Estrogen receptor 2b is the major determinant of sex-typical mating behavior and sexual preference in medaka.

Male and female animals typically display innate sex-specific mating behaviors, which, in vertebrates, are highly dependent on sex steroid signaling. While estradiol-17ß (E2) signaling through estrogen receptor 2 (ESR2) serves to defeminize male mating behavior in rodents, the available evidence suggests that E2 signaling is not required in teleosts for either male or female mating behavior. Here, we report that female medaka deficient for Esr2b, a teleost ortholog of ESR2, are not receptive to males but rather court females, despite retaining normal ovarian function with an unaltered sex steroid milieu. Thus, contrary to both prevailing views in rodents and teleosts, E2/Esr2b signaling in the brain plays a decisive role in feminization and demasculinization of female mating behavior and sexual preference in medaka. Further behavioral testing showed that mutual antagonism between E2/Esr2b signaling and androgen receptor-mediated androgen signaling in adulthood induces and actively maintains sex-typical mating behaviors and preference. Our results also revealed that the female-biased sexual dimorphism in esr2b expression in the telencephalic and preoptic nuclei implicated in mating behavior can be reversed between males and females by altering the sex steroid milieu in adulthood, likely via mechanisms involving direct E2-induced transcriptional activation. In addition, Npba, a neuropeptide mediating female sexual receptivity, was found to act downstream of E2/Esr2b signaling in these brain nuclei. Collectively, these functional and regulatory mechanisms of E2/Esr2b signaling presumably underpin the neural mechanism for induction, maintenance, and reversal of sex-typical mating behaviors and sexual preference in teleosts, at least in medaka.

Neuropeptide B mediates female sexual receptivity in medaka fish, acting in a female-specific but reversible manner.

Male and female animals display innate sex-specific mating behaviors. In teleost fish, altering the adult sex steroid milieu can effectively reverse sex-typical mating behaviors, suggesting remarkable sexual lability of their brains as adults. In the teleost medaka, neuropeptide B (NPB) is expressed female-specifically in the brain nuclei implicated in mating behavior. Here, we demonstrate that NPB is a direct mediator of estrogen action on female mating behavior, acting in a female-specific but reversible manner. Analysis of regulatory mechanisms revealed that the female-specific expression of NPB is dependent on direct transcriptional activation by estrogen via an estrogen-responsive element and is reversed in response to changes in the adult sex steroid milieu. Behavioral studies of NPB knockouts revealed that female-specific NBP mediates female receptivity to male courtship. The female-specific NPB signaling identified herein is presumably a critical element of the neural circuitry underlying sexual dimorphism and lability of mating behaviors in teleosts.

A conceptual framework for understanding sexual differentiation of the teleost brain.

Vertebrate brains are sexually differentiated, giving rise to differences in various physiological and behavioral phenotypes between the sexes. In developing mammals and birds, the neural substrate underlying sex-dependent physiology and behavior undergoes an irreversible process of sexual differentiation due to the effects of perinatal gonadal steroids and sex chromosome complement. The differentiated neural substrate is then activated in the adult by the sex-specific steroid milieu to facilitate the expression of sex-typical phenotypes. However, this well-established concept does not hold for teleost fish, whose sexual phenotypes (behavioral or otherwise) are highly labile throughout life and can be reversed even in adulthood. Indeed, the available evidence suggests that, in teleosts, neither gonadal steroids early in development nor the sex chromosome complement contribute much to brain sexual differentiation; instead, steroids in adulthood serve to both differentiate the neural substrate and activate it to elicit sex-typical phenotypes in a transient and reversible manner. Evidence further suggests that marked sexual dimorphisms and adult steroid-dependent lability in the neural expression of sex steroid receptors constitute the primary molecular basis for sexual differentiation and lability of the teleost brain. The consequent sexually dimorphic but reversible steroid sensitivity in response to the adult steroid milieu may enable the teleost brain to maintain lifelong sexual lability and to undergo phenotypic sex reversal.