Key Points
-
Many sex differences in the rodent brain are established during a sensitive period in early life.
-
Gonadal steroid hormones determine sex differences, but there is also a contribution of sex chromosome complement.
-
Epigenetic modifications in key brain regions both establish and maintain sex differences.
-
Neuroimmune and inflammatory signalling pathways are essential contributors to the masculinization of brain and behaviour.
-
Higher male vulnerability to neurodevelopmental disorders may have its origins in naturally occurring higher levels of inflammatory signalling molecules early in life.
Abstract
The study of sex differences in the brain is a topic of neuroscientific study that has broad reaching implications for culture, society and biomedical science. Recent research in rodent models has led to dramatic shifts in our views of the mechanisms underlying the sexual differentiation of the brain. These include the surprising discoveries of a role for immune cells and inflammatory mediators in brain masculinization and a role for epigenetic suppression in brain feminization. How and to what degree these findings will translate to human brain development will be questions of central importance in future research in this field.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Griew, S. Age and sex differences in probability learning of rats in a swimming T-maze. Gerontologia 14, 197–203 (1968).
Maren, S., De Oca, B. & Fanselow, M. S. Sex differences in hippocampal long-term potentiation (LTP) and Pavlovian fear conditioning in rats: positive correlation between LTP and contextual learning. Brain Res. 661, 25–34 (1994).
Perrot-Sinal, T. S. Sex differences in performance in the Morris water maze and the effects of initial nonstationary hidden platform training. Behav. Neurosci. 110, 1309–1320 (1996).
Roof, R. L. Neonatal exogenous testosterone modifies sex difference in radial arm and Morris water maze perfromance in prebubescent and adult rats. Behav. Brain Res. 53, 1–10 (1993).
Munoz-Cueto, J. A., Garcia-Segura, L. M. & Ruiz-Marcos, A. Developmental sex differences and effect of ovariectomy on the number of cortical pyramidal cell dendritic spines. Brain Res. 515, 64–68 (1990).
Sacher, J., Neumann, J., Okon-Singer, H., Gotowiec, S. & Villringer, A. Sexual dimorphism in the human brain: evidence from neuroimaging. Magn. Reson. Imaging 31, 366–375 (2013).
Ingalhalikar, M. et al. Sex differences in the structural connectome of the human brain. Proc. Natl Acad. Sci. USA 111, 823–828 (2014). In this study, diffusion tensory imaging of nearly 1,000 human brains reveals sex differences in intra-hemispheric versus inter-hemispheric connectivity.
Tunc, B. et al. Establishing a link between sex-related differences in the structural connectome and behaviour. Phil. Trans. R. Soc. B 371, 20150111 (2016).
Joel, D. & Tarrasch, R. On the mis-presentation and misinterpretation of gender-related data: the case of Ingalhalikar's human connectome study. Proc. Natl Acad. Sci. USA 111, E637 (2014).
Joel, D. & Fausto-Sterling, A. Beyond sex differences: new approaches for thinking about variation in brain structure and function. Phil. Trans. R. Soc. B 371, 20150451 (2016).
McCarthy, M., De Vries, G. & Forger, N. in Hormones, Brain and Behavior (ed. Pfaff, D. W. & Joëls, M.) 3–32 (Elsevier, 2017).
Phoenix, C. H., Goy, R. W., Gerall, A. A. & Young, W. C. Organizing action of prenatally administered testosterone proprionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369–382 (1959).
Bakker, J. et al. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat. Neurosci. 9, 220–226 (2006).
Bakker, J. & Baum, M. J. Role for estradiol in female-typical brain and behavioral sexual differentiation. Front. Neuroendocrinol. 29, 1–16 (2008).
Arnold, A. P. & Chen, X. What does the “four core genotypes” mouse model tell us about sex differences in the brain and other tissues? Front. Neuroendocrinol. 30, 1–9 (2009).
Arnold, A. P. et al. The importance of having two X chromosomes. Phil. Trans. R. Soc. B 371, 20150113 (2016).
Bramble, M. S. et al. Sex-specific effects of testosterone on the sexually dimorphic transcriptome and epigenome of embryonic neural stem/progenitor cells. Sci. Rep. 6, 36916 (2016). This study shows that, in mouse embryonic stem cells, the transcriptional response to testosterone exposure is different in males versus females in both expression levels and numbers of genes responding.
Goodfellow, P. N. & Lovell-Badge, R. SRY and sex determination in mammals. Annu. Rev. Genet. 27, 71–92 (1993).
Dewing, P. et al. Direct regulation of adult brain function by the male-specific factor SRY. Curr. Biol. 16, 415–420 (2006).
Czech, D. P. et al. The human testis-determining factor SRY localizes in midbrain dopamine neurons and regulates multiple components of catecholamine synthesis and metabolism. J. Neurochem. 122, 260–271 (2012).
De Vries, G. J. et al. A model system for study of sex chromosome effects on sexually dimorphic neural and behavioral traits. J. Neurosci. 22, 9005–9014 (2002).
Chen, X. et al. Sex difference in neural tube defects in p53-null mice is caused by differences in the complement of X not Y genes. Dev. Neurobiol. 68, 265–273 (2008).
Gioiosa, L., Chen, X., Watkins, R., Umeda, E. A. & Arnold, A. P. Sex chromosome complement affects nociception and analgesia in newborn mice. J. Pain 9, 962–969 (2008).
Arnold, A. P. et al. Minireview: sex chromosomes and brain sexual differentiation. Endocrinology 145, 1057–1062 (2004).
