Abstract
The modulation of brain function and behavior by steroid hormones was classically associated with their secretion by peripheral endocrine glands. The discovery that the brain expresses the enzyme aromatase, which produces estradiol from testosterone, expanded this traditional concept. One of the best-studied roles of brain estradiol synthesis is the control of reproductive behavior. In addition, there is increasing evidence that estradiol from neural origin is also involved in a variety of non-reproductive functions. These include the regulation of neurogenesis, neuronal development, synaptic transmission, and plasticity in brain regions not directly related with the control of reproduction. Central aromatase is also involved in the modulation of cognition, mood, and non-reproductive behaviors. Furthermore, under pathological conditions aromatase is upregulated in the central nervous system. This upregulation represents a neuroprotective and likely also a reparative response by increasing local estradiol levels in order to maintain the homeostasis of the neural tissue. In this paper, we review the non-reproductive functions of neural aromatase and neural-derived estradiol under physiological and pathological conditions. We also consider the existence of sex differences in the role of the enzyme in both contexts.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abdelgadir SE, Roselli CE, Choate JV, Resko JA (1997) Distribution of aromatase cytochrome P450 messenger ribonucleic acid in adult rhesus monkey brains. Biol Reprod 57:772–777
Alward BA, de Bournonville C, Chan TT et al (2016) Aromatase inhibition rapidly affects in a reversible manner distinct features of birdsong. Sci Rep 6:32344. https://doi.org/10.1038/srep32344
Arevalo MA, Azcoitia I, Garcia-Segura LM (2015) The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci 16:17–29. https://doi.org/10.1038/nrn3856
Azcoitia I, Sierra A, Veiga S et al (2001) Brain aromatase is neuroprotective. J Neurobiol 47(4):318–329. https://doi.org/10.1002/neu.1038
Azcoitia I, Sierra A, Veiga S, Garcia-Segura LM (2003) Aromatase expression by reactive astroglia is neuroprotective. Ann N Y Acad Sci 1007:298–305
Azcoitia I, Yague JG, Garcia-Segura LM (2011) Estradiol synthesis within the human brain. Neuroscience 191:139–147. https://doi.org/10.1016/j.neuroscience.2011.02.012
Azcoitia I, Arevalo MA, Garcia-Segura LM (2018) Neural-derived estradiol regulates brain plasticity. J Chem Neuroanat 89:53–59. https://doi.org/10.1016/j.jchemneu.2017.04.004
Bailey DJ, Ma C, Soma KK, Saldanha CJ (2013) Inhibition of hippocampal aromatization impairs spatial memory performance in a male songbird. Endocrinology 154:4707–4714. https://doi.org/10.1210/en.2013-1684
Bailey DJ, Makeyeva YV, Paitel ER et al (2017) Hippocampal aromatization modulates spatial memory and characteristics of the synaptic membrane in the male zebra finch. Endocrinology 158:852–859. https://doi.org/10.1210/en.2016-1692
Balthazart J, Ball GF (2006) Is brain estradiol a hormone or a neurotransmitter? Trends Neurosci 29:241–249. https://doi.org/10.1016/j.tins.2006.03.004
Balthazart J, Foidart A, Harada N (1990) Immunocytochemical localization of aromatase in the brain. Brain Res 514:327–333
Balthazart J, Foidart A, Surlemont C, Harada N (1991) Distribution of aromatase-immunoreactive cells in the mouse forebrain. Cell Tissue Res 263:71–79
Balthazart J, Baillien M, Ball GF (2002) Interactions between aromatase (estrogen synthase) and dopamine in the control of male sexual behavior in quail. Comp Biochem Physiol B Biochem Mol Biol 132:37–55
Balthazart J, Baillien M, Charlier TD et al (2003) The neuroendocrinology of reproductive behavior in Japanese quail. Domest Anim Endocrinol 25:69–82
