Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Sexual differentiation of the vertebrate nervous system

Nature Neuroscience volume 7, pages 1034–1039 (2004)Cite this article

Abstract

Understanding the mechanisms that give rise to sex differences in the behavior of nonhuman animals may contribute to the understanding of sex differences in humans. In vertebrate model systems, a single factor—the steroid hormone testosterone—accounts for most, and perhaps all, of the known sex differences in neural structure and behavior. Here we review some of the events triggered by testosterone that masculinize the developing and adult nervous system, promote male behaviors and suppress female behaviors. Testosterone often sculpts the developing nervous system by inhibiting or exacerbating cell death and/or by modulating the formation and elimination of synapses. Experience, too, can interact with testosterone to enhance or diminish its effects on the central nervous system. However, more work is needed to uncover the particular cells and specific genes on which testosterone acts to initiate these events.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sexual dimorphisms in the brain.
Figure 2: The conversion of testosterone into estrogen.

Debbie Maizels

Figure 3: Before birth, the SNB system is present in both male and female rats, and motor neurons have established a functional neuromuscular junction.

Debbie Maizels

Figure 4: In newly hatched zebra finches, axons from HVC reach the vicinity of their target in RA, but do not actually enter RA in significant numbers unless estrogen receptors are stimulated.

Debbie Maizels

References

  1. Wilson, J.D. The role of androgens in male gender role behavior. Endocrine Rev. 20, 726–737 (1999).

    Article  CAS  Google Scholar 

  2. Phoenix, C.H., Goy, R.W., Gerall, A.A. & Young, W.C. Organizing action of prenatally administered testosterone propionate on the tissues mediating mating behavior in the female guinea pig. Endocrinology 65, 369–82 (1959).

    Article  CAS  PubMed  Google Scholar 

  3. Meisel, R.L. & Sachs, B.D. The physiology of male sexual behavior. in The Physiology of Reproduction Edn. 2 (eds. Knobil, E. & Neill, J.D.) 3–105 (Raven Press, New York, 1994).

    Google Scholar 

  4. Dejonge, F.H. et al. Lesions of the Sdn-Poa inhibit sexual behavior of male Wistar rats. Brain Res. Bull. 23, 483–492 (1989).

    Article  CAS  Google Scholar 

  5. Dohler, K.D. et al. Prenatal and postnatal influence of testosterone propionate and diethylstilbestrol on differentiation of the sexually dimorphic nucleus of the preoptic area in male and female rats. Brain Res. 302, 291–295 (1984).

    Article  CAS  PubMed  Google Scholar 

  6. Davis, E.C., Popper, P. & Gorski, R.A. The role of apoptosis in sexual differentiation of the rat sexually dimorphic nucleus of the preoptic area. Brain Res. 734, 10–18 (1996).

    Article  CAS  PubMed  Google Scholar 

  7. Gorski, R.A., Gordon, J.H., Shryne, J.E. & Southam, A.M. Evidence for a morphological sex difference within medial preoptic area of rat-brain. Brain Res. 148, 333–346 (1978).

    Article  CAS  PubMed  Google Scholar 

  8. Park, J.J., Tobet, S.A. & Baum, M.J. Cell death in the sexually dimorphic dorsal preoptic area anterior hypothalamus of perinatal male and female ferrets. J. Neurobiol. 34, 242–252 (1998).

    Article  CAS  PubMed  Google Scholar 

  9. Young, J.K. A comparison of hypothalami of rats and mice: lack of gross sexual dimorphism in the mouse. Brain Res. 239, 233–239 (1982).

    Article  CAS  PubMed  Google Scholar 

  10. Shah, N.M. et al. Visualizing sexual dimorphism in the brain. Neuron 43, 313–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  11. Simerly, R.B. Wired for reproduction: organization and development of sexually dimorphic circuits in the mammalian forebrain. Annu. Rev. Neurosci. 25, 507–536 (2002).

