Both estrogen receptor-alpha and -beta are required for sexual differentiation of the anteroventral periventricular area in mice

Sexual dimorphisms in the hypothalamus are mediated in several cases by local aromatization of androgens to estrogens during the perinatal period. In this series of experiments, the contributions of the two estrogen receptors (ERs), ERalpha and ERbeta, to the differentiation of the sexually dimorphic subpopulation of dopaminergic neurons in the anteroventral periventricular area (AVPV) was examined. In the first experiment, numbers of tyrosine hydroxylase (TH) immunoreactive (-ir) AVPV neurons in ERbeta knockout and wild-type (WT) mice of both sexes were measured. In the second experiment, the average number of TH-ir neurons in the medial portion of the AVPV in ERalpha knockout, ERbeta knockout, double-ER knockout, and WT mice of both sexes was calculated. In both experiments TH-ir cell numbers were sexually dimorphic as expected, with female individuals of all genotypes exhibiting more TH-ir neurons than WT males. Interestingly the average number of TH-ir neurons in all knockout males was significantly higher than in WT male littermates. In fact, TH-ir cell numbers in all knockout males were equivalent to females. In a final experiment, C57BL/6J female mice were treated during the first 3 postnatal days with either estradiol, or a specific agonist for one of the two ERs. Additional male and female pups received vehicle injections. Treatments with estradiol or either ER-specific agonist significantly reduced the number of TH-ir AVPV neurons in female brains. Our data demonstrate that both ERalpha and ERbeta are involved in the sexual differentiation of the AVPV in mice.     

Estrogen receptor beta regulates sexually dimorphic neural responses to estradiol

Estrogen receptors (ERs) mediate many sexual dimorphisms in the neuroendocrine system and in behavior. We examined the consequences of the loss of functional estrogen receptor beta (ERbeta) on two sexually differentiated neural responses to estrogen. In wild type (WT) male mice, but not in females, estradiol (E(2)) treatment decreased estrogen receptor alpha immunoreactive (ERalpha-ir) cell numbers in the arcuate nucleus (ARC), the preoptic area (POA), and the ventromedial nucleus (VMN). These sex differences were reversed in ERbeta knockout (ERbetaKO) mice. Castrated ERbetaKOs did not show any change in ERalpha-ir cell number after E(2) treatment. Yet, E(2) decreased ERalpha-ir cell number in ovariectomized ERbetaKOs. Estradiol treatment increased progesterone receptor immunoreactive (PR-ir) cell number in WT female VMN and POA, but no change was noted in brains of WT castrates. In ERbetaKO mice the opposite relationship was found, E(2) treatment increased PR-ir cell number in male, but not in female, brains. Our results show that ERbeta influences several sexually dimorphic neural responses to estrogen. Moreover the data clearly show that ERbeta can modulate neural expression of ERalpha.     

The androgen receptor is selectively involved in organization of sexually dimorphic social behaviors in mice

It is well established that sexually dimorphic neural regions are organized by steroid hormones during development. In many species, neonatal males are exposed to more testosterone than their female littermates, and ultimately it is the estradiol, produced by aromatization of testosterone, that affects sexual differentiation. However, the androgen receptor also plays an important role in the masculinization of brain and behavior. Here we tested the hypothesis that sexually dimorphic social and odor preference behaviors can be differentiated by a nonaromatizable androgen during development by treating female mice on the day of birth (PN0) with dihydrotestosterone (DHT). Control mice received a single vehicle injection on PN0. Adults were gonadectomized, treated with estradiol, and tested for social behaviors. In contrast with control females, females treated on PN0 with DHT, like male controls, exhibited a preference for female-soiled vs. male-soiled bedding, a preference to investigate a female vs. a male and reduced c-Fos-immunoreactivity (ir) in several neural areas after exposure to male-soiled bedding. However, females treated with DHT on PN0 had normal female-typical sexual behavior. The number of calbindin-ir cells in the preoptic area is sexually dimorphic (males more than females), but females given DHT on PN0 had intermediate numbers of calbindin-ir neurons, not significantly different from control males or females. Our data demonstrate that organization of social and olfactory preferences in mice can be affected by perinatal DHT and lends support to the role of androgen receptor in organization of sexual differentiation of brain and behaviors.     

