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.

Serotonin is a biogenic monoamine conserved across phyla that is implicated in diverse physiological and behavioural functions. On examining the expression of the rate-limiting enzymes in serotonin synthesis, tryptophan hydroxylases (TPHs), in the teleost medaka ( Oryzias latipes ), we found that males have much higher levels of tph1 expression as compared with females. This robust sexual dimorphism was found to probably result from the direct stimulation of tph1 transcription by androgen/androgen receptor binding to canonical bipartite androgen-responsive elements in its proximal promoter region. Our results further revealed that tph1 expression occurs exclusively in pro-opiomelanocortin ( pomc )-expressing cells and that the resulting serotonin and its derivative melatonin inhibit the expression of the pituitary hormone genes, fshb , sl and tshb . This suggests that serotonin and/or melatonin synthesized in pomc -expressing cells act in a paracrine manner to suppress pituitary hormone levels. Consistent with these findings and the male-biased expression of tph1 , the expression levels of fshb , sl and tshb were all higher in females than in males. Taken together, the male bias in tph1 expression and consequent serotonin/melatonin production presumably contribute to sex differences in the expression of pituitary hormones and ultimately in the physiological functions mediated by them.

26Male and female animals display innate sex-specific mating behaviors. Among vertebrates, teleosts are 27 unique in that altering the adult sex steroid milieu can reverse sex-typical mating behaviors, suggesting 28 sexual lability of their brains. In the teleost medaka, neuropeptide B (NPB) is expressed female-29 specifically in the brain nuclei implicated in mating behavior. Here, we demonstrate that NPB is a direct 30 mediator of estrogen action on female mating behavior, acting in a female-specific but reversible manner. 31Analysis of regulatory mechanisms revealed that the female-specific expression of NPB is dependent 32 on direct transcriptional activation by estrogen via an estrogen-responsive element and is reversed in 33 response to changes in the adult sex steroid milieu. Behavioral studies of NPB knockouts revealed that 34 female-specific NBP mediates female receptivity to male courtship. The female-specific NPB signaling 35 identified herein is presumably a critical element of the neural circuitry underlying sexual dimorphism 36 and lability of mating behaviors in teleosts. 37 Introduction 38 39 From invertebrates to humans, males and females of a given species exhibit profound differences 40 in mating behavior; in general, males perform elaborate courtship displays to attract females for mating, 41 and females evaluate male courtship displays to decide whether to mate. Such differences in mating 42 behavior between males and females result from sexually dimorphic development and activation of the 43 underlying neural circuits (Yang and Shah, 2016). In vertebrates, sex-typical mating behaviors and the 44 underlying neural circuits are highly dependent on the sex steroid hormone milieu, which is unique to 45 each sex (McCarthy and Arnold, 2011; McCarthy et al., 2017). Males have higher circulating levels of 46 androgen derived from the testis, whereas females have a cyclic pattern of estrogen and progestin arising 47 from the ovary. Sex steroids largely exert their effects by binding to intracellular receptors, which 48 subsequently interact with sex steroid-responsive elements in the genome to modulate the transcription 49 of target genes. Recent work, particularly in rodents and songbirds, has identified sex steroid-responsive 50 neural circuits that underlie the divergent mating behaviors of males versus females, as well as the genes 51 downstream of sex steroids that mediate these behaviors. However, the identity of the sex-specific direct 52 transcriptional targets of sex steroids that mediate sex-typical mating behaviors remains elusive (Yang 53 and Shah, 2014). 54Differences between the sexes in mating behavior are evidently robust and irreversible in many 55 vertebrate taxa, including mammals and birds. Interestingly, however, this is not the case in teleost fish. 56In teleosts, experimental manipulations that alter the sex steroid milieu lead to the reversal of sex-typical 57 mating behaviors, even in adulthood (Munakata and Kobayashi, 2010; Paul-Prasanth et al., 2013; 58 Göppert et al....