Neuroestrogens in the control of sexual behavior: Past, present, and future

Endocrinology, Diabetes and Metabolism; aromatase; social behavior network; circuit mapping; estrogen synthesis; genomic action; membrane-initiated action

Abstract :

[en] This short review focuses on the mechanisms of action of brain derived estrogens, also called neuroestrogens, on male sexual behavior, one of the best characterized examples of estrogen synthesis/action on behavior. After summarizing the modes of regulation of estrogen synthesis and action in the context of this behavior, we identify questions remaining in our under- standing of how neuroestrogens influence complex behaviors and describe the most recent findings providing a beginning of answers to these questions. These questions relate mostly to the characterization of the circuits formed by aromatase neu- rons, the timing of their regulation and the link between behavior-induced fluctuations in neuronal activity and estrogen synthesis/action. Addressing these questions are key steps to understand how neuroestrogens influence complex behaviors.

Research Center/Unit :

GIGA Neurosciences-Neuroendocrinology - ULiège

Disciplines :

Neurosciences & behavior

Author, co-author :

Cornil, Charlotte ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Neuroendocrinology

Court, Lucas ; Université de Liège - ULiège > GIGA > GIGA Neurosciences - Neuroendocrinology

Language :

English

Title :

Neuroestrogens in the control of sexual behavior: Past, present, and future

Publication date :

June 2022

Journal title :

Current Opinion in Endocrine and Metabolic Research

ISSN :

2451-9650

Publisher :

Elsevier BV

Volume :

Pages :

100334

Peer reviewed :

Peer reviewed

Additional URL :

https://api.elsevier.com/content/article/PII:S2451965022000199?httpAccept=text/xml

Funders :

F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]

Available on ORBi :