The effect of aromatase inhibition on the sexual differentiation of the sheep brain

This study tested the hypothesis that aromatization of testosterone to estradiol is necessary for sexual differentiation of the sheep brain. Pregnant ewes (n=10) were treated with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione (ATD) during the period of gestation when the sheep brain is maximally sensitive to the behavior-modifying effects of exogenous testosterone (embryonic d 50–80; 147 d is term). Control (n=10) ewes received vehicle injections. Fifteen control lambs (7 males and 8 females) and 17 ATD-exposed lambs (7 males and 10 females) were evaluated for sexually dimorphic behavioral and neuroendocrine traits as adults. Prenatal ATD exposure had no significant effect on serum concentrations of androgen at birth, growth rates, expression of juvenile play behaviors, or the onset of puberty in male and female lambs. Rams exposed to ATD prenatally exhibited a modest, but significant, decrease in mounting behavior at 18 mo of age. However, prenatal ATD exposure did not interfere with defeminization of adult sexual partner preferences, receptive behavior, or the LH surge mechanism. In summary, our results indicate that aromatization is necessary for complete behavioral masculinization in sheep. However, before we can conclude that aromatization does not play a role in defeminization of the sheep brain, it will be necessary to evaluate whether intrauterine exposure of male fetuses to higher doses of ATD for a more extended period of time can disrupt normal neuroendocrine and behavioral development.     

Survival of reproductive behaviors in estrogen receptor beta gene-deficient (betaERKO) male and female mice.

Previously, it was shown that the lack of a functional estrogen receptor (ER) alpha gene (ERalpha) greatly affects reproduction-related behaviors in both female and male mice. However, widespread expression of a novel second ER gene, ERbeta, demanded that we examine the possible participation of ERbeta in regulation of these behaviors. In dramatic contrast to our results with ERalpha knockout (alphaERKO) males, betaERKO males performed at least as well as wild-type controls in sexual behavior tests. Moreover, not only did betaERKO 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 beta 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 ERalpha for the normal expression of natural reproductive behaviors in both sexes and also provide a background for future studies evaluating ERbeta gene contributions to other, nonreproductive behaviors.     

11-ketotestosterone induces male-type sexual behavior and gonadotropin secretion in gynogenetic crucian carp, Carassius auratus langsdorfii.

To determine if a gynogenetic teleost might have a sexually bipotential brain, we tested whether implantation of 11-ketotestosterone (KT) induces male-type sexual behavior and gonadotropin (GTH) secretion in adult gynogenetic crucian carp, "ginbuna," Carassius auratus langsdorfii. KT-implanted female ginbuna were tested for male spawning behavior by pairing them with a stimulus female in which sexual receptivity and attractivity were induced by prostaglandin F(2alpha) (PG) injection. When KT-implanted female ginbuna were paired with a PG-injected stimulus female ginbuna, all the KT-implanted fish tested showed male spawning behavior in response to the PG-injected females. KT-implanted fish also showed female spawning behavior when they were injected with PG. When the KT-implanted female ginbuna were exposed to waterborne 17alpha,20beta-dihydroxy-4-pregnen-3-one (a female sex pheromone that stimulates male-typical GTH secretion in goldfish), all the KT-implanted fish showed an elevation of plasma GTH levels in response to the pheromone. These results demonstrate that gynogenetically evolved ginbuna, like goldfish, is sexually plastic and can be behaviorally and endocrinologically masculinized by androgen treatment without behavioral defeminization. These results support our hypothesis that adult teleosts retain a sexually bipotential brain regardless of reproductive strategy, i.e., hermaphroditism, gonochorism, or gynogenesis.     

