Since the dawn of time, or at least since the first man was kicked out of the cave by a woman companion with a sniff and a statement of “you should know what you did,” we have known there was a difference in the way men and women think, that our brains just function differently. “Men are from Mars, Women are from Venus,” right? Many homes probably still have a copy of this book stuck on a shelf somewhere in the house.
While there is quite a bit of overlap, we each have our own strengths – men have a much higher degree of network connections within each hemisphere, relating to improved sensorimotor tasks; women have a greater amount of intraconnectivity between both sides of the brain, increasing our performance in social cognition and non-verbal reasoning tasks3. This is not to say that we can’t all excel at either type of task, but there is a pretty strong correlation to suggest the sexes have their fortes.
For decades we have known our hormones play a huge role in brain differences– men have a high level of testosterone, while women have cyclical levels of estrogen and progesterone. Within the last several years, it has been realized that actually your immune system also plays an essential role to the masculinization of the brain and sexual behavior.
Within your brain there are cells called microglia – a type of non-neuronal cell in your nervous system – that are involved in maintaining normal function (homeostasis) by responding to injury and inflammation. One response is to produce proinflammatory molecules to help your immune response, such as prostaglandins (remember this one, it comes up later, but I promise there won’t be a quiz!). They can even recognize infectious agents and eliminate damaged neurons/synapses – pretty powerful little cells! Because many antibodies can’t cross the blood-brain barrier, microglia take up a lot of their responsibilities within the brain.
Microglia also have high “plasticity,” meaning they are capable of changing their physical shape. When they are inactive (also called ramified or quiescent) they have a small cell body and many long branch-like projections that constantly are feeling out the local environment for any changes. When they are active the branches retract, and they are left with an amoeboid shape that allows them to move around and do their job.
Soon after birth the microglia exist mainly in this activated amoeboid shape state, but after a few weeks they change to their resting state1. This change is a result from an influx of testosterone to the brain – the testosterone is changed to estradiol within the brain and induces brain “masculinization,” resulting in a brain that promotes male copulatory behavior. (Get comfy with the word copulatory because I will have to use it a bunch, and I apologize in advance for having to talk about mouse sex, but we are all adults here).
The expression of the male copulatory behaviors is driven by the Preoptic Area (POA) of the brain, which is part of the hypothalamus (in the simplest terms, it’s the part that is highly linked to your hormones). The cells in this region of the brain have a high degree of gender bias – the nuclei are much larger in males than in females, and the neurons have many more dendritic spines, and the astrocytes have a much more complex appearance. Together these are considered “masculinized” traits.
While it’s not necessarily important to know all the names of the cells in the brain, it is important to know that this sexual dimorphism is due to the hormone estradiol. Estradiol increases the production of prostaglandin-2 (PGE2) — remember, I said this one would come back up! Previous studies have show that PGE2 is required for masculinization, and it is so potent that a SINGLE DOSE given to female mouse pups the day they are born is enough to permanently masculinize their brain.
But how do these microglia have any affect on masculinization?
Microglia have a receptor for prostaglandins and also are capable of producing prostaglandins. So a research group hypothesized that the microglia control a process by which the presence of PGE2 begets more PGE2.
They compared the Preoptic Area in male and female mouse pups and found females had significantly fewer total number of microglia and significantly fewer activated microglia.
When they gave the females estradiol it increased the total number of microglia to the levels seen in males. However, when they added in a microglial inhibitor (to keep the microglia from functioning) to this estradiol cocktail, it prevented the masculinization effect. This means that the microglia themselves are affecting the total number of microglia, not just the estradiol.
They found giving females PGE2 increased the number of activated amoeboid microglia to male levels, and when they gave the inhibitor to male pups, it decreased the number of amoeboid microglia to levels seen in normal females. Therefore, PGE2 affects the shape differences seen between the sexes.
In fact, this induced masculinization is a life-long effect. Females given estradiol were raised to adulthood to study their sexual behavior. For measures of masculine sexual behavior, they look at the number of mounts and intromission and the downtime between mounts/intromissions (as a measure of sexual motivation). They found that these masculinized females showed mount rates comparable to males and increased intromission-like behaviors (because obviously females are not capable of actual intromission). As before, the females co-treated with the microglial blockers did not show increases in these male-typical copulatory behaviors.
Overall, when they blocked the function of the microglia, they prevented the increases in PGE2 caused by the estradiol, thereby showing that activated microglia are necessary for the masculinization process.
