Estrogen Receptor β Activation Rapidly Modulates Male Sexual Motivation through the Transactivation of Metabotropic Glutamate Receptor 1a
; Balthazart, Jacques ; et al
in Journal of Neuroscience (2015), 35(38), 13110-23
In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes ... [more ▼]
In addition to the transcriptional activity of their liganded nuclear receptors, estrogens, such as estradiol (E2), modulate cell functions, and consequently physiology and behavior, within minutes through membrane-initiated events. The membrane-associated receptors (mERs) underlying the acute effects of estrogens on behavior have mostly been documented in females where active estrogens are thought to be of ovarian origin. We determined here, by acute intracerebroventricular injections of specific agonists and antagonists, the type(s) of mERs that modulate rapid effects of brain-derived estrogens on sexual motivation in male Japanese quail. Brain aromatase blockade acutely inhibited sexual motivation. Diarylpropionitrile (DPN), an estrogen receptor β (ERβ)-specific agonist, and to a lesser extent 17α-estradiol, possibly acting through ER-X, prevented this effect. In contrast, drugs targeting ERα (PPT and MPP), GPR30 (G1 and G15), and the Gq-mER (STX) did not affect sexual motivation. The mGluR1a antagonist LY367385 significantly inhibited sexual motivation but mGluR2/3 and mGluR5 antagonists were ineffective. LY367385 also blocked the behavioral restoration induced by E2 or DPN, providing functional evidence that ERβ interacts with metabotropic glutamate receptor 1a (mGluR1a) signaling to acutely regulate male sexual motivation. Together these results show that ERβ plays a key role in sexual behavior regulation and the recently uncovered cooperation between mERs and mGluRs is functional in males where it mediates the acute effects of estrogens produced centrally in response to social stimuli. The presence of an ER-mGluR interaction in birds suggests that this mechanism emerged relatively early in vertebrate history and is well conserved. Significance statement: The membrane-associated receptors underlying the acute effects of estrogens on behavior have mostly been documented in females, where active estrogens are thought to be of ovarian origin. Using acute intracerebroventricular injections of specific agonists and antagonists following blockade of brain aromatase, we show here that brain-derived estrogens acutely facilitate male sexual motivation through the activation of estrogen receptor β interacting with the metabotropic glutamate receptor 1a. This behavioral effect occurring within minutes provides a mechanistic explanation of how an estrogen receptor not intrinsically coupled to intracellular effectors can signal from the membrane to govern behavior in a very rapid fashion. It suggests that different subtypes of estrogen receptors could regulate the motivation versus performance aspects of behavior. [less ▲]Detailed reference viewed: 23 (5 ULg)
The dual action of estrogen hypothesis
Cornil, Charlotte ; ; Balthazart, Jacques
in Trends in Neurosciences (2015), 38(7), 408-16
Estradiol (E2) can act in the brain in a relatively fast manner (i.e., seconds to minutes) usually through signaling initiated at the cell membrane. Brain-derived E2 has thus been considered as another ... [more ▼]
Estradiol (E2) can act in the brain in a relatively fast manner (i.e., seconds to minutes) usually through signaling initiated at the cell membrane. Brain-derived E2 has thus been considered as another type of neurotransmitter. Recent work found that behaviors indicative of male sexual motivation are activated by estrogenic metabolites of testosterone (T) in a fast manner, while sexual performance (copulatory behavior per se) is regulated by brain E2 in a slower manner via nucleus-initiated actions. This functional division between these two types of action appears to generalize to other behavioral systems regulated by E2. We propose the dual action of estrogen hypothesis to explain this functional distinction between these two different modes of action. [less ▲]Detailed reference viewed: 33 (0 ULg)
Local modulation of steroid action: rapid control of enzymatic activity.
