Skip to main content
Log in

Gender differences in neurodevelopment and epigenetics

  • Invited Review
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The concept that the brain differs in make-up between males and females is not new. For example, it is well established that anatomists in the nineteenth century found sex differences in human brain weight. The importance of sex differences in the organization of the brain cannot be overstated as they may directly affect cognitive functions, such as verbal skills and visuospatial tasks in a sex-dependent fashion. Moreover, the incidence of neurological and psychiatric diseases is also highly dependent on sex. These clinical observations reiterate the importance that gender must be taken into account as a relevant possible contributing factor in order to understand thepathogenesis of neurological and psychiatric disorders. Gender-dependent differentiation of the brain has been detected at every level of organization—morphological, neurochemical, and functional—and has been shown to be primarily controlled by sex differences in gonadal steroid hormone levels during perinatal development. In this review, we discuss howthe gonadal steroid hormone testosterone and its metabolites affect downstream signaling cascades, including gonadal steroid receptor activation, and epigenetic events in order to differentiate the brain in a gender-dependent fashion.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Abramovich DR, Rowe P (1973) Foetal plasma testosterone levels at mid-pregnancy and at term: relationship to foetal sex. J Endocrinol 56(3):621–622

    PubMed  CAS  Google Scholar 

  2. Albert DJ, Petrovic DM, Walsh ML, Jonik RH (1989) Medial accumbens lesions attenuate testosterone-dependent aggression in male rats. Physiol Behav 46(4):625–631

    PubMed  CAS  Google Scholar 

  3. Alheid GF, Beltramino CA, De Olmos JS, Forbes MS, Swanson DJ, Heimer L (1998) The neuronal organization of the supracapsular part of the stria terminalis in the rat: the dorsal component of the extended amygdala. Neuroscience 84(4):967–996

    PubMed  CAS  Google Scholar 

  4. Allen LS, Gorski RA (1990) Sex difference in the bed nucleus of the stria terminalis of the human brain. J Comp Neurol 302(4):697–706. doi:10.1002/cne.903020402

    PubMed  CAS  Google Scholar 

  5. Allen LS, Hines M, Shryne JE, Gorski RA (1989) Two sexually dimorphic cell groups in the human brain. J Neurosci 9(2):497–506

    PubMed  CAS  Google Scholar 

  6. Arai Y, Murakami S, Nishizuka M (1994) Androgen enhances neuronal degeneration in the developing preoptic area: apoptosis in the anteroventral periventricular nucleus (AVPvN-POA). Horm Behav 28(4):313–319. doi:10.1006/hbeh.1994.1027

    PubMed  CAS  Google Scholar 

  7. Arai Y, Sekine Y, Murakami S (1996) Estrogen and apoptosis in the developing sexually dimorphic preoptic area in female rats. Neurosci Res 25(4):403–407

    PubMed  CAS  Google Scholar 

  8. Arendash GW, Gorski RA (1983) Effects of discrete lesions of the sexually dimorphic nucleus of the preoptic area or other medial preoptic regions on the sexual behavior of male rats. Brain Res Bull 10(1):147–154

    PubMed  CAS  Google Scholar 

  9. Arends MJ, Morris RG, Wyllie AH (1990) Apoptosis. The role of the endonuclease. Am J Pathol 136(3):593–608

    PubMed  CAS  Google Scholar 

  10. Arnold AP, Gorski RA (1984) Gonadal steroid induction of structural sex differences in the central nervous system. Annu Rev Neurosci 7:413–442. doi:10.1146/annurev.ne.07.030184.002213

    PubMed  CAS  Google Scholar 

  11. Auger AP, Blaustein JD (1995) Progesterone enhances an estradiol-induced increase in Fos immunoreactivity in localized regions of female rat forebrain. J Neurosci 15(3 Pt 2):2272–2279

    PubMed  CAS  Google Scholar 

  12. Auger CJ, Coss D, Auger AP, Forbes-Lorman RM (2011) Epigenetic control of vasopressin expression is maintained by steroid hormones in the adult male rat brain. Proc Natl Acad Sci U S A 108(10):4242–4247. doi:10.1073/pnas.1100314108

    PubMed  CAS  Google Scholar 

  13. Auger AP, Perrot-Sinal TS, Auger CJ, Ekas LA, Tetel MJ, McCarthy MM (2002) Expression of the nuclear receptor coactivator, cAMP response element-binding protein, is sexually dimorphic and modulates sexual differentiation of neonatal rat brain. Endocrinology 143(8):3009–3016

    PubMed  CAS  Google Scholar 

  14. Auger AP, Tetel MJ, McCarthy MM (2000) Steroid receptor coactivator-1 (SRC-1) mediates the development of sex-specific brain morphology and behavior. Proc Natl Acad Sci U S A 97(13):7551–7555

    PubMed  CAS  Google Scholar 

  15. Bakker J, Baum MJ (2008) Role for estradiol in female-typical brain and behavioral sexual differentiation. Front Neuroendocrinol 29(1):1–16. doi:10.1016/j.yfrne.2007.06.001

    PubMed  CAS  Google Scholar 

  16. Bakker J, Brand T, van Ophemert J, Slob AK (1993) Hormonal regulation of adult partner preference behavior in neonatally ATD-treated male rats. Behav Neurosci 107(3):480–487

    PubMed  CAS  Google Scholar 

  17. Bakker J, van Ophemert J, Slob AK (1995) Postweaning housing conditions and partner preference and sexual behavior of neonatally ATD-treated male rats. Psychoneuroendocrinology 20(3):299–310

    PubMed  CAS  Google Scholar 

  18. Bakker J, van Ophemert J, Timmerman MA, de Jong FH, Slob AK (1995) Endogenous reproductive hormones and nocturnal rhythms in partner preference and sexual behavior of ATD-treated male rats. Neuroendocrinology 62(4):396–405

    PubMed  CAS  Google Scholar 

  19. Balthazart J, Ball GF (1998) New insights into the regulation and function of brain estrogen synthase (aromatase). Trends Neurosci 21(6):243–249

