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...
Estrogens are known to increase running wheel activity of rodents primarily by acting on the medial preoptic area (mPOA). The mechanisms of this estrogenic regulation of running wheel activity are not completely understood. In particular, little is known about the separate roles of two types of estrogen receptors, ERalpha and ERbeta, both of which are expressed in mPOA neurons. In the present study the effects of continuous estrogen treatment on running wheel activity were examined in male and female mice specifically lacking either the ERalpha (alphaERKO) or the ERbeta (betaERKO) gene. Mice were gonadectomized and 1 wk later implanted with either a low dose (16 ng/d) or a high dose (160 ng/d) of estradiol benzoate (EB) or with a placebo control pellet. Home cage running wheel activity was recorded for 9 d starting 10 d after EB implants. The same mice were also tested for open field activity before and after EB implants. In both female and male alphaERKO mice, running wheel activity was not different from that in corresponding wild-type (alphaWT) mice in placebo control groups. In both females and males it was increased by EB only in alphaWT, not alphaERKO, mice. In betaERKO mice, on the other hand, both doses of EB equally increased running wheel activity in both sexes just as they did in betaWT mice. Absolute numbers of daily revolutions of EB-treated groups, however, were significantly lower in betaERKO females compared with betaWT females. Before EB treatment, gonadectomized alphaERKO female were significantly less active than alphaWT mice in open field tests, whereas betaERKO females tended to be more active than betaWT mice. In male mice there were no effect of ERalpha or ERbeta gene knockout on open field activity. Unlike its effect on running wheel activity, EB treatment induced only a small increase in open field activity in female, but not male, mice. These findings indicate that 1) in both sexes estrogenic regulation of running wheel activity is primarily mediated through the ERalpha, not the ERbeta; and 2) hormone/genotype effects are specific to the type of locomotor activity (i.e. home cage running wheel activity and open field activity) measured.
The ventromedial hypothalamus (VMH) plays a central role in the regulation of the female reproductive behavior lordosis, a behavior dependent upon the sequential activation of receptors for the ovarian steroid hormones estradiol (E) and progesterone (P). These receptors function as transcription factors to alter the expression of target genes. To discover behaviorally relevant genes targeted by E and P in the VMH, we used the differential display PCR to identify messenger RNAs that are differentially expressed in the hypothalamus of ovariectomized (ovx) rats treated with E alone compared with ovariectomized rats treated with E and P. We show here that one interesting mRNA within the hypothalamus that is repressed by P after E priming encodes the protein 25-Dx, the rat homolog of the human membrane-associated P-binding protein Hpr6.6. Neurons in the brain containing the highest levels of 25-Dx are located in several nuclei of the basal forebrain, including the VMH. 25-Dx expression is also higher in the hypothalamus of female P receptor ''knockout'' mice than in their wild-type littermates. These findings suggest a mechanism in which the activation of nuclear P receptor represses expression of a membrane P receptor, 25-Dx, during lordosis facilitation. L ordosis is a reproductive behavior, characterized by the rigid dorsiflexion of the spinal column and elevation of the hind quarters observed in mating female rodents. The lordosis posture allows intromission by the male and is due to elevated circulating levels of estradiol (E) and progesterone (P) from the ovaries, which occurs during proestrus, accompanied by gentle pressure on the vagina from the male (1). Lordosis is also observed in ovariectomized (ovx) females given exogenous hormone followed by gentle pressure on the perineum (1). This model system underscores the behavior's dependence on E, P, and tactile stimulation (2) and is widely used to examine the influence of E, P, and somatosensory effects on an easily identifiable reproductive behavior.By tracing the somatosensory input, Pfaff et al. (2) have constructed a detailed map of the neural circuitry responsible for lordosis. One brain structure important for integrating the endocrine aspect with other neural events surrounding lordosis is the ventromedial hypothalamus (VMH) (2). The VMH contains an abundance of E and P receptors (2), ligand-activated transcription factors (3) that act within the nuclei of VMH neurons. Under a lordosis-producing hormone regimen, E, operating through the transcriptional activity of the activated estrogen receptor, has been shown to increase the transcription of oxytocin and the oxytocin receptor, gonadotropin-releasing hormone and the gonadotropin-releasing hormone receptor, preproenkephalin (PPE), the opioid receptor, and the progesterone receptor (PR) (4). The transcriptional targets of activated PR within this brain region have been more difficult to ascertain, but recent work has identified a few P-responsive genes in the brain that may reside within the lordosis pat...
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