Suppose a couple has two children, a boy and a girl.
Most likely, they both grow up with normal, healthy brains.
But if either sibling's brain development is altered or they experience mental health problems, it is possible that the path of both siblings will be different.
The male child's differences might appear first.
Other things being equal, he is four times more likely than his sister to be diagnosed with autism.
Rates of other neurodevelopmental disorders and disabilities are also higher in children.
As he grows into a young man, her chances of developing schizophrenia will be two to three times greater than his sister's.
When they both hit puberty, those relative risks will change.
The sister will be almost twice as likely to suffer from depression or an anxiety disorder.
Much later in life, she will be at increased risk of developing Alzheimer's.
Those tendencies aren't hard and fast rules, of course: Men can suffer from depression and Alzheimer's;
some girls develop autism;
and women are not immune to schizophrenia.
Male and female brains are more alike than different.
But scientists are learning that there is more to these different risk profiles than, say, the pressures women face in a patriarchal society or the fact that women tend to live longer, allowing time for aging-related diseases to emerge. .
Subtle biological differences between male and female brains, and bodies, are important factors.
To explain these differences between the sexes there are some obvious places to look for answers.
The two female X chromosomes and the single male copy is one such place.
Different sex hormones—particularly testosterone in men and estrogen in women—is another.
But an ever-growing field of research points to a less obvious influence: immune system cells and molecules.
Scientists have long had evidence linking immune activity to brain differences and disorders, but the science that incorporates gender into that equation is still developing.
Until the last decade, neuroscientists used only male animals in their experiments for fear that female hormone cycles would interfere with the results.
In the end, that turned out to be much less of a problem than originally thought.
Furthermore, scientists now know that hormones in male rodents can also fluctuate in much the same way—not in a fixed cycle, but in response to factors such as their position in the social hierarchy of their cage group.
In recent studies, neuroscientists have discovered that immune cells called microglia function differently in the developing brains of male and female rodents, even in the absence of any infection.
These microglial actions, reflected in human studies, may predispose children to early onset neuronal differences and disorders, the researchers speculate, but could protect them as they grow older.
Scientists have also identified several genes involved in immune responses that could help explain the increased risks for girls and women after puberty.
Over time, a better understanding of these differences could lead to gender-specific treatments.
"We're starting to dig into this," says Justin Bollinger, a neuroscientist at the University of Cincinnati.
"It's very important and very sad that, for a long time, researchers felt that men were enough, that men and women acted in the same way, that they responded to the same things."
Immunity in the developing brain
One of the first clues linking brain development and immune responses emerged in the late 1980s, when researchers examined birth registries and mental hospital records in Finland, where there was a flu epidemic in the fall of 1957. Scientists found that if pregnant women were through their second trimester of pregnancy that fall, their adult children were 50 percent more likely to be admitted to hospital with a diagnosis of schizophrenia than the children of women who had past their first or third trimester during the epidemic.
Other studies supported this finding, suggesting that if a woman's immune system must fight an infection during pregnancy it may predispose her offspring to schizophrenia.
“That has really drawn a lot of attention to how the immune system can cause the developing brain to go awry,” says Margaret McCarthy, a neuroscientist at the University of Maryland School of Medicine in Baltimore.
Meanwhile, researchers in New York documented a variety of neurological challenges in the children of mothers who contracted rubella during a 1964 outbreak, including an unusually high rate of autism.
To mimic the effects of outbreaks in human populations and to investigate possible mechanisms, scientists have injected non-infectious fragments of bacteria or viruses into pregnant rats and mice.
This triggers an immune response in the mother, which in turn influences the immune activity of her offspring.
The researchers then study the pups after they are born.
These studies have supported the idea that maternal infection affects the baby's brain.
While it's hard to tell whether a rodent is experiencing specific signs of autism or schizophrenia, scientists note that the pups are more anxious and less sociable than those born to mothers who did not face an immune challenge.
The pups also have more microglia, and more active ones.
These cells, which make up 10% of the brain, are the organ's resident immune cells: their job is to absorb invading bacteria, viruses and fungi, as well as consume regular cellular debris.
But they do much more than that.
Microglia also release chemicals known as growth factors, which help the brain.
And during fetal development they break unnecessary connections between nerve cells, or even eliminate cells entirely—actions that shape the brain's wiring.
If microglia are exposed to infection during this critical time, some scientists suggest that the wiring could go awry and the brain suffer long-term consequences.
So far, the evidence for these effects is more limited in humans, but brain scan studies and autopsies find unusually high numbers of active microglia in people with schizophrenia or autism.
male and female microglia
Sex adds another variable to the link between microglia and brain development: These cells behave differently in certain parts of the developing male and female brain, even when everything is going normally.
Take, for example, McCarthy's 2019 findings made in young rats while they were playing.
Play in young animals is influenced by a region of the brain called the amygdala, and the effect of testosterone on the amygdala is known to predispose males to rough play—this tendency is not seen in females.
The researchers found that microglia in the amygdala were more active in males, due to exposure to testosterone in the womb.
Highly active male microglia ate another type of star-shaped cell called astrocytes.
"Basically, they're in the business of killing cells," says McCarthy.
In female rats, the scientists observed that these astrocytes survive and appear to dampen the firing of amygdala nerve cells, and this damping, in turn, appears to reduce violence.
