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...

Male mice with a knockout of the estrogen receptor (ER)-␣ gene, a ligand-activated transcription factor, showed reduced levels of intromissions and no ejaculations whereas simple mounting behavior was not affected. In contrast, all components of sexual behaviors were intact in male mice lacking the novel ER-␤ gene. Here we measure the extent of phenotype in mice that lack both ER-␣ and ER-␤ genes (␣␤ERKO). ␣␤ERKO male mice did not show any components of sexual behaviors, including simple mounting behavior. Nor did they show ultrasonic vocalizations during behavioral tests with receptive female mice. On the other hand, reduced aggressive behaviors of ␣␤ERKO mice mimicked those of single knockout mice of ER-␣ gene (␣ERKO). They showed reduced levels of lunge and bite aggression, but rarely showed offensive attacks. Thus, either one of the ERs is sufficient for the expression of simple mounting in male mice, indicating a redundancy in function. Offensive attacks, on the other hand, depend specifically on the ER-␣ gene. Different patterns of natural behaviors require different patterns of functions by ER genes.testosterone ͉ mounts ͉ intromissions ͉ ejaculation ͉ aggression I ntracellular estrogen receptors (ERs) play key roles in the neuroendocrine regulation of reproduction. Binding of ovarian steroid, estradiol, to ERs in female rodents triggers a series of molecular and neurochemical processes that lead to the induction of lordosis behavior, an essential behavioral component for successful reproduction (1). Normal expression of male reproductive behaviors also may depend on activation of ER, because the male gonadal steroid, testosterone, acts not only through androgen receptors (ARs) in its original form or 5␣-reduced form (dihydrotestosterone), but also through ERs after being aromatized to estradiol.Two types of ERs, ER␣ and ER␤, which bind to estradiol with a similar affinity, are identified in the brain (2-4). This field of work is well enough developed that we can attempt to move beyond the classical Beadle and Tatum ''one gene, one enzyme'' formulation, to discover patterns of gene activation influencing patterns of behavior.In knockout (KO) mice that lack the gene for either ER␣ (␣ERKO) or ER␤ (␤ERKO) individually (5, 6), male sexual behaviors are only partially disrupted or even virtually normal. ␣ERKO mice, although they rarely ejaculated and were infertile, showed almost normal levels of mounts and just reduced levels of intromissions (7). In contrast, all three components of sexual behaviors were present and robust in intact ␤ERKO males (8). Because earlier findings indicated some unique ovarian phenotype in double KO mice compared with either ␣ERKO or ␤ERKO (9), it was necessary to determine what pattern of behavioral deficits would appear in KO mice that lack both ER␣ and ER␤ genes (␣␤ERKO).In aromatase KO (ArKO) male mice sexual behaviors are strongly modified including the reduction of mount frequency and the prolonged mount latency (10). However, male ArKO mice are known to be fertile (11). It i...

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