It’s a lot of nitty-gritty science detail, but it is an amazing concept that our immune cells interact with our hormones in order to determine if we have male or female brain patterning.
It also has some pretty large implications in the world of neurodevelopmental disorders, as microglia are involved in neurodevelopment processes2. Therein, too, lies a gender bias, where boys are more likely to suffer disorders in youth and women are more likely to suffer disorders in adulthood. What connection do these microglia have and how can they affect our risk factors?
1Lenz, K. M., Nugent, B. M., Haliyur, R., & Mccarthy, M. M. (2013). Microglia Are Essential to Masculinization of Brain and Behavior. Journal of Neuroscience,33(7), 2761-2772. doi:10.1523/jneurosci.1268-12.2013
2Lenz, K. M., Pickett, L. A., Wright, C. L., Davis, K. T., Galan, A., & Mccarthy, M. M. (2018). Mast Cells in the Developing Brain Determine Adult Sexual Behavior. Journal of Neuroscience,38(37), 8044-8059. doi:10.1101/205559
3Mccarthy, M. M., Nugent, B. M., & Lenz, K. M. (2017). Neuroimmunology and neuroepigenetics in the establishment of sex differences in the brain. Nature Reviews Neuroscience,18(8), 471-484. doi:10.1038/nrn.2017.61
Aristotle famously said, “The Law is Reason, free from Passion,” by which he meant the law is rooted in logic and should not to be ruled by desire or emotions. By extension, I believe that statement should apply to the sciences, as they are a study of the laws of the natural world around us – the Laws of Nature, if you will, not to be confused with Natural Law. Think Newton, not Locke.
From hereon our maxim will be: “Science is Reason, free from Passion.”
When I was studying to become a biologist, I had a professor who taught me two very important things:
- In Science, there is never a ‘conclusion,’ only a starting point for your next question
- Your own Beliefs of Truth are infinitesimal in importance when compared to the Body of Evidence
To say a scientific query was concluded meant you had no more to learn or discover – you might as well pack up your notebooks, put away the beakers and Bunsen burners, and close up the lab. In reality this is never the case; there is always something left to learn. Therefore, one should never say that science is ‘proven’ or ‘settled’. We know as much as we can, given the methods of understanding available to us at the time. Science is constantly changing and improving – just look at what CRISPER-Cas9 has done for genome editing since 2013 alone! One day, with better technology, we may find our current understanding is not, in fact, altogether correct.
For the second statement, this is a means of checking our own biases. It didn’t matter what we thought was the truth when faced with reproducible empirical results. Science is not a religion; we don’t have to have faith in something unseen or intangible in order to believe it. We can study it and pick it apart, finding the answers to every little question our minds can conjure, then put the puzzle back together to see the system as a whole. Good science has no personal biases; therefore, one cannot simply go looking for evidence to prove their beliefs to the detriment of the evidence. So when we are presented with evidence contrary to our original hypotheses, we must incorporate the new data and readjust our hypotheses for the next study.
When you put these two axioms together, we realize that every scientific endeavor should be undertaken with a dose of skepticism on the side. Science is not gospel; we can’t take it all for gods-honest truth. This is why many ‘Scientific Theories’ never become ‘Scientific Laws’. Everything that we know today (at least that which is not Law) is fair game and could be up for either revision or the chopping block tomorrow.
Any scientist worth their salt should be able to look at these statements understand the reason within them.
These two mantras are necessary to any honest scientific endeavor. Science is not perfect, but we do the best we can, to the best of our ability at the time.
A few years ago, I wouldn’t have felt it necessary to provide a disclaimer to scientific evidence, but the climate of today’s platform gives me enough pause I feel it necessary to establish the milieu for these articles. If scientific evidence contradicts your belief system or a belief about yourself, it doesn’t make the science wrong, but the job of reasoning is incumbent upon you; you must search within yourself to determine if what you believe is true and how your beliefs and the evidence fit together. This goes for religious beliefs, climate change, transgenderism, etc. – all topics that require a bit of faith in order to believe all their principles in full because each has an inherent element of intangibility. My goal is to bring to you tangible pieces of the puzzle so that we all can find reason in a world filled with questions.
Because of the role of hormones in brain development and sex determination, masculinization and feminization will be discussed; it will be dichotomous, without shades of grey. There is a highly reproducible norm between the female (XX) and male (XY) brain, so they will be the baseline for the measures of study.