Neuroestrogens facilitate male-typical behaviors by potentiating androgen receptor signaling in medaka

In rodents, estrogens aromatized from androgens in the brain, also known as neuroestrogens, 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 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 neuroestrogens are pivotal for male-typical behaviors even in non-rodents. Our results further suggest that neuroestrogens facilitate male-typical behaviors by potentiating androgen action in the brain via the direct stimulation of androgen receptor transcription, thereby revealing a previously unappreciated mechanism of action of neuroestrogens. We additionally show that female fish lacking Cyp19a1b are less receptive to male courtship and conversely court other females, highlighting the significance of neuroestrogens in establishing sex-typical behaviors in both sexes. ### Competing Interest Statement Kataaki Okubo is an inventor on a patent application related to this work filed by Regional Fish Institute and the University of Tokyo (Japanese patent application no. JP2023-205555, filed on 5 December 2023).