Sex differences in male-typical copulatory behaviors in response to androgen and estrogen treatment in rats

The present experiment was performed to test the hypothesis that gender differences in the capacity for brain estrogen synthesis could constitute a sexually dimorphic mechanism that limits the activational effects of testosterone (T) in females, and enhances them in males. We determined the effects of treatments with equivalent levels of either T or estradiol (E2) on olfactory behavior and mounting in age-matched heterosexually naive gonadectomized male and female rats that were genitally ansthetized with lidocaine paste in order to minimize the contribution of sexually dimorphic somatosensory inputs to the expression of copulatory behavior. We found that T stimulated mounting to a greater extent in males than in females, but had equivalent effects on mount latency and genital investigation in the two sexes. On the other hand, E2 stimulated equivalent levels of mounting in males and females and reduced mount latency to a similar extent in males and females. However, E2 had a pronounced effect on the levels of genital investigation in males but not in females. Serum steroid levels and the levels of nuclear steroid receptor occupation in the brain were not different between males and females, suggesting that the behavioral differences between males and females cannot be attributed to differences in peripheral steroid metabolism or brain uptake. The results obtained corroborate previous studies suggesting that female rats normally undergo considerable male-typical behavioral masculinization during fetal development. However, such male-typical features of normal development in female rats do not extend to the regulation of preoptic aromatase activity or to the capacity of females to display olfactory behaviors in response to adult E2 exposure, functions which are sexually dimorphic even in the rat. The present results support the view that gender differences in the capacity for brain estrogen synthesis contribute to the sexually dimorphic display of T-stimulated male-typical sexual motivation and copulatory behavior in rats.     

Androgenic influences on feminine sexual behavior in male and female rats: defeminization blocked by prenatal antiandrogen treatment

The prenatal influence of androgen on the development of female sexual behavior in rats was investigated. The nonsteroidal antiandrogen, flutamide (4'-nitro-3'-trifluoromethylisobutyrylanilide; SCH), was administered to pregnant female rats from days 10--22 of gestation in dosages of either 1 mg/mother-day or 5 mg/mother-day. Males and females were gonadectomized in adulthood and tested for the display of lordosis in response to estradiol benzoate (EB) alone or EB with progesterone (P). Males exposed prenatally to either the 1- or 5-mg dosage of flutamide exhibited significantly higher lordosis quotients than controls when given EB alone. The addition of P was without effect in all male groups with regard to estrogen-induced lordosis. Females exposed prenatally to flutamide had significantly higher lordosis quotients than controls when given either 0.175 or 0.25 micrograms EB daily for 3 days. Addition of P to EB treatment significantly facilitated lordosis display in control and flutamide-treated females. The increase of feminine sexual behavior in both males and females of feminine sexual behavior in both males and females resulting from prenatal antiandrogen treatment suggests that androgen, prenatally, inhibits development of female sexual behavior. This androgenic inhibition of sexual receptivity (defeminization) seems to be related to the animal's sensitivity to estrogen in adulthood.     

Sexual differentiation of brain and behavior in birds.

It is currently accepted that most sex differences in brain and behavior do not result from direct genomic actions, but develop following early exposure to a sexually differentiated endocrine milieu. In Japanese quail (Coturnix japonica), in contrast to rodents, the male reproductive phenotype appears to develop in the absence of endocrine influence, and estradiol secreted by the ovary of the female embryo is responsible for the physiologic demasculinization of females. In zebra finches (Taeniopygia guttata), estrogens administered early in life demasculinize copulatory behavior in males, but masculinize the vocal control regions in the brain and singing behavior of females. It is difficult to understand how these behaviors differentiate given that normal untreated males sing and copulate in a male-typical manner, whereas females never show these behaviors. All attempts to resolve this paradox with experiments based on the rodent model of sexual differentiation have been unsuccessful. We propose that copulatory behavior in zebra finches is differentiated in a manner similar to what has been described in quail, but that novel approaches need to be considered to understand the differentiation of the telencephalic song control system. In particular, the possible involvement of afferent input that may differentiate in a steroid-dependent or -independent manner should be thoroughly tested.     