    PubMed  CAS  Google Scholar 

  20. Bamshad M, Novak MA, De Vries GJ (1993) Sex and species differences in the vasopressin innervation of sexually naive and parental prairie voles, Microtus ochrogaster and meadow voles, Microtus pennsylvanicus. J Neuroendocrinol 5(3):247–255

    PubMed  CAS  Google Scholar 

  21. Bao AM, Swaab DF (2011) Sexual differentiation of the human brain: relation to gender identity, sexual orientation and neuropsychiatric disorders. Front Neuroendocrinol 32(2):214–226. doi:10.1016/j.yfrne.2011.02.007

    PubMed  Google Scholar 

  22. Berta P, Hawkins JR, Sinclair AH, Taylor A, Griffiths BL, Goodfellow PN, Fellous M (1990) Genetic evidence equating SRY and the testis-determining factor. Nature 348(6300):448–450. doi:10.1038/348448a0

    PubMed  CAS  Google Scholar 

  23. Berthold AA (1849) Transplantion der Hoden. Arch Anat Physiol Wissensch

  24. Bird A (2007) Perceptions of epigenetics. Nature 447(7143):396–398

    PubMed  CAS  Google Scholar 

  25. Bird AP, Wolffe AP (1999) Methylation-induced repression—belts, braces, and chromatin. Cell 99(5):451–454

    PubMed  CAS  Google Scholar 

  26. Blaustein JD, Turcotte JC (1989) Estradiol-induced progestin receptor immunoreactivity is found only in estrogen receptor-immunoreactive cells in guinea pig brain. Neuroendocrinology 49(5):454–461

    PubMed  CAS  Google Scholar 

  27. Bleier R, Byne W, Siggelkow I (1982) Cytoarchitectonic sexual dimorphisms of the medial preoptic and anterior hypothalamic areas in guinea pig, rat, hamster, and mouse. J Comp Neurol 212(2):118–130. doi:10.1002/cne.902120203

    PubMed  CAS  Google Scholar 

  28. Bloch GJ, Eckersell C, Mills R (1993) Distribution of galanin-immunoreactive cells within sexually dimorphic components of the medial preoptic area of the male and female rat. Brain Res 620(2):259–268

    PubMed  CAS  Google Scholar 

  29. Brown TJ, Hochberg RB, Zielinski JE, MacLusky NJ (1988) Regional sex differences in cell nuclear estrogen-binding capacity in the rat hypothalamus and preoptic area. Endocrinology 123(4):1761–1770

    PubMed  CAS  Google Scholar 

  30. Budefeld T, Grgurevic N, Tobet SA, Majdic G (2008) Sex differences in brain developing in the presence or absence of gonads. Dev Neurobiol 68(7):981–995. doi:10.1002/dneu.20638

    PubMed  CAS  Google Scholar 

  31. Byne W, Lasco MS, Kemether E, Shinwari A, Edgar MA, Morgello S, Jones LB, Tobet S (2000) The interstitial nuclei of the human anterior hypothalamus: an investigation of sexual variation in volume and cell size, number and density. Brain Res 856(1–2):254–258

    PubMed  CAS  Google Scholar 

  32. Calaresu FR, Henry JL (1971) Sex difference in the number of the sympathetic neurons in the spinal cord of the cat. Science (New York, NY) 173(3994):343–344

    CAS  Google Scholar 

  33. Canteras NS, Simerly RB, Swanson LW (1994) Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris–leucoagglutinin study in the rat. J Comp Neurol 348(1):41–79. doi:10.1002/cne.903480103

    PubMed  CAS  Google Scholar 

  34. Champagne FA, Weaver IC, Diorio J, Dymov S, Szyf M, Meaney MJ (2006) Maternal care associated with methylation of the estrogen receptor-alpha1b promoter and estrogen receptor-alpha expression in the medial preoptic area of female offspring. Endocrinology 147(6):2909–2915

    PubMed  CAS  Google Scholar 

  35. Chan WY, Yew DT (1998) Apoptosis and Bcl-2 oncoprotein expression in the human fetal central nervous system. Anat Rec 252(2):165–175

    PubMed  CAS  Google Scholar 

  36. Chung WCJ, De Vries GJ, Swaab DF (2002) Sexual differentiation of the bed nucleus of the stria terminalis in humans may extend into adulthood. J Neurosci 22(3):1027–1033

    PubMed  CAS  Google Scholar 

  37. Chung WCJ, Pak TR, Suzuki S, Pouliot WA, Andersen ME, Handa RJ (2007) Detection and localization of an estrogen receptor beta splice variant protein (ERbeta2) in the adult female rat forebrain and midbrain regions. J Comp Neurol 505(3):249–267. doi:10.1002/cne.21490

    PubMed  CAS  Google Scholar 

  38. Chung WCJ, Pak TR, Weiser MJ, Hinds LR, Andersen ME, Handa RJ (2006) Progestin receptor expression in the developing rat brain depends upon activation of estrogen receptor alpha and not estrogen receptor beta. Brain Res 1082(1):50–60. doi:10.1016/j.brainres.2006.01.109

    PubMed  CAS  Google Scholar 

  39. Chung WCJ, Swaab DF, De Vries GJ (2000) Apoptosis during sexual differentiation of the bed nucleus of the stria terminalis in the rat brain. J Neurobiol 43(3):234–243. doi:10.1002/(SICI)1097-4695(20000605)43:3<234::AID-NEU2>3.0.CO;2-3

    PubMed  CAS  Google Scholar 

  40. Commins D, Yahr P (1984) Acetylcholinesterase activity in the sexually dimorphic area of the gerbil brain: sex differences and influences of adult gonadal steroids. J Comp Neurol 224(1):123–131. doi:10.1002/cne.902240111