Barakat R, Oakley O, Kim H et al (2016) Extra-gonadal sites of estrogen biosynthesis and function. BMB Rep 49:488–496. https://doi.org/10.5483/BMBRep.2016.49.9.141
Bayer J, Rune G, Schultz H et al (2015) The effect of estrogen synthesis inhibition on hippocampal memory. Psychoneuroendocrinology 56:213–225. https://doi.org/10.1016/j.psyneuen.2015.03.011
Bender RA, Zhou L, Vierk R et al (2017) Sex-dependent regulation of aromatase-mediated synaptic plasticity in the basolateral amygdala. J Neurosci 37:1532–1545. https://doi.org/10.1523/JNEUROSCI.1532-16.2016
Beyer C (1999) Estrogen and the developing mammalian brain. Anat Embryol (Berl) 199:379–390
Bian C, Zhu K, Guo Q et al (2012) Sex differences and synchronous development of steroid receptor coactivator-1 and synaptic proteins in the hippocampus of postnatal female and male C57BL/6 mice. Steroids 77:149–156. https://doi.org/10.1016/j.steroids.2011.11.002
Biegon A (2016) In vivo visualization of aromatase in animals and humans. Front Neuroendocrinol 40:42–51. https://doi.org/10.1016/j.yfrne.2015.10.001
Biegon A, Kim SW, Alexoff DL et al (2010) Unique distribution of aromatase in the human brain: in vivo studies with PET and [N-methyl-11C]vorozole. Synapse 64:801–807. https://doi.org/10.1002/syn.20791
Borbélyová V, Domonkos E, Csongová M et al (2017) Sex-dependent effects of letrozole on anxiety in middle-aged rats. Clin Exp Pharmacol Physiol 44(Suppl 1):93–98. https://doi.org/10.1111/1440-1681.12731
Bowers JM, Waddell J, McCarthy MM (2010) A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol. Biol Sex Differ 1:8. https://doi.org/10.1186/2042-6410-1-8
Brandt N, Vierk R, Rune GM (2013) Sexual dimorphism in estrogen-induced synaptogenesis in the adult hippocampus. Int J Dev Biol 57:351–356. https://doi.org/10.1387/ijdb.120217gr
Burul-Bozkurt N, Pekiner C, Kelicen P (2010) Diabetes alters aromatase enzyme levels in sciatic nerve and hippocampus tissues of rats. Cell Mol Neurobiol 30:445–451. https://doi.org/10.1007/s10571-009-9469-0
Cambiasso MJ, Cisternas CD, Ruiz-Palmero I et al (2017) Interaction of sex chromosome complement, gonadal hormones and neuronal steroid synthesis on the sexual differentiation of mammalian neurons. J Neurogenet 31:300–306. https://doi.org/10.1080/01677063.2017.1390572
Carrier N, Saland SK, Duclot F et al (2015) The anxiolytic and antidepressant-like effects of testosterone and estrogen in gonadectomized male rats. Biol Psychiatry 78:259–269. https://doi.org/10.1016/j.biopsych.2014.12.024
Carswell HV, Dominiczak AF, Garcia-Segura LM et al (2005) Brain aromatase expression after experimental stroke: topography and time course. J Steroid Biochem Mol Biol 96:89–91. https://doi.org/10.1016/j.jsbmb.2005.02.016
Chamniansawat S, Chongthammakun S (2012) A priming role of local estrogen on exogenous estrogen-mediated synaptic plasticity and neuroprotection. Exp Mol Med 44:403–411. https://doi.org/10.3858/emm.2012.44.6.046
Cisternas CD, Tome K, Caeiro XE et al (2015) Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain. Mol Cell Endocrinol 414:99–110. https://doi.org/10.1016/j.mce.2015.07.027
Coumailleau P, Kah O (2014) Cyp19a1 (aromatase) expression in the Xenopus brain at different developmental stages. J Neuroendocrinol 26:226–236. https://doi.org/10.1111/jne.12142
Coumailleau P, Pellegrini E, Adrio F et al (2015) Aromatase, estrogen receptors and brain development in fish and amphibians. Biochim Biophys Acta 1849:152–162. https://doi.org/10.1016/j.bbagrm.2014.07.002
Dalla C, Antoniou K, Papadopoulou-Daifoti Z et al (2004) Oestrogen-deficient female aromatase knockout (ArKO) mice exhibit depressive-like symptomatology. Eur J Neurosci 20:217–228. https://doi.org/10.1111/j.1460-9568.2004.03443.x