Smith-Bouvier, D. L. et al. A role for sex chromosome complement in the female bias in autoimmune disease. J. Exp. Med. 205, 1099–1108 (2008).
Du, S. et al. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 111, 2806–2811 (2014). This study shows that the impact of chromosome complement on disease progression in an animal model of multiple sclerosis is opposite in peripheral versus central nervous system tissues.
Voskuhl, R. Preclinical studies of sex differences: a clinical perspective. Biol. Sex Differ. 7, 7 (2016).
Grimm, S. L., Hartig, S. M. & Edwards, D. P. Progesterone receptor signaling mechanisms. J. Mol. Biol. 428, 3831–3849 (2016).
Stanisic, V., Lonard, D. M. & O'Malley, B. W. Modulation of steroid hormone receptor activity. Prog. Brain Res. 181, 153–176 (2010).
Katzenellenbogen, B. S. et al. Structure-function relationships in estrogen receptors and the characterization of novel selective estrogen receptor modulators with unique pharmacological profiles. Ann. NY Acad. Sci. 949, 6–15 (2001).
Quan, N. & Banks, W. A. Brain-immune communication pathways. Brain Behav. Immun. 21, 727–735 (2007).
McAllister, A. K. & van de Water, J. Breaking boundaries in neural–immune interactions. Neuron 64, 9–12 (2009).
Kipnis, J. Multifaceted interactions between adaptive immunity and the central nervous system. Science 353, 766–771 (2016).
Vezzani, A. & Viviani, B. Neuromodulatory properties of inflammatory cytokines and their impact on neuronal excitability. Neuropharmacology 96, 70–82 (2015).
Rostene, W., Kitabgi, P. & Parsadaniantz, S. M. Chemokines: a new class of neuromodulator? Nat. Rev. Neurosci. 8, 895–903 (2007).
Rivest, S. Regulation of innate immune responses in the brain. Nat. Rev. Immunol. 9, 429–439 (2009).
Alliot, F., Godin, I. & Pessac, B. Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain Res. Dev. Brain Res. 117, 145–152 (1999).
Ginhoux, F. et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845 (2010).
Cuadros, M. A. & Navascues, J. The origin and differentiation of microglial cells during development. Prog. Neurobiol. 56, 173–189 (1998).
Verney, C., Monier, A., Fallet-Bianco, C. & Gressens, P. Early microglial colonization of the human forebrain and possible involvement in periventricular white-matter injury of preterm infants. J. Anat. 217, 436–448 (2010).
Ajami, B., Bennett, J. L., Krieger, C., Tetzlaff, W. & Rossi, F. M. Local self-renewal can sustain CNS microglia maintenance and function throughout adult life. Nat. Neurosci. 10, 1538–1543 (2007).
Schwarz, J., Sholar, P. W. & Bilbo, S. D. Sex differences in microglial colonization of the developing rat brain. J. Neurochem. 120, 948–963 (2012). This is the first report of a sex difference in microglia, showing that males have higher numbers of microglia that are more activated at early stages and that there is a switch to female preponderance around puberty.
Lenz, K. M., Nugent, B. M., Haliyur, R. & McCarthy, M. M. Microglia are essential to masculinization of brain and behavior. J. Neurosci. 33, 2761–2772 (2013). This study establishes a functional role for more activated microglia in the developing POA mediating masculinization of synaptic profile and adult copulatory behaviour.
Hull, E. M. & Dominguez, J. M. Sexual behavior in male rodents. Horm. Behav. 52, 45–55 (2007).
Keller, M., Baum, M. J., Brock, O., Brennan, P. A. & Bakker, J. The main and the accessory olfactory systems interact in the control of mate recognition and sexual behavior. Behav. Brain Res. 200, 268–276 (2009).
Amateau, S. K., Alt, J. J., Stamps, C. L. & McCarthy, M. M. Brain estradiol content in newborn rats: sex differences, regional heterogeneity, and possible de novo synthesis by the female telencephalon. Endocrinology 145, 2906–2917 (2004).
Amateau, S. K. & McCarthy, M. M. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostglandin-E2. J. Neurosci. 22, 8586–8596 (2002).
Amateau, S. K. & McCarthy, M. M. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat. Neurosci. 7, 643–650 (2004). This study identifies a prostaglandin as both necessary and sufficient for masculinizing the synaptic profile of POA neurons and adult copulatory behaviour.
Wright, C. L., Burks, S. R. & McCarthy, M. M. Identification of prostaglandin E2 receptors mediating perinatal masculinization of adult sex behavior and neuroanatomical correlates. Dev. Neurobiol. 68, 1406–1419 (2008).
Wright, C. L. & McCarthy, M. M. Prostaglandin E2-induced masculinization of brain and behavior requires protein kinase A, AMPA/kainate, and metabotropic glutamate receptor signaling. J. Neurosci. 29, 13274–13282 (2009).
Lenz, K. M., Wright, C. L., Martin, R. C. & McCarthy, M. M. Prostaglandin E regulates AMPA receptor phosphorylation and promotes membrane insertion in preoptic area neurons and glia during sexual differentiation. PLoS ONE 6, e18500 (2011).
VanRyzin, J. W., Yu, S. J., Perez-Pouchoulen, M. & McCarthy, M. M. Temporary depletion of microglia during the early postnatal period induces lasting sex-dependent and sex-independent effects on behavior in rats. eNeuro http://dx.doi.org/10.1523/ENEURO.0297-16.2016 (2016).