    PubMed  CAS  Google Scholar 

  41. Corbier P, Dehennin L, Castanier M, Mebazaa A, Edwards DA, Roffi J (1990) Sex differences in serum luteinizing hormone and testosterone in the human neonate during the first few hours after birth. J Clin Endocrinol Metab 71(5):1344–1348

    PubMed  CAS  Google Scholar 

  42. Corbier P, Kerdelhue B, Picon R, Roffi J (1978) Changes in testicular weight and serum gonadotropin and testosterone levels before, during, and after birth in the perinatal rat. Endocrinology 103(6):1985–1991

    PubMed  CAS  Google Scholar 

  43. Davies AM (1994) Neurotrophic factors. Switching neurotrophin dependence. Curr Biol 4(3):273–276

    PubMed  CAS  Google Scholar 

  44. Davis EC, Popper P, Gorski RA (1996) The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain Res 734(1–2):10–18

    PubMed  CAS  Google Scholar 

  45. Davis EC, Shryne JE, Gorski RA (1995) A revised critical period for the sexual differentiation of the sexually dimorphic nucleus of the preoptic area in the rat. Neuroendocrinology 62(6):579–585

    PubMed  CAS  Google Scholar 

  46. De Jonge FH, Louwerse AL, Ooms MP, Evers P, Endert E, van de Poll NE (1989) Lesions of the SDN-POA inhibit sexual behavior of male Wistar rats. Brain Res Bull 23(6):483–492

    PubMed  Google Scholar 

  47. De Vries GJ, Best W, Sluiter AA (1983) The influence of androgens on the development of a sex difference in the vasopressinergic innervation of the rat lateral septum. Brain Res 284(2–3):377–380

    PubMed  Google Scholar 

  48. De Vries GJ, Buijs RM, Swaab DF (1981) Ontogeny of the vasopressinergic neurons of the suprachiasmatic nucleus and their extrahypothalamic projections in the rat brain—presence of a sex difference in the lateral septum. Brain Res 218(1–2):67–78

    PubMed  Google Scholar 

  49. De Vries GJ, Rissman EF, Simerly RB, Yang LY, Scordalakes EM, Auger CJ, Swain A, Lovell-Badge R, Burgoyne PS, Arnold AP (2002) A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J Neurosci 22(20):9005–9014

    PubMed  Google Scholar 

  50. Del Abril A, Segovia S, Guillamon A (1987) The bed nucleus of the stria terminalis in the rat: regional sex differences controlled by gonadal steroids early after birth. Brain Res 429(2):295–300

    PubMed  Google Scholar 

  51. Dohler KD, Wuttke W (1975) Changes with age in levels of serum gonadotropins, prolactin and gonadal steroids in prepubertal male and female rats. Endocrinology 97(4):898–907

    PubMed  CAS  Google Scholar 

  52. Dominguez R, Micevych P (2010) Estradiol rapidly regulates membrane estrogen receptor alpha levels in hypothalamic neurons. J Neurosci 30(38):12589–12596. doi:10.1523/jneurosci.1038-10.2010

    PubMed  CAS  Google Scholar 

  53. Donahue JE, Stopa EG, Chorsky RL, King JC, Schipper HM, Tobet SA, Blaustein JD, Reichlin S (2000) Cells containing immunoreactive estrogen receptor-alpha in the human basal forebrain. Brain Res 856(1–2):142–151

    PubMed  CAS  Google Scholar 

  54. DonCarlos LL, Handa RJ (1994) Developmental profile of estrogen receptor mRNA in the preoptic area of male and female neonatal rats. Brain Res Dev Brain Res 79(2):283–289

    PubMed  CAS  Google Scholar 

  55. Ducret E, Gaidamaka G, Herbison AE (2010) Electrical and morphological characteristics of anteroventral periventricular nucleus kisspeptin and other neurons in the female mouse. Endocrinology 151(5):2223–2232. doi:10.1210/en.2009-1480

    PubMed  CAS  Google Scholar 

  56. Dunn JD (1987) Plasma corticosterone responses to electrical stimulation of the bed nucleus of the stria terminalis. Brain Res 407(2):327–331

    PubMed  CAS  Google Scholar 

  57. Edelmann MN, Auger AP (2011) Epigenetic impact of simulated maternal grooming on estrogen receptor alpha within the developing amygdala. Brain Behav Immun 25(7):1299–1304. doi:10.1016/j.bbi.2011.02.009

    PubMed  CAS  Google Scholar 

  58. Emery DE, Sachs BD (1976) Copulatory behavior in male rats with lesions in the bed nucleus of the stria terminalis. Physiol Behav 17(5):803–806

    PubMed  CAS  Google Scholar 

  59. Evans RM (1988) The steroid and thyroid hormone receptor superfamily. Science (New York, NY) 240(4854):889–895

    CAS  Google Scholar 

  60. Forbes-Lorman RM, Rautio JJ, Kurian JR, Auger AP, Auger CJ (2012) Neonatal MeCP2 is important for the organization of sex differences in vasopressin expression. Epigenetics 7(3):230–238. doi:10.4161/epi.7.3.19265

    PubMed  CAS  Google Scholar 

  61. Fraga MF, Ballestar E, Paz MF, Ropero S, Setien F, Ballestar ML, Heine-Suner D, Cigudosa JC, Urioste M, Benitez J, Boix-Chornet M, Sanchez-Aguilera A, Ling C, Carlsson E, Poulsen P, Vaag A, Stephan Z, Spector TD, Wu YZ, Plass C, Esteller M (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proc Natl Acad Sci U S A 102(30):10604–10609

    PubMed  CAS  Google Scholar 

  62. Fried G, Andersson E, Csoregh L, Enmark E, Gustafsson JA, Aanesen A, Osterlund C (2004) Estrogen receptor beta is expressed in human embryonic brain cells and is regulated by 17beta-estradiol. Eur J Neurosci 20(9):2345–2354. doi:10.1111/j.1460-9568.2004.03693.x