; Cornil, Charlotte ; et al
in Frontiers in neuroscience (2015), 9
Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects ... [more ▼]
Estrogens can induce rapid, short-lived physiological and behavioral responses, in addition to their slow, but long-term, effects at the transcriptional level. To be functionally relevant, these effects should be associated with rapid modulations of estrogens concentrations. 17beta-estradiol is synthesized by the enzyme aromatase, using testosterone as a substrate, but can also be degraded into catechol-estrogens via hydroxylation by the same enzyme, leading to an increase or decrease in estrogens concentration, respectively. The first evidence that aromatase activity (AA) can be rapidly modulated came from experiments performed in Japanese quail hypothalamus homogenates. This rapid modulation is triggered by calcium-dependent phosphorylations and was confirmed in other tissues and species. The mechanisms controlling the phosphorylation status, the targeted amino acid residues and the reversibility seem to vary depending of the tissues and is discussed in this review. We currently do not know whether the phosphorylation of the same amino acid affects both aromatase and/or hydroxylase activities or whether these residues are different. 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: 142 (1 ULg)
Anatomically discrete sex differences in neuroplasticity in zebra finches as reflected by perineuronal nets.
; ; Cornil, Charlotte et al
in PloS one (2015), 10(4), 0123199
Large morphological sex differences in the vertebrate brain were initially identified in song control nuclei of oscines. Besides gross differences between volumes of nuclei in males and females, sex ... [more ▼]
Large morphological sex differences in the vertebrate brain were initially identified in song control nuclei of oscines. Besides gross differences between volumes of nuclei in males and females, sex differences also concern the size and dendritic arborization of neurons and various neurochemical markers, such as the calcium-binding protein parvalbumin (PV). Perineuronal nets (PNN) of the extracellular matrix are aggregates of different compounds, mainly chondroitin sulfate proteoglycans, that surround subsets of neurons, often expressing PV. PNN develop in zebra finches song control nuclei around the end of the sensitive period for song learning and tutor deprivation, known to delay the end of the song learning sensitive period, decreases the numbers of PNN in HVC. We demonstrate here the existence in zebra finches of a major sex difference (males > females) affecting the number of PNN (especially those surrounding PV-positive cells) in HVC and to a smaller extent the robust nucleus of the arcopallium, RA, the two main nuclei controlling song production. These differences were not present in Area X and LMAN, the lateral magnocellular nucleus of the anterior nidopallium. A dense expression of material immunoreactive for chondroitin sulfate was also detected in several nuclei of the auditory and visual pathways. This material was often organized in perineuronal rings but quantification of these PNN did not reveal any sex difference with the exception that the percentage of PNN surrounding PV-ir cells in the dorsal lateral mesencephalic nucleus, MLd, was larger in females than in males, a sex difference in the opposite direction compared to what is seen in HVC and RA. These data confirm and extend previous studies demonstrating the sex difference affecting PNN in HVC-RA by showing that this sex difference is anatomically specific and does not concern visual or auditory pathways. [less ▲]Detailed reference viewed: 31 (1 ULg)
Mate selection, Sexual orientation and Pair bonding
Balthazart, Jacques ;
in Plant, Tony M.; Zelenik, Anthony J. (Eds.) Knobil and Neill's Physiology of Reproduction (2015)Detailed reference viewed: 102 (0 ULg)
Reversing song behavior phenotype: Testosterone driven induction of singing and measures of song quality in adult male and female canaries (Serinus canaria)
; ; Balthazart, Jacques et al
in General and comparative endocrinology (2015), 215
In songbirds, such as canaries (Serinus canaria), the song control circuit has been shown to undergo a remarkable change in morphology in response to exogenous testosterone (T). It is also well ... [more ▼]
In songbirds, such as canaries (Serinus canaria), the song control circuit has been shown to undergo a remarkable change in morphology in response to exogenous testosterone (T). It is also well established that HVC, a telencephalic nucleus involved in song production, is significantly larger in males than in females. T regulates seasonal changes in HVC volume in males, and exposure to exogenous T in adult females increases HVC volume and singing activity such that their song becomes more male-like in frequency and structure. However, whether there are sex differences in the ability of T to modulate changes in the song system and song behavior has not been investigated in canaries. In this study, we compared the effects of increasing doses of T on singing and song control nuclei volumes in adult male and female American Singer canaries exposed to identical environmental conditions. Males were castrated and all birds were placed on short days (8L:16D) for 8weeks. Males and females were implanted either with a 2, 6 or 12mm long Silastic implant filled with crystalline T or an empty 12mm implant as control. Birds were then housed individually in sound-attenuated chambers. Brains were collected from six birds from each group after 1week or 3weeks of treatment. Testosterone was not equally effective in increasing singing activity in both males and females. Changes in song quality and occurrence rate took place after a shorter latency in males than in females; however, females did undergo marked changes in a number of measures of song behavior if given sufficient time. Males responded with an increase in HVC volume at all three doses. In females, T-induced changes in HVC volume only had limited amplitude and these volumes never reached male-typical levels, suggesting that there are sex differences in the neural substrate that responds to T. [less ▲]Detailed reference viewed: 17 (3 ULg)
Male song quality modulates c-Fos expression in the auditory forebrain of the female canary.
