Survival of reproductive behaviors in estrogen receptor β gene-deficient (βERKO) male and female mice

Abstract

Previously, it was shown that the lack of a functional estrogen receptor (ER) ␣ gene (ER␣) greatly affects reproduction-related behaviors in both female and male mice. However, widespread expression of a novel second ER gene, ER␤, demanded that we examine the possible participation of ER␤ in regulation of these behaviors. In dramatic contrast to our results with ER␣ knockout (␣ERKO) males, ␤ERKO males performed at least as well as wildtype controls in sexual behavior tests. Moreover, not only did ␤ERKO males exhibit normal male-typical aggressive behavior, including offensive attacks, but they also showed higher levels of aggression than wild-type mice under certain conditions of social experience. These data revealed a significant interaction between genotype and social experience with respect to aggressive behavior. Finally, females lacking a functional ␤ isoform of the ER gene showed normal lordosis and courtship behaviors, extending in some cases beyond the day of behavioral estrus. These results highlight the importance of ER␣ for the normal expression of natural reproductive behaviors in both sexes and also provide a background for future studies evaluating ER␤ gene contributions to other, nonreproductive behaviors.testosterone ͉ progesterone ͉ lordosis ͉ sexual behavior ͉ aggression O ne of the most reliable phenomena in neuroendocrinology is the facilitation of the female reproductive behavior, lordosis, by estrogens (1). The neural circuitry for this behavior has been well defined (2). Estrogen binding to neurons in the ventromedial nucleus of the hypothalamus (VMH) is the first neuroendocrine step activating neural circuitry for the behavior (3). In particular, antiestrogens delivered directly to the VMH block the behavior, thus revealing the essential nature of this particular hormone action (4). The neurobiological effects of estrogen binding in brain were long conceived to depend exclusively on the classical estrogen receptor (ER) (now renamed as ER␣). Indeed, we have demonstrated that the classical ER␣ gene is required for normal expression of a number of reproduction-related social behaviors in female mice regardless of their hormonal status (5, 6). ER␣-deficient knockout (␣ERKO) female mice showed no sign of lordosis behavior, greatly reduced pup-caring behavior, and elevated levels of infanticide and aggression. These results suggest that the presence of ER␤, a novel ER, by itself may not be sufficient to compensate for behavioral changes caused by the lack of the ER␣ gene. However, widespread expression of ER␤ in the central nervous system (7-9) led us to hypothesize that the presence of ER␤ also may be important for normal performance of female reproductive behaviors. In the present study, we tested this possibility by the use of ER␤ gene-specific KO (␤ERKO) mice (10, 11).In the male, brain mechanisms underlying the regulation of reproductive behaviors by gonadal androgenic hormones have received much attention (reviewed in ref. 12). Notably, it is known that conversion of testosterone to estr...

Age-related changes in the expression of ER-β mRNA in the female rat brain

“…ER-α knockout male and female mice showed various abnormalities in reproductive aspects, including infertility, no sign of lordosis, and infanticide (Lubahn et al, 1993;Ogawa et al, 1996;Ogawa et al, 1998;Simpson, 1998;Rissman et al, 1999). In contrast, the analyses of reproductive behaviors of ER-β knockout mice indicated the possibility that ER-β is not essential for such behaviors (Krege et al, 1998), since ER-β knockout male and female mice exhibited normal reproductive behaviors (Krege et al, 1998;Ogawa et al, 1999). Taken together, these findings suggest that ER-α, but not ER-β, may be critical to age-related reductions in reproductive function in aged rats.…”

Mating Stimulation Required for Mating-Induced Estrous Abbreviation in Female Rats: Effects of Repeated Testing

“…Alternatively, it has been suggested that activation of estrogen receptor-␤ (ER␤)-containing cells may contribute to the termination of sexual behavior (Greco, Blasberg, Kosinski, and Blaustein, unpublished results). Although ER␤ genedisrupted mice show normal sexual behavior, they continue to show sexual behavior considerably longer than do wild-type controls (Ogawa, Chan, Chester, Gustafsson, Korach, and Pfaff, 1999), suggesting that ER␤ is necessary for the normal termination of sexual behavior. Thus, ER␤ may contribute to the termination and/or abbreviation of sexual receptivity.…”

Rapid and estrogen receptor beta mediated actions in the hippocampus mediate some functional effects of estrogen

“…Although these data imply distinct functional effects of these receptors, the interaction of these ER subtypes for function is of interest. For example, βERKO mice do not show the same levels of sexual dysfunction as ERα mice demonstrate, and, furthermore, have slightly enhanced sexual receptivity than do their WT counterparts [83]. ERβ-selective phytoestrogens (e.g.…”