    PubMed  CAS  Google Scholar 

  63. Gorski RA, Gordon JH, Shryne JE, Southam AM (1978) Evidence for a morphological sex difference within the medial preoptic area of the rat brain. Brain Res 148(2):333–346

    PubMed  CAS  Google Scholar 

  64. Grafstrom RH, Yuan R, Hamilton DL (1985) The characteristics of DNA methylation in an in vitro DNA synthesizing system from mouse fibroblasts. Nucleic Acids Res 13(8):2827–2842

    PubMed  CAS  Google Scholar 

  65. Gu GB, Simerly RB (1997) Projections of the sexually dimorphic anteroventral periventricular nucleus in the female rat. J Comp Neurol 384(1):142–164

    PubMed  CAS  Google Scholar 

  66. Guillamon A, Segovia S, del Abril A (1988) Early effects of gonadal steroids on the neuron number in the medial posterior region and the lateral division of the bed nucleus of the stria terminalis in the rat. Brain Res Dev Brain Res 44(2):281–290

    PubMed  CAS  Google Scholar 

  67. Handa RJ, Ogawa S, Wang JM, Herbison AE (2012) Roles for oestrogen receptor beta in adult brain function. J Neuroendocrinol 24(1):160–173. doi:10.1111/j.1365-2826.2011.02206.x

    PubMed  CAS  Google Scholar 

  68. Herman JP, Cullinan WE, Watson SJ (1994) Involvement of the bed nucleus of the stria terminalis in tonic regulation of paraventricular hypothalamic CRH and AVP mRNA expression. J Neuroendocrinol 6(4):433–442

    PubMed  CAS  Google Scholar 

  69. Hestiantoro A, Swaab DF (2004) Changes in estrogen receptor-alpha and -beta in the infundibular nucleus of the human hypothalamus are related to the occurrence of Alzheimer's disease neuropathology. J Clin Endocrinol Metab 89(4):1912–1925

    PubMed  CAS  Google Scholar 

  70. Hines M, Allen LS, Gorski RA (1992) Sex differences in subregions of the medial nucleus of the amygdala and the bed nucleus of the stria terminalis of the rat. Brain Res 579(2):321–326

    PubMed  CAS  Google Scholar 

  71. Hines M, Davis FC, Coquelin A, Goy RW, Gorski RA (1985) Sexually dimorphic regions in the medial preoptic area and the bed nucleus of the stria terminalis of the guinea pig brain: a description and an investigation of their relationship to gonadal steroids in adulthood. J Neurosci 5(1):40–47

    PubMed  CAS  Google Scholar 

  72. Hisasue S, Seney ML, Immerman E, Forger NG (2010) Control of cell number in the bed nucleus of the stria terminalis of mice: role of testosterone metabolites and estrogen receptor subtypes. J Sex Med 7(4 Pt 1):1401–1409. doi:10.1111/j.1743-6109.2009.01669.x

    PubMed  CAS  Google Scholar 

  73. Hofman MA, Swaab DF (1989) The sexually dimorphic nucleus of the preoptic area in the human brain: a comparative morphometric study. J Anat 164:55–72

    PubMed  CAS  Google Scholar 

  74. Honda K, Sawada H, Kihara T, Urushitani M, Nakamizo T, Akaike A, Shimohama S (2000) Phosphatidylinositol 3-kinase mediates neuroprotection by estrogen in cultured cortical neurons. J Neurosci Res 60(3):321–327

    PubMed  CAS  Google Scholar 

  75. Honda K, Shimohama S, Sawada H, Kihara T, Nakamizo T, Shibasaki H, Akaike A (2001) Nongenomic antiapoptotic signal transduction by estrogen in cultured cortical neurons. J Neurosci Res 64(5):466–475

    PubMed  CAS  Google Scholar 

  76. Hutton LA, Gu G, Simerly RB (1998) Development of a sexually dimorphic projection from the bed nuclei of the stria terminalis to the anteroventral periventricular nucleus in the rat. J Neurosci 18(8):3003–3013

    PubMed  CAS  Google Scholar 

  77. Ishunina TA, Kruijver FP, Balesar R, Swaab DF (2000) Differential expression of estrogen receptor alpha and beta immunoreactivity in the human supraoptic nucleus in relation to sex and aging. J Clin Endocrinol Metab 85(9):3283–3291

    PubMed  CAS  Google Scholar 

  78. Ishunina TA, Swaab DF (2012) Decreased alternative splicing of estrogen receptor-alpha mRNA in the Alzheimer's disease brain. Neurobiol Aging 33(2):286 e283–296 e283. doi:10.1016/j.neurobiolaging.2010.03.010

    Google Scholar 

  79. Ishunina TA, Unmehopa UA, van Heerikhuize JJ, Pool CW, Swaab DF (2001) Metabolic activity of the human ventromedial nucleus neurons in relation to sex and ageing. Brain Res 893(1–2):70–76

    PubMed  CAS  Google Scholar 

  80. Jacobson CD, Arnold AP, Gorski RA (1987) Steroid autoradiography of the sexually dimorphic nucleus of the preoptic area. Brain Res 414(2):349–356

    PubMed  CAS  Google Scholar 

  81. Jacobson CD, Davis FC, Gorski RA (1985) Formation of the sexually dimorphic nucleus of the preoptic area: neuronal growth, migration and changes in cell number. Brain Res 353(1):7–18

    PubMed  CAS  Google Scholar 

  82. Jacobson CD, Gorski RA (1981) Neurogenesis of the sexually dimorphic nucleus of the preoptic area in the rat. J Comp Neurol 196(3):519–529. doi:10.1002/cne.901960313

    PubMed  CAS  Google Scholar 

  83. Jacobson CD, Shryne JE, Shapiro F, Gorski RA (1980) Ontogeny of the sexually dimorphic nucleus of the preoptic area. J Comp Neurol 193(2):541–548. doi:10.1002/cne.901930215

    PubMed  CAS  Google Scholar 

  84. Jager RJ, Anvret M, Hall K, Scherer G (1990) A human XY female with a frame shift mutation in the candidate testis-determining gene SRY. Nature 348(6300):452–454. doi:10.1038/348452a0