    Article  CAS  PubMed  Google Scholar 

  12. Breedlove, S.M. & Arnold, A.P. Hormone accumulation in a sexually dimorphic motor nucleus of the rat spinal-cord. Science 210, 564–566 (1980).

    Article  CAS  PubMed  Google Scholar 

  13. Forger, N.G. & Breedlove, S.M. Sexual dimorphism in human and canine spinal-cord: role of early androgen. Proc. Natl. Acad. Sci. USA 83, 7527–7531 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Holmes, M.M. & Wade, J. Characterization of projections from a sexually dimorphic motor nucleus in the spinal cord of adult green anoles. J. Comp. Neurol. 471, 180–187 (2004).

    Article  PubMed  Google Scholar 

  15. Cihak, R., Gutmann, E. & Hanzliko, V. Involution and hormone-induced persistence of M sphincter-(levator)-ani in female rats. J. Anat. 106, 93–110 (1970).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Nordeen, E.J., Nordeen, K.W., Sengelaub, D.R. & Arnold, A.P. Androgens prevent normally occurring cell-death in a sexually dimorphic spinal nucleus. Science 229, 671–673 (1985).

    Article  CAS  PubMed  Google Scholar 

  17. Freeman, L.M., Watson, N.V. & Breedlove, S.M. Androgen spares androgen-insensitive motoneurons from apoptosis in the spinal nucleus of the bulbocavernosus in rats. Horm. Behav. 30, 424–433 (1996).

    Article  CAS  PubMed  Google Scholar 

  18. Ibanez, M.A., Gu, G.B. & Simerly, R.B. Target-dependent sexual differentiation of a limbic-hypothalamic neural pathway. J. Neurosci. 21, 5652–5659 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zup, S.L. et al. Overexpression of Bcl-2 reduces sex differences in neuron number in the brain and spinal cord. J. Neurosci. 23, 2357–2362 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Young, L.J. & Wang, Z. The neurobiology of pair bonding. Nat. Neurosci. 7, 1048–1054 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Zhou, L., Blaustein, J.D. & Devries, G.J. Distribution of androgen receptor immunoreactivity in vasopressin-immunoreactive and oxytocin-immunoreactive neurons in the male rat brain. Endocrinology 134, 2622–2627 (1994).

    Article  CAS  PubMed  Google Scholar 

  22. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Morris, J.A., Jordan, C.L. & Breedlove, S.M. Medial amygdala volume is sexually dimorphic in mice. Horm. Behav. 44, 65 (2003).

    Google Scholar 

  24. Cooke, B.M., Breedlove, S.M. & Jordan, C.L. Both estrogen receptors and androgen receptors contribute to testosterone-induced changes in the morphology of the medial amygdala and sexual arousal in male rats. Horm. Behav. 43, 336–346 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Breedlove, S.M. & Arnold, A.P. Sexually dimorphic motor nucleus in the rat lumbar spinal cord: response to adult hormone manipulation, absence in androgen-insensitive rats. Brain Res. 225, 297–307 (1981).

    Article  CAS  PubMed  Google Scholar 

  26. Watson, N.V., Freeman, L.M. & Breedlove, S.M. Neuronal size in the spinal nucleus of the bulbocavernosus: direct modulation by androgen in rats with mosaic androgen insensitivity. J. Neurosci. 21, 1062–1066 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Forger, N.G., Fishman, R.B. & Breedlove, S.M. Differential effects of testosterone metabolites upon the size of sexually dimorphic motoneurons in adulthood. Horm. Behav. 26, 204–213 (1992).