Dalla C, Antoniou K, Papadopoulou-Daifoti Z et al (2005) Male aromatase-knockout mice exhibit normal levels of activity, anxiety and “depressive-like” symptomatology. Behav Brain Res 163:186–193. https://doi.org/10.1016/j.bbr.2005.04.020
de Bournonville C, Smolders I, Van Eeckhaut A et al (2017) Glutamate released in the preoptic area during sexual behavior controls local estrogen synthesis in male quail. Psychoneuroendocrinology 79:49–58. https://doi.org/10.1016/j.psyneuen.2017.02.002
De Groof G, Balthazart J, Cornil CA, Van der Linden A (2017) Topography and lateralized effect of acute aromatase inhibition on auditory processing in a seasonal songbird. J Neurosci 37:4243–4254. https://doi.org/10.1523/JNEUROSCI.1961-16.2017
Di Mauro M, Tozzi A, Calabresi P et al (2017) Different synaptic stimulation patterns influence the local androgenic and estrogenic neurosteroid availability triggering hippocampal synaptic plasticity in the male rat. Eur J Neurosci 45:499–509. https://doi.org/10.1111/ejn.13455
Dieni CV, Ferraresi A, Sullivan JA et al (2018) Acute inhibition of estradiol synthesis impacts vestibulo-ocular reflex adaptation and cerebellar long-term potentiation in male rats. Brain Struct Funct 223:837–850. https://doi.org/10.1007/s00429-017-1514-z
Diotel N, Le Page Y, Mouriec K et al (2010) Aromatase in the brain of teleost fish: expression, regulation and putative functions. Front Neuroendocrinol 31:172–192. https://doi.org/10.1016/j.yfrne.2010.01.003
Duncan KA, Saldanha CJ (2011) Neuroinflammation induces glial aromatase expression in the uninjured songbird brain. J Neuroinflammation 8:81. https://doi.org/10.1186/1742-2094-8-81
Evrard HC, Harada N, Balthazart J (2004) Immunocytochemical localization of aromatase in sensory and integrating nuclei of the hindbrain in Japanese quail (Coturnix japonica). J Comp Neurol 473:194–212. https://doi.org/10.1002/cne.20068
Fester L, Rune GM (2015) Sexual neurosteroids and synaptic plasticity in the hippocampus. Brain Res 1621:162–169. https://doi.org/10.1016/j.brainres.2014.10.033
Fester L, Ribeiro-Gouveia V, Prange-Kiel J et al (2006) Proliferation and apoptosis of hippocampal granule cells require local oestrogen synthesis. J Neurochem 97:1136–1144. https://doi.org/10.1111/j.1471-4159.2006.03809.x
Fester L, Zhou L, Ossig C et al (2017) Synaptopodin is regulated by aromatase activity. J Neurochem 140:126–139. https://doi.org/10.1111/jnc.13889
Foidart A, Balthazart J (1995) Sexual differentiation of brain and behavior in quail and zebra finches: studies with a new aromatase inhibitor, R76713. J Steroid Biochem Mol Biol 53:267–275
Forlano PM, Deitcher DL, Myers DA, Bass AH (2001) Anatomical distribution and cellular basis for high levels of aromatase activity in the brain of teleost fish: aromatase enzyme and mRNA expression identify glia as source. J Neurosci 21:8943–8955. https://doi.org/10.1523/JNEUROSCI.21-22-08943.2001
Frick KM, Tuscher JJ, Koss WA et al (2018) Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females. Physiol Behav 187:57–66. https://doi.org/10.1016/j.physbeh.2017.07.028
Gao P, Ding X-W, Dong L et al (2017) Expression of aromatase in the rostral ventromedial medulla and its role in the regulation of visceral pain. CNS Neurosci Ther 23:980–989. https://doi.org/10.1111/cns.12769
Garcia-Segura LM (2008) Aromatase in the brain: not just for reproduction anymore. J Neuroendocrinol 20:705–712. https://doi.org/10.1111/j.1365-2826.2008.01713.x
Garcia-Segura LM, Wozniak A, Azcoitia I et al (1999) Aromatase expression by astrocytes after brain injury: implications for local estrogen formation in brain repair. Neuroscience 89:567–578
Garcia-Segura LM, Veiga S, Sierra A et al (2003) Aromatase: a neuroprotective enzyme. Prog Neurobiol 71(1):31–41. https://doi.org/10.1016/j.pneurobio.2003.09.005