Nelson, L. H. & Lenz, K. M. Microglia depletion in early life programs persistent changes in social, mood-related, and locomotor behavior in male and female rats. Behav. Brain Res. 316, 279–293 (2017).
Waters, E. M. & Simerly, R. B. Estrogen induces caspase-dependent cell death during hypothalamic development. J. Neurosci. 29, 9714–9718 (2009).
Krishnan, S., Intlekofer, K. A., Aggison, L. K. & Petersen, S. L. Central role of TRAF-interacting protein in a new model of brain sexual differentiation. Proc. Natl Acad. Sci. USA 106, 16692–16697 (2009). This study shows that the higher cell death in the developing male AVPV is mediated by the suppression of the TNF receptor-associated cell survival pathway.
Petersen, S. L., Krishnan, S., Aggison, L. K., Intlekofer, K. A. & Moura, P. J. Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical NfκB signaling pathway. Front. Neuroendocrinol. 33, 36–44 (2012).
Radjavi, A., Smirnov, I. & Kipnis, J. Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav. Immun. 35, 58–63 (2014).
Filiano, A. J. et al. Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535, 425–429 (2016).
Rilett, K. C. et al. Loss of T cells influences sex differences in behavior and brain structure. Brain Behav. Immun. 46, 249–260 (2015). In this study, null mutations in T-cell receptors both reveal and eliminate sex differences in brain and behaviour in mice.
del Abril, A., Segovia, S. & Guillamon, A. The bed nucleus of the stria terminalis in the rat: regional sex differences controlled by gonadal steroids early after birth. Dev. Brain Res. 32, 295–300 (1987).
Okayama, Y. & Kawakami, T. Development, migration, and survival of mast cells. Immunol. Res. 34, 97–115 (2006).
Silver, R. & Curley, J. P. Mast cells on the mind: new insights and opportunities. Trends Neurosci. 36, 513–521 (2013).
Khalil, M. H., Silverman, A. J. & Silver, R. Mast cells in the rat brain synthesize gonadotropin-releasing hormone. J. Neurobiol. 56, 113–124 (2003).
Kriegsfeld, L. J. et al. Brain mast cells are influenced by chemosensory cues associated with estrus induction in female prairie voles (Microtus ochrogaster). Horm. Behav. 44, 377–384 (2003).
Mackey, E. et al. Sexual dimorphism in the mast cell transcriptome and the pathophysiological responses to immunological and psychological stress. Biol. Sex Differ. 7, 60 (2016).
Sweatt, J. D. The emerging field of neuroepigenetics. Neuron 80, 624–632 (2013).
Reardon, P. K. et al. An allometric analysis of sex and sex chromosome dosage effects on subcortical anatomy in humans. J. Neurosci. 36, 2438–2448 (2016). This study reveals that sex differences in the size of two subcortical structures are further modified by sex chromosome aneuploidies in both men and women.
Torchia, J., Glass, C. & Rosenfeld, M. G. Co-activators and co-repressors in the integration of transcriptional responses. Curr. Opin. Cell Biol. 10, 373–383 (1998).
Klinge, C. M. Estrogen receptor interaction with co-activators and co-repressors. Steroids 65, 227–251 (2000).
De Vries, G. J. et al. Sexual differentiation of vasopressin innervation of the brain: cell death versus phenotypic differentiation. Endocrinology 149, 4632–4637 (2008).
Wang, Z. & De Vries, G. J. Androgen and estrogen effects on vasopressin messenger RNA expression in the medial amygdaloid nucleus in male and female rats. J. Neuroendocrinol. 7, 827–831 (1995).
Forbes-Lorman, R. M., Rautio, J. J., Kurian, J. R., Auger, A. P. & Auger, C. J. Neonatal MeCP2 is important for the organization of sex differences in vasopressin expression. Epigenetics 7, 230–238 (2012). In this study, a transient reduction in MeCP2 early in life permanently removed the sex difference in medial amygdala vasopressin expression by reducing it in males to female levels.
Argue, K. J. & McCarthy, M. M. Characterization of juvenile play in rats: importance of sex of self and sex of partner. Biol. Sex Differ. 6, 16 (2015).
Kurian, J. R., Olesen, K. M. & Auger, A. P. Sex differences in epigenetic regulation of the estrogen receptor-alpha promoter within the developing preoptic area. Endocrinology 151, 2297–2305 (2010).
Schwarz, J. M., Nugent, B. M. & McCarthy, M. M. Developmental and hormone-induced epigenetic changes to estrogen and progesterone receptor genes in brain are dynamic across the life span. Endocrinology 151, 4871–4881 (2010).
Nugent, B. M. & McCarthy, M. M. Epigenetic underpinnings of developmental sex differences in the brain. Neuroendocrinology 93, 150–158 (2011).
Nugent, B. M., Schwarz, J. M. & McCarthy, M. M. Hormonally mediated epigenetic changes to steroid receptors in the developing brain: implications for sexual differentiation. Horm. Behav. 59, 338–344 (2010).
Ghahramani, N. M. et al. The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging. Biol. Sex Differ. 5, 8 (2014). In this study, the short-term effects of neonatal hormone treatment were modest, but the number of genes with altered methylation increased by 20-fold in adulthood.
Nugent, B. M. et al. Brain feminization requires active repression of masculinization via DNA methylation. Nat. Neurosci. 18, 690–697 (2015). This study demonstrates that higher levels of DNA methylation in the POA of females repress the gene expression programme that is required for normal masculinization, an effect that can be reversed by hormone treatment and is dependent on DNMT activity.