since 30 March 2022

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Bibliography

Balthazart, J., Ball, G.F., Brain aromatase, estrogens and behavior. 2013, Oxford University Press.
Balthazart, J., Membrane-initiated actions of sex steroids and reproductive behavior: a historical account. Mol Cell Endocrinol, 538, 2021, 111463.
Brann, D.W., Lu, Y., Wang, J., Zhang, Q., Thakkar, R., Sareddy, G.R., Pratap, U.P., Tekmal, R.R., Vadlamudi, R.K., Brain-derived estrogen and neural function. Neurosci Biobehav Rev 132 (2021), 793–817.
Duncan, K.A., Saldanha, C.J., Central aromatization: a dramatic and responsive defense against threat and trauma to the vertebrate brain. Front Neuroendocrinol, 56, 2020, 100816.
Schlinger, B.A., Remage-Healey, L., Saldanha, C.J., The form, function, and evolutionary significance of neural aromatization. Front Neuroendocrinol, 64, 2021, 100967.
McCarthy, M.M., de Vries, G.J., Forger, N.G., Sexual differentiation of the brain: a fresh look at mode, mechanisms, and meaning, hormones brain and behavior. 2017, Academic Press, 3–32.
Hull, E.M., Rodriguez-Manzo, G., Male sexual behavior. Pfaff, D.W., Joëls, M., (eds.) Hormones, Brain and Behavior, 2017, 1–58.
Terasawa, E., Neuroestradiol in regulation of GnRH release. Horm Behav 104 (2018), 138–145.
Balthazart, J., Steroid metabolism in the brain: from bird watching to molecular biology, a personal journey. Horm Behav 93 (2017), 137–150.
Roselli, C.E., Liu, M., Hurn, P.D., Brain aromatization: classic roles and new perspectives. Semin Reprod Med 27 (2009), 207–217.
Balthazart, J., Baillien, M., Ball, G.F., Rapid and reversible inhibition of brain aromatase activity. BiochemJ 13 (2001), 63–73.
Balthazart, J., Baillien, M., Charlier, T.D., Ball, G.F., Calcium-dependent phosphorylation processes control brain aromatase in quail. Eur J Neurosci 17 (2003), 1591–1606.
Balthazart, J., Baillien, M., Ball, G.F., Rapid control of brain aromatase activity by glutamatergic inputs. Endocrinology 147 (2006), 359–366.
Charlier, T.D., Harada, N., Balthazart, J., Cornil, C.A., Human and quail aromatase activity is rapidly and reversibly inhibited by phosphorylating conditions. Endocrinology 152 (2011), 4199–4210.
Remage-Healey, L., Dong, S., Maidment, N.T., Schlinger, B.A., Presynaptic control of rapid estrogen fluctuations in the songbird auditory forebrain. J Neurosci 31 (2011), 10034–10038.
Cornil, C.A., Leung, C.H., Pletcher, E.R., Naranjo, K.C., Blauman, S.J., Saldanha, C.J., Acute and specific modulation of presynaptic aromatization in the vertebrate brain. Endocrinology 153 (2012), 2562–2567.
Storman, E.M., Liu, N.J., Gintzler, A.R., Relevance of c-Src and protein phosphatase 2A to aromatase activity: evidence of an acute self-regulating oestrogenic signalling complex in rat central nervous system. J Neuroendocrinol, 2022, e13089.
Storman, E.M., Liu, N.J., Wessendorf, M.W., Gintzler, A.R., Physical linkage of estrogen receptor α and aromatase in rat: oligocrine and endocrine actions of CNS-produced estrogens. Endocrinology 159 (2018), 2683–2697.
de Bournonville, C., Dickens, M.J., Ball, G.F., Balthazart, J., Cornil, C.A., Dynamic changes in brain aromatase activity following sexual interactions in males: where, when and why?. Psychoneuroendocrinology 38 (2013), 789–799.
Dickens, M.J., de Bournonville, C., Balthazart, J., Cornil, C.A., Relationships between rapid changes in local aromatase activity and estradiol concentrations in male and female quail brain. Horm Behav 65 (2014), 154–164.
de Bournonville, C., Smolders, I., Van Eeckhaut, A., Ball, G.F., Balthazart, J., Cornil, C.A., Glutamate released in the preoptic area during sexual behavior controls local estrogen synthesis in male quail. Psychoneuroendocrinology 79 (2017), 49–58.
Dominguez, J.M., Gil, M., Hull, E.M., Preoptic glutamate facilitates male sexual behavior. J Neurosci 26 (2006), 1699–1703.
de Bournonville, M.P., de Bournonville, C., Vandries, L.M., Nys, G., Fillet, M., Ball, G.F., Balthazart, J., Cornil, C.A., Rapid changes in brain estrogen concentration during male sexual behavior are site and stimulus specific. Sci Rep, 11, 2021, 20130 Using in vivo microdialysis this study reported rapid (10 min) changes in estrogen extracellular concentration in the POM and BST respectively induced by copulatory behavior and seeing a female. These fastest changes in brain estrogen concentration ever reported demonstrated that transient and spatially restricted changes in estrogen availability occur in behaviorally relevant contexts.
Cornil, C.A., Ball, G.F., Balthazart, J., Differential control of appetitive and consummatory sexual behavior by neuroestrogens in male quail, Hormones and behavior. 2018.
de Bournonville, C., McGrath, A., Remage-Healey, L., Testosterone synthesis in the female songbird brain. Horm Behav, 121, 2020, 104716.
Finkelstein, J.S., Lee, H., Burnett-Bowie, S.A., Pallais, J.C., Yu, E.W., Borges, L.F., Jones, B.F., Barry, C.V., Wulczyn, K.E., Thomas, B.J., Leder, B.Z., Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 369 (2013), 1011–1022.
Court, L., Balthazart, J., Ball, G.F., Cornil, C.A., Effect of chronic intracerebroventricular administration of an aromatase inhibitor on the expression of socio-sexual behaviors in male Japanese quail. Behav Brain Res, 410, 2021, 113315.
Brooks, D.C., Coon, V.J., Ercan, C.M., Xu, X., Dong, H., Levine, J.E., Bulun, S.E., Zhao, H., Brain aromatase and the regulation of sexual activity in male mice. Endocrinology, 161, 2020.
Balthazart, J., Foidart, A., Hendrick, C., The induction by testosterone of aromatase activity in the preoptic area and activation of copulatory behavior. Physiol Behav 47 (1990), 83–94.
Taziaux, M., Cornil, C.A., Balthazart, J., Aromatase inhibition blocks the expression of sexually-motivated cloacal gland movements in male quail. Behav Process 67 (2004), 461–469.
Vagell, M.E., McGinnis, M.Y., The role of aromatization in the restoration of male rat reproductive behavior. J Neuroendocrinol 9 (1997), 415–421.
Roselli, C.E., Cross, E., Poonyagariyagorn, H.K., Stadelman, H.L., Role of aromatization in anticipatory and consummatory aspects of sexual behavior in male rats. Horm Behav 44 (2003), 146–151.
Charlier, T.D., Ball, G.F., Balthazart, J., Inhibition of steroid receptor coactivator-1 blocks estrogen and androgen action on male sex behavior and associated brain plasticity. J Neurosci 25 (2005), 906–913.
Niessen, N.A., Balthazart, J., Ball, G.F., Charlier, T.D., Steroid receptor coactivator 2 modulates steroid-dependent male sexual behavior and neuroplasticity in Japanese quail (Coturnix japonica). J Neurochem 119 (2011), 579–593.
Cornil, C.A., Ball, G.F., Balthazart, J., Rapid control of male typical behaviors by brain-derived estrogens. Front Neuroendocrinol 33 (2012), 425–446.
Seredynski, A.L., Balthazart, J., Ball, G.F., Cornil, C.A., Estrogen receptor beta activation rapidly modulates male sexual motivation through the transactivation of metabotropic glutamate receptor 1a. J Neurosci 35 (2015), 13110–13123.
Seredynski, A.L., Balthazart, J., Christophe, V.J., Ball, G.F., Cornil, C.A., Neuroestrogens rapidly regulate sexual motivation but not performance. J Neurosci 33 (2013), 164–174.
Wersinger, S.R., Sannen, K., Villalba, C., Lubahn, D.B., Rissman, E.F., De Vries, G.J., Masculine sexual behavior is disrupted in male and female mice lacking a functional estrogen receptor alpha gene. Horm Behav 32 (1997), 176–183.
Sano, K., Tsuda, M.C., Musatov, S., Sakamoto, T., Ogawa, S., Differential effects of site-specific knockdown of estrogen receptor α in the medial amygdala, medial pre-optic area, and ventromedial nucleus of the hypothalamus on sexual and aggressive behavior of male mice. Eur J Neurosci 37 (2013), 1308–1319.
Musatov, S., Chen, W., Pfaff, D.W., Kaplitt, M.G., Ogawa, S., RNAi-mediated silencing of estrogen receptor {alpha} in the ventromedial nucleus of hypothalamus abolishes female sexual behaviors. Proc Natl Acad Sci USA 103 (2006), 10456–10460.
Ogawa, S., Tsukahara, S., Choleris, E., Vasudevan, N., Estrogenic regulation of social behavior and sexually dimorphic brain formation. Neurosci Biobehav Rev 110 (2020), 46–59.
Khbouz, B., de Bournonville, C., Court, L., Taziaux, M., Corona, R., Arnal, J.F., Lenfant, F., Cornil, C.A., Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain. Eur J Neurosci 52 (2019), 2627–2645 A mouse model invalidated for ERα palmitoylation (ERα C451A), which prevents membrane ERα (mERα) signaling but conserves nuclear actions, reveals a role for mERα in brain sexual differentiation in males. Reduced numbers of preoptic calbindin neurons and increased numbers of kisspeptin neurons are observed in males, while there is no change in these numbers in females. Mutated males also show reduced sexual behavior demonstrating that mERα is involved in the perinatal programming of the male brain.
Hawley, W.R., Battista, C., Divack, S.R., Morales Núñez, N.B., The role of estrogen G-protein coupled receptor 30 (GPR30) and sexual experience in sexual incentive motivation in male rats. Physiol Behav 177 (2017), 176–181.
Balthazart, J., Ball, G.F., Is brain estradiol a hormone or a neurotransmitter?. Trends Neurosci 29 (2006), 241–249.
Biegon, A., In vivo visualization of aromatase in animals and humans. Front Neuroendocrinol 40 (2016), 42–51.
Foidart, A., Reid, J., Absil, P., Yoshimura, N., Harada, N., Balthazart, J., Critical re-examination of the distribution of aromatase-immunoreactive cells in the quail forebrain using antibodies raised against human placental aromatase and against the recombinant quail, mouse or human enzyme. JChemNeuroanat 8 (1995), 267–282.
Wu, M.V., Manoli, D.S., Fraser, E.J., Coats, J.K., Tollkuhn, J., Honda, S.I., Harada, N., Shah, N.M., Estrogen masculinizes neural pathways and sex-specific behaviors. Cell 139 (2009), 61–72.
Stanic, D., Dubois, S., Chua, H.K., Tonge, B., Rinehart, N., Horne, M.K., Boon, W.C., Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors alpha and beta, and androgen receptors. PLoS One, 9, 2014, e90451.
O'Connell, L.A., Hofmann, H.A., The vertebrate mesolimbic reward system and social behavior network: a comparative synthesis. J Comp Neurol 519 (2011), 3599–3639.
Watson, J.T., Adkins-Regan, E., Testosterone implanted in the preoptic area of male Japanese quail must be aromatized to activate copulation. HormBehav 23 (1989), 432–447.
de Bournonville, M.P., Vandries, L.M., Ball, G.F., Balthazart, J., Cornil, C.A., Site-specific effects of aromatase inhibition on the activation of male sexual behavior in male Japanese quail (Coturnix japonica). Horm Behav 108 (2019), 42–49.
Clancy, A.N., Zumpe, D., Michael, R.P., Intracerebral infusion of an aromatase inhibitor, sexual behavior and brain estrogen receptor-like immunoreactivity in intact male rats. Neuroendocrinology 61 (1995), 98–111.
Russell, N.V., Ogaga-Mgbonyebi, E.V., Habteab, B., Dunigan, A.I., Tesfay, M.A., Clancy, A.N., Sexual responses of the male rat medial preoptic area and medial amygdala to estrogen II: site specific effects of selective estrogenic drugs. Horm Behav 62 (2012), 58–66.
Huddleston, G.G., Michael, R.P., Zumpe, D., Clancy, A.N., Estradiol in the male rat amygdala facilitates mounting but not ejaculation. Physiol Behav 79 (2003), 239–246.
Unger, E.K., Burke, K.J. Jr., Yang, C.F., Bender, K.J., Fuller, P.M., Shah, N.M., Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 10 (2015), 453–462.
Bayless, D.W., Yang, T., Mason, M.M., Susanto, A.A.T., Lobdell, A., Shah, N.M., Limbic neurons shape sex recognition and social behavior in sexually naive males. Cell 176 (2019), 1190–1205 e20 This study demonstrates that aromatase neurons of the bed nucleus of the stria terminalis are active during sexual encounters and that ablating or disrupting their activity impairs both the preference for female pheromones and sexual behavior.
Spool, J.A., Bergan, J.F., Remage-Healey, L., A neural circuit perspective on brain aromatase. Front Neuroendocrinol, 65, 2021, 100973.
Balthazart, J., Panzica, G.C., Krohmer, R.W., Anatomical relationships between aromatase-immunoreactive neurons and nitric oxide synthase as evidenced by NOS immunohistochemistry or NADPH diaphorase histochemistry in the quail forebrain. J Chem Neuroanat 25 (2003), 39–51.
Balthazart, J., Absil, P., Identification of catecholaminergic inputs to and outputs from aromatase-containing brain areas of the Japanese quail by tract tracing combined with tyrosine hydroxylase immunocytochemistry. J Comp Neurol 382 (1997), 401–428.
Balthazart, J., Absil, P., Viglietti-Panzica, C., Panzica, G.C., Vasotocinergic innervation of areas containing aromatase-immunoreactive cells in the quail forebrain. J Neurobiol 33 (1997), 45–60.
Balthazart, J., Foidart, A., Baillien, M., Harada, N., Ball, G.F., Anatomical relationship between aromatase and tyrosine hydroxylase in the quail brain: double-label immunocytochemical studies. J Comp Neurol 391 (1998), 214–226.
Absil, P., Riters, L., Balthazart, J., Preoptic aromatase cells project to the mesencephalic central gray in the male Japanese quail (Coturnix japonica). Horm Behav 40 (2001), 369–383.
Carere, C., Ball, G.F., Balthazart, J., Sex differences in projections from preoptic area aromatase cells to the periaqueductal gray in Japanese quail. J Comp Neurol 500 (2007), 894–907.
Michael, V., Goffinet, J., Pearson, J., Wang, F., Tschida, K., Mooney, R., Circuit and synaptic organization of forebrain-to-midbrain pathways that promote and suppress vocalization. Elife, 9, 2020 Using trans-synaptic tract-tracing and an activity-dependent labeling strategy this study identified two populations of inhibitory neurons projecting to the periaqueductal gray (PAG) with opposing roles in the production of ultrasonic vocalization, one of which lies in the preoptic area, is estrogen sensitive and its activation elicits USVs.
Cornil, C.A., Ball, G.F., Balthazart, J., Sexually differentiated and neuroanatomically specific co-expression of aromatase neurons and GAD67 in the male and female quail brain. Eur J Neurosci 52 (2020), 2963–2981.
Ikeda, M.Z., Krentzel, A.A., Oliver, T.J., Scarpa, G.B., Remage-Healey, L., Clustered organization and region-specific identities of estrogen-producing neurons in the forebrain of Zebra Finches (Taeniopygia guttata). J Comp Neurol 525 (2017), 3636–3652 This study identified a clustered-organization of aromatase neurons in the zebra finch auditory cortex and a key region of the song system. This suggests the ability for a coordinated regulation of estrogen synthesis possibly through gap junction. This study also indicated that aromatase neurons in the auditory cortex, the hippocampus and selected regions of the song system express calbindin a marker of inhibitory interneurons.
Moffitt, J.R., Bambah-Mukku, D., Eichhorn, S.W., Vaughn, E., Shekhar, K., Perez, J.D., Rubinstein, N.D., Hao, J., Regev, A., Dulac, C., Zhuang, X., Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region. Science (New York, NY), 362, 2018 This study mapped the molecular heterogeneity and spatial organization of the preoptic hypothalamic area. It identified different clusters of aromatase neurons. Most clusters express androgen receptors, while the expression of estrogen and progesterone receptors is more variable.
Billing, A., Henrique Correia, M., Kelly, D.A., Li, G.L., Bergan, J.F., Synaptic connections of aromatase circuits in the medial amygdala are sex specific. eNeuro, 7, 2020 This study identified sexually different inputs from the anterior accessory olfactory bulb to aromatase neurons of the medial amygdala (MeA). Moreover as previously suggested in bird species, MeA neurons show very similar electrophysiological properties as non-aromatase neurons with the exception that they respond to stimulation by producing more action potentials. No sex difference in electrophysiological activity was found.
Inbar, T., Davis, R., Bergan, J.F., A sex-specific feedback projection from aromatase-expressing neurons in the medial amygdala to the accessory olfactory bulb. J Comp Neurol 530 (2021), 648–655 This study identified two new populations of aromatase neurons: one is specific to the accessory olfactory bulb and the other is estrogen sensitive, located in the ventral medial amygdala sending projections to the AOB and exhibits a sex difference in neuronal number and size (Male > Female).
Cornil, C.A., On the role of brain aromatase in females: why are estrogens produced locally when they are available systemically?. J Comp Physiol A Sens Neural Behav Physiol 204 (2018), 31–49.
Wit, J.M., Hero, M., Nunez, S.B., Aromatase inhibitors in pediatrics, Nature reviews. Endocrinology 8 (2011), 135–147.
Gervais, N.J., Remage-Healey, L., Starrett, J.R., Pollak, D.J., Mong, J.A., Lacreuse, A., Adverse effects of aromatase inhibition on the brain and behavior in a nonhuman primate. J Neurosci 39 (2019), 918–928.
Alia-Klein, N., Preston-Campbell, R.N., Kim, S.W., Pareto, D., Logan, J., Wang, G.J., Moeller, S.J., Fowler, J.S., Biegon, A., Human cognitive ability is modulated by aromatase availability in the brain in a sex-specific manner. Front Neurosci, 14, 2020, 565668.
Biegon, A., Alia-Klein, N., Alexoff, D.L., Fowler, J.S., Kim, S.W., Logan, J., Pareto, D., Preston-Campbell, R., Wang, G.J., Hildebrandt, T., Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women. Proc Natl Acad Sci USA 117 (2020), 22962–22966.
Konkle, A.T., McCarthy, M.M., Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152 (2011), 223–235.
Amateau, S.K., McCarthy, M.M., Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat Neurosci 7 (2004), 643–650.
Mong, J.A., Nuñez, J.L., McCarthy, M.M., GABA mediates steroid-induced astrocyte differentiation in the neonatal rat hypothalamus. J Neuroendocrinol 14 (2002), 45–55.
Tsukahara, S., Sex differences and the roles of sex steroids in apoptosis of sexually dimorphic nuclei of the preoptic area in postnatal rats. J Neuroendocrinol 21 (2009), 370–376.
Schwarz, J.M., Liang, S.L., Thompson, S.M., McCarthy, M.M., Estradiol induces hypothalamic dendritic spines by enhancing glutamate release: a mechanism for organizational sex differences. Neuron 58 (2008), 584–598.
Wartenberg, P., Farkas, I., Csillag, V., Colledge, W.H., Hrabovszky, E., Boehm, U., Sexually dimorphic neurosteroid synthesis regulates neuronal activity in the murine brain. J Neurosci 41 (2021), 9177–9191 This study demonstrated an aromatase neuronal network of around 6000 neurons and its relationship with ERα in developping male and female mice and identified an acute effect of neuroestrogens on the activity of kisspeptin neurons of the arcuate nucleus.
Balthazart, J., New concepts in the study of the sexual differentiation and activation of reproductive behavior, a personal view. Front Neuroendocrinol, 55, 2019, 100785.
Court, L., Vandries, L., Balthazart, J., Cornil, C.A., Key role of estrogen receptor β in the organization of brain and behavior of the Japanese quail. Horm Behav, 125, 2020, 104827.
Bakker, J., The role of steroid hormones in the sexual differentiation of the human brain. J Neuroendocrinol, 2021, e13050.
Cornil, C.A., Ball, G.F., Balthazart, J., The dual action of estrogen hypothesis. Trends Neurosci 38 (2015), 408–416.