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

Abstract

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....

Cystic proliferation of germline stem cells is necessary to reproductive success and normal mating behavior in medaka

“…Although we observed that the mutated individuals did not present changes in secondary sexual characteristics, such as the separation of hindmost rays from other rays in the dorsal fin ( Figure 4E-H), which is strongly related to the presence of androgens in males (Ngamniyom et a., 2009), the corroboration of androgen levels is necessary because they are related to reproductive behavioral changes in adults of medaka (Hiraki-Kajiyama et al, 2019). 11-KT quantification did not show differences between wild-type and sgN1b males in a reproductive trial (…”

“…Sexual behavior has been found to be strongly controlled by the brain (Hiraki-Kajiyama et al, 2019;Mitchell et al, 2020;Yang and Shah, 2014), and levels of sex steroid hormones (Hiraki-Kajiyama et al, 2019;Munakata and Kobayashi, 2010). Here, it is important to note that in medaka, the secondary sex characters are induced by sex steroid hormones (Kikuchi et al, 2019;Sato et al, 2008).…”

“…Moreover, the level of the main androgen in fish, 11-KT, did not show differences between wild-type and ndrg1b mutants, thus establishing that sex steroid synthesis is not impaired in these animals. Regarding sexual behavior, in studies where the regulation of sex hormones was altered, changes in sexual behavior were primarily related to courtship, such as the frequencies of following, dancing, and latency from the first courtship (Hiraki-Kajiyama et al, 2019;Oshima et al, 2003). Additionally, when brain regulators were altered, such as arginine-vasotocin (Yokoi et al, 2015), oxytocin ligand (oxt) (Yokoi et al, 2020) and TN-GnRH3 (Okuyama et al, 2014), changes in courtship display and sexual motivation, latency to mating and number of courtships displays, and latency to mating, were observed, respectively.…”

“…To explore a possible cause of the lower spawning of control females paired with male ndrg1b mutants, our next step explored the sexual behavior of these couples. Fortunately, the sexual behavior of medaka consists of a sequence of actions that are easily quantified (Hiraki-Kajiyama et al, 2019;Ono and Uematsu, 1957;Walter and Hamilton, 1970). Briefly, the sequences begin with the male approaching and following the female closely.…”

The Role of Neuropeptide B and Its Receptors in Controlling Appetite, Metabolism, and Energy Homeostasis

“…However, importantly, Ishi et al demonstrated that NPBWR1-deficient male mice exhibited a sex-specific phenotype of adult-onset obesity [ 30 ]. Additional studies showing the importance of NPB in reproduction and the expression of NBP in the CNS of medaka teleost fish ( Oryzias latipes ) were published by Kikuchi et al [ 20 ] and Hiraki-Kajiyma et al [ 19 ]. Both studies confirmed that NPB is preferentially expressed in the female medaka brain, in populations of Vs/Vp and PMm/PMg neurons, whose expression is known to be estrogen-dependent and associated with female sexual receptivity [ 18 ].…”