Matsuda, K. I. et al. Histone deacetylation during brain development is essential for permanent masculinization of sexual behavior. Endocrinology 152, 2760–2767 (2011). This study shows that inhibition of HDAC2 and HDAC4 early in development prevents normal male sex behaviour in adulthood, perhaps in part by modifying sex-specific patterns of acetylation of oestrogen receptor-α and aromatase promoter regions.
Murray, E. K., Hien, A., de Vries, G. J. & Forger, N. G. Epigenetic control of sexual differentiation of the bed nucleus of the stria terminalis. Endocrinology 150, 4241–4247 (2009). In this study, treatment with the HDAC inhibitor valproic acid prevented the increased cell survival that normally occurs in males resulting in a BNST volume similar to that of females.
Berger, S. L. The complex language of chromatin regulation during transcription. Nature 447, 407–412 (2007).
Shen, E. Y. et al. Epigenetics and sex differences in the brain: a genome-wide comparison of histone-3 lysine-4 trimethylation (H3K4me3) in male and female mice. Exp. Neurol. 268, 21–29 (2015).
Arnold, A. P. & Lusis, A. J. Understanding the sexome: measuring and reporting sex differences in gene systems. Endocrinology 153, 2551–2555 (2012).
Bianchi, I., Lleo, A., Gershwin, M. E. & Invernizzi, P. The X chromosome and immune associated genes. J. Autoimmun. 38, J187–J192 (2012).
Schwarz, J. M., Hutchinson, M. R. & Bilbo, S. D. Early-life experience decreases drug-induced reinstatement of morphine CPP in adulthood via microglial-specific epigenetic programming of anti-inflammatory IL-10 expression. J. Neurosci. 31, 17835–17847 (2011).
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators. Prevalence of autism spectrum disorder among children aged 8 years — autism and developmental disabilities monitoring network, 11 sites, United States, 2010. MMWR Surveill. Summ. 63, 1–21 (2014).
Halladay, A. K. et al. Sex and gender differences in autism spectrum disorder: summarizing evidence gaps and identifying emerging areas of priority. Mol. Autism 6, 36 (2015).
Werling, D. M. & Geschwind, D. H. Sex differences in autism spectrum disorders. Curr. Opin. Neurol. 26, 146–153 (2013).
Kosidou, K. et al. Maternal polycystic ovary syndrome and the risk of autism spectrum disorders in the offspring: a population-based nationwide study in Sweden. Mol. Psychiatry 21, 1441–1448 (2016).
Ingudomnukul, E., Baron-Cohen, S., Wheelwright, S. & Knickmeyer, R. Elevated rates of testosterone-related disorders in women with autism spectrum conditions. Horm. Behav. 51, 597–604 (2007).
Baron-Cohen, S. et al. Elevated fetal steroidogenic activity in autism. Mol. Psychiatry 20, 369–376 (2015).
Windham, G. C., Lyall, K., Anderson, M. & Kharrazi, M. Autism spectrum disorder risk in relation to maternal mid-pregnancy serum hormone and protein markers from prenatal screening in California. J. Autism Dev. Disord. 46, 478–488 (2016).
Baron-Cohen, S. The extreme male brain theory of autism. Trends Cogn. Sci. 6, 248–254 (2002).
Voineagu, I. et al. Transcriptomic analysis of autistic brain reveals convergent molecular pathology. Nature 474, 380–384 (2011).
Gupta, S. et al. Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism. Nat. Commun. 5, 5748 (2014).
Werling, D. M., Parikshak, N. N. & Geschwind, D. H. Gene expression in human brain implicates sexually dimorphic pathways in autism spectrum disorders. Nat. Commun. 7, 10717 (2016). Re-analyses of existing transcriptomic data sets reveal sex differences in the fetal brain, including an increase in microglia-associated and activated astrocyte-associated genes in males. The same pattern was observed in adult males with ASD compared to neurotypic males.
Aleman, A., Kahn, R. S. & Selten, J. P. Sex differences in the risk of schizophrenia: evidence from meta-analysis. Arch. Gen. Psychiatry 60, 565–571 (2003).
Castle, D. J. & Murray, R. M. The neurodevelopmental basis of sex differences in schizophrenia. Psychol. Med. 21, 565–575 (1991).
Goldstein, J. M. Sex, hormones and affective arousal circuitry dysfunction in schizophrenia. Horm. Behav. 50, 612–622 (2006).
Goldstein, J. M. et al. Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch. Gen. Psychiatry 59, 154–164 (2002).
Moffitt, T. E. & Caspi, A. Childhood predictors differentiate life-course persistent and adolescence-limited antisocial pathways among males and females. Dev. Psychopathol. 13, 355–375 (2001).
Craig, A., Hancock, K., Tran, Y., Craig, M. & Peters, K. Epidemiology of stuttering in the community across the entire life span. J. Speech Lang. Hear. Res. 45, 1097–1105 (2002).
Rutter, M. et al. Sex differences in developmental reading disability: new findings from 4 epidemiological studies. JAMA 291, 2007–2012 (2004).
Quinn, J. M. & Wagner, R. K. Gender differences in reading impairment and in the identification of impaired readers: results from a large-scale study of at-risk readers. J. Learn. Disabil. 48, 433–445 (2015).
Wang, H. S. & Kuo, M. F. Tourette's syndrome in Taiwan: an epidemiological study of tic disorders in an elementary school at Taipei County. Brain Dev. 25 (Suppl. 1), S29–S31 (2003).