; ; et al
in Physiology & behavior (2015), 147
In canaries, specific phrases of male song (sexy songs, SS) that are difficult to produce are especially attractive for females. Females exposed to SS produce more copulation displays and deposit more ... [more ▼]
In canaries, specific phrases of male song (sexy songs, SS) that are difficult to produce are especially attractive for females. Females exposed to SS produce more copulation displays and deposit more testosterone into their eggs than females exposed to non-sexy songs (NS). Increased expression of the immediate early genes c-Fos or zenk (a.k.a. egr-1) has been observed in the auditory forebrain of female songbirds hearing attractive songs. C-Fos immunoreactive (Fos-ir) cell numbers were quantified here in the brain of female canaries that had been collected 30min after they had been exposed for 60min to the playback of SS or NS or control white noise. Fos-ir cell numbers increased in the caudomedial mesopallium (CMM) and caudomedial nidopallium (NCM) of SS birds as compared to controls. Song playback (pooled SS and NS) also tended to increase average Fos-ir cell numbers in the mediobasal hypothalamus (MBH) but this effect did not reach full statistical significance. At the individual level, Fos expression in CMM was correlated with its expression in NCM and in MBH but also with the frequency of calls that females produced in response to the playbacks. These data thus indicate that male songs of different qualities induce a differential metabolic activation of NCM and CMM. The correlation between activation of auditory regions and of the MBH might reflect the link between auditory stimulation and changes in behavior and reproductive physiology. [less ▲]Detailed reference viewed: 17 (0 ULg)
Seasonal changes in the neuroendocrine system: Introduction to the special issue.
; Balthazart, Jacques
in Frontiers in neuroendocrinology (2015), 37Detailed reference viewed: 13 (2 ULg)
Glutamate controls brain estrogen synthesis during sexual interactions
de Bournonville, Catherine ; ; et al
Poster (2014, November 17)
Besides their long-lasting effects mediated by a modulation of gene transcription, brain-derived estrogens can rapidly regulate (within minutes) reproductive behaviors. In vitro, the activity of aromatase ... [more ▼]
Besides their long-lasting effects mediated by a modulation of gene transcription, brain-derived estrogens can rapidly regulate (within minutes) reproductive behaviors. In vitro, the activity of aromatase (AA), the enzyme responsible for the conversion of androgens into estrogens, is also regulated on a similar short time-scale, via phosphorylation of the enzyme resulting from changes in neuronal activity or glutamate release. Acute changes in AA have been documented ex vivo in specific brain regions following exposure to social or stressful stimuli but the mechanism underlying these regulations is not known. To investigate whether glutamate is implicated in these rapid changes in AA, male quail received a unilateral injection of kainate in the medial preoptic nucleus (POM). The left and right preoptic areas were collected 20 min later and assayed separately by the tritiated water technique for AA. As shown previously in preoptic explants maintained in vitro, AA was downregulated in the kainate-injected hemisphere as compared to the non-injected side. To determine whether the decline in AA detected in the POM after a sexual interaction could be mediated by an increased release of glutamate in this region, extracellular glutamate concentration was measured by in vivo microdialysis with a probe implanted in the POM of sexually mature males. Dialysate was collected every 3 minutes over three periods of 15 min when the male was (1) alone, (2) allowed to freely copulate with a female and (3) alone again. A transient rise in extracellular glutamate concentration was observed specifically and immediately after the expression of cloacal contact movements, when semen is transferred to the female. Glutamate returned to a basal level after the female was removed. Together, these results indicate that the mechanism of acute regulation of aromatase activity by glutamate identified in vitro is potentially responsible for the acute regulation of the enzyme observed in vivo following copulation. As rapid changes in brain estrogen synthesis and its actions are apparently related to the control of sexual motivation rather than sexual performance, follow up experiments should now determine whether the release of glutamate in the POM occurs in parallel with an increase in motivation or follows the termination of the copulatory sequence. [less ▲]Detailed reference viewed: 59 (3 ULg)
