When you choose to publish with PLOS, your research makes an impact. Make your work accessible to all, without restrictions, and accelerate scientific discovery with options like preprints and published peer review that make your work more Open.

PLOS BLOGS The Official PLOS Blog

‘@PLOSNeuro #SfN14 highlights: There is no male or female brain — it’s a mosaic.

By Lina Jamis

SfN 14 Lecture: Surprising Origins of Sex Differences in the Brain 
Margaret M. McCarthy, PhD
University of Maryland School of Medicine
Sunday, Nov. 16, 1–2:10 p.m.

Men are from Mars, and women are from Venus, as the old adage goes. It’s a silly expression but it attempts to illustrate that men and women are worlds away in understanding each other — but this might be because our brains are actually different.


Dr. Margaret McCarthy’s talk on the origin of sex differences in the brain at the Society for Neuroscience’s conference in Washington, DC, aimed to explain some of these differences and how they come about. In the beginning, starts McCarthy, the universe was hot and expansive and sex differences all came about with the big bang — although not the astrophysics kind (this lady is seriously funny). 62bb226e520c4403b4c134be838b4797

Until eight weeks old, every fetal brain looks female — i.e. the female sex is nature’s default gender setting, until a large testosterone surge beginning in the eighth week turns the default into male.

Surprising origins 

Traditional studies into sex differences in the brain always pinpoint hormones as the master regulators of sex differences, but McCarthy postulates that 1) there are potent variables other than classic regulators of development that govern sex differences and that 2) the cellular mechanisms establishing sex differences in the brain are unique to each endpoint and region.

McCarthy’s research group targeted the preoptic area (POA), an area of the hypothalamus that has been on radar for its regulation of male sexual behavior. It has been shown to receive indirect input from every sensory modality and sends projections to structures that are critical for the initiation and patterning of…well… sexy times.

The POA’s role in the regulation of male sexual behavior was confirmed by ablation (removal) studies conducted by McCarthy’s lab. Damage to the POA impaired male sexual behavior. McCarthy’s group also found that male rats had twice as many dendritic spines — small knobby protrusions from a neuron’s dendrite that typically receive input from a single synapse of an axon — as females. Furthermore, when females were treated with estradiol, dendritic spine density increased to comparative levels. If supplied with testosterone, these female rats would permit the expression of male sexual behavior into adulthood. McCarthy concluded that the induction of the dendritic spine patterning is mediated entirely by estradiol — but how?

Schematic representation of brain sexual differentiation (McCarthy, et al. 2008).

Roles of non-traditional, non-hormonal regulators 

The answer was via prostaglandins, specifically, PGE2. McCarthy’s group showed that an increase in PGE2 to females induced a twofold increase in dendritic spines (the male pattern) in the MPOA and the expression of masculine sexual behavior in adulthood. McCarthy then focused her gaze on how it was that PGE2 would induce dendritic spine synaptogenesis. The answer appeared to involve glutamate. Her model described a situation in which increasing PGE2 production and release would act on neighboring astrocytes to induce glutamate release, which would then communicate back to nearby neurons, telling them to increase their dendritic spines.

At this point, McCarthy noticed something funny: the amount of microglia (resident macrophages) in the POA were positively associated with masculinity — i.e. males were shown to have more microglia than females, and estradiol increased this number in females. Microglia both produce and respond to prostaglandins, so could there be a connection? Indeed, there was. Male rats showed greater microglia than their female counterparts, which, when treated with estradiol, increased their microglial counts to those of males. Furthermore, when males were treated with microglial inhibitors, masculinization of dendritic spine patterning and reproductive behavior in adulthood were disrupted.

Clearly, McCarthy had found variables that were non-traditional (i.e. not hormones) regulators of sex differentiation in the brain.

McCarthy’s group began to look towards the amygdala for more answers when she found that sex differences in cell proliferation existed in the medial amygdala that was mediated by endocannabinoids, with females having higher cell proliferation rates and less active (read: less phagocytic) microglia than males. McCarthy wondered if the rates of microglial activation in male amygdalas were related to lower levels of cell proliferation, and again, she found a connection. It turns out that these microglia were participating in synaptic pruning, or “nibbling” of newborn neurons in the amygdala, resulting in reduced proliferation in males; just another difference between male and female brains.