Gelinas D, Callard GV (1997) Immunolocalization of aromatase- and androgen receptor-positive neurons in the goldfish brain. Gen Comp Endocrinol 106:155–168. https://doi.org/10.1006/gcen.1997.6891
Ghorbanpoor S, Garcia-Segura LM, Haeri-Rohani A et al (2014) Aromatase inhibition exacerbates pain and reactive gliosis in the dorsal horn of the spinal cord of female rats caused by spinothalamic tract injury. Endocrinology 155:4341–4355. https://doi.org/10.1210/en.2014-1158
Graham BM, Milad MR (2014) Inhibition of estradiol synthesis impairs fear extinction in male rats. Learn Mem 21(7):347–350. https://doi.org/10.1101/lm.034926.114
Grassi S, Frondaroli A, Dieni C et al (2009) Long-term potentiation in the rat medial vestibular nuclei depends on locally synthesized 17beta-estradiol. J Neurosci 29:10779–10783. https://doi.org/10.1523/JNEUROSCI.1697-09.2009
Grassi S, Tozzi A, Costa C et al (2011) Neural 17β-estradiol facilitates long-term potentiation in the hippocampal CA1 region. Neuroscience 192:67–73. https://doi.org/10.1016/j.neuroscience.2011.06.078
Hajszan T, MacLusky NJ, Leranth C (2004) Dehydroepiandrosterone increases hippocampal spine synapse density in ovariectomized female rats. Endocrinology 145:1042–1045. https://doi.org/10.1210/en.2003-1252
Hedges VL, Chen G, Yu L et al (2018) Local estrogen synthesis regulates parallel fiber-Purkinje cell neurotransmission within the cerebellar cortex. Endocrinology 159:1328–1338. https://doi.org/10.1210/en.2018-00039
Hill RA, Pompolo S, Jones MEE et al (2004) Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice. Mol Cell Neurosci 27:466–476. https://doi.org/10.1016/j.mcn.2004.04.012
Hill RA, McInnes KJ, Gong ECH et al (2007) Estrogen deficient male mice develop compulsive behavior. Biol Psychiatry 61:359–366. https://doi.org/10.1016/j.biopsych.2006.01.012
Hill RA, Chua HK, Jones MEE et al (2009) Estrogen deficiency results in apoptosis in the frontal cortex of adult female aromatase knockout mice. Mol Cell Neurosci 41:1–7. https://doi.org/10.1016/j.mcn.2008.12.009
Hoffman JF, Wright CL, McCarthy MM (2016) A critical period in Purkinje cell development is mediated by local estradiol synthesis, disrupted by inflammation, and has enduring consequences only for males. J Neurosci 36:10039–10049. https://doi.org/10.1523/JNEUROSCI.1262-16.2016
Hojo Y, Hattori T-A, Enami T et al (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci U S A 101:865–870. https://doi.org/10.1073/pnas.2630225100
Hojo Y, Higo S, Ishii H et al (2009) Comparison between hippocampus-synthesized and circulation-derived sex steroids in the hippocampus. Endocrinology 150:5106–5112. https://doi.org/10.1210/en.2009-0305
Hutchison JB (1997) Gender-specific steroid metabolism in neural differentiation. Cell Mol Neurobiol 17:603–626
Ikeda MZ, Krentzel AA, Oliver TJ et al (2017) Clustered organization and region-specific identities of estrogen-producing neurons in the forebrain of Zebra Finches (Taeniopygia guttata). J Comp Neurol 525:3636–3652. https://doi.org/10.1002/cne.24292
Ishunina TA, van Beurden D, van der Meulen G et al (2005) Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer’s disease. Neurobiol Aging 26:173–194. https://doi.org/10.1016/j.neurobiolaging.2004.03.010
Iwabuchi J, Wako S, Tanaka T et al (2007) Analysis of the p450 aromatase gene expression in the Xenopus brain and gonad. J Steroid Biochem Mol Biol 107:149–155. https://doi.org/10.1016/j.jsbmb.2007.01.007
Kato A, Hojo Y, Higo S et al (2013) Female hippocampal estrogens have a significant correlation with cyclic fluctuation of hippocampal spines. Front Neural Circuits 7:149. https://doi.org/10.3389/fncir.2013.00149
Kokras N, Pastromas N, Papasava D et al (2018) Sex differences in behavioral and neurochemical effects of gonadectomy and aromatase inhibition in rats. Psychoneuroendocrinology 87:93–107. https://doi.org/10.1016/j.psyneuen.2017.10.007
