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See detailImportance of steroid receptor coregulators for neuronal phenotype determination: Modulation of steroid action
Charlier, Thierry ULg

in Trabajos del Instituto Cajal (2009), LXXXII

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent ... [more ▼]

Steroid receptors such as estrogen receptors alpha and beta and androgen receptors are transcription factors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelching, between two different nuclear receptors introduced the notion that common cofactors might be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors, which are now known as coactivators, are involved in chromatin remodeling and stabilization of the general transcription machinery. Since the characterization of the steroid receptor coactivator 1 or SRC-1, more than 100 different cofactors have been identified. Although an increasingly large amount of information has been collected about the in vitro function of these coregulatory proteins, relatively little is known regarding their physiological role in vivo, particularly in the brain. Our laboratory and others have demonstrated the importance of SRC-1 in the differentiation and activation of steroid-dependent sexual behaviors and the related neural genes. In Japanese quail, the inhibition of SRC-1 expression by intracerebroventricular antisense injections blocked the activating effects of exogenous testosterone on male sexual behaviors and the steroid-dependent vasotocine expression and increase of the median preoptic area volume defined by Nissl staining as well as by aromatase immunoreactivity. These data therefore strongly suggested that SRC-1 is required to modulate estrogen receptor dependent gene-expression. It is however interesting to note that steroid receptors and SRC-1 are not always colocalized. For example, both glial cells and neurons in the hippocampus express estrogen receptor alpha but SRC-1 is rarely observed in glia. It is therefore possible that estrogen receptor alpha in glial cell require another coactivator or set of coactivators to induce estrogen-dependent gene transcription. It has been suggested very recently that SRC-1 is associated with neuronal differentiation of neural stem cell derived from the ganglionic eminence of mouse embryos. These stem cells differentiating into glial cell (GFAP-positive) did not express SRC-1. The presence of a specific coactivator could therefore determine a specific cell phenotype (neuronal vs glial). Another coactivator, the coactivator-associated arginine methyl transferase 1 or CARM-1 seems to be important to keep progenitor cells in a dividing state. The inhibition of CARM-1 expression leads to neuronal differentiation. Neurogenesis can therefore offers an excellent model to define the spatio-temporal role of different coactivators. It is indeed possible to study a subset of coactivators associated to various stages phenotype determination (proliferation vs. differentiation). The study of neurogenesis in the dentate gyrus of the hippocampus in female adult rats shows that around 40 % of proliferative cells express SRC-1 or CARM-1. Interestingly, 70% of proliferative cells express SRC-1 but only a very few cells (<5%) express CARM-1. We are currently investigating the temporal pattern of expression of these two coactivators during the neurogenesis in the hilus and dentate gyrus. The expression of the coactivators CARM-1 and SRC-1 is analyzed in proliferating and differentiating cells. We expect that proliferating and differentiating cells will differentially express the two coactivators. It seems that the presence of a precise subset of coactivators could help defining the phenotype of the cell by modulating a specific downstream pathway after steroid receptor activation. The very large number of coactivators and their association into preformed complexes potentially allows the determination of hundreds of different phenotypes. The study of the expression of the coactivator and their function in vivo is required to fully understand steroid action and specificity in the brain. [less ▲]

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See detailImportance of steroid receptor coactivators in the modulation of steroid action on brain and behavior
Charlier, Thierry ULg

in Psychoneuroendocrinology (2009), 34

Steroid receptors such as estrogen and androgen receptors are nuclear receptors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent protein expression in the ... [more ▼]

