‘@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). 

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?

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.

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