Everyone has an opinion on whether men and women think differently, but there is no debating the differences in health risk attributable to gender.

Disorders of the brain are robustly influenced by gender, particularly those with origins in early life. One person who studies the cellular mechanisms that establish sex differences in brain development is Margaret McCarthy, Ph.D., professor and chair of the Department of Pharmacology at the University of Maryland School of Medicine.

As the invited speaker for the 2018 Hans L. Falk Memorial Lecture, McCarthy talked about the discoveries she and her research group are making in the field. Deputy Chief of the NIEHS Neurobiology Laboratory Serena Dudek, Ph.D., hosted the Nov. 13 seminar (see text box).

McCarthy’s presentation was titled, 'Microglia as Purveyors of Sex Differences in Brain Development and Adult Behavior.' (Photo courtesy of Steve McCaw)

It is not easy being male

McCarthy reminded the audience that in humans, males are conceived at substantially higher rates than females and are more likely to die in utero. They are also more likely to be born prematurely and have an injury at birth. If they do have an injury at birth, males tend to have a worse outcome than a sister who may have the same injury. In addition, McCarthy said, several brain disorders occur more often in human males than females.

'Males are more likely to be diagnosed with a neuropsychiatric or neurological disorder, such as autism, schizophrenia, dyslexia, ADHD, and Tourette’s syndrome,' McCarthy said. 'Understanding why this happens forms the basis of my work.'

NIEHS Director Linda Birnbaum, Ph.D., standing, introduced the speaker as members of the Falk family — Donald, Raymond, Gabrielle, and Stephen — looked on from the front row. (Photo courtesy of Steve McCaw)

POA controls male behavior

According to McCarthy, the part of the brain called the preoptic area (POA) has nothing to do with vision. Instead, it houses a group of cells in the hypothalamus that serves as ground zero for male sexual behavior.

Scientists have found that if a lesion appears in this region, male rodents, primates, canines, and most other animals lose all interest in sex. Stimulate the POA, and males lose interest in everything except sex. McCarthy has reported that dendritic spines, or branchlike extensions of neurons that transmit impulses, are twice as dense in males as females.

Immunity’s surprising role

NIEHS postdoc Salahuddin Syed, Ph.D., president of the NIEHS Trainees Assembly, was among the audience members who closely followed McCarthy’s talk. (Photo courtesy of Steve McCaw)

Further research from McCarthy’s group found that POA neurons make prostaglandins, a group of proteins that act like hormones and are normally associated with being sick. When team members exposed the brains of male and female rats to prostaglandins the day of and day after birth, both males and females displayed male sexual behavior when they became adults. The females thought they were male.

Inhibiting prostaglandin synthesis in newborn males using common drugs like aspirin results in adult males that do not engage in typical sexual behavior.

However, POA neurons are not the only tissues that make prostaglandins. Microglia, the brain’s immune cells, also make prostaglandins. Even more surprisingly, mast cells — immune cells that originate in bone marrow — release histamine, which stimulates the microglia to make more prostaglandins. McCarthy found that these two immune cells communicate with each other to differentiate the sexes during brain development.

Epigenetic repression

Each Hans L. Falk Memorial Lecture Series speaker receives a beautiful plaque emblazoned with the likeness of Dr. Falk. (Photo courtesy of Steve McCaw)

Genetic studies demonstrated that immune genes in female rats are epigenetically repressed. In other words, methyl groups attach themselves to these genes and shut them off. In contrast, the male immune genes were not methylated like females, which meant males expressed many immune genes.

McCarthy explained her hypothesis. 'During pregnancy, the mother’s immune system must be repressed for the fetus to survive, but due to genes on the Y chromosome, her immune response is not as strongly repressed against a male fetus as a female fetus,' McCarthy said.

McCarthy theorizes that the maternal immune attack causes inflammation in the developing male brain. Human studies have shown that early-life inflammation is the leading environmental predictor for developmental psychiatric disorders like schizophrenia and autism spectrum disorder, both of which are either more severe or more common in males.