UCSF

All vertebrates require testosterone for male sexual and territorial behaviors. Testosterone acts on numerous tissues throughout the body, including the brain and reproductive tract. Additionally, testosterone acts at multiple developmental stages. Early in development, testosterone masculinizes the brain; in adulthood testosterone permits these masculinized neural circuits to generate male-typical sexual and territorial behaviors. However, how testosterone acts in the brain at a cellular and molecular level to regulate the development and activation of circuits that control behavior remains unclear.

Surprisingly, estrogen is also necessary and sufficient for male behaviors in the mouse. All estrogen is derived from androgens such as testosterone, via the enzyme aromatase. Aromatase and estrogen receptors are expressed in brain regions known to control sexually dimorphic behavior, which suggests that the behavioral effects of testosterone may result from the conversion of testosterone to estrogen within the brain, and the subsequent activation of estrogen receptors. Indeed, treatment of female neonatal mice with estrogen is sufficient to masculinize mating and territorial behavior patterns. Estrogen signaling is also necessary for male-typical behaviors: male mice with deletions of the estrogen receptors or aromatase exhibit dramatic reductions in male mating and aggression. These results raise the possibility that testosterone may act simply as a prohormone for estrogen in the brain, and that testosterone's cognate receptor, androgen receptor (AR), may be dispensable in the brain for male behaviors.

In my thesis, I present data demonstrating that AR is required for males to exhibit wildtype levels of mating and territorial behaviors, indicating that AR regulates activation of these behaviors. However, when the behaviors do occur, they appear qualitatively male, suggesting that the development of the neural circuits for male behaviors proceeds independent of AR. This finding is corroborated by a dearth of AR-expressing neurons in the developing brain during the time window critical for masculinization. Together with previous findings, these results suggest a model in which estrogen signaling controls the development of neural circuits for male sexual and territorial behaviors, while AR regulates the extent of these behaviors in adulthood.