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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.
  1. gender difference is a topographical picture and the significance for words like sex difference and the like are, for humans, a functional convenience to express; in the realm of nature, or, evolution it is only the species preserving behaviors , fashioned for the copulating behavior and the development of organs and movements towards that end, which, on the other end, demands male and female forms, reckoned by human observation, in order to be engaged, unconsciously, in species preserving tendencies; in the lesser form of drive reduction behaviors such as eating to satiate hunger, it is not the gender difference that is the involved factor, from the perspectives of unconscious natural urges, which, to all probability, stem from the same basis where the arch drive is there to copulate, or to be man and woman. Seeing that ” The brain is not a blend, but rather a mosaic of relative femaleness, maleness, and neutralness.” and a theoretical sanction for this observation, is the most desired, allowing precise insights in to the nature of mental illness and so forth, the assessment of which is attributable to gender differentials in the brain (as this post suggests) and causal factors for gender roles, promoted in social behavior

  2. I think what Ashok may be trying to say was expressed by Simon Le Vay in his book: Gay, Straight, and the Reason Why: The Science of Sexual Orientation (p. 210)

    “…[James Kohl] believes that pheromones may have a primary influence in setting up a person’s basic sexual orientation. Other, more consciously perceived aspects of attractiveness, such as facial appearance, are attached to a person’s basic orientation through a process of association during early postnatal life, according to Kohl. 35”

    This model is attractive in that it solves the “binding problem” of sexual attraction. By that I mean the problem of why all the different features of men or women (visual appearance and feel of face, body, and genitals; voice quality, smell; personality and behavior, etc.) attract people as a more or less coherent package representing one sex, rather than as an arbitrary collage of male and female characteristics. If all these characteristics come to be attractive because they were experienced in association with a male- or female-specific pheromone, then they will naturally go together even in the absence of complex genetically coded instructions.

    Still, even in fruit flies, other sensory input besides pheromones — acoustic, tactile, and visual stimuli — play a role in sexual attraction, and sex specific responses to these stimuli appear to be innate rather than learned by association [36.]”

    It is important to place this into the perspective of “Feedback loops link odor and pheromone signaling with reproduction”

    “Indications that GnRH peptide plays an important role in the control of sexual behaviors suggest that pheromone effects on these behaviors might also involve GnRH neurons.” (p 683)

    Feedback loops epigenetically link food odors and pheromones to behavior via the GnRH neuronal system of all vertebrates. Affects of all other sensory input are conditioned to occur in the context of hormone-organized and hormone-activated changes in vertebrates and invertebrates via conserved molecular mechanisms.

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