and behavior, and that androgens acting on ARs also play a role. The testicular feminization mutation (Tfm) in rodents, which produces a nonfunctional AR protein, provides an excellent model to probe the role of ARs in the development of brain and behavior. Tfm rodent models indicate that ARs are normally involved in the masculinization of many sexually dimorphic brain regions and a variety of behaviors, including sexual behaviors, stress response and cognitive processing. We review the role of ARs in the development of the brain and behavior, with an emphasis on what has been learned from Tfm rodents as well as from related mutations in humans causing complete androgen insensitivity.

Figure 1

(Left) Brain and body weights of adult wildtype (wt) male, Tfm male, and wt female mice and (Right) rats. Note different scales on the Y axes for the two species. All animals were between 120–150 days old at the time of sacrifice. Brain weight measurements did not include the olfactory bulb and were taken after prolonged postfixation in 10% formalin. Wt males show an increased brain weight compared to females, and Tfm males resemble wt males, in both mice and rats. Tfm males show a body weight intermediate between wt males and females. * indicates p< .05 compared to wt males.

Figure 2

The posterodorsal medial amygdala (MePD) in Nissl-stained coronal sections from a wildtype (wt) male (top), a Tfm male with a dysfunctional androgen receptor (middle), and a female rat (bottom). The panels on the left are from the caudalmost appearance of the MePD, which served as an anchor point to assess changes in the nucleus across the rostrocaudal dimension. The appearance of the MePD, as well as the optic tract (ot), the stria terminalis (st), the anterolateral part of the amygdalohippocampal transition area (AHiAL), and the lateral ventricle (v) are equivalent in wt males (a), Tfm males (b), and females (c), indicating that the caudal termination of the MePD occurs in the homologous region of the brain across groups. The panels on the right are from the approximate middle of the rostrocaudal extent of the MePD where the nucleus is larger in wt males (d) than in females (f) and is intermediate in size in Tfm males (e). The MePD also extends farther rostrally in wt males and Tfm males than in females (Morris et al., 2005). Scale bar = 250 m in a (applies to a–c), d (applies to d–f).

Figure 3

Time spent visiting a novel object in adult male wt and Tfm mice that were placed first in an empty open field and after five minutes were briefly removed and placed back into the open field that contained a small object (a 2″× 2″Petri dish with red and blue tape) in the center. (a) Upon exposure to a novel object, wt males spent more time exploring the novel object than did Tfm males. (b) Wt male mice castrated as adults spent less time visiting the object, an effect that was averted if they were treated with testosterone (T) rather than blank capsules. T had no effect in Tfm males, indicating that androgen receptors mediate this effect. * indicates p< .05 compared to (a) Tfm males or (b) T-treated Tfm males.

Figure 4

Plasma corticosterone levels 20 minutes after initial exposure to the 10 minute open field/novel object test were significantly greater in Tfm male mice compared to wt male mice. * indicates p< .01 compared to Tfm males.