'Historically, scientists have only studied men'

Study shows how brain cells of males and females respond differently to stress

Researchers have long recognized variations in how men and women experience depression, anxiety and PTSD; now they are looking at them on the molecular level

Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.

Illustrative. A stressed woman before her computer. (Katarzyna Bialasiewicz; iStock by Getty Images)
Illustrative. A stressed woman before her computer. (Katarzyna Bialasiewicz; iStock by Getty Images)

A new study from Prof. Alon Chen’s joint laboratory at the Weizmann Institute in Rehovot and the Max Planck Institute of Psychiatry in Munich, Germany shows how the brains of males and females respond differently to stress.

The researchers hope that the findings will eventually lead to sex-tailored therapies for stress-related related psychiatric disorders such as anxiety, depression, post-traumatic stress disorder (PTSD), and also some stress-related disorders such as diabetes.

“Historically, scientists have only studied men, based on gender assigned at birth. Since the 1980s, researchers have been required to include women in clinical trials, but it is only now that there is a movement starting with the [NIH – National Institutes of Health] saying that both males and females must be studied on the cellular and molecular level in basic research,” Dr. Elena Brivio said.

Brivio, originally from Italy, led the study published this month in the peer-reviewed Cell Reports as the main part of her doctoral studies in Chen’s lab. She now has a postdoc position at IGBMC – Institut de génétique et de biologie moléculaire et cellulaire in France.

Speaking with The Times of Israel, Brivio emphasized that the study was done on mice, and therefore dealt with sex differences and not gender differences.

“Gender is a human construct and applies only to humans,” she explained.

“But we used mice because mice brains are a very good model for human brains. They even exhibit depression-like behavior similar to what we see in humans,” she said.

Illustrative: A research assistant holding a mouse used to study autism, December 15, 2021. (Jeff Roberson/AP)

For years, clinical studies and observations have demonstrated differences between men and women in terms of their responses to stress. Stress presents differently in men and women in terms of prevalence and symptoms. For example, two-thirds of depression diagnoses are in women. And while men diagnosed with depression tend to show more anger, women exhibit more anhedonia, or social withdrawal, loss of motivation, and a lack of enjoyment.

“We also know that some drugs for stress-related pathologies work better in males and some work better in females, but we don’t know why. This is partially because we don’t know much about the disorders themselves… But it is also partially because nobody has bothered to study female biology,” Brivio said.

She and her colleagues used the powerful research tool of RNA sequencing, which looks at gene expression and regulation. They applied the tool to the cells of the tissue of of the paraventricular nucleus (PVN) of the hypothalamus in the mice, which is the part of the brain in all mammals that coordinates the stress response.

There were three particular questions the team sought to answer: how each cell type in that part of the brain responds to stress, how each cell type previously exposed to chronic stress responds to a new stress experience, and how these responses differ between males and females.

A section of a mouse brain under the microscope. The yellow color shows the complex structure of a mature oligodendrocyte, with numerous branches that reach out to the surrounding cells. (Courtesy of the Weizmann Institute)

Before looking at the mouse brain cells, the researchers exposed the mice to short-term and longer-term combinations of mild physical, psychological, and social stress. For example, a mouse’s nest would be taken away for a couple of hours and then returned. In another instance, a mouse was taken away from its usual social group and deposited with a group of unfamiliar mice for 15 minutes.

When later applying RNA sequencing to the mouse PVN cells, they looked at all the cells there — not only at the neurons (nerve cells). They discovered that different types of cells respond to stress in different ways and that there were sex differences.

“We found some cells that responded to stress in the females, but not the males, and the other way around. And then when we looked at these cells, and their response after chronic stress, we found some cells that were particularly sensitive. The response was different from after normal stress, and also here there were differences between males and females,” Brivio reported.

The researchers then focused on the oligodendrocyte – a subtype of glial cell that provides support to neurons and plays an important role in regulating brain activity. Of all the types of cells in the PVN, the oligodendrocytes were the most sensitive to stress.

“Oligodendrocytes are characterized by a very complex structure, a lot of branches. The ones in the male mice, after stress exposure, were simpler looking and they were characterized by a more immature expression of genes. This was not true for the oligodendrocytes in the females brains, which retained their complex structure,”  Brivio said.

From left: Dr. Juan Pablo Lopez, Dr. Elena Brivio and Prof. Alon Chen (Courtesy of the Weizmann Institute)

As part of the study, and in keeping with the principles of open-access science, the researchers decided to make the entire detailed mapping of their work on the mice brains publicly available on a dedicated interactive website. The findings on oligodendrocytes may also be of use to researchers of myelin-related disorders such as multiple sclerosis, as these cells’ primary function is myelin production, and multiple sclerosis is more common among women than men.

“We are showing that oligodendrocytes are indeed important cell types for stress. They are possibly important for good brain function, but this is not true in both sexes. And we need to keep this in mind for future studies and as we consider that maybe altering oligodendrocytes and their activity could be something that we can target in drug development,” Brivio said.

In addition to investigating in the future whether the findings in mice are the same as in humans, Brivio emphasized that the value of the sex differences she and her colleagues found is not yet clear.

“The differences could be positive or they could be negative. It could be that these changes in the cells that we observed in the males are a sort of protective change, or it could be a detrimental change,” she said.

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