McCarthy closed with Waddington’s epigenetic landscape, in which each sex represents a possible path or canal. Like any change in the brain, sex differences appear to be canalized, or selected for, according to each organism’s genetic and epigenetic program. But what McCarthy probed was whether canalization contributes to a gender bias in disease.

Are males much more prone — to autism, ADHD, dyslexia, and schizophrenia, and women more prone to depression, anorexia, OCD, and anxiety — because of certain patterns in the sexualized brain?



McCarthy was a fantastic speaker (must be a Maryland thing) — witty, on target, and a great story-teller. She managed to weave a narrative of a process that unwittingly happens in all of us — one which we know so little about, and even less about the ‘minor players’ that bring about sexual differentiation.

 Here are some of McCarthy’s take-aways:

1) Feminization is a separate process from masculinization, not the opposite. The opposite is asexuality.

2) There are potent variables other than classic regulators of development that govern sex differences.

3) There is no male or female brain — it’s a mosaic.

4) The same pattern and magnitude of sex differences exist in almost every endpoint. Males are two times more expressive. When females are treated with male hormones, they catch up. Males treated with hormones doesn’t double their expressivity.

0-fDqat3qsWI9u8fzx (1)PLOS Neuro blogger Lina Jamis received her neuroscience degree at Georgetown University and is currently studying biophysics at Penn State’s College of Medicine, with a thesis is on the role of human muscle myosin in sensory systems. Her interests include crossfitting, writing about science, and studying biomaterials and electronic devices to develop next-generation neural interfaces. @linajamis

  1. “One straightforward hypothesis is that neurons with different genomes will have distinct molecular phenotypes because of altered transcriptional or epigenetic landscapes.”

    Mosaic Copy Number Variation in Human Neurons http://www.sciencemag.org/content/342/6158/632.abstract

    In our 1996 Hormones and Behavior review, we linked the conserved molecular epigenetics of RNA-mediated cell type differentiation from sex differences in yeasts to sex differences in the cell types of mammals. The model was subsequently extended by others to hormone-organized and hormone-activated insect behavior and to life history transitions in the honeybee model organism before being reviewed in Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.nlm.nih.gov/pubmed/24693353

  2. Interesting–

    Just another way that cells in the body show unique expression patterns. I suspect that there are other mechanisms besides copy number variation at the transcript level. But CNVs can have very large effects in downstream expression.

    Thank you for bringing this study to my attention!


  3. http://www.economist.com/news/books-and-arts/21633782-how-quantum-theory-helping-explain-mysteries-life-science-nature

    Others have since moved on to quantum consciousness, from quantum physics, quantum smell, and the quantum biology of cell type differentiation that Peg and others, like Donald Pfaff, are now addressing without mention of nutrient-dependent changes in the microRNA/messenger RNA balance. They mention microRNAs in passing but not the fact that the changes obviously link the RNA-mediated events we detailed to genetically predisposed cell type differentiation in all cells of all tissues of all organs in all organ systems of all vertebrates.

    What also appears to be consistently missing is the pheromone-controlled physiology of reproduction, which links the biodiversity of morphological and behavioral phenotypes across all species via conserved molecular mechanisms.

    I wonder how much longer it will be until they link food odors and pheromones to the GnRH neuronal system and sexual differentiation of cell types. We started with sex differences in yeasts, and others seem to have ignored the fact that they are nutrient-dependent and pheromone-controlled even though Nobel Laureate, Linda Buck linked them to GnRH in an article she co-authored in 2005.

    Feedback loops link odor and pheromone signaling with reproduction http://www.sciencedirect.com/science/article/pii/S0092867405009815 “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.

Leave a Reply

Your email address will not be published. Required fields are marked *

Add your ORCID here. (e.g. 0000-0002-7299-680X)

Back to top