Age-dependent and age-independent effects of testosterone in male quail
Cornil, Charlotte ; ; de Bournonville, Catherine et al
in General and Comparative Endocrinology (2014), 208C
Various studies in rodents recently concluded that puberty should be considered as a second period of organization of brain and behavior and that action of sex steroids at that time is long lasting and ... [more ▼]
Various studies in rodents recently concluded that puberty should be considered as a second period of organization of brain and behavior and that action of sex steroids at that time is long lasting and possibly permanent. We tested this notion in male Japanese quail that had been castrated before 3 weeks post- hatch by analyzing whether a similar treatment with exogenous testosterone initiated at 3, 5 or 7 weeks post-hatch has a differential influence on the development of testosterone-dependent morphological, behavioral and neural characteristics that are known to be sexually differentiated. The growth of the androgen-dependent cloacal gland was significantly faster when testosterone treatment was initiated later in life indicating that the target tissue is not ready to fully respond to androgens at 3 weeks post- hatch. The three groups of birds nevertheless developed a gland of the same size typical of intact sexually mature birds. When adults, all birds expressed copulatory behavior with the same frequencies and laten- cies and they displayed the same level of aromatase activity and of vasotocinergic innervation in the pre- optic area as gonadally intact males despite the fact that they had been treated with testosterone for different durations starting at different ages. Surprisingly, the frequency of cloacal sphincter contractions, a measure of appetitive sexual behavior, was significantly higher when testosterone treatment had been initiated later. Together these data provide no clear evidence for an organizational action of testosterone during sexual maturation of male quail but additional experiments should investigate whether estrogens have such an action in females. [less ▲]Detailed reference viewed: 21 (7 ULg)
Is it useful to view the brain as a secondary sexual characteristic?
; Balthazart, Jacques ;
in Neuroscience and biobehavioral reviews (2014), 46 Pt 4
Many sex differences in brain and behavior related to reproduction are thought to have evolved based on sexual selection involving direct competition for mates during male-male competition and female ... [more ▼]
Many sex differences in brain and behavior related to reproduction are thought to have evolved based on sexual selection involving direct competition for mates during male-male competition and female choice. Therefore, certain aspects of brain circuitry can be viewed as secondary sexual characteristics. The study of proximate causes reveals that sex differences in the brain of mammals and birds reflect organizational and activational effects of sex steroids as articulated by Young and collaborators. However, sex differences in brain and behavior have been identified in the cognitive domain with no obvious link to reproduction. Recent views of sexual selection advocate for a broader view of how intra-sexual selection might occur including such examples as competition within female populations for resources that facilitate access to mates rather than mating competition per se. Sex differences can also come about for other reasons than sexual selection and recent work on neuroendocrine mechanisms has identified a plethora of ways that the brain can develop in a sex specific manner. Identifying the brain as sexually selected requires careful hypothesis testing so that one can link a sex-biased aspect of a neural trait to a behavior that provides an advantage in a competitive mating situation. [less ▲]Detailed reference viewed: 14 (2 ULg)
Reprint of: Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich et al.
; Balthazart, Jacques ; et al
in Hormones and behavior (2014)Detailed reference viewed: 11 (2 ULg)
Endogenous versus exogenous markers of adult neurogenesis in canaries and other birds: advantages and disadvantages.
