Rapid control of male typical behaviors by brain-derived estrogens
Cornil, Charlotte ; ; Balthazart, Jacques
in Frontiers in Neuroendocrinology (2012)
Beside their genomic mode of action, estrogens also activate a variety of cellular signaling pathways through non-genomic mechanisms. Until recently, little was known regarding the functional significance ... [more ▼]
Beside their genomic mode of action, estrogens also activate a variety of cellular signaling pathways through non-genomic mechanisms. Until recently, little was known regarding the functional significance of such actions in males and the mechanism that control local estrogen concentration with a spatial and time resolution compatible with these non-genomic actions had rarely been examined. Here, we review evidence that estrogens rapidly modulate a variety of behaviors in male vertebrates. Then, we present in vitro work supporting the existence of a control mechanism of local brain estrogen synthesis by aromatase along with in vivo evidence that rapid changes in aromatase activity also occur in a region-specific manner in response to changes in the social or environmental context. Finally, we suggest that the brain estrogen provision may also play a significant role in females. Together these data bolster the hypothesis that brain-derived estrogens should be considered as neuromodulators. [less ▲]Detailed reference viewed: 50 (7 ULg)
Brain aromatase and circulating corticosterone are rapidly regulated by combined acute stress and sexual interaction in a sex specific manner.
; Balthazart, Jacques ; Cornil, Charlotte
in Journal of Neuroendocrinology (2012), 24(10), 1322-34
Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in ... [more ▼]
Neural production of 17β-oestradiol via aromatisation of testosterone may play a critical role in rapid, non-genomic regulation of physiological and behavioural processes. In brain nuclei implicated in the control of sexual behaviour, sexual or stressfull stimuli induce respectively a rapid inhibition or increase in preoptic aromatase activity (AA). Here, we tested quail that were either non-stressed or acutely stressed (15 min restraint) immediately prior to sexual interaction (5 min) with stressed or non-stressed partners. We measured nuclei-specific AA changes, corresponding behavioural output, fertilisation rates and corticosterone (CORT) concentrations. In males, sexual interaction rapidly reversed stress-induced increases of AA in the medial preoptic nucleus (POM). This time scale (<5min) highlights the dynamic potential of the aromatase system to integrate input from stimuli that drive AA in opposing directions. Moreover, acute stress had minimal effects on male behaviour suggesting that the input from the sexual stimuli on POM AA may actively preserve sexual behaviour despite stress exposure. We also found distinct sex differences in contextual physiological responses: while males did not show any effect of partner status, females responded to both their stress exposure and the male partner's stress exposure at the level of circulating CORT and AA. In addition, fertilisation rates and female CORT correlated with the male partner's exhibition of sexually aggressive behaviour suggesting that female perception of the male can affect their physiology as much as direct stress. Overall, male reproduction appears relatively simple - sexual stimuli, irrespective of stress, drives major neural changes including rapid reversal of stress-induced changes of AA. In contrast, female reproduction appears more nuanced and context specific, with subjects responding physiologically and behaviourally to stress, the male partner's stress exposure, and female-directed male behaviour. [less ▲]Detailed reference viewed: 29 (3 ULg)
Milestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research.
