Nuclear receptor coactivators function in estrogen receptor- and progestin receptor-dependent aspects of sexual behavior in female rats

Abstract

The ovarian hormones, estradiol (E) and progesterone (P) facilitate the expression of sexual behavior in female rats. E and P mediate many of these behavioral effects by binding to their respective intracellular receptors in specific brain regions. Nuclear receptor coactivators, including Steroid Receptor Coactivator-1 (SRC-1) and CREB Binding Protein (CBP), dramatically enhance ligand-dependent steroid receptor transcriptional activity in vitro. Previously, our lab has shown that SRC-1 and CBP modulate estrogen receptor (ER)-mediated induction of progestin receptor (PR) gene expression in the ventromedial nucleus of the hypothalamus (VMN) and hormone-dependent sexual receptivity in female rats. Female sexual behaviors can be activated by high doses of E alone in ovariectomized rats, and thus are believed to be ER-dependent. However, the full repertoire of female sexual behavior, in particular, proceptive behaviors such as hopping, darting and ear wiggling, are considered to be PR-dependent. In the present experiments, the function of SRC-1 and CBP in distinct ER- (Exp. 1) and PR- (Exp. 2) dependent aspects of female sexual behavior was investigated. In Exp. 1, infusion of antisense oligodeoxynucleotides to SRC-1 and CBP mRNA into the VMN decreased lordosis intensity in rats treated with E alone, suggesting that these coactivators modulate ER-mediated female sexual behavior. In Exp. 2, antisense to SRC-1 and CBP mRNA around the time of P administration reduced PR-dependent ear wiggling and hopping and darting. Taken together, these data suggest that SRC-1 and CBP modulate ER and PR action in brain and influence distinct aspects of hormone-dependent sexual behaviors. These findings support our previous studies and provide further evidence that SRC-1 and CBP function together to regulate ovarian hormone action in behaviorally-relevant brain regions.

Nuclear Receptor Coactivators Are Coexpressed with Steroid Receptors and Regulated by Estradiol in Mouse Brain

“…Taken together with previous findings, the present results identify putative sites of functional interaction of ovarian steroid receptors (ERα and PR) with nuclear receptor coactivators (SRC-1 and SRC-2) in reproductively relevant brain regions. These results support and extend our previous findings that the majority of E-induced PR cells in the rat hypothalamus express SRC-1 and CBP [48] and support the findings that SRC-1 and SRC-2 function in the hypothalamus to modulate hormone-dependent female sexual behavior [54,61,64]. In addition, these results provide neuroanatomical support for the concept that these coactivators are important in ER transactivation of the PR gene in brain [54,61].…”

“…These coactivators modulate ER-mediated transactivation of the PR gene in the brain and ER- and PR-dependent reproductive behaviors in female rodents [54,61,64]. In order for nuclear receptor coactivators to function with steroid receptors in brain, both coactivator and receptor must be expressed in the same cell.…”

“…SRC-1 [48,49,50,51,52,53,54,55,56,57] and SRC-2 [58,59,60] are expressed at high levels in the cortex, hypothalamus and hippocampus of rodents. Our laboratory and others have found that SRC-1 and SRC-2 are important for hormone-dependent sexual differentiation of the brain [53], gene expression in brain [54,61,62,63] and sexual behavior [54,61,62,63,64]. Finally, SRC-1 and SRC-2 from rodent brain physically interact with ER and PR in a receptor subtype- and brain region-specific manner [58,65].…”

Estrous behavior in dairy cows: identification of underlying mechanisms and gene functions

“…Estrogen signaling in the brain Brain areas that are known to be involved in the regulation of female sexual behavior include the arcuate nucleus (ARC), ventromedial nucleus (VMN) and preoptic area (POA) of the hypothalamus (reviewed by Molenda-Figueira et al, 2006). In addition to these areas of the hypothalamus, the hippocampus and amygdala are known to regulate the behavioral aspects of estrus.…”

“…E2 increases the sensitivity of neurons for itself by inducing ER gene expression Frye, 2006 and. The E2-receptor complex acts as transcription factor that regulates the expression of a large number of genes (Molenda-Figueira et al, 2006). Apart from genomic (classical ER) signaling, the estrogenic control of estrous behavior also involves membrane signaling mechanisms via secondary messengers like phosphoinositide 3 kinase, cAMP response element binding proteins and extracellular signal regulated kinases ERa 5 estrogen receptor-a; ERb 5 estrogen receptor-b; E2 5 estradiol; P4 5 progesterone; GnRH 5 gonadotropin releasing hormone; GnRH-R 5 gonadotropin releasing hormone receptor; PI3K 5 phosphoinositide 3 kinase; IGF-1 5 insulin-like growth factor-1; LH 5 luteinizing hormone.…”