Steroid receptors such as estrogen and androgen receptors are nuclear receptors involved in the transcriptional regulation of a large number of target genes. Steroid-dependent protein expression in the brain controls a large array of biological processes including spatial cognition, copulatory behavior and neuroprotection. The discovery of a competition, or squelch- ing, between two different nuclear receptors introduced the notion that common cofactors may be involved in the modulation of transcriptional activity of nuclear receptors. These cofactors or coregulatory proteins are functionally divided into coactivators and corepressors and are involved in chromatin remodeling and stabilization of the general transcription machinery. Although a large amount of information has been collected about the in vitro function of these coregulatory proteins, relatively little is known regarding their physiological role in vivo, particularly in the brain. Our laboratory and others have demonstrated the importance of SRC-1 in the differentia- tion and activation of steroid-dependent sexual behaviors and the related neural genes. For example, we report that the inhibition of SRC-1 expression blocks the activating effects of exogenous testosterone on male sexual behaviors and increases the volume of the median preoptic area. Other coactivators are likely to be involved in the modulation in vivo of steroid receptor activity and it seems that the presence of a precise subset of coactivators could help define the phenotype of the cell by modulating a specific downstream pathway after steroid receptor activation. The very large number of coactivators and their association into preformed complexes potentially allows the determination of hundreds of different phenotypes. The study of the expression of the coactivator and their function in vivo is required to fully understand steroid action and specificity in the brain. [less ▲]

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See detailEffects of aggressive encounters on plasma corticosteroid-binding globulin and its ligands in white-crowned sparrows.
Charlier, Thierry ULg; Underhill, Caroline; Hammond, Geoffrey L. et al

in Hormones & Behavior (2009), 56(3), 339-47

In birds, corticosteroid-binding globulin (CBG) binds corticosterone, progesterone and testosterone. The concentration of each ligand can alter the binding of the other ligands through competitive ... [more ▼]

In birds, corticosteroid-binding globulin (CBG) binds corticosterone, progesterone and testosterone. The concentration of each ligand can alter the binding of the other ligands through competitive interactions. Thus, an increase in corticosterone or progesterone may displace testosterone bound to CBG, leading to an increase in bioactive free testosterone levels without affecting total testosterone levels in the circulation. Aggressive interactions increase plasma total testosterone levels in some birds but not in others. Here, we tested the hypothesis that aggressive encounters in the late breeding season would not increase total testosterone levels in plasma, but would alter CBG, total corticosterone or total progesterone levels in such a way as to modify the number of available binding sites and therefore occupancy by testosterone. A marked decrease in CBG occupancy by testosterone would indirectly suggest an increase in free testosterone levels in plasma. Wild male white-crowned sparrows were exposed to a simulated territorial intrusion (STI) or control for 30 min. Subjects were then caught and bled. We measured CBG using a ligand-binding assay and corticosterone, progesterone and testosterone using highly sensitive radioimmunoassays. STI significantly increased aggressive behaviors but did not affect plasma total testosterone levels. STI significantly increased plasma CBG and total corticosterone levels and decreased plasma total progesterone levels. We predict that CBG occupancy by corticosterone will increase slightly following an aggressive encounter. However, this small change is unlikely to increase free testosterone levels, because of the large number of seemingly unoccupied CBG binding sites in these subjects. [less ▲]

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See detailWho's in charge? Nuclear receptor coactivator and corepressor function in brain and behavior.
Tetel, M. J.; Auger, A. P.; Charlier, Thierry ULg

in Frontiers in Neuroendocrinology (2009), 30

Steroid hormones act in brain and throughout the body to regulate a variety of functions, including development, reproduction, stress and behavior. Many of these effects of steroid hormones are mediated ... [more ▼]

Steroid hormones act in brain and throughout the body to regulate a variety of functions, including development, reproduction, stress and behavior. Many of these effects of steroid hormones are mediated by their respective receptors, which are members of the steroid/nuclear receptor superfamily of transcriptional activators. A variety of studies in cell lines reveal that nuclear receptor coregulators are critical in modulating steroid receptor-dependent transcription. Thus, in addition to the availability of the hormone and the expression of its receptor, nuclear receptor coregulators are essential for efficient steroid-dependent transactivation of genes. This review will highlight the importance of nuclear receptor coregulators in modulating steroid-dependent gene expression in brain and the regulation of behavior. [less ▲]

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See detailReproductive experience alters corticosterone and CBG levels in the rat dam.
Pawluski, Jodi L; Charlier, Thierry ULg; Lieblich, Stephanie E et al

in Physiology & Behavior (2009), 96(1), 108-14

Reproductive experience has significant effects on the brain, behavior and hormone profiles of the mother. Recent work has demonstrated that primiparous rats exhibit decreased dendritic arborizations in ... [more ▼]