; Balthazart, Jacques ; et al
in Journal of Neuroendocrinology (2012), 24(1), 1-15
During the last 10 years, the conference on 'Steroids and Nervous System' held in Torino (Italy) has been an important international point of discussion for scientists involved in this exciting and ... [more ▼]
During the last 10 years, the conference on 'Steroids and Nervous System' held in Torino (Italy) has been an important international point of discussion for scientists involved in this exciting and expanding research field. The present review aims to recapitulate the main topics that have been presented through the various meetings. Two broad areas have been explored: the impact of gonadal hormones on brain circuits and behaviour, as well as the mechanism of action of neuroactive steroids. Relationships among steroids, brain and behaviour, the sexual differentiation of the brain and the impact of gonadal hormones, the interactions of exogenous steroidal molecules (endocrine disrupters) with neural circuits and behaviour, and how gonadal steroids modulate the behaviour of gonadotrophin-releasing hormone neurones, have been the topics of several lectures and symposia during this series of meetings. At the same time, many contributions have been dedicated to the biosynthetic pathways, the physiopathological relevance of neurosteroids, the demonstration of the cellular localisation of different enzymes involved in neurosteroidogenesis, the mechanisms by which steroids may exert some of their effects, both the classical and nonclassical actions of different steroids, the role of neuroactive steroids on neurodegeneration, neuroprotection, and the response of the neural tissue to injury. In these 10 years, this field has significantly advanced and neuroactive steroids have emerged as new potential therapeutic tools to counteract neurodegenerative events. [less ▲]Detailed reference viewed: 41 (0 ULg)
Sex differences in brain aromatase activity: genomic and non-genomic controls
Balthazart, Jacques ; Charlier, Thierry ; Cornil, Charlotte et al
in Frontiers in Endocrinology (2011), 2
Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail ... [more ▼]
Aromatization of testosterone into estradiol in the preoptic area plays a critical role in the activation of male copulation in quail and in many other vertebrate species. Aromatase expression in quail and in other birds is higher than in rodents and other mammals, which has facilitated the study of the controls and functions of this enzyme. Over relatively long time periods (days to months), brain aromatase activity (AA), and transcription are markedly (four- to sixfold) increased by genomic actions of sex steroids. Initial work indicated that the preoptic AA is higher in males than in females and it was hypothesized that this differential production of estrogen could be a critical factor responsible for the lack of behavioral activation in females. Subsequent studies revealed, however, that this enzymatic sex difference might contribute but is not sufficient to explain the sex difference in behavior. Studies of AA, immunoreactivity, and mRNA concentrations revealed that sex differences observed when measuring enzymatic activity are not necessarily observed when one measures mRNA concentrations. Discrepancies potentially reflect post-translational controls of the enzymatic activity. AA in quail brain homogenates is rapidly inhibited by phosphorylation processes. Similar rapid inhibitions occur in hypothalamic explants maintained in vitro and exposed to agents affecting intracellular calcium concentrations or to glutamate agonists. Rapid changes in AA have also been observed in vivo following sexual interactions or exposure to short-term restraint stress and these rapid changes in estrogen production modulate expression of male sexual behaviors. These data suggest that brain estrogens display most if not all characteristics of neuromodulators if not neurotransmitters. Many questions remain however concerning the mechanisms controlling these rapid changes in estrogen production and their behavioral significance. [less ▲]Detailed reference viewed: 174 (27 ULg)
Male sexual behavior rapidly modulates the synthesis of estrogens in discrete preoptic and hypothalamic regions.
de Bournonville, Catherine ; ; Balthazart, Jacques et al
Poster (2011, January 31)Detailed reference viewed: 56 (5 ULg)
Rapid activation of phosphorylated mitogen-activated protein kinase after sexual stimulation in male mice.
Taziaux, Mélanie ; ; Balthazart, Jacques et al
in Neuroreport (2011), 22(6), 294-8
We mapped cells immunoreactive for the phosphorylated form (p44/p42) of the mitogen-activated protein kinase (pMAPK--also known as ERK1/2) in the brain of male mice after exposure to female olfactory cues ... [more ▼]
We mapped cells immunoreactive for the phosphorylated form (p44/p42) of the mitogen-activated protein kinase (pMAPK--also known as ERK1/2) in the brain of male mice after exposure to female olfactory cues or after the display of male copulatory behaviors. Exposure to soiled bedding from estrous females or the display of coital behaviors rapidly (within 10 min) induced MAPK phosphorylation in most of the brain regions known to be involved in the processing of olfactory cues (main and accessory olfactory bulbs, amygdala, and medial preoptic area) and in the control of copulatory behavior (amygdala and medial preoptic area). MAPK phosphorylation thus seems to be a useful marker to study short-term neural activation associated with the expression of specific behaviors. [less ▲]Detailed reference viewed: 23 (2 ULg)
