UCSF

Males and females of most species display differences in behavior. The steroid hormones testosterone and estrogen each play integral roles in the regulation of these sex specific behaviors. How these two hormone signaling pathways interact to control differentiation of the male brain and behavior is still unclear. This dissertation discusses the contribution of gonadal steroid hormones to the development of the male brain and male specific behavior.

Testosterone in male circulation is converted, via the enzyme aromatase, to estrogen in the brain to regulate male behavior. In order to visualize where estrogen is synthesized in the brain, we generated mice in which aromatase+ cells also express reporters which allow for labeling of both cell soma and cell membranes. We find that aromatase expression is sexually dimorphic and that male differentiation of aromatase expression is independent of androgen signaling. In fact, we find that neonatal estrogen is sufficient to masculinize aromatase expression in females via estrogen mediated cell survival.

We also find that females given exogenous estrogen at birth display male specific territorial behaviors. These behaviors can also be elicited in males mutant for the androgen receptor, suggesting that androgen signaling is not necessary for the display of these behaviors. In fact, there is little to no androgen receptor expression in the male brain at birth, suggesting that early in development, testosterone serves as a precursor which is converted to estrogen, which then regulates male behaviors. Estrogen signaling is also required in adulthood for acute activation of male typical behaviors. Testosterone signaling via the androgen receptor appears to control the levels of male typical behavior. We generated mice in which the androgen receptor is deleted specifically in the nervous system and find that these mice exhibit male sexual and territorial behaviors but at a lower intensity than wildtype males.

Taken together, this thesis presents a model whereby early in development testosterone is converted to estrogen, which signals via the estrogen receptors to masculinize the brain and behavior. Activation of male behaviors also requires estrogen signaling, but the intensity of these displays is regulated by testosterone signaling via the androgen receptor.