Reproductive experience has significant effects on the brain, behavior and hormone profiles of the mother. Recent work has demonstrated that primiparous rats exhibit decreased dendritic arborizations in the hippocampus, and enhanced hippocampus-dependent spatial memory performance at the time of weaning compared to nulliparous and, to a lesser degree, multiparous rats. Interestingly, enhanced spatial learning and reduced dendritic arbors are seen in nulliparous female rats exposed to chronic stress or repeated corticosterone administration. Based on these observations, we hypothesized that corticosterone may be altered in primiparous rats compared to multiparous and nulliparous rats. The present study investigated whether the levels of circulating corticosterone and its binding protein, corticosteroid binding globulin (CBG), are altered with reproductive experience and pup-exposure during late pregnancy and the postpartum. Total serum corticosterone and CBG were assayed from five groups; multiparous, primiparous, nulliparous, primip-no-pups, and sensitized rats during gestation (days 14 and 19) and the postpartum period (days 1, 5, 14, 21, and 35). Results show that primiparous rats had significantly elevated total corticosterone on postpartum day 1. In addition, primiparous and multiparous rats had significantly lower CBG throughout the postpartum period than all other groups, with primiparous rats exhibiting lower levels than multiparous rats during mid-lactation. These data suggest that free corticosterone is elevated in both primiparous and multiparous dams and is elevated to a greater degree in primiparous compared to multiparous dams during lactation. Corticosterone and CBG levels were positively correlated with specific maternal behaviors during the first week postpartum in parturient rats, but not in sensitized rats, suggesting a role for corticosterone in the modulation of maternal behavior in parturient rats alone. [less ▲]

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See detailModulation of steroid action: Importance of steroid binding globulins
Charlier, Thierry ULg

Scientific conference (2008)

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See detailNeurosteroids, immunosteroids, and the Balkanization of endocrinology.
Schmidt, Kim L; Pradhan, Devaleena S; Shah, Amit H et al

in General and Comparative Endocrinology (2008), 157(3), 266-74

Traditionally, the production and regulation of steroid hormones has been viewed as a multi-organ process involving the hypothalamic-pituitary-gonadal (HPG) axis for sex steroids and the hypothalamic ... [more ▼]

Traditionally, the production and regulation of steroid hormones has been viewed as a multi-organ process involving the hypothalamic-pituitary-gonadal (HPG) axis for sex steroids and the hypothalamic-pituitary-adrenal (HPA) axis for glucocorticoids. However, active steroids can also be synthesized locally in target tissues, either from circulating inactive precursors or de novo from cholesterol. Here, we review recent work demonstrating local steroid synthesis, with an emphasis on steroids synthesized in the brain (neurosteroids) and steroids synthesized in the immune system (immunosteroids). Furthermore, recent evidence suggests that other components of the HPG axis (luteinizing hormone and gonadotropin-releasing hormone) and HPA axis (adrenocorticotropic hormone and corticotropin-releasing hormone) are expressed locally in target tissues, potentially providing a mechanism for local regulation of neurosteroid and immunosteroid synthesis. The balance between systemic and local steroid signals depends critically on life history stage, species adaptations, and the costs of systemic signals. During particular life history stages, there can be a shift from systemic to local steroid signals. We propose that the shift to local synthesis and regulation of steroids within target tissues represents a "Balkanization" of the endocrine system, whereby individual tissues and organs may become capable of autonomously synthesizing and modulating local steroid signals, perhaps independently of the HPG and HPA axes. [less ▲]

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See detailDevelopment of a technique to measure 17β-estradiol in discrete brain regions in zebra finch
Charlier, Thierry ULg; Po, Kelvin WL; Shah, Amit H et al

Poster (2008)

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See detailEffect of aggressive interactions on aromatase activity in discrete brain regions in wild male white-crowned sparrows
Charlier, Thierry ULg; Newman, Amy EM; Soma, Kiran K

Poster (2008)

Testosterone (T) is a critical endocrine factor involved in the activation of aggressive behaviors. In many vertebrate species, circulating T levels rapidly increase after aggressive encounters during the ... [more ▼]