Konkle ATM, McCarthy MM (2011) Developmental time course of estradiol, testosterone, and dihydrotestosterone levels in discrete regions of male and female rat brain. Endocrinology 152:223–235. https://doi.org/10.1210/en.2010-0607
Kretz O, Fester L, Wehrenberg U et al (2004) Hippocampal synapses depend on hippocampal estrogen synthesis. J Neurosci 24:5913–5921. https://doi.org/10.1523/JNEUROSCI.5186-03.2004
Kriegstein A, Alvarez-Buylla A (2009) The glial nature of embryonic and adult neural stem cells. Annu Rev Neurosci 32:149–184. https://doi.org/10.1146/annurev.neuro.051508.135600
Le Page Y, Diotel N, Vaillant C et al (2010) Aromatase, brain sexualization and plasticity: the fish paradigm. Eur J Neurosci 32:2105–2115. https://doi.org/10.1111/j.1460-9568.2010.07519.x
Leranth C, Hajszan T, MacLusky NJ (2004) Androgens increase spine synapse density in the CA1 hippocampal subfield of ovariectomized female rats. J Neurosci 24:495–499. https://doi.org/10.1523/JNEUROSCI.4516-03.2004
Li R, He P, Staufenbiel M, Harada N, Shen Y (2013) Brain endogenous estrogen levels determine responses to estrogen replacement therapy via regulation of BACE1 and NEP in female Alzheimer’s transgenic mice. Mol Neurobiol 47:857–867. https://doi.org/10.1007/s12035-012-8377-3
Liu M, Hurn PD, Roselli CE, Alkayed NJ (2007) Role of P450 aromatase in sex-specific astrocytic cell death. J Cereb Blood Flow Metab 27:135–141. https://doi.org/10.1038/sj.jcbfm.9600331
Liu M, Oyarzabal EA, Yang R et al (2008) A novel method for assessing sex-specific and genotype-specific response to injury in astrocyte culture. J Neurosci Methods 171:214–217. https://doi.org/10.1016/j.jneumeth.2008.03.002
Liu M, Huangfu X, Zhao Y et al (2015) Steroid receptor coactivator-1 mediates letrozole induced downregulation of postsynaptic protein PSD-95 in the hippocampus of adult female rats. J Steroid Biochem Mol Biol 154:168–175. https://doi.org/10.1016/j.jsbmb.2015.07.011
Liu NJ, Murugaiyan V, Storman EM et al (2017) Estrogens synthesized and acting within a spinal oligomer suppress spinal endomorphin 2 antinociception: ebb and flow over the rat reproductive cycle. Pain 158:1903–1914. https://doi.org/10.1097/j.pain.0000000000000991
Luchetti S, Bossers K, Van de Bilt S et al (2011) Neurosteroid biosynthetic pathways changes in prefrontal cortex in Alzheimer’s disease. Neurobiol Aging 32:1964–1976. https://doi.org/10.1016/j.neurobiolaging.2009.12.014
Luchetti S, van Eden CG, Schuurman K et al (2014) Gender differences in multiple sclerosis: induction of estrogen signaling in male and progesterone signaling in female lesions. J Neuropathol Exp Neurol 73:123–135. https://doi.org/10.1097/NEN.0000000000000037
Martínez-Cerdeño V, Noctor SC, Kriegstein AR (2006) Estradiol stimulates progenitor cell division in the ventricular and subventricular zones of the embryonic neocortex. Eur J Neurosci 24:3475–3488. https://doi.org/10.1111/j.1460-9568.2006.05239.x
Mehos CJ, Nelson LH, Saldanha CJ (2016) A Quantification of the injury-induced changes in central aromatase, oestrogenic milieu and steroid receptor expression in the Zebra finch. J Neuroendocrinol 28:12348. https://doi.org/10.1111/jne.12348
Moradpour F, Naghdi N, Fathollahi Y (2006) Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats. Behav Brain Res 175:223–232. https://doi.org/10.1016/j.bbr.2006.08.037
Moraga-Amaro R, van Waarde A, Doorduin J, de Vries EFJ (2018) Sex steroid hormones and brain function: PET imaging as a tool for research. J Neuroendocrinol 30:e12565. https://doi.org/10.1111/jne.12565
Mouriec K, Pellegrini E, Anglade I et al (2008) Synthesis of estrogens in progenitor cells of adult fish brain: evolutive novelty or exaggeration of a more general mechanism implicating estrogens in neurogenesis? Brain Res Bull 75:274–280. https://doi.org/10.1016/j.brainresbull.2007.10.030
Mouriec K, Lareyre JJ, Tong SK et al (2009) Early regulation of brain aromatase (cyp19a1b) by estrogen receptors during zebrafish development. Dev Dyn 238:2641–2651. https://doi.org/10.1002/dvdy.22069
Mukai H, Tsurugizawa T, Ogiue-Ikeda M et al (2006) Local neurosteroid production in the hippocampus: influence on synaptic plasticity of memory. Neuroendocrinology 84:255–263. https://doi.org/10.1159/000097747
Naftolin F, MacLusky NJ (1982) Aromatase in the central nervous system. Cancer Res 42:3274 s–3276 s
Naftolin F, Ryan KJ, Petro Z (1971) Aromatization of androstenedione by limbic system tissue from human foetuses. J Endocrinol 51:795–796
Naftolin F, Ryan KJ, Petro Z (1972) Aromatization of androstenedione by the anterior hypothalamus of adult male and female rats. Endocrinology 90:295–298. https://doi.org/10.1210/endo-90-1-295
Naftolin F, Horvath TL, Jakab RL et al (1996a) Aromatase immunoreactivity in axon terminals of the vertebrate brain. An immunocytochemical study on quail, rat, monkey and human tissues. Neuroendocrinology 63:149–155. https://doi.org/10.1159/000126951
Naftolin F, Horvath TL, Jakab RL, Leranth C, Harada N, Balthazart J (1996b) Aromatase immunoreactivity in axon terminals of the vertebrate brain. An immunocytochemical study on quail, rat, monkey and human tissues. Neuroendocrinology 63:149–155. https://doi.org/10.1159/000126951
Nelson BS, Black KL, Daniel JM (2016) Circulating estradiol regulates brain-derived estradiol via actions at GnRH receptors to impact memory in ovariectomized rats. eNeuro. https://doi.org/10.1523/ENEURO.0321-16.2016
Pedersen AL, Saldanha CJ (2017) Reciprocal interactions between prostaglandin E2- and estradiol-dependent signaling pathways in the injured zebra finch brain. J Neuroinflammation 14:262. https://doi.org/10.1186/s12974-017-1040-1
Pedersen AL, Brownrout JL, Saldanha CJ (2018) Neuroinflammation and neurosteroidogenesis: reciprocal modulation during injury to the adult zebra finch brain. Physiol Behav 187:51–56. https://doi.org/10.1016/j.physbeh.2017.10.013
Pellegrini E, Mouriec K, Anglade I et al (2007) Identification of aromatase-positive radial glial cells as progenitor cells in the ventricular layer of the forebrain in zebrafish. J Comp Neurol 501:150–167. https://doi.org/10.1002/cne.21222
Peterson RS, Saldanha CJ, Schlinger BA (2001) Rapid upregulation of aromatase mRNA and protein following neural injury in the zebra finch (Taeniopygia guttata). J Neuroendocrinol 13:317–323
Peterson RS, Lee DW, Fernando G, Schlinger BA (2004) Radial glia express aromatase in the injured zebra finch brain. J Comp Neurol 475:261–269. https://doi.org/10.1002/cne.20157
Peterson RS, Yarram L, Schlinger BA, Saldanha CJ (2005) Aromatase is pre-synaptic and sexually dimorphic in the adult zebra finch brain. Proc Biol Sci 272:2089–2096. https://doi.org/10.1098/rspb.2005.3181
Pietranera L, Bellini MJ, Arévalo MA et al (2011) Increased aromatase expression in the hippocampus of spontaneously hypertensive rats: effects of estradiol administration. Neuroscience 174:151–159. https://doi.org/10.1016/j.neuroscience.2010.11.044
Prange-Kiel J, Wehrenberg U, Jarry H, Rune GM (2003) Para/autocrine regulation of estrogen receptors in hippocampal neurons. Hippocampus 13:226–234. https://doi.org/10.1002/hipo.10075
Remage-Healey L, Maidment NT, Schlinger BA (2008) Forebrain steroid levels fluctuate rapidly during social interactions. Nat Neurosci 11:1327–1334. https://doi.org/10.1038/nn.2200
Rohmann KN, Schlinger BA, Saldanha CJ (2007) Subcellular compartmentalization of aromatase is sexually dimorphic in the adult zebra finch brain. Dev Neurobiol 67:1–9. https://doi.org/10.1002/dneu.20303