    Article  CAS  PubMed  Google Scholar 

  28. Hegstrom, C.D., Jordan, C.L. & Breedlove, S.M. Photoperiod and androgens act independently to induce spinal nucleus of the bulbocavernosus neuromuscular plasticity in the Siberian hamster, Phodopus sungorus. J. Neuroendocrinol. 14, 368–374 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Cooke, B.M., Hegstrom, C.D., Keen, A. & Breedlove, S.M. Photoperiod and social cues influence the medial amygdala but not the bed nucleus of the stria terminalis in the Siberian hamster. Neurosci. Lett. 312, 9–12 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Cooke, B.M., Hegstrom, C.D. & Breedlove, S.M. Photoperiod-dependent response to androgen in the medial amygdala of the Siberian hamster, Phodopus sungorus. J. Biol. Rhythms 17, 147–154 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Nottebohm, F. & Arnold, A.P. Sexual dimorphism in vocal control areas of songbird brain. Science 194, 211–213 (1976).

    Article  CAS  PubMed  Google Scholar 

  32. Nottebohm, F. Testosterone triggers growth of brain vocal control nuclei in adult female canaries. Brain Res. 189, 429–436 (1980).

    Article  CAS  PubMed  Google Scholar 

  33. Paton, J.A. & Nottebohm, F.N. Neurons generated in the adult brain are recruited into functional circuits. Science 225, 1046–1048 (1984).

    Article  CAS  PubMed  Google Scholar 

  34. Arnold, A.P. The effects of castration and androgen replacement on song, courtship, and aggression in zebra finches (Poephila guttata). J. Exp. Zool. 191, 309–26 (1975).

    Article  CAS  PubMed  Google Scholar 

  35. Gurney, M.E. Hormonal control of cell form and number in the zebra finch song system. J. Neurosci. 1, 658–673 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Konishi, M. & Akutagawa, E. Hormonal control of cell death in a sexually dimorphic song nucleus in the zebra finch. Ciba Found. Symp. 126, 173–85 (1987).

    CAS  PubMed  Google Scholar 

  37. Arnold, A.P., Wade, J., Grisham, W., Jacobs, E.C. & Campagnoni, A.T. Sexual differentiation of the brain in songbirds. Devel. Neurosci. 18, 124–136 (1996).

    Article  CAS  Google Scholar 

  38. Arnold, A.P. Genetically triggered sexual differentiation of brain and behavior. Horm. Behav. 30, 495–505 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Holloway, C.C. & Clayton, D.F. Estrogen synthesis in the male brain triggers development of the avian song control pathway in vitro. Nat. Neurosci. 4, 170–5 (2001).

    Article  CAS  PubMed  Google Scholar 

  40. Agate, R.J. et al. Neural, not gonadal, origin of brain sex differences in a gynandromorphic finch. Proc. Natl. Acad. Sci. USA 100, 4873–4878 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Arnold, A.P. et al. Minireview: sex chromosomes and brain sexual differentiation. Endocrinology 145, 1057–1062 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Wagner, C.K. et al. Neonatal mice possessing an Sry transgene show a masculinized pattern of progesterone receptor expression in the brain independent of sex chromosome status. Endocrinology 145, 1046–1049 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Brenowitz, E.A. & Lent, K. Act locally and think globally: intracerebral testosterone implants induce seasonal-like growth of adult avian song control circuits. Proc. Natl. Acad. Sci. USA 99, 12421–12426 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Grisham, W., Mathews, G.A. & Arnold, A.P. Local intracerebral implants of estrogen masculinize some aspects of the zebra finch song system. J. Neurobiol. 25, 185–196 (1994).