    PubMed  CAS  Google Scholar 

  85. Jakab RL, Harada N, Naftolin F (1994) Aromatase- (estrogen synthetase) immunoreactive neurons in the rat septal area. A light and electron microscopic study. Brain Res 664(1–2):85–93

    PubMed  CAS  Google Scholar 

  86. Janowsky JS, Finlay BL (1983) Cell degeneration in early development of the forebrain and cerebellum. Anat Embryol 167(3):439–447

    PubMed  CAS  Google Scholar 

  87. Ju G, Swanson LW (1989) Studies on the cellular architecture of the bed nuclei of the stria terminalis in the rat: I. Cytoarchitecture. J Comp Neurol 280(4):587–602. doi:10.1002/cne.902800409

    PubMed  CAS  Google Scholar 

  88. Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26(4):239–257

    PubMed  CAS  Google Scholar 

  89. Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31(2):89–97

    PubMed  CAS  Google Scholar 

  90. Kolbinger W, Trepel M, Beyer C, Pilgrim C, Reisert I (1991) The influence of genetic sex on sexual differentiation of diencephalic dopaminergic neurons in vitro and in vivo. Brain Res 544(2):349–352

    PubMed  CAS  Google Scholar 

  91. Koopman P (2001) The genetics and biology of vertebrate sex determination. Cell 105(7):843–847

    PubMed  CAS  Google Scholar 

  92. Kruijver FP, Balesar R, Espila AM, Unmehopa UA, Swaab DF (2003) Estrogen-receptor-beta distribution in the human hypothalamus: similarities and differences with ER alpha distribution. J Comp Neurol 466(2):251–277. doi:10.1002/cne.10899

    PubMed  Google Scholar 

  93. Kruijver FP, Zhou JN, Pool CW, Hofman MA, Gooren LJ, Swaab DF (2000) Male-to-female transsexuals have female neuron numbers in a limbic nucleus. J Clin Endocrinol Metab 85(5):2034–2041

    PubMed  CAS  Google Scholar 

  94. Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (1996) Cloning of a novel receptor expressed in rat prostate and ovary. Proc Natl Acad Sci U S A 93(12):5925–5930

    PubMed  CAS  Google Scholar 

  95. Kurian JR, Bychowski ME, Forbes-Lorman RM, Auger CJ, Auger AP (2008) Mecp2 organizes juvenile social behavior in a sex-specific manner. J Neurosci 28(28):7137–7142

    PubMed  CAS  Google Scholar 

  96. Kurian JR, Olesen KM, Auger AP (2010) Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology 151(5):2297–2305

    PubMed  CAS  Google Scholar 

  97. Lauber AH, Mobbs CV, Muramatsu M, Pfaff DW (1991) Estrogen receptor messenger RNA expression in rat hypothalamus as a function of genetic sex and estrogen dose. Endocrinology 129(6):3180–3186

    PubMed  CAS  Google Scholar 

  98. LeVay S (1991) A difference in hypothalamic structure between heterosexual and homosexual men. Science (New York, NY) 253(5023):1034–1037

    CAS  Google Scholar 

  99. Lisciotto CA, Morrell JI (1993) Circulating gonadal steroid hormones regulate estrogen receptor mRNA in the male rat forebrain. Brain Res Mol Brain Res 20(1–2):79–90

    PubMed  CAS  Google Scholar 

  100. Liu YC, Salamone JD, Sachs BD (1997) Lesions in medial preoptic area and bed nucleus of stria terminalis: differential effects on copulatory behavior and noncontact erection in male rats. J Neurosci 17(13):5245–5253

    PubMed  CAS  Google Scholar 

  101. MacLusky NJ, Philip A, Hurlburt C, Naftolin F (1985) Estrogen formation in the developing rat brain: sex differences in aromatase activity during early post-natal life. Psychoneuroendocrinology 10(3):355–361

    PubMed  CAS  Google Scholar 

  102. Maerkel K, Durrer S, Henseler M, Schlumpf M, Lichtensteiger W (2007) Sexually dimorphic gene regulation in brain as a target for endocrine disrupters: developmental exposure of rats to 4-methylbenzylidene camphor. Toxicol Appl Pharmacol 218(2):152–165

    PubMed  CAS  Google Scholar 

  103. Manin M, Baron S, Goossens K, Beaudoin C, Jean C, Veyssiere G, Verhoeven G, Morel L (2002) Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt pathway in normal and tumoral epithelial cells. Biochem J 366(Pt 3):729–736. doi:10.1042/bj20020585

    PubMed  CAS  Google Scholar 

  104. Matsumoto A, Arai Y (1983) Sex difference in volume of the ventromedial nucleus of the hypothalamus in the rat. Endocrinol Jpn 30(3):277–280

    PubMed  CAS  Google Scholar 

  105. Matsumoto A, Arai Y (1986) Male–female difference in synaptic organization of the ventromedial nucleus of the hypothalamus in the rat. Neuroendocrinology 42(3):232–236

    PubMed  CAS  Google Scholar 

  106. Mayer A, Lahr G, Swaab DF, Pilgrim C, Reisert I (1998) The Y-chromosomal genes SRY and ZFY are transcribed in adult human brain. Neurogenetics 1(4):281–288

    PubMed  CAS  Google Scholar 

  107. Mayer A, Mosler G, Just W, Pilgrim C, Reisert I (2000) Developmental profile of Sry transcripts in mouse brain. Neurogenetics 3(1):25–30

    PubMed  CAS  Google Scholar 

  108. McDonald PG, Doughty C (1974) Effect of neonatal administration of different androgens in the female rat: correlation between aromatization and the induction of sterilization. J Endocrinol 61(1):95–103

    PubMed  CAS  Google Scholar 

  109. McEwen BS, Lieberburg I, Chaptal C, Krey LC (1977) Aromatization: important for sexual differentiation of the neonatal rat brain. Horm Behav 9(3):249–263