Testosterone (T) is a critical endocrine factor involved in the activation of aggressive behaviors. In many vertebrate species, circulating T levels rapidly increase after aggressive encounters during the breeding season. In contrast, we recently showed that circulating T concentrations did not change in white-crowned sparrows in the late breeding season after simulated territorial intrusions. We suggested that changes in local metabolism of T might be more important than changes in systemic T levels. Neural aromatization of T into 17􀀁-estradiol (E2) often mediates the physiological and behavioral actions of T. In vertebrates, aromatase is expressed in several discrete brain regions. We hypothesized that in the late breeding season, brain aromatase is rapidly modulated after aggressive interaction, leading to changes in local concentrations of E2. Wild male white-crowned sparrows were exposed to simulated territorial intrusion with song playback and decoy (STI) or control (CON) for 30 min. STI significantly increased aggressive behaviors. Birds were then caught, rapidly bled and sacrificed. Brains were collected and rapidly frozen on dry ice. We used 0.9 mm diameter punches from 300 μm coronal sections to isolate 13 different brain nuclei. Aromatase activity was analyzed in punches from the left side of the brain, while E2 was analyzed in punches from the right side of the brain. Aromatase activity was quantified by measuring the release of tritiated water during aromatization of [1􀀁-3H]-androstenedione. As expected, aromatase activity was high in the medial preoptic area, ventromedial nucleus of the hypothalamus, hippocampus, bed nucleus of the stria terminalis, nucleus taeniae of the amygdala, and caudomedial nidopallium. Aromatase activity was low in the medial magnocellular nucleus of anterior nidopallium, HVC, Area X, nucleus robustus of the arcopallium, optic lobes, periaqueductal gray and cerebellum. Aromatase activity was not different between the STI and CON groups in any region. There were no significant correlations between aromatase activity and aggressive behaviors or endocrine measures (plasma T, progesterone, corticosterone and corticosteroid binding globulin). These data provide no evidence for rapid modulation of brain aromatase activity following aggressive interactions. It is however possible that aromatase activity is more rapidly modulated (e.g. within 5 min) and these changes were not observed in our 30 min paradigm. We are currently investigating whether local E2 is affected by aggressive interactions. [less ▲]

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See detaillocalized modulation of testosterone action: Function of steroid receptor coactivators in the brain
Charlier, Thierry ULg; Balthazart, Jacques ULg

in Ardis, L. I. (Ed.) New research on testosterone (2008)

Testosterone, through its activation of androgen and estrogen receptors, has been shown to play a critical role in brain development and physiology. Recent studies have shown that the activity of these ... [more ▼]

Testosterone, through its activation of androgen and estrogen receptors, has been shown to play a critical role in brain development and physiology. Recent studies have shown that the activity of these receptors can be modulated by the interaction with several proteins and, in particular, that coactivators are required to enhance their transcriptional activity. The steroid receptor coactivator-1, SRC-1 is the best-characterized coactivator and we review here the current knowledge on the distribution, regulation of expression and function of this protein in the brain, focusing mostly on our work in Japanese quail. As expected for a ubiquitous coactivator, SRC-1 is present throughout the brain in both mammalian and avian species but is found in particularly high concentrations in testosterone-sensitive areas such as the preoptic area in rat and Japanese quail and in the song control nuclei in songbirds. Further analysis demonstrates that the expression of SRC-1 is not constitutive but regulated in specific brain areas by the sex, acute stress and testosterone treatment. In addition, the protein concentration appears to fluctuate through the day in some brain regions. These modulations of SRC-1 expression by endogenous (sex) and exogenous (stress) factors could potentially exacerbate at specific times the competition or squelching between different nuclear receptors and therefore decrease the biological response induced by one or another hormonal system. Although the existence of such a phenomenon has not yet been demonstrated in a functionally intact biological system, the effects of SRC-1 antisense treatments clearly strengthen this hypothesis. Indeed, the decrease of SRC-1 expression in the hypothalamus induced by antisense oligonucleotide injections clearly inhibited both estrogen-dependent male sexual behavior and androgen-dependent pre- and post-copulatory displays (strut) in Japanese quail, therefore demonstrating a role of the coactivator in the transcriptional activation induced by both estrogen and androgen receptors. Interestingly, the inhibitory effect on sexual behavior of SRC-1 knock down was not systematically associated with modifications of several histological (definition of median preoptic nucleus [POM] using Nissl staining), immunohistochemical (aromatase and vasotocin cells and fibers in the POM) and biochemical (aromatase enzymatic activity) markers of testosterone action in the brain. This dissociation of the effects of SRC-1 on behavior on the one hand and on aromatase and POM neurochemistry on another hand suggests that other system(s) involved in the activation of male sexual behavior are likely more sensitive to a decrease of SRC-1 expression. In future research, it will be essential to determine the other cofactors involved in specific physiological responses and to define whether these coactivators act synergistically, in parallel or independently in the modulation of the activity of one or several nuclear receptors linked to a particular physiological event. In several biological models, the observed changes in concentration of the circulating hormone and /or its receptors are apparently not sufficient to explain the physiological and behavioral responses observed after testosterone treatment. The discovery of steroid receptor coactivators opens new perspectives in the study of the molecular basis of steroid action at the level of the organism and a complete understanding of the mechanisms of steroid action will not be achieved without a detailed characterization of nuclear receptor cofactors. [less ▲]

