Israeli and German researchers have discovered that the brain cells of male and female mice respond differently to stress, potentially paving the way for personalized therapies for stress-related disorders.
Mental and physical disorders caused by chronic stress are constantly on the rise, putting a significant strain on society. They affect both men and women, but not necessarily in the same way. Although plenty of evidence suggests that men and women deal differently with stress, the causes of these differences are not yet fully understood. A significant majority of life sciences studies, including those involving mice, have historically focused on males, potentially leading to incomplete or biased findings.
Recognizing this challenge, Israeli and German sought to address the issue by investigating how stress affects male and female mice differently at the cellular level.
Israeli researchers working in the laboratory of Dr. Alon Chen of the Rehovot-based Weizmann Institute of Science were joined by German researchers from the Max Planck Institute of Psychiatry and the Leibniz Institute for Neurobiology.
“Our findings show that, when it comes to stress-related health conditions, from depression to diabetes, it’s very important to take the sex variable into account, since it has a significant impact on how different brain cells respond to stress,” Chen explained.
Until the 1980s, clinical trials of new drugs were conducted on men alone. The accepted view was that including women was unnecessary, and that it would only complicate the research, bringing into play new variables such as menstruation and hormonal changes.
On the Cellular Level
Led by Planck’s Dr. Elena Brivio, the researchers analyzed brain activity in the paraventricular nucleus of the hypothalamus – a critical area associated with the stress response. They employed advanced techniques that allowed them to examine gene expression in more than 35,000 individual brain cells, providing an unprecedented level of detail into the differences between how males and females perceive and process stress.
“By sequencing the RNA molecules in that part of the brain on the level of the individual cell, we were able to map the stress response in male and female mice along three main axes: 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,” Brivio said.
The researchers made their detailed map publicly available on a dedicated interactive website, which went live at the same time the study was published.
“The website will, for example, allow researchers who are focusing on a specific gene to see how that gene’s expression changes in a certain cell type in response to stress, in males as well as females,” Brivio explained.
The findings showed, among other things, that certain brain cells respond differently to stress in males and females. The most significant difference was found in a type of brain cell called the oligodendrocyte – a subtype of glial cell that provides support to nerve cells and plays an important role in regulating brain activity.
In males, exposure to stress conditions, especially chronic stress, changed not only the gene expression in the oligodendrocyte cells and their interactions with surrounding nerve cells but also their very structure. In females, however, no significant change was observed in these cells, and they were not susceptible to stress exposure.
“Even if a study does not specifically focus on the differences between males and females, it’s essential to include female animals in the research, especially in neuroscience and behavioral science, just as it is important to implement the most sensitive research methods, in order to obtain as complete a picture of brain activity as possible,” Brivio said.
The research and findings were published in Cell Reports, a peer-reviewed journal on July 29.