Estrogen receptor beta expression in the embryonic brain regulates development of calretinin-immunoreactive GABAergic interneurons

Our previous studies with estrogen receptor beta knockout (ERbeta(-/-)) mice demonstrated that ERbeta is necessary for embryonic development of the brain as early as embryonic day 14.5 (E14.5) and is involved in neuronal migration. Such early effects of ER were unexpected because estradiol synthesis and action in the brain occur at E18.5. In the present study, we examined the distribution of ERbeta in the developing brain and identified a population of ERbeta-regulated interneurons. ERbeta appears in the brain at E12.5, mainly localized in the wall of the midbrain, neuromere, hypothalamus, thalamus, and basal plate of pons. At E15.5 and E16.5, ERbeta expression increased in the hypothalamus, thalamus, and midbrain and appeared in the limbic forebrain. At E18.5, ERbeta expression was strongly expressed throughout the brain, including the cerebellum and striatum, whereas there were very few positive cells in the ventricular region. In the paraventricular thalamic nucleus and parafascicular nucleus, most of the calretinin-immunopositive interneurons expressed ERbeta. In ERbeta(-/-) mice, calretinin expression was markedly lower than in WT mice in the hippocampus, thalamus, and amygdala both at E16.5 and at E18.5. Epidermal growth factor receptor expression was lower in the cortex of ERbeta(-/-) than in WT mice at E15.5 and, unlike WT mice, was absent from the superficial marginal zone. These findings suggest that ERbeta in the embryonic brain is necessary for the development of calretinin-immunoreactive GABAergic interneurons and for neuronal migration in the cortex through modulating epidermal growth factor receptor expression at middle and later embryonic stages.     

Testosterone selectively affects aromatase and 5α-reductase activities in the green anole lizard brain

Testosterone (T) and its metabolites are important in the regulation of reproductive behavior in males of a variety of vertebrate species. Aromatase converts T to estradiol and 5α-reductase converts T to 5α-dihydrotestosterone (DHT). Male green anole reproduction depends on androgens, yet 5α-reductase in the brain is not sexually dimorphic and does not vary with season. In contrast, aromatase activity in the male brain is increased during the breeding compared to non-breeding season, and males have higher levels than females during the breeding season. Aromatase is important for female, but not male, sexual behaviors. The present experiment was conducted to determine whether 5α-reductase and aromatase are regulated by T. Enzyme activity was quantified in whole brain homogenates in both the breeding and non-breeding seasons in males and females that had been treated with either a T or blank implant. In males only, T increased 5α-reductase activity regardless of season and up-regulated aromatase during the breeding season specifically. Thus, regulation of both enzymes occurs in males, whereas females do not show parallel sensitivity to T. When considered with previous results, the data suggest that aromatase might influence a male function associated with the breeding season other than sexual behavior. 5α-Reductase can be mediated by T availability, but this regulation may not serve a sex- or season-specific purpose.     

Perinatal Aromatase Activity in Male and Female Rats: Effect of Prenatal Alcohol Exposure

Fetal alcohol exposure has been shown to produce long-term feminizing and demasculinizing effects on male rat behaviors which are organizationally dependent upon perinatal androgen levels. Such exposure has previously been shown to suppress the normal surge of testosterone during the critical prenatal period. Since defeminization of male rat behavior is dependent upon estrogen derived from the aromatization of testosterone in brain, brain aromatase activity was measured during the perinatal period in males and females exposed to alcohol beginning on Day 14 of gestation. Aromatase activity was measured in whole hypothalamus of fetuses from Day 16 through 20 of gestation and in the hypothalamic preoptic area and amygdala of animals 6-12 hr postparturition. Hypothalamic aromatase activity was elevated in fetal alcohol exposed males compared to controls on Days 18 and 19 of gestation and on postnatal Day 1. No effect of prenatal alcohol exposure was found in females. A sex effect in aromatase activity in the amygdala was evident on Day 1 when activity was found to be greater in males than females. Overall, these findings indicate that fetal alcohol exposure will elevate regional brain aromatase activity in males, but not females during the perinatal period of neurobehavioral sexual differentiation.     