    PubMed  CAS  Google Scholar 

  110. Mensah PL (1982) An electron microscopical study of neuronal cell clustering in postnatal mouse striatum, with special emphasis on neuronal cell death. Anat Embryol 164(3):387–401

    PubMed  CAS  Google Scholar 

  111. Metivier R, Gallais R, Tiffoche C, Le PC, Jurkowska RZ, Carmouche RP, Ibberson D, Barath P, Demay F, Reid G, Benes V, Jeltsch A, Gannon F, Salbert G (2008) Cyclical DNA methylation of a transcriptionally active promoter. Nature 452(7183):45–50

    PubMed  CAS  Google Scholar 

  112. Micevych PE, Park SS, Akesson TR, Elde R (1987) Distribution of cholecystokinin-immunoreactive cell bodies in the male and female rat: I. Hypothalamus. J Comp Neurol 255(1):124–136. doi:10.1002/cne.902550110

    PubMed  CAS  Google Scholar 

  113. Morris JA, Jordan CL, Breedlove SM (2004) Sexual differentiation of the vertebrate nervous system. Nat Neurosci 7(10):1034–1039. doi:10.1038/nn1325

    PubMed  CAS  Google Scholar 

  114. Mosselman S, Polman J, Dijkema R (1996) ER beta: identification and characterization of a novel human estrogen receptor. FEBS Lett 392(1):49–53

    PubMed  CAS  Google Scholar 

  115. Mott NN, Pak TR (2012) Characterisation of human oestrogen receptor beta (ERbeta) splice variants in neuronal cells. J Neuroendocrinol 24(10):1311–1321. doi:10.1111/j.1365-2826.2012.02337.x

    PubMed  CAS  Google Scholar 

  116. Murray EK, Hien A, De Vries GJ, Forger NG (2009) Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150(9):4241–4247

    PubMed  CAS  Google Scholar 

  117. Naftolin F, Horvath TL, Jakab RL, Leranth C, Harada N, Balthazart J (1996) Aromatase immunoreactivity in axon terminals of the vertebrate brain. An immunocytochemical study on quail, rat, monkey and human tissues. Neuroendocrinology 63(2):149–155

    PubMed  CAS  Google Scholar 

  118. Nanney DL (1958) Epigenetic control systems. Proc Natl Acad Sci U S A 44(7):712–717

    PubMed  CAS  Google Scholar 

  119. Nishizuka M, Arai Y (1983) Regional difference in sexually dimorphic synaptic organization of the medial amygdala. Exp Brain Res 49(3):462–465

    PubMed  CAS  Google Scholar 

  120. Nishizuka M, Sumida H, Kano Y, Arai Y (1993) Formation of neurons in the sexually dimorphic anteroventral periventricular nucleus of the preoptic area of the rat: effects of prenatal treatment with testosterone propionate. J Neuroendocrinol 5(5):569–573

    PubMed  CAS  Google Scholar 

  121. Nottebohm F, Arnold AP (1976) Sexual dimorphism in vocal control areas of the songbird brain. Science (New York, NY) 194(4261):211–213

    CAS  Google Scholar 

  122. Olster DH, Blaustein JD (1989) Development of progesterone-facilitated lordosis in female guinea pigs: relationship to neural estrogen and progestin receptors. Brain Res 484(1–2):168–176

    PubMed  CAS  Google Scholar 

  123. Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501. doi:10.1146/annurev.ne.14.030191.002321

    PubMed  CAS  Google Scholar 

  124. Orikasa C, Sakuma Y (2010) Estrogen configures sexual dimorphism in the preoptic area of C57BL/6J and ddN strains of mice. J Comp Neurol 518(17):3618–3629. doi:10.1002/cne.22419

    PubMed  CAS  Google Scholar 

  125. Osterlund MK, Gustafsson JA, Keller E, Hurd YL (2000) Estrogen receptor beta (ERbeta) messenger ribonucleic acid (mRNA) expression within the human forebrain: distinct distribution pattern to ERalpha mRNA. J Clin Endocrinol Metab 85(10):3840–3846

    PubMed  CAS  Google Scholar 

  126. Osterlund M, Kuiper GG, Gustafsson JA, Hurd YL (1998) Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain. Brain Res Mol Brain Res 54(1):175–180

    PubMed  CAS  Google Scholar 

  127. Pak TR, Chung WCJ, Hinds LR, Handa RJ (2009) Arginine vasopressin regulation in pre- and postpubertal male rats by the androgen metabolite 3beta-diol. Am J Physiol Endocrinol Metab 296(6):E1409–E1413. doi:10.1152/ajpendo.00037.2009

    PubMed  CAS  Google Scholar 

  128. Pakkenberg B, Gundersen HJ (1997) Neocortical neuron number in humans: effect of sex and age. J Comp Neurol 384(2):312–320

    PubMed  CAS  Google Scholar 

  129. Patisaul HB, Whitten PL, Young LJ (1999) Regulation of estrogen receptor beta mRNA in the brain: opposite effects of 17beta-estradiol and the phytoestrogen, coumestrol. Brain Res Mol Brain Res 67(1):165–171

    PubMed  CAS  Google Scholar 

  130. Pfaff DW, Sakuma Y (1979) Deficit in the lordosis reflex of female rats caused by lesions in the ventromedial nucleus of the hypothalamus. J Physiol 288:203–210

    PubMed  CAS  Google Scholar 

  131. Pfaff DW, Sakuma Y (1979) Facilitation of the lordosis reflex of female rats from the ventromedial nucleus of the hypothalamus. J Physiol 288:189–202

    PubMed  CAS  Google Scholar 

  132. Phoenix CH, Goy RW, Gerall AA, Young WC (1959) Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65:369–382

    PubMed  CAS  Google Scholar 

  133. Polanco JC, Koopman P (2007) Sry and the hesitant beginnings of male development. Dev Biol 302(1):13–24. doi:10.1016/j.ydbio.2006.08.049