And when the researchers used an antibody to prevent microglia from killing the relevant astrocytes in the male pups, the animals stopped playing abruptly.
McCarthy says that astrocytes, when present, suppress neural activity in real time to prevent rough play.
There are many other reported ways in which microglia act differently in the brains of male and female rodents at a very young age.
And those differences can have long-term consequences, particularly if the mother has an infection or if scientists cause one in the lab.
For example, the authors of a 2020 study looked at microglia in the adult offspring of female mice exposed to a synthetic molecule that mimics the genetic material of a virus.
They focused on a part of the brain called the dentate gyrus, a region involved in learning and memory that is typically smaller in people with schizophrenia.
In the study, male mice born to mothers treated with the viral mimic had a higher density of synapses — connections between nerve cells — than is usually found in the dentate gyrus.
This was true both for excitatory synapses, in which one neuron excites the activity of the next, and for inhibitory synapses, in which one neuron dampens the activity of another.
In women, by contrast, viral mimicry treatment resulted in fewer excitatory synapses and few changes in inhibitory ones.
These changes in the ratios of the “on” and “off” synapses have similarities to the synapse imbalances seen in human schizophrenia and further suggest that the pattern differs between men and women.
Based on this and other research, the working hypothesis is that immune activation in the brain, very early in life, changes microglia and somehow “primes” the brain for differences that arise later on.
It's not clear exactly how this might work, says Jaclyn Schwarz, a neuroscientist at the University of Delaware in Newark.
One possibility is that male microglia, distracted by fighting an infection, skip some of the neural pruning work they normally do during fetal development.
Alternatively, Schwarz speculates, perhaps male microglia become overactive in the long term, pruning too many neural connections as the brain continues to develop throughout childhood, adolescence, and adulthood.
the female brain
In human adolescents, the general pattern of gender differences in mental illness is reversed.
Women and adolescent girls are more susceptible to mood disorders like depression and anxiety, which have less to do with the brain's wiring during development and more to do with ongoing chemical processes within the brain, Schwarz says. .
The brain isn't the only place where the immune system differs by sex: Women tend to mount a stronger immune response to infections than men.
When neuroscientists studied only male rodents, immunologists, by contrast, often focused on females and their cells because they offer a more robust response, says Natalie Tronson, a behavioral neuroscientist at the University of Michigan in Ann Arbor.
Women pay a price for that powerful response with a higher rate of autoimmune diseases, such as lupus.
Researchers have analyzed the genes that are turned on and off in the brain tissue of people suffering from depression and found that patterns of gene use differed by gender.
“What happens in the brain of a depressed man or a woman is very different,” says Georgia Hodes, a neuroscientist at Virginia Tech at Virginia State University in Blacksburg and a co-author on that research.
One pattern they have seen in women is changes in the activity of genes involved in inflammation, a key immune mechanism.
Brain inflammation is also closely linked to Alzheimer's disease, and gender also plays a role in risk: The first symptoms usually appear in your 60s, and women are more likely than men to be diagnosed.
In a 2021 study, Marina Sirota, a bioinformatician at the University of California, San Francisco, and her colleagues examined which genes were turned on or off in the brains of people with Alzheimer's who had died.
In the work they discovered alterations in the activity of genes that could influence immune activity in women who had Alzheimer's compared to those who did not.
They did not see that difference in men.
Sirota says there is more work to be done to understand why these genetic patterns change in women and how they might influence the course of dementia.
(In fact, her specialty is integrating complex immunity data; she recently wrote a review on the subject for the Annual Review of Biomedical Data Science.)
As for older men, microglia that may increase risk during development could be beneficial in old age.
Another study of brain tissue from people with Alzheimer's found that microglia in the brains of men were more likely to take on an amoeba-like shape, associated with protective activity, than microglia in women.
Studies in mice indicate that there are differences even between healthy male and female brains as the animals age.
Researchers led by Bill Freeman, a neuroscientist at the Oklahoma Medical Research Foundation in Oklahoma City, examined the patterns of gene activity and proteins in the brains of two-year-old mice (mature age for a mouse).
Thus, they found that while inflammation increased with age in the brains of both sexes, the change was more prominent in females.
Thus, while studies in men point to microglia as a relevant player in both early risk and later protection, the situation in women appears to involve a number of immune genes that may influence inflammation risk, mood disorders and dementia, in a way that is not yet fully understood.
A step towards health equity
Scientists for now can only speculate as to why these differences evolved, but many point to the simple fact that females can become pregnant.
The mother's immune system should not attack the fetus, even if it is genetically different from her own body.
Therefore, pregnancy causes a series of changes in immunity, some of which dampen the mother's defense system, making her more prone to serious illnesses caused by some infections, such as covid 19 and chickenpox.
"Men don't seem to have that flexibility in their immune systems," says Hodes.
"They always have the same immune responses throughout their lives, with some changes as they age."
But female immune flexibility—needed to protect the fetus—can come at a cost to a woman's brain.
No one is designing pink and blue pills yet.
But cataloging those differences is an important first step in understanding how sex, the brain, and the immune system interact in health and disease.
Getting to the root of those differences and ultimately developing different treatments for different people is crucial to achieving health equity.
“We're trying to understand biology, we're trying to improve health,” Freeman says.
“That means understanding the diversity of our human species.”
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