Balthazart, Jacques ;
in The Journal of comparative neurology (2014), 522(18), 4100-20
Although the existence of newborn neurons had originally been suggested, but not broadly accepted, based on studies in adult rodent brains, the presence of an active neurogenesis process in adult ... [more ▼]
Although the existence of newborn neurons had originally been suggested, but not broadly accepted, based on studies in adult rodent brains, the presence of an active neurogenesis process in adult homoeothermic vertebrates was first firmly established in songbirds. Adult neurogenesis was initially studied with the tritiated thymidine technique, later replaced by the injection and detection of the marker of DNA replication 5-bromo-2'-deoxyuridine (BrdU). More recently, various endogenous markers were used to identify young neurons or cycling neuronal progenitors. We review here the respective advantages and pitfalls of these different approaches in birds, with specific reference to the microtubule-associated protein, doublecortin (DCX), that has been extensively used to identify young newly born neurons in adult brains. All these techniques of course have limitations. Exogenous markers label cells replicating their DNA only during a brief period and it is difficult to select injection doses that would exhaustively label all these cells without inducing DNA damage that will also result in some form of labeling during repair. On the other hand, specificity of endogenous markers is difficult to establish due to problems related to the specificity of antibodies (these problems can be, but are not always, addressed) and more importantly because it is difficult, if not impossible, to prove that a given marker exhaustively and specifically labels a given cell population. Despite these potential limitations, these endogenous markers and DCX staining in particular clearly represent a useful approach to the detailed study of neurogenesis especially when combined with other techniques such as BrdU. [less ▲]Detailed reference viewed: 9 (1 ULg)
Doublecortin is a highly valuable endogenous marker of adult neurogenesis in canaries. Commentary on Vellema M et al. (2014): Evaluating the predictive value of doublecortin as a marker for adult neurogenesis in canaries (Serinus canaria) . J Comparative Neurol 522:1299-1315.
Balthazart, Jacques ;
in Brain, behavior and evolution (2014), 84(1), 1-4Detailed reference viewed: 13 (2 ULg)
Dissociable effects of social context on song and doublecortin immunoreactivity in male canaries.
; ; et al
in The European journal of neuroscience (2014), 40(6), 2941-7
Variation in environmental factors such as day length and social context greatly affects reproductive behavior and the brain areas that regulate these behaviors. One such behavior is song in songbirds ... [more ▼]
Variation in environmental factors such as day length and social context greatly affects reproductive behavior and the brain areas that regulate these behaviors. One such behavior is song in songbirds, which males use to attract a mate during the breeding season. In these species the absence of a potential mate leads to an increase in the number of songs produced, while the presence of a mate greatly diminishes singing. Interestingly, although long days promote song behavior, producing song itself can promote the incorporation of new neurons in brain regions controlling song output. Social context can also affect such neuroplasticity in these song control nuclei. The goal of the present study was to investigate in canaries (Serinus canaria), a songbird species, how photoperiod and social context affect song and the incorporation of new neurons, as measured by the microtubule-associated protein doublecortin (DCX) in HVC, a key vocal production brain region of the song control system. We show that long days increased HVC size and singing activity. In addition, male canaries paired with a female for 2 weeks showed enhanced DCX-immunoreactivity in HVC relative to birds housed alone. Strikingly, however, paired males sang fewer songs that exhibited a reduction in acoustic features such as song complexity and energy, compared with birds housed alone, which sang prolifically. These results show that social presence plays a significant role in the regulation of neural and behavioral plasticity in songbirds and can exert these effects in opposition to what might be expected based on activity-induced neurogenesis. [less ▲]Detailed reference viewed: 13 (1 ULg)
Fos expression in monoaminergic cell groups in response to sociosexual interactions in male and female Japanese quail.