    PubMed  CAS  Google Scholar 

  134. Pozzo Miller LD, Aoki A (1991) Stereological analysis of the hypothalamic ventromedial nucleus. II. Hormone-induced changes in the synaptogenic pattern. Brain Res Dev Brain Res 61(2):189–196

    PubMed  CAS  Google Scholar 

  135. Raisman G, Field PM (1971) Sexual dimorphism in the preoptic area of the rat. Science (New York, NY) 173(3998):731–733

    CAS  Google Scholar 

  136. Raisman G, Field PM (1973) Sexual dimorphism in the neuropil of the preoptic area of the rat and its dependence on neonatal androgen. Brain Res 54:1–29

    PubMed  CAS  Google Scholar 

  137. Rakic S, Zecevic N (2000) Programmed cell death in the developing human telencephalon. Eur J Neurosci 12(8):2721–2734

    PubMed  CAS  Google Scholar 

  138. Ramsahoye BH, Biniszkiewicz D, Lyko F, Clark V, Bird AP, Jaenisch R (2000) Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. Proc Natl Acad Sci U S A 97(10):5237–5242

    PubMed  CAS  Google Scholar 

  139. Razin A, Riggs AD (1980) DNA methylation and gene function. Science (New York, NY) 210(4470):604–610

    CAS  Google Scholar 

  140. Robyr D, Wolffe AP, Wahli W (2000) Nuclear hormone receptor coregulators in action: diversity for shared tasks. Mol Endocrinol 14(3):329–347

    PubMed  CAS  Google Scholar 

  141. Sasano H, Takashashi K, Satoh F, Nagura H, Harada N (1998) Aromatase in the human central nervous system. Clin Endocrinol 48(3):325–329

    CAS  Google Scholar 

  142. Savic I, Berglund H, Gulyas B, Roland P (2001) Smelling of odorous sex hormone-like compounds causes sex-differentiated hypothalamic activations in humans. Neuron 31(4):661–668

    PubMed  CAS  Google Scholar 

  143. Shammah-Lagnado SJ, Beltramino CA, McDonald AJ, Miselis RR, Yang M, de Olmos J, Heimer L, Alheid GF (2000) Supracapsular bed nucleus of the stria terminalis contains central and medial extended amygdala elements: evidence from anterograde and retrograde tracing experiments in the rat. J Comp Neurol 422(4):533–555

    PubMed  CAS  Google Scholar 

  144. Sharma M, Chuang WW, Sun Z (2002) Phosphatidylinositol 3-kinase/Akt stimulates androgen pathway through GSK3beta inhibition and nuclear beta-catenin accumulation. J Biol Chem 277(34):30935–30941. doi:10.1074/jbc.M201919200

    PubMed  CAS  Google Scholar 

  145. Shughrue P, Scrimo P, Lane M, Askew R, Merchenthaler I (1997) The distribution of estrogen receptor-beta mRNA in forebrain regions of the estrogen receptor-alpha knockout mouse. Endocrinology 138(12):5649–5652

    PubMed  CAS  Google Scholar 

  146. Shupnik MA, Pitt LK, Soh AY, Anderson A, Lopes MB, Laws ER Jr (1998) Selective expression of estrogen receptor alpha and beta isoforms in human pituitary tumors. J Clin Endocrinol Metab 83(11):3965–3972

    PubMed  CAS  Google Scholar 

  147. Sibug R, Kuppers E, Beyer C, Maxson SC, Pilgrim C, Reisert I (1996) Genotype-dependent sex differentiation of dopaminergic neurons in primary cultures of embryonic mouse brain. Brain Res Dev Brain Res 93(1–2):136–142

    PubMed  CAS  Google Scholar 

  148. Simerly RB, Chang C, Muramatsu M, Swanson LW (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 294(1):76–95. doi:10.1002/cne.902940107

    PubMed  CAS  Google Scholar 

  149. Simerly RB, Swanson LW, Gorski RA (1985) Reversal of the sexually dimorphic distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus by treatment with perinatal androgen. Brain Res 340(1):91–98

    PubMed  CAS  Google Scholar 

  150. Simerly RB, Young BJ (1991) Regulation of estrogen receptor messenger ribonucleic acid in rat hypothalamus by sex steroid hormones. Mol Endocrinol 5(3):424–432

    PubMed  CAS  Google Scholar 

  151. Simonati A, Tosati C, Rosso T, Piazzola E, Rizzuto N (1999) Cell proliferation and death: morphological evidence during corticogenesis in the developing human brain. Microsc Res Tech 45(6):341–352. doi:10.1002/(sici)1097-0029(19990615)45:6<341::aid-jemt2>3.0.co;2-u

    PubMed  CAS  Google Scholar 

  152. Sinclair AH, Berta P, Palmer MS, Hawkins JR, Griffiths BL, Smith MJ, Foster JW, Frischauf AM, Lovell-Badge R, Goodfellow PN (1990) A gene from the human sex-determining region encodes a protein with homology to a conserved DNA-binding motif. Nature 346(6281):240–244. doi:10.1038/346240a0

    PubMed  CAS  Google Scholar 

  153. Suzuki S, Handa RJ (2005) Estrogen receptor-beta, but not estrogen receptor-alpha, is expressed in prolactin neurons of the female rat paraventricular and supraoptic nuclei: comparison with other neuropeptides. J Comp Neurol 484(1):28–42. doi:10.1002/cne.20457

    PubMed  CAS  Google Scholar 

  154. Swaab DF, Chung WCJ, Kruijver FP, Hofman MA, Ishunina TA (2001) Structural and functional sex differences in the human hypothalamus. Horm Behav 40(2):93–98. doi:10.1006/hbeh.2001.1682

    PubMed  CAS  Google Scholar 

  155. Swaab DF, Fliers E (1985) A sexually dimorphic nucleus in the human brain. Science (New York, NY) 228(4703):1112–1115