    Article  CAS  PubMed  Google Scholar 

  46. Monks, D.A., Vanston, C.M. & Watson, N.V. Direct androgenic regulation of calcitonin gene-related peptide expression in motoneurons of rats with mosaic androgen insensitivity. J. Neurosci. 19, 5597–5601 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Forger, N.G., Roberts, S.L., Wong, V. & Breedlove, S.M. Ciliary neurotrophic factor maintains motoneurons and their target muscles in developing rats. J. Neurosci. 13, 4720–4726 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Forger, N.G., Wong, V. & Breedlove, S.M. Ciliary neurotrophic factor arrests muscle and motoneuron degeneration in androgen-insensitive rats. J. Neurobiol. 28, 354–362 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Xu, J., Gingras, K.M., Bengston, L., Di Marco, A. & Forger, N.G. Blockade of endogenous neurotrophic factors prevents the androgenic rescue of rat spinal motoneurons. J. Neurosci. 21, 4366–4372 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Forger, N.G. et al. Sexual dimorphism in the spinal cord is absent in mice lacking the ciliary neurotrophic factor receptor. J. Neurosci. 17, 9605–9612 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Forger, N.G. et al. Cardiotrophin-like cytokine/cytokine-like factor 1 is an essential trophic factor for lumbar and facial motoneurons in vivo. J. Neurosci. 23, 8854–8858 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Amateau, S.K. & McCarthy, M.M. Induction of PGE2 by estradiol mediates developmental masculinization of sex behavior. Nat. Neurosci. 7, 643–650 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Amateau, S.K. & McCarthy, M.M. A novel mechanism of dendritic spine plasticity involving estradiol induction of prostaglandin-E2. J. Neurosci. 22, 8586–8596 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Berenbaum, S.A. Effects of early androgens on sex-typed activities and interests in adolescents with congenital adrenal hyperplasia. Horm. Behav. 35, 102–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Hines, M., Brook, C. & Conway, G.S. Androgen and psychosexual development: core gender identity, sexual orientation and recalled childhood gender role behavior in women and men with congenital adrenal hyperplasia (CAH). J. Sex Res. 41, 75–81 (2004).

    Article  PubMed  Google Scholar 

  56. Money, J., Ehrhardt, A.A. & Masica, D.N. Fetal feminization induced by androgen insensitivity in the testicular feminizing syndrome: effect on marriage and maternalism. Johns Hopkins Med. J. 123, 105–114 (1968).

    CAS  PubMed  Google Scholar 

  57. Wisniewski, A.B. et al. Complete androgen insensitivity syndrome: long-term medical, surgical, and psychosexual outcome. J. Clin. Endocrinol. Metab. 85, 2664–2669 (2000).

    CAS  PubMed  Google Scholar 

  58. Rahman, Q., Kumari, V. & Wilson, G.D. Sexual orientation-related differences in prepulse inhibition of the human startle response. Behav. Neurosci. 117, 1096–1102 (2003).

    Article  PubMed  Google Scholar 

  59. McFadden, D. & Pasanen, E.G. Comparison of the auditory systems of heterosexuals and homosexuals: Click-evoked otoacoustic emissions. Proc. Natl. Acad. Sci. USA 95, 2709–2713 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Williams, T.J. et al. Finger-length ratios and sexual orientation. Nature 404, 455–456 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Martin, J.T. & Nguyen, D.H. Anthropometric analysis of homosexuals and hetero-sexuals: implications for early hormone exposure. Horm. Behav. 45, 31–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  62. LeVay, S. A difference in hypothalamic structure between heterosexual and homosexual men. Science 253, 1034–1037 (1991).

    Article  CAS  PubMed  Google Scholar 

  63. Roselli, C.E., Larkin, K., Resko, J.A., Stellflug, J.N. & Stormshak, F. The volume of a sexually dimorphic nucleus in the ovine medial preoptic area/anterior hypo-thalamus varies with sexual partner preference. Endocrinology 145, 478–483 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Neuroscience Program, Michigan State University, East Lansing, 48824, Michigan, USA

    John A Morris, Cynthia L Jordan & S Marc Breedlove

Authors
  1. John A Morris
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Cynthia L Jordan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Marc Breedlove
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Marc Breedlove.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Morris, J., Jordan, C. & Breedlove, S. Sexual differentiation of the vertebrate nervous system. Nat Neurosci 7, 1034–1039 (2004). https://doi.org/10.1038/nn1325

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1325

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing