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Surprising Origins of Sex Differences in the Brain, by Rayna M. Harris and Karina Albab

By Rayna M. Harris and Karina Albab

Dr. Margaret M. McCarthy’s career has been focused on the effects of hormones on brain development and behavior. Because societal and environmental influences can make studying sex differences difficult in humans, McCarthy uses rodent models for her research. In the last decade, Dr. McCarthy has uncovered a few intriguing surprises, which she shared at a special lecture “Origins of Sex Difference in the Brain” at the annual Society for Neuroscience conference #SfN14. Here, we highlight some of the most surprising findings shared during her talk.

The first surprise: prostaglandins and microglia masculinize the brain!

Stuart Amateau, MD, PhD measured the spines on dendrites and discovered that males have twice as many dendritic spines than females. Treating females with estradiol during a developmentally critical period actually increases their number of spines. But, how did estradiol exert it effects? Was it a neurotransmitter? Nope. Prostaglandin E2 (PGE2) functions as a downstream effector of estradiol to permanently masculinize the brain.

Later, the McCarthy lab did some follow up studies to on microglia, which bind to and produce PGE2. Dr. Katie Lenz discovered that males had significantly more microglia per area than females and that treating females with estradiol increased the number of microglia. In fact, when female pups were injected with PGE2 during a critical period, their adult behavior was completely masculinized. Even more surprisingly, a single injection of PGE2 was sufficient to masculinize behavior for life!

Estradiol up-regulates cyclooxygenase (COX) enzymes leading to increased production of PGE2 in neurons and microglia, which which leads to sexually dimorphic patterning of dendritic spine synapses in the preoptic area and results in male-typical copulating behavior. Figure from Lenz & McCarthy (2014) Neuroscientist, available online.

The second surprise: Feminization is NOT the default!

Feminization requires active repression of masculinization via DNA methylation. Masculinization is an in fact an escape from repression. McCarthy and Dr. Bridget Nugent wanted to discover how these synaptic patterns were maintained over a lifetime. The clues pointed toward DNA methylation and epigenetic mechanisms. They found that females have significantly more DNA methylation than males and that this methylation is reduced by estradiol. Estradiol not only blocks methylation, but it also induces de-methylation.

Live tweet from #SfN14

The third surprise: Sex differentiation is regulated by a “quartet of cells”!

In addition to neurons and microglia, mast cells also play a role. These cells are covered with filopodia, packed with vesicles, and respond and produce prostaglandin. McCarthy and her trainees have found found that estradiol treatment in females increases mast cell count. In addition, these de-granulated mast cells had more microglia with phagocytic cups than males. Surprisingly, when the lab stimulated the mast cells to de-granulate, the phagocytic activity reduced.

“Who can’t love a cell who changes its shape to show you how its feeling!”

However, this response is different to how they would respond in the event of an injury. This suggests that there is a requisite partnership between microglia and mast cells for the masculinization of dendrites in the preoptic area. Thus, immune signaling is a crucial and unappreciated factor that shapes sex-specific brain development, physiology, and behavior throughout the lifespan.

Concluding remarks

The Mosaic Brain. From

“The brain is not a blend, but rather a mosaic of relative femaleness, maleness, and neutralness.”

Cellular mechanisms are unique to each endpoint and to each brain region. For example, in the amygdala, endocannabannoid modulated cell death is associated with masculinization.

We see the same patterns and magnitudes over and over again; none of the treatments super-masculinized the brain. This suggests that there are forces that push the sexes apart and others that pull them back together. You can only diverge from where you start.

Moving foward

Sex differences are cropping up everywhere. One of the more popular studies this year showed that there are sex differences in idiotic behavior, as evidenced by the vast majority of Darwin Awards going to men rather than women.

88.7% of Darwin Award winners are males!

Always remember to ask yourself whether your system has sex differences. These differences should not be ignored rather they should be embraced! Sex differences in the brain have important implications for susceptibility to certain diseases, such as ADHD and autism in males and depression and anorexia in females. Thus, the basic and biomedical researcher should continue to study the development and maintenance of sex differences and the many mechanisms by which they occur.


Many thanks to Dr. Donna Maney and the SfN program committee for inviting Dr. Margaret McCarthy to speak at SfN, to the PLOS Neuroscience Community for the opportunity to contribute a blog on this topic, and finally to Dr. McCarthy for an entertaining sense of humor and for a lifetime of excellent research into the development and maintenance of sex differences.

The views expressed in this post belong to the author and are not necessarily those of PLOS.

RaynaMHarrisRayna Harris studies the neuromolecular basis of social behavior and is involved in several initiatives to enhance training in the life sciences.
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