Steroid receptor coactivator 2 modulates steroid-dependent male sexual behavior and neuroplasticity in Japanese quail (Coturnix japonica)
Niessen, Neville-Andrew ; Balthazart, Jacques ; et al
in Journal of Neurochemistry (2011), 119Detailed reference viewed: 34 (6 ULg)
Organizing effects of sex steroids on brain aromatase activity in quail
Cornil, Charlotte ; ; Balthazart, Jacques et al
in PLoS ONE (2011), 6(4), 19196Detailed reference viewed: 32 (10 ULg)
Human and Quail Aromatase Activity Is Rapidly and Reversibly Inhibited by Phosphorylating Conditions
Charlier, Thierry ; ; Balthazart, Jacques et al
in Endocrinology (2011), 152(11), 4199-210
Besides their slow genomic actions, estrogens also induce rapid physiological responses. To be functionally relevant, these effects must be associated with rapid changes in local concentrations of ... [more ▼]
Besides their slow genomic actions, estrogens also induce rapid physiological responses. To be functionally relevant, these effects must be associated with rapid changes in local concentrations of estrogens. Rapid changes in aromatase activity (AA) controlled by calcium-dependent phosphorylations of the enzyme can alter in a rapid manner local estrogen concentrations, but so far this mechanism was identified only in the avian (quail) brain. We show here that AA is also rapidly down-regulated by phosphorylating conditions in quail ovary homogenates and in various cell lines transfected with human aromatase (HEK 293, Neuro2A, and C6). Enzymatic activity was also rapidly inhibited after depolarization of aromatase-expressing HEK 293 cells with 100 mm KCl, and activity was fully restored when cells returned to control conditions. Western blot analysis demonstrated that the reduction of enzymatic activity is not due to protein degradation. We next investigated by site-directed mutagenesis the potential implication in the control of AA of specific aromatase residues identified by bioinformatic analysis. Mutation of the amino acids S118, S247, S267, T462, T493, or S497 to alanine, alone or in combination, did not block the rapid inhibition of enzymatic activity induced by phosphorylating conditions, but basal AA was markedly decreased in the S118A mutant. Altogether, these results demonstrate that the rapid inhibition of AA is a widespread and fully reversible process and that phosphorylation of specific residues modulate AA. These processes provide a new general mechanism by which local estrogen concentration can be rapidly altered in the brain and other tissues. [less ▲]Detailed reference viewed: 30 (4 ULg)
Acute Stress Differentially Affects Aromatase Activity in Specific Brain Nuclei of Adult Male and Female Quail
; Cornil, Charlotte ; Balthazart, Jacques
in Endocrinology (2011), 52(11), 4242-51
The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic ... [more ▼]
The rapid and temporary suppression of reproductive behavior is often assumed to be an important feature of the adaptive acute stress response. However, how this suppression operates at the mechanistic level is poorly understood.The enzyme aromatase converts testosterone to estradiol in the brain to activate reproductive behavior in male Japanese quail (Coturnix japonica). The discovery of rapid and reversible modification of aromatase activity (AA) provides a potential mechanism for fast, stress induced changes in behavior. We investigated the effects of acute stress on AA in both sexes by measuring enzyme activity in all aromatase-expressing brain nuclei before, during, and after 30 min of acute restraint stress. We show here that acute stress rapidly alters AA in the male and female brain and that these changes are specific to the brain nuclei and sex of the individual. Specifically, acute stress rapidly (5 min) increased AA in the male medial preoptic nucleus, a region controlling male reproductive behavior; in females, a similar increase was also observed, but it appeared delayed (15min) and had smaller amplitude. In the ventromedial and tuberal hypothalamus, regions associated with female reproductive behavior, stress induced a quick and sustained decrease in AA in females, but in males, only a slight increase (ventromedial) or no change (tuberal) in AA was observed. Effects of acute stress on brain estrogen production, therefore, represent one potential way through which stress affects reproduction. [less ▲]Detailed reference viewed: 26 (1 ULg)
Rapid changes of aromatase activity in discrete brain regions following social interactions
de Bournonville, Catherine ; ; Balthazart, Jacques et al
in Trabajos del Instituto Cajal (2011), LXXXIIIDetailed reference viewed: 38 (18 ULg)
Postnatal maternal fluoxetine exposure affects glucocorticoid responsiveness in adolescent offspring hippocampus in a model of maternal depression
Niessen, Neville-Andrew ; ; et al
Poster (2011)Detailed reference viewed: 34 (0 ULg)
Maternal fluoxetine exposure, regardless of prenatal stress, affects physiological systems involved in sexual development of offspring
; Charlier, Thierry ; et al
Conference (2011)Detailed reference viewed: 42 (2 ULg)
Rapid regulation by glutamate of aromatase activity
Charlier, Thierry ; ; Balthazart, Jacques
Poster (2011)Detailed reference viewed: 22 (0 ULg)
Rapid increase in aggressive behavior precedes the decrease in brain aromatase activity during socially mediated sex change in Lythrypnus dalli.