Variation in aromatase activity in the medial preoptic area and plasma progesterone is associated with the onset of paternal behavior

The effects of aromatase within the brain on sexual behavior have been studied in a wide variety of species. Relatively few non-mating behaviors have been considered, despite evidence that estrogen affects many social behaviors. Testosterone promotes paternal behavior in California mouse (Peromyscus californicus) fathers, acting primarily via aromatization to estradiol. Virgin male California mice rarely exhibit paternal behavior, so we investigated whether aromatase in the brain changed with the onset of paternal behavior in California mouse fathers. In the medial preoptic area (MPOA), a brain area known to regulate parental behavior in rodents, we found that fathers had significantly more aromatase activity than mated males without pups, suggesting that an increase in estrogen production in this brain area contributes to the onset of paternal behavior. We also found that progesterone (P(4)) levels were lower in fathers compared to sexually inexperienced males and that P(4) was negatively correlated with aromatase activity in the MPOA. These P(4) findings agree with a recent study that found an inhibitory effect of P(4) on paternal behavior. Overall, we found that aromatase activity and P(4) levels change in association with an important life history transition, and may provide a mechanistic basis for plasticity in paternal behavior.     

Effects of aromatase or estrogen receptor gene deletion on masculinization of the principal nucleus of the bed nucleus of the stria terminalis of mice

The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) is a sexually dimorphic nucleus, and the male BNSTp is larger and has more neurons than the female BNSTp. To assess the roles of neuroestrogen synthesized from testicular androgen by brain aromatase in masculinization of the BNSTp, we performed morphometrical analyses of the adult BNSTp in aromatase knockout (ArKO), estrogen receptor-α knockout (αERKO), and estrogen receptor-β knockout (βERKO) mice and their respective wild-type littermates. In wild-type littermates, the BNSTp of males had a larger volume and greater numbers of neuronal and glial cells than did that of females. The volume and neuron number of the BNSTp in ArKO and αERKO males and glial cell number of the BNSTp in αERKO males were significantly smaller than those of wild-type male littermates, and they were not significantly different from those in female mice with either gene knockout. In contrast, there was no significant morphological difference in the BNSTp between βERKO and wild-type mice. Next, we examined the BNSTp of ArKO males subcutaneously injected with estradiol benzoate (EB) on postnatal days 1, 2, and 3 (1.5 μg/day). EB-treated ArKO males had a significantly greater number of BNSTp neurons than did oil-treated ArKO males. The number of BNSTp neurons in EB-treated ArKO males was comparable to that in wild-type males. These findings suggested that masculinization of the BNSTp in mice involves the actions of neuroestrogen that was synthesized by aromatase and that this estrogen mostly binds to ERα during the postnatal period.     

Endocrine control of sexual behavior in teleost fish

Sexual behavior is one of the most profound events during the life cycle of animals that reproduce sexually. After completion of gonadal development that is mediated by various hormones, oviparous teleosts perform a suite of behaviors, often termed as spawning behavior. This is particularly important for teleosts that have their gametes fertilized externally as the behavior patterns ensures the close proximity of both sexes for gamete release, fusion and ultimately the production of offspring. As in other vertebrates, sexual behavior of fish is also under the control of hormones. Testicular androgen is a requirement for male sexual behavior to occur in most fish species that have been studied. Unlike tetrapods, however, ovarian estrogen does not appear to be essential for the occurrence of female sexual behavior for fish that have their gametes fertilized externally. Prostaglandins produced in the ovary after ovulation act as a trigger in some teleosts to induce female sexual behavior. Potentiating effects of gonadotropin-releasing hormone in the brain on sexual behavior are reported in some species.Under endocrine regulation, male and female fish exhibit gender-typical behavior during spawning, but in some fish species there is also some plasticity in their sexual behavior. Sex changing fish can perform both male-typical and female-typical sexual behaviors during their lifetime and this sexual plasticity can also be observed in non-sex changing fish when undergoing hormonal treatment. Although the neuroanatomical basis is not clear in fish, results of field and laboratory observations suggest that some teleosts possess a sexually bipotential brain which can regulate two types of behaviors unlike most other vertebrates which have a discrete sex differentiation of their brain and can only perform gender-typical sexual behavior.     

