Origins of Sex Differentiation of Brain and Behavior

Abstract

Sex differences in adult brain and behavior are often established early in development when the brain is remarkably immature. In adults sex differences take on many forms including latent variables, dimorphisms, frequency, and more. Androgens and estrogens from the developing male fetal testis masculinize the brain, so that physiology and behavior are in synchrony and harmony with gonadal phenotype. This differentiation process occurs during a critical window in males, but females remain sensitive to exogenous steroid treatment for a longer developmental period. The cellular mechanisms of sexual differentiation are diverse but often involve inflammatory signaling molecules and immune cells. This may have consequences for the higher vulnerability of males to neurological and neuropsychiatric disorders of development.

Key References

• Amateau and McCarthy (2004)—This was the first report in which masculinization of a female brain was achieved by a downstream signaling molecule from steroid action, as opposed to treating directly with steroids. This opened a new era in understanding of the novel mechanisms by which steroids can impact the brain, including through the enhancement of immune system signaling.

• Beery and Zucker (2010)—An in depth analyses of a large number of publications across a wide swatch of biomedical research revealed the over reliance on male animals, especially in neuroscience. Almost six times as many studies used exclusively male rats and mice. Subsequent to this publication the NIH mandated the incorporation of sex as a biological variable in all preclinical research.

• De Vries (2004)—This minireview proposed the novel idea that sometimes the two sexes evolve mechanisms to try and be more similar, not more different. Using the example of the biparental vole, DeVries highlights how males have evolved a new neural circuit that promotes parenting and is active in the absence of the hormones of pregnancy and parturition that are so important to females.

• Nottebohm and Arnold (1976)—Arguably the first robust neuroanatomical sex difference discovered in a vertebrate brain, this land mark publication led to increased scrutiny of the mammalian brain and the discovery of multiple sex differences in the size of various brain regions and subnuclei.

• Nugent et al. (2015)—One of a small number of studies that revealed sex differences in the epigenome and in this case demonstrates functional significance for the sexual differentiation of sexual behavior.

• Werling et al. (2016)—Secondary analyses of the transcriptome from human fetal postmortem cortical tissue found that more genes associated with inflammation, activated astrocytes and microglia are up regulated in the male compared to the female. Preclinical studies in animals were essential to interpretation of these findings as indicative of normal healthy brain development in males.