; Balthazart, Jacques ; et al
in General and Comparative Endocrinology (2011), 170(1), 119-24
In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study ... [more ▼]
In the bluebanded goby, Lythrypnus dalli, removal of the male from a social group results in a rapid behavioral response where one female becomes dominant and changes sex to male. In a previous study, within hours of male removal, aromatase activity in the brain (bAA) of dominant females was almost 50% lower than that of control females from a group in which the male had not been removed. For those females that displayed increased aggressive behavior after the male was removed, the larger the increase in aggressive behavior, the greater the reduction in bAA. To investigate whether decreased bAA leads to increased aggression, the present study used a more rapid time course of behavioral profiling and bAA assay, looking within minutes of male removal from the group. There were no significant differences in bAA between control females (large females from groups with the male still present), females that doubled their aggressive behavior by 10 or 20 min after male removal, or females that did not double their aggressive behavior within 30 min after male removal. Further, individual variation in bAA and aggressive behavior were not correlated in these fish. Whole brain decreases in aromatase activity thus appear to follow, rather than precede, rapid increases in aggressive behavior, which provides one potential mechanism underlying the rapid increase in androgens that follows aggressive interactions in many vertebrate species. For fish species that change sex from female to male, this increase in androgens could subsequently facilitate sex change. [less ▲]Detailed reference viewed: 28 (3 ULg)
Effects of sex steroids on aromatase mRNA expression in the male and female quail brain.
; ; Balthazart, Jacques
in General and Comparative Endocrinology (2011), 170(1), 180-8
Castrated male quail display intense male-typical copulatory behavior in response to exogenous testosterone but ovariectomized females do not. The behavior of males is largely mediated by the central ... [more ▼]
Castrated male quail display intense male-typical copulatory behavior in response to exogenous testosterone but ovariectomized females do not. The behavior of males is largely mediated by the central aromatization of testosterone into estradiol. The lack of behavioral response in females could result from a lower rate of aromatization. This is probably not the case because although the enzymatic sex difference is clearly present in gonadally intact sexually mature birds, it is not reliably found in gonadectomized birds treated with testosterone, in which the behavioral sex difference is always observed. We previously discovered that the higher aromatase activity in sexually mature males as compared to females is not associated with major differences in aromatase mRNA density. A reverse sex difference (females>males) was even detected in the bed nucleus of the stria terminalis. We analyzed here by in situ hybridization histochemistry the density of aromatase mRNA in gonadectomized male and female quail that were or were not exposed to a steroid profile typical of their sex. Testosterone and ovarian steroids (presumably estradiol) increased aromatase mRNA concentration in males and females respectively but mRNA density was similar in both sexes. A reverse sex difference in aromatase mRNA density (females>males) was detected in the bed nucleus of subjects exposed to sex steroids. Together these data suggest that although the induction of aromatase activity by testosterone corresponds to an increased transcription of the enzyme, the sex difference in enzymatic activity results largely from post-transcriptional controls that remain to be identified. [less ▲]Detailed reference viewed: 70 (2 ULg)
Sexual arousal, is it for mammals only?
; Balthazart, Jacques
in Hormones and Behavior (2011), 59(5), 645-55
Sexual arousal has many dimensions and has consequently been defined in various ways. In humans, sexual arousal can be assessed based in part on verbal communication. In male non-human mammalian species ... [more ▼]
Sexual arousal has many dimensions and has consequently been defined in various ways. In humans, sexual arousal can be assessed based in part on verbal communication. In male non-human mammalian species, it has been argued that arousal can only be definitively inferred if the subject exhibits a penile erection in a sexual context. In non-mammalian species that lack an intromittent organ, as is the case for most avian species, the question of how to assess sexual arousal has not been thoroughly addressed. Based on studies performed in male Japanese quail, we argue that several behavioral or physiological characteristics provide suitable measures of sexual arousal in birds and probably also in other tetrapods. These indices include, the performance of appetitive sexual behavior in anticipation of copulation (although anticipation and arousal are not synonymous), the activation of specific brain area as identified by the detection of the expression of immediate early genes (fos, egr-1) or by 2-deoxygucose quantitative autoradiography, and above all, by the release of dopamine in the medial preoptic area as measured by in vivo dialysis. Based on these criteria, it is possible to assess in birds sexual arousal in its broadest sense but meeting the more restrictive definition of arousal proposed for male mammals (erection in an explicit sexual context) is and will probably remain impossible in birds until refinement of in vivo imaging techniques such fMRI allow us to match in different species, with and without an intromittent organ, the brain areas that are activated in the presence of specific stimuli. [less ▲]Detailed reference viewed: 22 (4 ULg)
Sex differences in the rapid control of aromatase activity in the quail preoptic area.