Selective activation of estrogen receptor alpha in Japanese quail embryos affects reproductive organ differentiation but not the male sexual behavior or the parvocellular vasotocin system

Estradiol is crucial for normal female differentiation in birds. Developmental effects of estrogen are believed to be mediated by slow genomic actions through the nuclear estrogen receptors alpha (ERalpha) and/or beta (ERbeta). Consequently, exogenous compounds that interfere with the ERs may disrupt sexual differentiation of the reproductive organs and of the brain areas controlling sexual behaviors. The present study was conducted to elucidate the role of ERalpha in xenoestrogen-induced disruption of sexual differentiation in the Japanese quail (Coturnix japonica). Embryonic treatment with the synthetic estrogen, ethinylestradiol (EE(2)), and with the ERalpha-selective agonist, propyl pyrazole triol (PPT), induced oviductal malformations in females and retention of oviducts in males. Both EE(2) and PPT caused weight asymmetry between left and right testes and reduced the cloacal gland area in males. EE(2) significantly reduced the copulatory behavior in males whereas PPT had no effect on this behavior. The sexually dimorphic parvocellular vasotocin-immunoreactive (VT-ir) system in the medial preoptic nucleus (POM), the lateral septum (SL) and the medial part of the nucleus of the stria terminalis (BSTm), was not affected by EE(2) or PPT. Our results suggest that xenoestrogen-induced effects on reproductive organ differentiation are mediated by ERalpha, whereas demasculinization of male copulatory behavior and the VT-ir system appears not to be induced by activation of ERalpha alone.     

Enhanced sexual behaviors and androgen receptor immunoreactivity in the male progesterone receptor knockout mouse

Reproductive and behavioral functions of progesterone receptors (PRs) in males were assessed by examining consequences of PR gene deletion. Basal hormone levels were measured in male progesterone receptor knockout (PRKO) mice and compared to wild-type (WT) counterparts. RIA of serum LH, testosterone, and progesterone levels revealed no significant differences. Levels of FSH were moderately but significantly lower and inhibin levels were higher in PRKOs; these differences were not accompanied by gross differences in testicular weight or morphology. PRKOs exhibited significant alterations in sexual behavior. In initial tests PRKOs exhibited reduced latency to mount, compared with WT. In second sessions, PRKOs again showed a significantly reduced latency to mount and increased likelihood of achieving ejaculation. RU486 treatment in WT produced increased mount and intromission frequency and decreased latency to intromission. In anxiety-related behavior tests, PRKO mice exhibited intermediate anxiety levels, compared with WT, suggesting that enhanced sexual behavior in PRKOs is not secondary to reduced anxiety. Immunohistochemical analysis revealed significantly enhanced androgen receptor expression in the medial preoptic nucleus and bed nucleus of the stria terminalis of PRKO. We conclude that testicular development and function and homeostatic regulation of the hypothalamic-pituitary testicular axis are altered to a lesser extent by PR gene deletion. In contrast, PR appears to play a substantial role in inhibiting the anticipatory/motivational components of male sexual behavior in the mouse. The biological significance of this inhibitory mechanism and the extent to which it is mediated by reduced androgen receptor expression remain to be clarified.     

