Sexual Differentiation of the Brain and Behavior: A Primer

Living reference work entry


A general theory of sexual differentiation of the brain derives from classic experiments performed in the twentieth century, which showed that androgens from the testes act early in the development to cause some regions of the male’s brain to develop differently from those in the female. Further sex differences in brain structure and function are induced also by the effects of sex hormones from both the testes and ovaries later in life. In addition, sex chromosome genes on the X and Y chromosome are expressed inherently differently in female and male brains and cause them to be different. The sex hormones create specific sex differences in brain function by regulating cell death and birth leading to sex differences in the number of neurons. Sex hormones also regulate the length of dendrites and number of synapses devoted to specific tasks. Sex hormones cause epigenetic changes with broad impact on a large number of molecular pathways. A general principle is that cellular and molecular mechanisms leading to sex differences are highly diverse, differing in each specific brain region. Moreover, in humans the effects of gendered environments interact with multiple biological factors to produce brains that are not necessarily uniformly masculine or feminine, but a unique mixture in each individual.


Sex hormones Sex chromosomes Cell death Synaptogenesis Epigenetic 


  1. Arnold AP (2009) The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues. Horm Behav 55:570–578CrossRefPubMedPubMedCentralGoogle Scholar

Further Reading

  1. Arnold AP (2004) Sex chromosomes and brain gender. Nat Rev Neurosci 5:701–708CrossRefPubMedGoogle Scholar
  2. Arnold AP (2011) The end of gonad-centric sex determination in mammals. Trends Genet 28:55–61CrossRefPubMedPubMedCentralGoogle Scholar
  3. Arnold AP, Gorski RA (1984) Gonadal steroid induction of structural sex differences in the CNS. Annu Rev Neurosci 7:413–442CrossRefPubMedGoogle Scholar
  4. Auger AP, Olesen KM (2009) Brain sex differences and the organisation of juvenile social play behaviour. J Neuroendocrinol 21:519–525CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bakker J, Honda S, Harada N, Balthazart J (2003) The aromatase knockout (ArKO) mouse provides new evidence that estrogens are required for the development of the female brain. Ann NY Acad Sci 1007:251–262CrossRefPubMedGoogle Scholar
  6. Bakker J, De MC, Douhard Q, Balthazart J, Gabant P, Szpirer J, Szpirer C (2006) Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat Neurosci 9:220–226CrossRefPubMedGoogle Scholar
  7. Bale TL, Epperson CN (2015) Sex differences and stress across the lifespan. Nat Neurosci 18:1413–1420CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bale TL, Baram TZ, Brown AS, Goldstein JM, Insel TR, McCarthy MM, Nemeroff CB, Reyes TM, Simerly RB, Susser ES, Nestler EJ (2010) Early life programming and neurodevelopmental disorders. Biol Psychiatry 68:314–319CrossRefPubMedPubMedCentralGoogle Scholar
  9. Baum MJ (2003) Activational and organizational effects of estradiol on male behavioral neuroendocrine function. Scand J Psychol 44:213–220CrossRefPubMedGoogle Scholar
  10. Cahill L (2010) Sex influences on brain and emotional memory: the burden of proof has shifted. Prog Brain Res 186:29–40CrossRefPubMedGoogle Scholar
  11. Capel B, Coveney D (2004) Frank Lillie’s freemartin: illuminating the pathway to 21st century reproductive endocrinology. J Exp Zool A Comp Exp Biol 301:853–856CrossRefPubMedGoogle Scholar
  12. Clayton JA, Collins FS (2014) Policy: NIH to balance sex in cell and animal studies. Nature 509:282–283CrossRefPubMedGoogle Scholar
  13. De Vries GJ (2004) Minireview: sex differences in adult and developing brains: compensation, compensation, compensation. Endocrinology 145:1063–1068CrossRefPubMedGoogle Scholar
  14. Forger NG (2006) Cell death and sexual differentiation of the nervous system. Neuroscience 138:929–938CrossRefPubMedGoogle Scholar
  15. Hines M (2002) Sexual differentiation of human brain and behavior. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT (eds) Hormones, brain and behavior. Academic, New York, pp 425–462CrossRefGoogle Scholar
  16. Hines M (2010) Sex-related variation in human behavior and the brain. Trends Cogn Sci 14:448–456CrossRefPubMedPubMedCentralGoogle Scholar
  17. Jost A, Vigier B, Prepin J, Perchellet JP (1973) Studies on sex differentiation in mammals. Recent Prog Horm Res 29:1–41PubMedGoogle Scholar
  18. Juntti SA, Coats JK, Shah NM (2008) A genetic approach to dissect sexually dimorphic behaviors. Horm Behav 53:627–637CrossRefPubMedPubMedCentralGoogle Scholar
  19. MacLusky NJ, Naftolin F (1981) Sexual differentiation of the central nervous system. Science 211:1294–1303CrossRefPubMedGoogle Scholar
  20. McCarthy MM, Arnold AP (2011) Reframing sexual differentiation of the brain. Nat Neurosci 14:677–683CrossRefPubMedPubMedCentralGoogle Scholar
  21. McCarthy MM, Arnold AP, Ball GF, Blaustein JD, De Vries GJ (2012) Sex differences in the brain: the not so inconvenient truth. J Neurosci 32:2241–2247CrossRefPubMedPubMedCentralGoogle Scholar
  22. McCarthy MM, Pickett LA, VanRyzin JW, Kight KE (2015) Surprising origins of sex differences in the brain. Horm Behav 76:3–10CrossRefPubMedGoogle Scholar
  23. Schaafsma SM, Pfaff DW (2014) Etiologies underlying sex differences in autism spectrum disorders. Front Neuroendocrinol 35:255–271CrossRefPubMedGoogle Scholar
  24. Simerly RB (2002) Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu Rev Neurosci 25:507–536CrossRefPubMedGoogle Scholar
  25. Voskuhl RR, Gold SM (2012) Sex-related factors in multiple sclerosis susceptibility and progression. Nat Rev Neurol 8:255–263CrossRefPubMedPubMedCentralGoogle Scholar
  26. Wade J, Arnold AP (2004) Sexual differentiation of the zebra finch song system. Ann N Y Acad Sci 1016:540–559CrossRefPubMedGoogle Scholar
  27. Wallen K (2005) Hormonal influences on sexually differentiated behavior in nonhuman primates. Front Neuroendocrinol 26:7–26CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.Department of Integrative Biology and Physiology, and Laboratory of Neuroendocrinology of the Brain Research InstituteUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Pharmacology and Program in NeuroscienceUniversity of Maryland School of MedicineBaltimoreUSA

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