; Balthazart, Jacques
in Journal of Neuroendocrinology (2011), 23(5), 424-34
Adult male quail show high levels of aromatase activity in the preoptic area-hypothalamus (POA-HYP), which parallels the high number of aromatase-immunoreactive cells and elevated mRNA concentrations ... [more ▼]
Adult male quail show high levels of aromatase activity in the preoptic area-hypothalamus (POA-HYP), which parallels the high number of aromatase-immunoreactive cells and elevated mRNA concentrations detected in this brain region by in situ hybridisation. Interestingly, females display considerably lower aromatase activity than males but have almost equal numbers of aromatase-immunoreactive cells and express similar levels of aromatase mRNA. Aromatase activity in the male POA-HYP can be rapidly regulated by calcium-dependent phosphorylations, in the absence of changes in enzyme concentration. In the present study, we investigated whether aromatase activity is differentially regulated by phosphorylations in males and females. A linear increase in accumulation of aromatisation products was observed in both sexes as a function of time but the rate of conversion was slower in females. Saturation analysis confirmed the lower maximum velocities (V(max) ) in females but indicated a similar affinity (K(m) ) in both sexes. Aromatase activity in females reacted differentially to manipulations of intracellular calcium. In particular, chelating calcium with ethylene glycol tetraacetic acid (EGTA) resulted in a larger increase of enzymatic activity in males than in females, especially in the presence of ATP. A differential reaction to kinase inhibitors was also observed between males and females (i.e. a larger increase in aromatase activity in females than in males after exposure to specific inhibitors). These findings suggest that the nature of aromatase is conserved between the sexes, although the control of its activity by calcium appears to be different. Additional characterizations of intracellular calcium in both sexes would therefore be appropriate to better understand aromatase regulation. [less ▲]Detailed reference viewed: 98 (4 ULg)
Sexual differentiation of sexual behavior and its orientation.
; Balthazart, Jacques
in Frontiers in Neuroendocrinology (2011), 32(2), 109Detailed reference viewed: 54 (10 ULg)
Minireview: Hormones and Human Sexual Orientation.
in Endocrinology (2011)
Many people believe that sexual orientation (homosexuality vs. heterosexuality) is determined by education and social constraints. There are, however, a large number of studies indicating that prenatal ... [more ▼]
Many people believe that sexual orientation (homosexuality vs. heterosexuality) is determined by education and social constraints. There are, however, a large number of studies indicating that prenatal factors have an important influence on this critical feature of human sexuality. Sexual orientation is a sexually differentiated trait (over 90% of men are attracted to women and vice versa). In animals and men, many sexually differentiated characteristics are organized during early life by sex steroids, and one can wonder whether the same mechanism also affects human sexual orientation. Two types of evidence support this notion. First, multiple sexually differentiated behavioral, physiological, or even morphological traits are significantly different in homosexual and heterosexual populations. Because some of these traits are known to be organized by prenatal steroids, including testosterone, these differences suggest that homosexual subjects were, on average, exposed to atypical endocrine conditions during development. Second, clinical conditions associated with significant endocrine changes during embryonic life often result in an increased incidence of homosexuality. It seems therefore that the prenatal endocrine environment has a significant influence on human sexual orientation but a large fraction of the variance in this behavioral characteristic remains unexplained to date. Genetic differences affecting behavior either in a direct manner or by changing embryonic hormone secretion or action may also be involved. How these biological prenatal factors interact with postnatal social factors to determine life-long sexual orientation remains to be determined. [less ▲]Detailed reference viewed: 89 (17 ULg)