; ; Balthazart, Jacques et al
in Behavioral neuroscience (2014), 128(1), 48-60
Monoaminergic neurotransmitters regulate different components of sexual behaviors, but how the different monoaminergic cell groups selectively regulate these behaviors is not well understood. We examined ... [more ▼]
Monoaminergic neurotransmitters regulate different components of sexual behaviors, but how the different monoaminergic cell groups selectively regulate these behaviors is not well understood. We examined the potential contribution of these different cell groups in the control of different aspects of sexual behaviors in male and female quail. We used double-label immunohistochemistry, labeling the protein product of the immediate early gene, Fos, along with tyrosine hydroxylase (TH) or tryptophan hydroxylase (TPH), markers for catecholaminergic or indolaminergic cells, respectively. Rhythmic Cloacal Sphincter Movements (RCSM) were recorded as a measure of male appetitive sexual behavior. Consummatory sexual behaviors were evaluated based on the species-typical copulation sequence. Enhanced Fos expression in the medial preoptic nucleus and bed nucleus of the stria terminalis was observed in association with both physical and visual contact to the opposite sex for males, but not for females. Fos induction associated with physical contact was observed in the ventral tegmental area and anterior periaqueductal gray in both sexes. In males only, the number of Fos-immunoreactive (ir) cells increased in the visual contact condition in these 2 dopaminergic cell groups, however no significant effect was observed for double-labeled TH-Fos-ir cells. In addition, consummatory but not appetitive sexual behavior increased Fos expression in TPH-ir cells in the raphe pallidus of males. This increase following physical but not visual contact agrees with the notion that activation of the serotoninergic system is implicated in the development of sexual satiation but not activated by simply viewing a female, in contrast to the dopaminergic system. [less ▲]Detailed reference viewed: 15 (1 ULg)
Relationships between rapid changes in local aromatase activity and estradiol concentrations in male and female quail brain.
; de Bournonville, Catherine ; Balthazart, Jacques et al
in Hormones and behavior (2014), 65(2), 154-164
Estradiol-17beta (E2) synthesized in the brain plays a critical role in the activation of sexual behavior in many vertebrate species. Because E2 concentrations depend on aromatization of testosterone ... [more ▼]
Estradiol-17beta (E2) synthesized in the brain plays a critical role in the activation of sexual behavior in many vertebrate species. Because E2 concentrations depend on aromatization of testosterone, changes in aromatase enzymatic activity (AA) are often utilized as a proxy to describe E2 concentrations. Utilizing two types of stimuli (sexual interactions and acute restraint stress) that have been demonstrated to reliably alter AA within minutes in opposite directions (sexual interactions=decrease, stress=increase), we tested in Japanese quail whether rapid changes in AA are paralleled by changes in E2 concentrations in discrete brain areas. In males, E2 in the pooled medial preoptic nucleus/medial portion of the bed nucleus of the stria terminalis (POM/BST) positively correlated with AA following sexual interactions. However, following acute stress, E2 decreased significantly (approximately 2-fold) in the male POM/BST despite a significant increase in AA. In females, AA positively correlated with E2 in both the POM/BST and mediobasal hypothalamus supporting a role for local, as opposed to ovarian, production regulating brain E2 concentrations. In addition, correlations of individual E2 in POM/BST and measurements of female sexual behavior suggested a role for local E2 synthesis in female receptivity. These data demonstrate that local E2 in the male brain changes in response to stimuli on a time course suggestive of potential non-genomic effects on brain and behavior. Overall, this study highlights the complex mechanisms regulating local E2 concentrations including rapid stimulus-driven changes in production and stress-induced changes in catabolism. [less ▲]Detailed reference viewed: 22 (7 ULg)
The sexual behavior induced-inhibition of aromatase activity in the preoptic nucleus is mediated by glutamate release.
de Bournonville, Catherine ; ; et al
Poster (2014)Detailed reference viewed: 22 (2 ULg)
Involvement of estrogens in the control of female sexual motivation and receptivity
de Bournonville, Catherine ; ; Balthazart, Jacques et al
Poster (2014)Detailed reference viewed: 14 (1 ULg)
Policy decisions on endocrine disruptors should be based on science across disciplines: A response to Dietrich, et al.
; Balthazart, Jacques ; et al
in Frontiers in neuroendocrinology (2014), 35(1), 2-5Detailed reference viewed: 14 (7 ULg)