Brain-derived estrogens facilitate male-typical behaviors by potentiating androgen receptor signaling in medaka

In rodents, estrogens aromatized from androgens in the brain are essential for the development of male-typical behaviors. In many other vertebrates, including humans and teleost fish, however, androgens facilitate these behaviors directly via the androgen receptor without aromatization into estrogens. Here, we report that mutagenesis-derived male medaka fish lacking Cyp19a1b (a subtype of aromatase predominantly expressed in the brain) exhibit severely impaired male-typical mating and aggression, despite elevated brain androgen levels. These phenotypes can be rescued by estrogen administration, indicating that brain-derived estrogens are pivotal for male-typical behaviors even in teleosts. Our results further suggest that these estrogens facilitate male-typical behaviors by potentiating androgen action in the brain via the direct stimulation of androgen receptor transcription. Taken together, these findings reveal a previously unappreciated mode of action of brain-derived estrogens in facilitating male-typical behaviors.