Morphological studies of prolactin-secreting cells in estrogen receptor alpha and estrogen receptor beta knockout mice

Estrogens play a major role in the regulation of prolactin (PRL) secretion through activation of pituitary and hypothalamic estrogen receptors (ERs). In order to evaluate the relative role of ERalpha and ERbeta in the control of PRL density in the pituitary gland, we performed immunocytochemical localization of PRL and ERs in pituitaries of wild-type (WT), ERalpha knockout (KO) and ERbetaKO mice. In WT and ERbetaKO anterior pituitaries, the vast majority of secretory cells contained ERalpha immunoreactivity, while no ERalpha immunostaining could be found in ERalphaKO pituitaries. No ERbeta immunoreactivity could be detected in pituitaries of WT, ERalphaKO or ERbetaKO mice. At the light microscopic level, a large number of cells staining for PRL were present in pituitaries of female WT, while in female ERalphaKO pituitaries, the density of PRL cells was much lower. In WT male pituitaries, the density of PRL cells was lower than observed in female WT, while PRL staining was markedly decreased in male ERalphaKO as compared to male WT. In ERbetaKO mice of both sexes, the results were identical to those observed in WT animals. At the electron microscopic level, in WT mice of both sexes, type 1 PRL cells exhibited a well-developed Golgi apparatus and a large number of strongly stained large mature and immature secretory granules. Type 2 PRL cells were also present in the pituitary. Type 2 PRL cells contain small poorly labelled granules. In ERalphaKO mice of both sexes, type 1 PRL cells were atrophied with poorly developed Golgi apparatus, and no type 2 PRL cells could be observed. In ERalphaKO pituitaries, typical gonadectomy cells were found. No ultrastructural changes were observed in PRL cells of ERbetaKO mice. The present data strongly suggest that the positive regulation of PRL expression at the pituitary level by estrogens is mediated by ERalpha and does not involve ERbeta activation.     

Genomic imprinting mediates sexual experience-dependent olfactory learning in male mice

Mammalian imprinted genes are generally thought to have evolved as a result of conflict between parents; however, recent knockout studies suggest that coadaptation between mother and offspring may have been a significant factor. We present evidence that the same imprinted gene that regulates mammalian maternal care and offspring development also regulates male sexual behavior and olfaction. We have shown that the behavior of male mice carrying a knockout of the imprinted gene Peg3 does not change with sexual experience and that the mice are consequently unable to improve their copulatory abilities or olfactory interest in female odor cues after mating experience. Forebrain activation, as indexed by female odor-induced c-Fos protein induction, fails to increase with sexual experience, providing a neural basis for the behavioral deficits that the male mice display. The behavioral and neural effects of the Peg3 knockout show that this imprinted gene has evolved to regulate multiple and varied aspects of reproduction, from male sexual behavior to female maternal care, and the development of offspring. Moreover, sexual experience-driven behavioral changes may represent an adaptive response that enables males to increase their reproductive potential over their lifespan, and the effects we have found suggest that the evolution of genomic imprinting has been influenced by coadaptation between males and females as well as between females and offspring.     

Sex and regional differences in estradiol content in the prefrontal cortex, amygdala and hippocampus of adult male and female rats

In general, the behavioral and neural effects of estradiol administration to males and females differ. While much attention has been paid to the potential structural, cellular and sub-cellular mechanisms that may underlie such differences, as of yet there has been no examination of whether the differences observed may be related to differential uptake or storage of estradiol within the brain itself. We administered estradiol benzoate to gonadectomized male and female rats, and compared the concentration of estradiol in serum and brain tissue found in these rats to those of gonadectomized, oil-treated rats and intact rats of both sexes. Long-term gonadectomy (3 weeks) reduced estradiol concentration in the male and female hippocampus, but not in the male or female amygdala or in the female prefrontal cortex. Furthermore, exogenous treatment with estradiol increased estradiol content to levels above intact animals in the amygdala, prefrontal cortex and the male hippocampus. Levels of estradiol were undetectable in the prefrontal cortex of intact males, but were detectable in all other brain regions of intact rats. Here we demonstrate (1) that serum concentrations of estradiol are not necessarily reflective of brain tissue concentrations, (2) that within the brain, there are regional differences in the effects of gonadectomy and estradiol administration, and (3) that there is less evidence for local production of estradiol in males than females, particularly in the prefrontal cortex and perhaps the hippocampus. Thus there are regional differences in estradiol concentration in the prefrontal cortex, amygdala and hippocampus that are influenced by sex and hormone status.