Biederman, J. et al. Influence of gender on attention deficit hyperactivity disorder in children referred to a psychiatric clinic. Am. J. Psychiatry 159, 36–42 (2002).
Gershon, J. A meta-analytic review of gender differences in ADHD. J. Atten. Disord. 5, 143–154 (2002).
Dirlikov, B. et al. Distinct frontal lobe morphology in girls and boys with ADHD. Neuroimage Clin. 7, 222–229 (2015).
Jacobson, L. A. et al. Sex-based dissociation of white matter microstructure in children with attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 54, 938–946 (2015).
Biederman, J. et al. Sexually dimorphic effects of four genes (COMT, SLC6A2, MAOA, SLC6A4) in genetic associations of ADHD: a preliminary study. Am. J. Med. Genet B Neuropsychiatr. Genet. 147B, 1511–1518 (2008).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999).
Berletch, J. B., Yang, F., Xu, J., Carrel, L. & Disteche, C. M. Genes that escape from X inactivation. Hum. Genet. 130, 237–245 (2011).
Simerly, R. B. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25, 507–536 (2002).
Xu, J., Deng, X. & Disteche, C. M. Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PLoS ONE 3, e2553 (2008).
Xu, J., Deng, X., Watkins, R. & Disteche, C. M. Sex-specific differences in expression of histone demethylases Utx and Uty in mouse brain and neurons. J. Neurosci. 28, 4521–4527 (2008). This study shows that sex chromosome paralogue genes that escape X inactivation are differentially expressed in males and females in a brain region-specific manner.
Gorski, R. A., Gordon, J. H., Shryne, J. E. & Southam, A. M. Evidence for a morphological sex difference within the medial preoptic area of the rat brain. Brain Res. 148, 333–346 (1978).
Matsumoto, A. & Arai, Y. Sex difference in volume of the ventromedial nucleus of the hypothalamus in the rat. Endocrinol. Jpn. 30, 227–280 (1983).
Reid, S. N. M. & Juraska, J. M. Sex differences in the neuron number in binocular area of rat visual cortex. J. Comp. Neurol. 321, 448–455 (1992).
Mizukami, S., Nishizuka, M. & Arai, Y. Sexual difference in nuclear volume and its ontogeny in the rat amygdala. Exp. Neurol. 79, 569–575 (1983).
Van Eden, C. G., Uylings, H. B. & Van Pelt, J. Sex-difference and left-right asymmetries in the prefrontal cortex during postnatal development in the rat. Brain Res. 314, 146–153 (1984).
Davis, E. C., Shryne, J. E. & Gorski, R. A. Structural sexual dimorphisms in the anteroventral periventricular nucleus of the rat hypothalamus are sensitive to gonadal steroids perinatally, but develop peripubertally. Neuroendocrinology 63, 142–148 (1996).
Guillamon, A., de Blas, M. R. & Segovia, S. Effects of sex steroids on the development of the locus coeruleus in the rat. Brain Res. 468, 306–310 (1988).
Cooke, B. M., Tabibnia, G. & Breedlove, S. M. A brain sexual dimorphism controlled by adult circulating androgens. Proc. Natl Acad. Sci. USA 96, 7538–7540 (1999).
De Vries, G. J., Buds, M. R. & Swaab, D. F. Ontogeny of vassopressinergic 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, 67–78 (1981).
Simerly, R. B., Swanson, L. W. & Gorski, R. A. Reversal of the sexually dimorphic distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus by treatment with perinatal androgen. Brain Res. 340, 91–98 (1985).
Miller, M. A., Vician, L., Clifton, D. K. & Dorsa, D. M. Sex differences in vassopressin neurons in the bed nucleus of the stria terminalis by in situ hybridization. Peptides 10, 615–619 (1989).
Clarkson, J. & Herbison, A. E. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147, 5817–5825 (2006).
Raisman, G. & Field, P. M. Sexual dimorphism in the preoptic area of the rat. Science 173, 731–733 (1971).
Raisman, G. & Field, P. M. Sexual dimorphism in the neuropil of the preoptic area of the rat and its dependence on neonatal androgen. Brain Res. 54, 1–29 (1973).
Gould, E., Westlind-Danielsson, A., Frankfurt, M. & McEwen, B. S. Sex differences and thyroid hormone sensitivity of hippocampal pyramidal neurons. J. Neurosci. 10, 996–1003 (1990).
Matsumoto, A. & Arai, Y. Sexual dimorphism in 'wiring pattern' in the hypothalamic arcuate nucleus and its modification by neonatal hormonal environment. Brain Res. 19, 238–242 (1980).
Matsumoto, A. & Arai, Y. Male-female differences in synaptic organization of the ventromedial nucleus of the hypothalamus in the rat. Neuroendocrinolgy 42, 232–236 (1986).
Mong, J. A., Glaser, E. & McCarthy, M. M. Gonadal steroids promote glial differentiation and alter neuronal morphology in the developing hypothalamus in a regionally specific manner. J. Neurosci. 19, 1464–1472 (1999).
Shors, T. J., Chua, C. & Falduto, J. Sex differences and opposite effects of stress on dendritic spine density in the male versus female hippocampus. J. Neurosci. 21, 6292–6297 (2001).
Galea, L. A. M. et al. Sex differences in dendrtic atrophy of CA3 pyramidal neurons in response to chronic restraint stress. Neuroscience 81, 689–697 (1997).