Roselli CE, Resko JA (1987) The distribution and regulation of aromatase activity in the central nervous system. Steroids 50:495–508
Roselli CE, Horton LE, Resko JA (1985) Distribution and regulation of aromatase activity in the rat hypothalamus and limbic system. Endocrinology 117:2471–2477. https://doi.org/10.1210/endo-117-6-2471
Roselli CE, Abdelgadir SE, Resko JA (1997) Regulation of aromatase gene expression in the adult rat brain. Brain Res Bull 44:351–357
Rudolph LM, Cornil CA, Mittelman-Smith MA et al (2016) Actions of steroids: new neurotransmitters. J Neurosci 36:11449–11458. https://doi.org/10.1523/JNEUROSCI.2473-16.2016
Ruiz-Palmero I, Ortiz-Rodriguez A, Melcangi RC et al (2016) Oestradiol synthesized by female neurons generates sex differences in neuritogenesis. Sci Rep 6:31891. https://doi.org/10.1038/srep31891
Saldanha CJ, Rohmann KN, Coomaralingam L, Wynne RD (2005) Estrogen provision by reactive glia decreases apoptosis in the zebra finch (Taeniopygia guttata). J Neurobiol 64:192–201. https://doi.org/10.1002/neu.20147
Saldanha CJ, Remage-Healey L, Schlinger BA (2011) Synaptocrine signaling: steroid synthesis and action at the synapse. Endocr Rev 32:532–549. https://doi.org/10.1210/er.2011-0004
Sasano H, Takashashi K, Satoh F et al (1998) Aromatase in the human central nervous system. Clin Endocrinol (Oxf) 48:325–329
Scarduzio M, Panichi R, Pettorossi VE, Grassi S (2013) Synaptic long-term potentiation and depression in the rat medial vestibular nuclei depend on neural activation of estrogenic and androgenic signals. PloS ONE 8:e80792. https://doi.org/10.1371/journal.pone.0080792
Schaeffer V, Meyer L, Patte-Mensah C et al (2010) Sciatic nerve injury induces apoptosis of dorsal root ganglion satellite glial cells and selectively modifies neurosteroidogenesis in sensory neurons. Glia 58:169–180. https://doi.org/10.1002/glia.20910
Simpson E, Rubin G, Clyne C et al (1999) Local estrogen biosynthesis in males and females. Endocr Relat Cancer 6:131–137
Stanić D, Dubois S, Chua HK et al (2014) Characterization of aromatase expression in the adult male and female mouse brain. I. Coexistence with oestrogen receptors α and β, and androgen receptors. PloS ONE 9:e90451. https://doi.org/10.1371/journal.pone.0090451
Stoffel-Wagner B, Watzka M, Schramm J et al (1999) Expression of CYP19 (aromatase) mRNA in different areas of the human brain. J Steroid Biochem Mol Biol 70:237–241
Storman EM, Liu NJ, Wessendorf MW, Gintzler AR (2018) Physical linkage of estrogen receptor α and aromatase in rat: oligocrine and endocrine actions of CNS-produced estrogens. Endocrinology 159:2683–2697. https://doi.org/10.1210/en.2018-00319
Strobl-Mazzulla PH, Nuñez A, Pellegrini E et al (2010) Progenitor radial cells and neurogenesis in pejerrey fish forebrain. Brain Behav Evol 76:20–31. https://doi.org/10.1159/000316022
Sun C, Liu Y, Liu Y et al (2017) Characterization of aromatase expression in the spinal cord of an animal model of familial ALS. Brain Res Bull 132:180–189. https://doi.org/10.1016/j.brainresbull.2017.05.016
Tanaka M, Sokabe M (2012) Continuous de novo synthesis of neurosteroids is required for normal synaptic transmission and plasticity in the dentate gyrus of the rat hippocampus. Neuropharmacology 62:2373–2387. https://doi.org/10.1016/j.neuropharm.2012.02.007
Tozzi A, de Iure A, Tantucci M et al (2015) Endogenous 17β-estradiol is required for activity-dependent long-term potentiation in the striatum: interaction with the dopaminergic system. Front Cell Neurosci 9:192. https://doi.org/10.3389/fncel.2015.00192
Tran M, Kuhn JA, Bráz JM, Basbaum AI (2017) Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn. J Comp Neurol 525:3414–3428. https://doi.org/10.1002/cne.24269
Tuscher JJ, Szinte JS, Starrett JR et al (2016) Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice. Horm Behav 83:60–67. https://doi.org/10.1016/j.yhbeh.2016.05.001
