Glucocorticoid receptor exhibits sexually dimorphic expression in the medaka brain.

The differential impact of stress on brain functions of males and females has been widely observed in vertebrates. Recent evidence suggests that stress-induced glucocorticoid signaling affects sexual differentiation and sex changes in teleost fish. These facts led us to postulate that there were sex differences in glucocorticoid signaling in the teleost brain that underlie some sex differences in their physiological and behavioral traits. Here we found sexually dimorphic expression of a glucocorticoid receptor gene (gr1) in the brain of medaka fish (Oryzias latipes), with females having greater expression in several preoptic and thalamic nuclei. Further, gr1 exhibits female-biased expression in neurons of the anterior parvocellular preoptic nucleus that produce the neuropeptides vasotocin and gonadotropin-releasing hormone 1 (these neuropeptides have been implicated in the regulation of neuroendocrine and behavioral functions). These findings suggest that glucocorticoids have a greater influence on physiology and behavior mediated by these neuropeptides in females than in males, which may contribute to sex differences in the brain's response to stress.

Sexually dimorphic expression of the sex chromosome-linked genes cntfa and pdlim3a in the medaka brain.

In vertebrates, sex differences in the brain have been attributed to differences in gonadal hormone secretion; however, recent evidence in mammals and birds shows that sex chromosome-linked genes, independent of gonadal hormones, also mediate sex differences in the brain. In this study, we searched for genes that were differentially expressed between the sexes in the brain of a teleost fish, medaka (Oryzias latipes), and identified two sex chromosome genes with male-biased expression, cntfa (encoding ciliary neurotrophic factor a) and pdlim3a (encoding PDZ and LIM domain 3 a). These genes were found to be located 3-4 Mb from and on opposite sides of the Y chromosome-specific region containing the sex-determining gene (the medaka X and Y chromosomes are genetically identical, differing only in this region). The male-biased expression of both genes was evident prior to the onset of sexual maturity. Sex-reversed XY females, as well as wild-type XY males, had more pronounced expression of these genes than XX males and XX females, indicating that the Y allele confers higher expression than the X allele for both genes. In addition, their expression was affected to some extent by sex steroid hormones, thereby possibly serving as focal points of the crosstalk between the genetic and hormonal pathways underlying brain sex differences. Given that sex chromosomes of lower vertebrates, including teleost fish, have evolved independently in different genera or species, sex chromosome genes with sexually dimorphic expression in the brain may contribute to genus- or species-specific sex differences in a variety of traits.

Neuropeptide B is female-specifically expressed in the telencephalic and preoptic nuclei of the medaka brain.

In the brain of medaka (Oryzias latipes), a teleost fish, we recently found that the supracommissural/posterior nuclei of the ventral telencephalic area (Vs/Vp) and the magnocellular/gigantocellular portions of the magnocellular preoptic nucleus (PMm/PMg) express estrogen receptor (ER) and androgen receptor (AR) specifically in females. This finding led us to postulate that sex steroid hormones might induce gene expression unique to females in these nuclei. In the present study, we searched for genes differentially expressed between the sexes in the medaka brain and identified the gene encoding neuropeptide B (npb) as being female-specifically expressed in Vs/Vp and PMm/PMg. As expected, the neurons expressing npb female-specifically constituted a significant proportion of the ER/AR-expressing neurons in these nuclei. Subsequent analyses provided evidence that the female-specific expression of npb in Vs/Vp and PMm/PMg results from the reversible and transient action of estrogens secreted from the ovary and that this estrogenic action is most likely mediated by the direct transcriptional activation of npb through an estrogen-responsive element in its proximal promoter region. Vs/Vp and PMm/PMg are generally recognized in teleost fish as the sites where neurons expressing 2 other neuropeptides, isotocin and vasotocin, are present, but the female-specific npb/ER/AR-expressing neurons were distinct from, although adjacent to, isotocin and vasotocin neurons. Taken together, these data demonstrate that npb is female-specifically expressed in novel, as-yet undefined populations of Vs/Vp and PMm/PMg neurons, resulting from the direct stimulatory action of ovarian estrogens via female-specific ER in these neurons.