Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2011 Jun;14(6):677-83.
doi: 10.1038/nn.2834. Epub 2011 May 25.

Reframing sexual differentiation of the brain

Margaret M McCarthy  1 , Arthur P Arnold
Affiliations
Review

Reframing sexual differentiation of the brain

Margaret M McCarthy et al. Nat Neurosci. 2011 Jun.

Abstract

In the twentieth century, the dominant model of sexual differentiation stated that genetic sex (XX versus XY) causes differentiation of the gonads, which then secrete gonadal hormones that act directly on tissues to induce sex differences in function. This serial model of sexual differentiation was simple, unifying and seductive. Recent evidence, however, indicates that the linear model is incorrect and that sex differences arise in response to diverse sex-specific signals originating from inherent differences in the genome and involve cellular mechanisms that are specific to individual tissues or brain regions. Moreover, sex-specific effects of the environment reciprocally affect biology, sometimes profoundly, and must therefore be integrated into a realistic model of sexual differentiation. A more appropriate model is a parallel-interactive model that encompasses the roles of multiple molecular signals and pathways that differentiate males and females, including synergistic and compensatory interactions among pathways and an important role for the environment.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Twentieth-century linear view of sexual differentiation. For the past 50 years, the prevailing view of sexual differentiation of the brain has been a linear model in which chromosomal sex determines gonadal sex, which determines brain sex. Feminization of the brain is the default process that occurs in the absence of high levels of gonadal steroids during a perinatal sensitive period. Masculinization and defeminization are separate hormonally driven processes that organize the neural substrate to promote male-typic behaviors while suppressing female-typic behaviors. The organized neural substrate is activated by adult gonadal steroids and required for sex-typic behaviors to be expressed. This iconic model based on the organizational/activational hypothesis has proved a sturdy framework for elucidating some, but not all, of the aspects of sexual differentiation of the brain.
Figure 2
Figure 2
Genetics matter. The ability to distinguish the contributing role of genes versus gonads was markedly advanced by the development of the four core genotypes model of mice. These mice bear a Y chromosome from which the Sry gene has been deleted (denoted Y−) and carry Sry on an autosome, allowing the development of XX individuals with testes and XY individuals with ovaries. Analysis of this model supports the view that sexual differentiation of reproductive endpoints is largely driven by the testicular hormone testosterone or estradiol synthesized in the developing nervous system from this testosterone, consistent with the organizational/activational hypothesis. Conversely, many nonreproductive endpoints involve direct genetic contributions to variability between males and females.
Figure 3
Figure 3
Multiple mechanisms of estradiol-induced differentiation. In the rodent, estradiol is a masculinizing hormone, but it exerts multiple region-specific effects via distinct cellular mechanisms. Thus, during a perinatal sensitive period, the same hormone, estradiol, promotes cell survival, cell death and cell proliferation in separate brain regions. Estradiol also promotes the formation of new dendritic spine synapses in some brain regions while suppressing them in others. The enduring consequences of the organizational effects of estradiol may be mediated in part via epigenetic changes to the DNA and chromatin in processes that are region-specific, but are still poorly understood.
Figure 4
Figure 4
Redefining sexual differentiation. In a twenty-first-century view of sexual differentiation of the brain, the importance of genetics and environment are incorporated along with the effects of hormones to provide a more nuanced portrayal of the types of variables that cause sex differences. Included in this view are the principles that hormones, sex chromosome genes and sex-specific environments have independent parallel differentiating effects that can interact with each other, often synergistically, to cause sex differences in the brain. However, there are also compensatory sex-specific variables that act to reduce sex differences rather than induce them. The result is that some aspects of male and female brain, behavior and physiology are unique from each other, whereas others are highly similar. Two important aspects of the redefined view are not illustrated here: sex differences are pervasive throughout the brain and not restricted to reproductively relevant neural circuits, and variability in the degree to which brain regions are masculinized or feminized in one individual results in a mosaic of relative maleness or femaleness and thereby greatly increases the variance between individuals of the same sex in a population.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Cahill L. Why sex matters for neuroscience. Nat. Rev. Neurosci. 2006;7:477–484. - PubMed
    1. Mogil JS, Chanda ML. The case for the inclusion of female subjects in basic science studies of pain. Pain. 2005;117:1–5. - PubMed
    1. Voskuhl R. Sex differences in autoimmune diseases. Biol. Sex Differ. 2011;2:1. - PMC - PubMed
    1. Swaab DF, Hofman MA. Sexual differentiation of the human hypothalamus in relation to gender and sexual orientation. Trends Neurosci. 1995;18:264–270. - PubMed
    1. McCarthy M, De Vries G, Forger N. Ch. 17. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, editors. Hormones, Brain and Behavior. Vol. 3. Academic Press; 2009. pp. 1707–1744.

Publication types