Kolb, B. & Stewart, J. Sex-related differences in dendritic branching of cells in prefrontal cortex of rats. J. Neuroendocrinol. 3, 95–99 (1991).
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, 584–598 (2008).
Juraska, J. M., Fitch, J. M., Henderson, C. & Rivers, N. Sex differences in the dendritic branching of dentate granule cells following differential experience. Brain Res. 29, 73–80 (1985).
Verhovshek, T., Buckley, K. E., Sergent, M. A. & Sengelaub, D. R. Testosterone metabolites differentially maintain adult morphology in a sexually dimorphic neuromuscular system. Dev. Neurobiol. 70, 206–221 (2010).
Han, T. M. & De Vries, G. J. Organizational effects of testosterone, estradiol, and dihydrotestosterone on vasopressin mRNA expression in the bed nucleus of the stria terminalis. J. Neurobiol. 54, 502–510 (2003).
Shah, N. M. et al. Visualizing sexual dimorphism in the brain. Neuron 43, 313–319 (2004).
Yokosuka, M., Okamura, H. & Hayashi, S. 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, 81–93 (1997).
Kauffman, A. S. et al. Sexual differentiation of Kiss1 expression in the brain of the rat. Endocrinology 148, 1774–1783 (2006).
Carlsson, M., Svensson, K., Eriksson, E. & Carlsson, A. Rat brain serotonin: biochemical and functional evidence for a sex difference. J. Neural Transm. 63, 297–313 (1985).
Roselli, C. E. & Resko, J. A. Aromatase activity in the rat brain: hormonal regulation and sex differences. J. Steroid Biochem. Mol. Biol. 44, 499–508 (1993).
Yang, C. F. et al. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 153, 896–909 (2013). This study demonstrates that progesterone receptor-expressing neurons subserve distinct but related roles in males and females.
Quadros, P. S., Pfau, J. L., Goldstein, A. Y., De Vries, G. J. & Wagner, C. K. Sex differences in progesterone receptor expression: a potential mechanism for estradiol-mediated sexual differentiation. Endocrinology 143, 3727–3739 (2002).
Garcia-Segura, L. M. et al. The distribution of glial fibrillary acidic protein in the adult rat brain is influenced by the neonatal levels of sex steroids. Brain Res. 456, 357–363 (1988).
Johnson, R. T., Breedlove, S. M. & Jordan, C. L. Sex differences and laterality in astrocyte number and complexity in the adult rat medial amygdala. J. Comp. Neurol. 511, 599–609 (2008).
Tobet, S. A. & Fox, T. O. Sex- and hormone-dependent antigen immunoreactivity in developing rat hypothalamus. Proc. Natl Acad. Sci. USA 86, 382–386 (1989).
Marin-Husstega, M., Muggironi, M., Raban, D., Skoff, R. P. & Casacia-Bonnefil, P. Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev. Neurosci. 26, 245–254 (2004).
Pfau, D. R., Hobbs, N. J., Breedlove, S. M. & Jordan, C. L. Sex and laterality differences in medial amygdala neurons and astrocytes of adult mice. J. Comp. Neurol. 524, 2492–2502 (2016).
Nunez, J. L. & McCarthy, M. M. Evidence for an extended duration of GABA-mediated excitation in the developing male versus female hippocampus. Dev. Neurobiol. 67, 1879–1890 (2007).
Diaz, S. et al. Sex differences in the cannabinoid modulation of appetite, body temperature and neurotransmission at POMC synapses. Neuroendocrinology 89, 424–440 (2009).
Becker, J. B. & Beer, M. E. The influence of estrogen on nigrostriatal dopamine activity: behavioral and neurochemical evidence for both pre- and postsynaptic components. Behav. Brain Res. 19, 27–33 (1986).
Zhang, J.-M., Konkle, A. T. M., Zup, S. L. & McCarthy, M. M. Impact of sex and hormones on new cells in the developing rat hippocampus: a novel source of sex dimorphism? Eur. J. Neurosci. 27, 791–800 (2008).
Bowers, J. M., Waddell, J. & McCarthy, M. M. A developmental sex difference in hippocampal neurogenesis is mediated by endogenous oestradiol. Biol. Sex Differ. 1, 8 (2010). This is the first report of a sex difference in cell genesis and its modulation by endogenous possibly locally synthesized oestradiol.
Krebs-Kraft, D. L., Hill, M. N., Hillard, C. J. & McCarthy, M. M. Sex difference in cell proliferation in developing rat amygdala mediated by endocannabinoids has implications for social behavior. Proc. Natl Acad. Sci. USA 107, 20535–20540 (2010).
Pinos, H. et al. The development of sex differences in the locus coeruleus of the rat. Brain Res. Bull. 56, 73–78 (2001).
Ahmed, E. I. et al. Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions. Nat. Neurosci. 11, 995–997 (2008). This study shows that volumetric sex differences in three brain regions seem to be actively maintained by the addition of new cells during the peripubertal period.
Gillberg, C., Cederlund, M., Lamberg, K. & Zeijlon, L. Brief report: “the autism epidemic”. The registered prevalence of autism in a Swedish urban area. J. Autism Dev. Disord. 36, 429–435 (2006).
Fombonne, E. Epidemiology of pervasive developmental disorders. Pediatr. Res. 65, 591–598 (2009).
Loeber, R., Burke, J. D., Lahey, B. B., Winters, A. & Zera, M. Oppositional defiant and conduct disorder: a review of the past 10 years, part I. J. Am. Acad. Child Adolesc. Psychiatry 39, 1468–1484 (2000).
Trepat, E. & Ezpeleta, L. Sex differences in oppositional defiant disorder. Psicothema 23, 666–671 (2011).
Gaub, M. & Carlson, C. L. Gender differences in ADHD: a meta-analysis and critical review. J. Am. Acad. Child Adolesc. Psychiatry 36, 1036–1045 (1997).
Arcia, E. & Conners, C. K. Gender differences in ADHD? J. Dev. Behav. Pediatr. 19, 77–83 (1998).
Bergen, S. E. et al. Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history. Schizophr. Res. 154, 48–53 (2014).
Walder, D. J. et al. Sex differences in language dysfunction in schizophrenia. Am. J. Psychiatry 163, 470–477 (2006).
Castle, D. J., Abel, K., Takei, N. & Murray, R. M. Gender differences in schizophrenia: hormonal effect or subtypes. Schizophr. Bull. 21, 1–12 (1995).
Cyranowski, J. M., Frank, E., Young, E. & Shear, M. K. Adolescent onset of the gender difference in lifetime rates of major depression: a theoretical model. Arch. Gen. Psychiatry 57, 21–27 (2000).
Weissman, M. M. et al. Sex differences in rates of depression: cross-national perspectives. J. Affect. Disord. 29, 77–84 (1993).
Weissman, M. M. & Klerman, G. L. Sex differences and the epidemiology of depression. Arch. Gen. Psychiatry 34, 98–111 (1977).
Alonso, J. et al. Prevalence of mental disorders in Europe: results from the European Study of the Epidemiology of Mental Disorders (ESEMeD) project. Acta Psychiatr. Scand. Suppl. 109, 21–27 (2004).
Kessler, R. C. Epidemiology of women and depression. J. Affect. Disord. 74, 5–13 (2003).
Robb, J. C., Young, L. T., Cooke, R. G. & Joffe, R. T. Gender differences in patients with bipolar disorder influence outcome in the medical outcomes survey (SF-20) subscale scores. J. Affect. Disord. 49, 189–193 (1998).
Leibenluft, E. Women with bipolar illness: clinical and research issues. Am. J. Psychiatry 153, 163–173 (1996).
Arnold, L. M. Gender differences in bipolar disorder. Psychiatr. Clin. North Am. 26, 595–620 (2003).
Dao, D. T. et al. Mood disorder susceptibility gene CACNA1C modifies mood-related behaviors in mice and interacts with sex to influence behavior in mice and diagnosis in humans. Biol. Psychiatry 68, 801–810 (2010).
McLean, C. P., Asnaani, A., Litz, B. T. & Hofmann, S. G. Gender differences in anxiety disorders: prevalence, course of illness, comorbidity and burden of illness. J. Psychiatr. Res. 45, 1027–1035 (2011).
Kessler, R. C. et al. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch. Gen. Psychiatry 51, 8–19 (1994).
Breslau, N., Schultz, L. & Peterson, E. Sex differences in depression: a role for preexisting anxiety. Psychiatry Res. 58, 1–12 (1995).
Bogetto, F., Venturello, S., Albert, U., Maina, G. & Ravizza, L. Gender-related clinical differences in obsessive-compulsive disorder. Eur. Psychiatry 14, 434–441 (1999).
Kessler, R. C., Sonnega, A., Bromet, E., Hughes, M. & Nelson, C. B. Posttraumatic stress disorder in the National Comorbidity Survey. Arch. Gen. Psychiatry 52, 1048–1060 (1995).
Breslau, N., Davis, G. C., Andreski, P., Peterson, E. L. & Schultz, L. R. Sex differences in posttraumatic stress disorder. Arch. Gen. Psychiatry 54, 1044–1048 (1997).
Hudson, J. I., Hiripi, E., Pope, H. G. Jr & Kessler, R. C. The prevalence and correlates of eating disorders in the National Comorbidity Survey Replication. Biol. Psychiatry 61, 348–358 (2007).
Raevuori, A., Keski-Rahkonen, A. & Hoek, H. W. A review of eating disorders in males. Curr. Opin. Psychiatry 27, 426–430 (2014).
Bulik, C. M. et al. Prevalence, heritability, and prospective risk factors for anorexia nervosa. Arch. Gen. Psychiatry 63, 305–312 (2006).
Woodside, D. B. et al. Comparisons of men with full or partial eating disorders, men without eating disorders, and women with eating disorders in the community. Am. J. Psychiatry 158, 570–574 (2001).
Ceylan-Isik, A. F., McBride, S. M. & Ren, J. Sex difference in alcoholism: who is at a greater risk for development of alcoholic complication? Life Sci. 87, 133–138 (2010).
Lipton, R. B., Stewart, W. F., Diamond, S., Diamond, M. L. & Reed, M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41, 646–657 (2001).
Buse, D. C. et al. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache 53, 1278–1299 (2013).
Petrea, R. E. et al. Gender differences in stroke incidence and poststroke disability in the Framingham Heart Study. Stroke 40, 1032–1037 (2009).
Persky, R. W., Turtzo, L. C. & McCullough, L. D. Stroke in women: disparities and outcomes. Curr. Cardiol. Rep. 12, 6–13 (2010).
Orton, S. M. et al. Sex ratio of multiple sclerosis in Canada: a longitudinal study. Lancet Neurol. 5, 932–936 (2006).
Whitacre, C. C. Sex differences in autoimmune disease. Nat. Immunol. 2, 777–780 (2001).
Beeson, P. B. Age and sex associations of 40 autoimmune diseases. Am. J. Med. 96, 457–462 (1994).
Fratiglioni, L. et al. Very old women at highest risk of dementia and Alzheimer's disease: incidence data from the Kungsholmen Project, Stockholm. Neurology 48, 132–138 (1997).
Ott, A., Breteler, M. M., van Harskamp, F., Stijnen, T. & Hofman, A. Incidence and risk of dementia. The Rotterdam Study. Am. J. Epidemiol. 147, 574–580 (1998).
Di Carlo, A. et al. Incidence of dementia, Alzheimer's disease, and vascular dementia in Italy. The ILSA Study. J. Am. Geriatr. Soc. 50, 41–48 (2002).
Barnes, L. L. et al. Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch. Gen. Psychiatry 62, 685–692 (2005).
Haaxma, C. A. et al. Gender differences in Parkinson's disease. J. Neurol. Neurosurg. Psychiatry 78, 819–824 (2007).
McCombe, P. A. & Henderson, R. D. Effects of gender in amyotrophic lateral sclerosis. Gend. Med. 7, 557–570 (2010).
Acknowledgements
M.M.M. is supported by US National Institutes of Health (NIH) grant R01MH052716-19, R01DA039062 and R01MH091424. K.M.L. is supported by NIH grants F32NS076327 and R21MH105826, and NARSAD Young Investigator Award 2382.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Related links
FURTHER INFORMATION
Glossary
- Functional MRI
-
The detection of changes in regional brain activity through their effects on blood flow and blood oxygenation that in turn affect the brightness of magnetic resonance images.
- Diffusion tensor imaging
-
An MRI technique that provides a three-dimensional image of water diffusion in the brain. As water diffuses more readily along the axis of myelinated nerve fibre tracts, this method can be used to obtain a non-invasive estimate of anatomical connectivity between brain areas.
- Connectome
-
A comprehensive map of neural connections within the nervous system of an organism.
- Steroid hormone
-
A signalling molecule that is synthesized from cholesterol and is released into the circulation from endocrine glands including the gonads and adrenals. It binds to nuclear transcription factor receptors and can directly and indirectly modify gene expression.
- Early life programming
-
The phenomenon whereby events during development, such as stress, altered nutrition or endogenous hormone exposure, exert enduring influences on the nervous system in anticipation of the adult environment and experiences.
- Critical period
-
A developmental window during which specific cellular events must occur or will be forever precluded. Sexual differentiation of the brain mediated by steroid hormones occurs during a perinatal critical period in the rodent and prenatally in humans.
- Hormone response elements
-
Sequences of DNA in promoter regions that are recognized and bound to by steroid hormone receptors after binding of hormone, thereby promoting transcription.
- Humoral signalling
-
Signalling molecules released into the blood stream that then act at a distance, such as steroid hormones.
- Cytokine
-
Originally defined as an immune system protein that modifies biological responses; cytokines are now known to be released by most cells and are important in regulating intercellular communication, cell function and cell survival.
- Immune surveillance
-
The hypothesized process by which the immune system constantly monitors the body for both invading pathogens and aberrant cell pathology, such as that seen in cancer.
- Neuromodulators
-
Endogenous chemical substances that change the intrinsic properties of a neuron and the dynamics and strength of neurotransmission. Neuromodulators can modify neuronal responses to synaptic inputs on potentially long timescales.
- Neurohormones
-
Steroid hormones that are further modified in the brain or synthesized de novo from cholesterol in the brain and are thus distinguished from those synthesized in the endocrine glands. Other neurohormones are peptides synthesized in the brain and released into the periphery such as oxytocin and vasopressin.
- T cells
-
Lymphocytes produced by the thymus gland that actively participate in the immune response.
- Mast cells
-
Multigranular cells that function as stores for several key inflammatory and/or pain mediators (including nerve growth factor, tumour necrosis factor, chemokines and histamine) and that originate in bone marrow but have a resident population in the brain.
- Epigenetic marks
-
Modifications to the genome that do not change the nucleotide sequence but have an impact on gene regulation. Methylation groups added to cytosine nucleotides or histones on the chromatin, along with other chemical groups, are examples of epigenetic marks.
- Chemokines
-
A subfamily of inflammatory molecules that were initially described as regulators of the chemotaxis of inflammatory cells but that also have important roles in other processes, such as cell growth and differentiation.
Rights and permissions
About this article
Cite this article
McCarthy, M., Nugent, B. & Lenz, K. Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nat Rev Neurosci 18, 471–484 (2017). https://doi.org/10.1038/nrn.2017.61
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn.2017.61
This article is cited by
-
Microbial composition, functionality, and stress resilience or susceptibility: unraveling sex-specific patterns
Biology of Sex Differences (2024)
-
Relationship between sex biases in gene expression and sex biases in autism and Alzheimer’s disease
Biology of Sex Differences (2024)
-
Sex-biased gene and microRNA expression in the developing mouse brain is associated with neurodevelopmental functions and neurological phenotypes
Biology of Sex Differences (2023)
-
Comparison of predictive effect of the dietary inflammatory index and empirically derived food-based dietary inflammatory index on the menopause-specific quality of life and its complications
BMC Women's Health (2023)
-
Zebrafish gonad mutant models reveal neuroendocrine mechanisms of brain sexual dimorphism and male mating behaviors of different brain regions
Biology of Sex Differences (2023)