    CAS  Google Scholar 

  156. Swaab DF, Hofman MA (1984) Sexual differentiation of the human brain. A historical perspective. Prog Brain Res 61:361–374. doi:10.1016/s0079-6123(08)64447-7

    PubMed  CAS  Google Scholar 

  157. Swaab DF, Hofman MA (1988) Sexual differentiation of the human hypothalamus: ontogeny of the sexually dimorphic nucleus of the preoptic area. Brain Res Dev Brain Res 44(2):314–318

    PubMed  CAS  Google Scholar 

  158. Swaab DF, Hofman MA (1995) Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trends Neurosci 18(6):264–270

    PubMed  CAS  Google Scholar 

  159. Tetel MJ, Auger AP, Charlier TD (2009) Who's in charge? nuclear receptor coactivator and corepressor function in brain and behavior. Front Neuroendocrinol 30(3):328–342

    PubMed  CAS  Google Scholar 

  160. Tobet SA, Zahniser DJ, Baum MJ (1986) Sexual dimorphism in the preoptic/anterior hypothalamic area of ferrets: effects of adult exposure to sex steroids. Brain Res 364(2):249–257

    PubMed  CAS  Google Scholar 

  161. Toft D, Gorski J (1966) A receptor molecule for estrogens: isolation from the rat uterus and preliminary characterization. Proc Natl Acad Sci U S A 55(6):1574–1581

    PubMed  CAS  Google Scholar 

  162. Treit D, Aujla H, Menard J (1998) Does the bed nucleus of the stria terminalis mediate fear behaviors? Behav Neurosci 112(2):379–386

    PubMed  CAS  Google Scholar 

  163. Tremblay GB, Tremblay A, Copeland NG, Gilbert DJ, Jenkins NA, Labrie F, Giguere V (1997) Cloning, chromosomal localization, and functional analysis of the murine estrogen receptor beta. Mol Endocrinol 11(3):353–365

    PubMed  CAS  Google Scholar 

  164. Tsai HW, Grant PA, Rissman EF (2009) Sex differences in histone modifications in the neonatal mouse brain. Epigenetics 4(1):47–53

    PubMed  CAS  Google Scholar 

  165. van Kesteren PJ, Gooren LJ, Megens JA (1996) An epidemiological and demographic study of transsexuals in The Netherlands. Arch Sex Behav 25(6):589–600

    PubMed  Google Scholar 

  166. van Vliet J, Oates NA, Whitelaw E (2007) Epigenetic mechanisms in the context of complex diseases. Cell Mol Life Sci 64(12):1531–1538

    PubMed  Google Scholar 

  167. Vreeburg JT, van der Vaart PD, van der Schoot P (1977) Prevention of central defeminization but not masculinization in male rats by inhibition neonatally of oestrogen biosynthesis. J Endocrinol 74(3):375–382

    PubMed  CAS  Google Scholar 

  168. Wang Z, Hulihan TJ, Insel TR (1997) Sexual and social experience is associated with different patterns of behavior and neural activation in male prairie voles. Brain Res 767(2):321–332

    PubMed  CAS  Google Scholar 

  169. Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ (2004) Epigenetic programming by maternal behavior. Nat Neurosci 7(8):847–854

    PubMed  CAS  Google Scholar 

  170. Weisz J, Ward IL (1980) Plasma testosterone and progesterone titers of pregnant rats, their male and female fetuses, and neonatal offspring. Endocrinology 106(1):306–316

    PubMed  CAS  Google Scholar 

  171. Westberry JM, Trout AL, Wilson ME (2009) Epigenetic regulation of estrogen receptor alpha gene expression in the mouse cortex during early postnatal development. Endocrinology 151(2):731–740

    PubMed  Google Scholar 

  172. Westberry JM, Trout AL, Wilson ME (2011) Epigenetic regulation of estrogen receptor beta expression in the rat cortex during aging. Neuroreport 22(9):428–432. doi:10.1097/WNR.0b013e328346e1cf

    PubMed  CAS  Google Scholar 

  173. Wiegand SJ, Terasawa E (1982) Discrete lesions reveal functional heterogeneity of suprachiasmatic structures in regulation of gonadotropin secretion in the female rat. Neuroendocrinology 34(6):395–404

    PubMed  CAS  Google Scholar 

  174. Xu J, Disteche CM (2006) Sex differences in brain expression of X- and Y-linked genes. Brain Res 1126(1):50–55. doi:10.1016/j.brainres.2006.08.049

    PubMed  CAS  Google Scholar 

  175. Yamamoto Y, Carter CS, Cushing BS (2006) Neonatal manipulation of oxytocin affects expression of estrogen receptor alpha. Neuroscience 137(1):157–164

    PubMed  CAS  Google Scholar 

  176. Yao HH, Whoriskey W, Capel B (2002) Desert Hedgehog/Patched 1 signaling specifies fetal Leydig cell fate in testis organogenesis. Genes Dev 16(11):1433–1440. doi:10.1101/gad.981202

    PubMed  CAS  Google Scholar 

  177. Yokosuka M, Okamura H, Hayashi S (1997) Postnatal development and sex difference in neurons containing estrogen receptor-alpha immunoreactivity in the preoptic brain, the diencephalon, and the amygdala in the rat. J Comp Neurol 389(1):81–93

    PubMed  CAS  Google Scholar 

  178. Yoon HG, Chan DW, Reynolds AB, Qin J, Wong J (2003) N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso. Mol Cell 12(3):723–734

    PubMed  CAS  Google Scholar 

  179. Zhou JN, Hofman MA, Gooren LJ, Swaab DF (1995) A sex difference in the human brain and its relation to transsexuality. Nature 378(6552):68–70. doi:10.1038/378068a0

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Wilson C. J. Chung.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chung, W.C.J., Auger, A.P. Gender differences in neurodevelopment and epigenetics. Pflugers Arch - Eur J Physiol 465, 573–584 (2013). https://doi.org/10.1007/s00424-013-1258-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-013-1258-4

Keywords

Navigation