Oral Presentation The International Congress of Neuroendocrinology 2014

Surprising origins of sex differences in the brain (#74)

Margaret M McCarthy 1
  1. University of Maryland School of Medicine, Baltimore, MD, United States

The developing brain is permanently and differently organized in males and females as a result of variance in hormonal exposure, with perinatal males producing high levels of testicular androgens that are aromatized to estrogens in neurons. Developing females experience far less hormone exposure and feminization is considered the default pathway in the process of sexual differentiation.  Endpoints impacted by steroids in the developing brain include synaptic patterning, neurogenesis, glial genesis, differential cell death, migration and phenotypic differentiation. Multiple attempts to identify a neurotransmitter system subject to hormonal regulation and serving as the final common denominator of steroid-hormone induced masculinization of the brain have largely failed. We now understand this to be due to the origins of many sex differences in the brain being outside the realm of neurotransmission but instead involving inflammatory and immune mediators such as prostaglandins, microglia and mast cells, as well as another class of membrane derived signaling molecules, endocannabinoids, all of which are higher in males.  Cell-to-cell communication via diffusible but short lived signaling molecules expands the impact of steroids beyond those cells expressing steroid receptors and likely contributes to regional specificity.  Once sex differences are established, they must also be maintained into adulthood to assure reproductive behavior and physiology are in register.  Epigenetic modifications to the DNA imprint early life environment and experience onto the genome.  Emerging evidence suggests the default female pattern involves epigenetic repression of the male genome which is emancipated by gonadal steroid inhibition of DNMT activity and subsequent demethylation of key genes, allowing for their expression.   Understanding how male and female brains develop differently informs us as to sources of the well established gender bias in risk of developmental disorders which are more prevalent in males and increased in frequency and severity by early life injury or inflammation.