Unger EK, Burke KJ, Yang CF et al (2015) Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep 10:453–462. https://doi.org/10.1016/j.celrep.2014.12.040
Vahaba DM, Remage-Healey L (2018) Neuroestrogens rapidly shape auditory circuits to support communication learning and perception: evidence from songbirds. Horm Behav https://doi.org/10.1016/j.yhbeh.2018.03.007
van den Buuse M, Simpson ER, Jones MEE (2003) Prepulse inhibition of acoustic startle in aromatase knock-out mice: effects of age and gender. Genes Brain Behav 2:93–102
Van der Linden A, Balthazart J (2018) Rapid changes in auditory processing in songbirds following acute aromatase inhibition as assessed by fMRI. Horm Behav. https://doi.org/10.1016/j.yhbeh.2018.03.011
Vierk R, Glassmeier G, Zhou L et al (2012) Aromatase inhibition abolishes LTP generation in female but not in male mice. J Neurosci 32:8116–8126. https://doi.org/10.1523/JNEUROSCI.5319-11.2012
Wade J (2001) Zebra finch sexual differentiation: the aromatization hypothesis revisited. Microsc Res Tech 54:354–363. https://doi.org/10.1002/jemt.1148
Yague JG, Muñoz A, de Monasterio-Schrader P et al (2006) Aromatase expression in the human temporal cortex. Neuroscience 138:389–401. https://doi.org/10.1016/j.neuroscience.2005.11.054
Yague JG, Wang AC-J, Janssen WGM et al (2008) Aromatase distribution in the monkey temporal neocortex and hippocampus. Brain Res 1209:115–127. https://doi.org/10.1016/j.brainres.2008.02.061
Yague JG, Azcoitia I, DeFelipe J et al (2010) Aromatase expression in the normal and epileptic human hippocampus. Brain Res 1315:41–52. https://doi.org/10.1016/j.brainres.2009.09.111
Yuen EY, Wei J, Yan Z (2016) Estrogen in prefrontal cortex blocks stress-induced cognitive impairments in female rats. J Steroid Biochem Mol Biol 160:221–226. https://doi.org/10.1016/j.jsbmb.2015.08.028
Zhang QG, Wang R, Tang H et al (2014) Brain-derived estrogen exerts anti-inflammatory and neuroprotective actions in the rat hippocampus. Mol Cell Endocrinol 389:84–91. https://doi.org/10.1016/j.mce.2013.12.019
Zhang Z-L, Qin P, Liu Y et al (2017) Alleviation of ischaemia-reperfusion injury by endogenous estrogen involves maintaining Bcl-2 expression via the ERα signalling pathway. Brain Res 1661:15–23. https://doi.org/10.1016/j.brainres.2017.02.004
Zhao Y, He L, Zhang Y et al (2017) Estrogen receptor alpha and beta regulate actin polymerization and spatial memory through an SRC-1/mTORC2-dependent pathway in the hippocampus of female mice. J Steroid Biochem Mol Biol 174:96–113. https://doi.org/10.1016/j.jsbmb.2017.08.003
Zhou L, Fester L, von Blittersdorff B et al (2010) Aromatase inhibitors induce spine synapse loss in the hippocampus of ovariectomized mice. Endocrinology 151:1153–1160. https://doi.org/10.1210/en.2009-0254
Zuloaga KL, Davis CM, Zhang W, Alkayed NJ (2014) Role of aromatase in sex-specific cerebrovascular endothelial function in mice. Am J Physiol Heart Circ Physiol 306:H929–H937. https://doi.org/10.1152/ajpheart.00698.2013
Acknowledgements
Authors acknowledge support from Agencia Estatal de Investigación, Spain (BFU2017-82754-R), Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain, and Fondos FEDER. MEB was supported by an International Brain Research Organization (IBRO) research fellowship.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors report no conflict of interest.
Rights and permissions
About this article
Cite this article
Brocca, M.E., Garcia-Segura, L.M. Non-reproductive Functions of Aromatase in the Central Nervous System Under Physiological and Pathological Conditions. Cell Mol Neurobiol 39, 473–481 (2019). https://doi.org/10.1007/s10571-018-0607-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-018-0607-4