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See detailNovel mechanisms for neuroendocrine regulation of aggression.
Soma, Kiran K; Scotti, Melissa-Ann L; Newman, Amy E M et al

in Frontiers in Neuroendocrinology (2008), 29(4), 476-89

In 1849, Berthold demonstrated that testicular secretions are necessary for aggressive behavior in roosters. Since then, research on the neuroendocrinology of aggression has been dominated by the paradigm ... [more ▼]

In 1849, Berthold demonstrated that testicular secretions are necessary for aggressive behavior in roosters. Since then, research on the neuroendocrinology of aggression has been dominated by the paradigm that the brain receives gonadal hormones, primarily testosterone, which modulate relevant neural circuits. While this paradigm has been extremely useful, recent studies reveal important alternatives. For example, most vertebrate species are seasonal breeders, and many species show aggression outside of the breeding season, when gonads are regressed and circulating testosterone levels are typically low. Studies in birds and mammals suggest that an adrenal androgen precursor-dehydroepiandrosterone (DHEA)-may be important for the expression of aggression when gonadal testosterone synthesis is low. Circulating DHEA can be metabolized into active sex steroids within the brain. Another possibility is that the brain can autonomously synthesize sex steroids de novo from cholesterol, thereby uncoupling brain steroid levels from circulating steroid levels. These alternative neuroendocrine mechanisms to provide sex steroids to specific neural circuits may have evolved to avoid the "costs" of high circulating testosterone during particular seasons. Physiological indicators of season (e.g., melatonin) may allow animals to switch from one neuroendocrine mechanism to another across the year. Such mechanisms may be important for the control of aggression in many vertebrate species, including humans. [less ▲]

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See detailRapid action on neuroplasticity precedes behavioral activation by testosterone.
Charlier, Thierry ULg; Ball, Gregory F; Balthazart, Jacques ULg

in Hormones & Behavior (2008), 54(4), 488-95

Testosterone has been shown to increase the volume of steroid-sensitive brain nuclei in adulthood in several vertebrate species. In male Japanese quail the volume of the male-biased sexually dimorphic ... [more ▼]

Testosterone has been shown to increase the volume of steroid-sensitive brain nuclei in adulthood in several vertebrate species. In male Japanese quail the volume of the male-biased sexually dimorphic medial preoptic nucleus (POM), a key brain area for the control of male sexual behavior, is markedly increased by testosterone. Previous studies assessed this effect after a period of 8-14 days but the exact time course of these effects is unknown. We asked here whether testosterone-dependent POM plasticity could be observed at shorter latencies. Brains from castrated male quail were collected after 1, 2, 7 and 14 days of T treatment (CX+T) and compared to brains of untreated castrates (CX) collected after 1 or 14 days. POM volumes defined either by Nissl staining or by aromatase immunohistochemistry increased in a time-dependent fashion in CX+T subjects and almost doubled after 14 days of treatment with testosterone while no change was observed in CX birds. A significant increase in the average POM volume was detected after only one day of testosterone treatment. The optical density of Nissl and aromatase staining was also increased after one or two days of testosterone treatment. Activation of male copulatory behavior followed these morphological changes with a latency of approximately one day. This rapid neurochemical and neuroanatomical plasticity observed in the quail POM thus seems to limit the activation of male sexual behavior and offers an excellent model to analyze features of steroid-regulated brain structure and function that determine behavior expression. [less ▲]

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See detailEffect of aggressive encounters on plasma progesterone, corticosterone and corticosteroid binding capacity
Charlier, Thierry ULg; Hammond, Geoffrey L; Soma, Kiran K

Poster (2007)

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See detailRole of coactivators SRC-1 and CARM1 in estrogen receptor-alpha and beta-dependent cell proliferation in the dentate gyrus of adult female rats
Charlier, Thierry ULg; Lieblich, Stephanie E; Pawluski, Jodi L et al

Poster (2007)

Nuclear receptors such as the estrogen receptors (ER) require the presence of coactivator proteins, such as the steroid receptor coactivator (SRC-1) and coactivator-associated arginine methyltransferase ... [more ▼]

Nuclear receptors such as the estrogen receptors (ER) require the presence of coactivator proteins, such as the steroid receptor coactivator (SRC-1) and coactivator-associated arginine methyltransferase (CARM1) to enhance the transcription of target genes. Importantly, in vitro work suggests that ER􀀁 and ER􀀂 differ in the ability to recruit coactivators such as SRC-1. For example, SRC-1 has a strong affinity for ER􀀁 and a weaker affinity for ER􀀂. Interestingly, both ER􀀁 and ER􀀂 are individually involved in estradiol-enhanced cell proliferation in the dentate gyrus of adult female rats. In addition, previous work suggests a role for CARM1 in cell proliferation and for SRC-1 in cell differentiation, therefore the present study aimed to determine whether proliferating cells in the dentate gyrus of the hippocampus co-express the coactivators SRC-1 and CARM1. We also aimed to determine whether ER􀀁 and ER􀀂 agonists would result in altered expression of SRC-1 and CARM1 in new proliferating cells in the dentate gyrus. To investigate this, adult female rats were ovariectomized and treated with either the ER􀀁 agonist Propyl-pyrazole triol (PPT), the ER􀀂 agonist diarylpropionitrile (DPN), estradiol benzoate (EB), or vehicle (CTRL). Rats were then injected with BrdU (200 mg/kg) and sacrificed 24 hours later. Preliminary data suggests that DPN, PPT and EB increase cell proliferation in the dentate gyrus compared to the vehicle-injected group. Interestingly, the number of proliferating cell expressing SRC-1 is similar in all groups, suggesting that neither of the ER agonists nor EB treatment affects the co-expression of BrdU+ cells with SRC-1. However, additional measurements are currently being done to investigate whether CARM-1 is differentially expressed in proliferating cells in the hippocampus following selective ER agonist treatment. [less ▲]

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See detailRapid changes in production and behavioral action of estrogens.
Balthazart, Jacques ULg; Cornil, Charlotte ULg; Taziaux, Mélanie ULg et al

in Neuroscience (2006), 138(3), 783-91

It is well established that sex steroid hormones bind to nuclear receptors, which then act as transcription factors to control brain sexual differentiation and the activation of sexual behaviors ... [more ▼]

It is well established that sex steroid hormones bind to nuclear receptors, which then act as transcription factors to control brain sexual differentiation and the activation of sexual behaviors. Estrogens locally produced in the brain exert their behavioral effects in this way but mounting evidence indicates that estrogens also can influence brain functioning more rapidly via non-genomic mechanisms. We recently reported that, in Japanese quail, the activity of preoptic estrogen synthase (aromatase) can be modulated quite rapidly (within minutes) by non-genomic mechanisms, including calcium-dependent phosphorylations. Behavioral studies further demonstrated that rapid changes in estrogen bioavailability, resulting either from a single injection of a high dose of estradiol or from the acute inhibition of aromatase activity, significantly affect the expression of both appetitive and consummatory aspects of male sexual behavior with latencies ranging between 15 and 30 min. Together these data indicate that the bioavailability of estrogens in the brain can change on different time-scales (long- and short-term) that match well with the genomic and non-genomic actions of this steroid and underlie two complementary mechanisms through which estrogens modulate behavior. Estrogens produced locally in the brain should therefore be considered not only as neuroactive steroids but they also display many (if not all) functional characteristics of neuromodulators and perhaps neurotransmitters. [less ▲]

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