Recent mouse research could pave the way for tailored treatments for depression, anxiety, and other stress-induced disorders that are known to affect men and women differently.
Good science requires diversity. It is important to include both male and female researchers as well as individuals with different backgrounds and perspectives. This principle should also be applied to the design of scientific experiments. Nevertheless, a significant portion of life science research relies solely on male mice, which can skew results and limit the application of research findings to humans.
A new study by researchers at the Weizmann Institute of Science tackles this question, revealing in unprecedented detail how the brains of male and female mice respond differently to stress.
In a study published in cell report, researchers from the joint laboratory of Professor Aron Chen at the Weizmann Institute and the Max Planck Institute for Psychiatry in Munich have discovered that subcategories of brain cells respond to stress in very different ways in men and women. did. The findings could lead to a better understanding of health conditions affected by chronic stress, such as anxiety, depression, and even obesity and diabetes, paving the way for personalized treatments for these diseases. There is a possibility.
Mental and physical disorders caused by chronic stress are increasing year by year, placing a heavy burden on society. They affect both men and women, but not necessarily in the same way. Although there is ample evidence to suggest that men and women cope with stress differently, the causes of these differences are still not fully understood and, in any case, individualized treatments for men and women are needed. The law is still beyond the reach of medicine.
But researchers in Chen’s lab, which specializes in studying responses to stress, hypothesized that an innovative research method could help change the situation.
Previous studies in other laboratories have revealed specific sex differences in responses to stress, but these findings may mask important differences in specific cellular responses or may be relatively rare. It was obtained using research methods that could completely eliminate the role played by cells. In contrast, Chen’s lab uses advanced techniques that allow scientists to analyze brain activity with unprecedented resolution at the individual cell level, which could shed new light on the differences between men and women. There is a possibility that it can be done.
“We aimed the most sensitive research lens possible at the paraventricular nucleus (PVN) of the hypothalamus, a region of the brain that acts as the center of the stress response in mammals,” said Elena, who led the study. Dr. Brivio says. “By arranging them in order, RNA By analyzing molecules in that part of the brain at the level of individual cells, they were able to map the stress response of male and female mice along three major axes. It’s how each cell type in that part of the brain responds to stress, how each cell responds. How do individuals who have previously been exposed to chronic stress respond to new stressful experiences, and how do men and women differ in their responses? ”
The researchers mapped gene expression in more than 35,000 individual cells, generating vast amounts of data that provide an unprecedented picture of the stress response and how men and women perceive stress. This highlighted the differences in processing methods. As part of the study, and in accordance with the principles of open access science, the researchers decided to publish the entire detailed map on a dedicated interactive website. The website went live at the same time the study was published and provided information to other researchers. Convenient and user-friendly access to data. “For example, this website allows researchers focused on a particular gene to learn how the expression of that gene changes in certain cell types in response to stress, not only in women but also in men. “We will be able to see if it’s true,” Brivio explains.
Comprehensive mapping has already allowed researchers to identify a long list of gene expression differences between men and women, and between chronic and acute stress. The data showed, among other things, that certain brain cells respond differently to stress in men and women. Some cells are more sensitive to stress in women, while others are more sensitive to stress in men.
The most important differences were found in a type of brain cell called an oligodendrocyte. Oligodendrocytes are a subtype of glial cells that support nerve cells and play an important role in regulating brain activity. In men, exposure to stress conditions, particularly chronic stress, not only changed the gene expression and interactions of these cells with surrounding neurons, but also their very structure. However, no significant changes were observed in these cells in women and they were not affected by stress exposure.
“Although neurons have received the most scientific attention, they make up only about one-third of all cells in the brain. and their interactions,” said Dr. Juan Pablo López, a former postdoctoral fellow and current postdoctoral fellow in Cheng’s group. Research Group Head, Department of Neuroscience, Karolinska Institutet, Sweden.
basic diversity
Until the 1980s, clinical trials of new drugs were conducted only on men. The general consensus was that there was no need to include women, and that new variables such as menstruation and hormonal changes would only complicate the study. For the same reason, preclinical studies avoided the use of female animals until recently.
However, it is now known that variation in male animals at the molecular and behavioral level is usually greater than in females, so there is no reason to think that females would complicate experiments more than males. Despite this, it is still common in basic research to conduct experiments only on men.
“Our findings show that it is critical to consider the gender variable when it comes to stress-related health conditions, from depression to diabetes. “This is because it has a huge impact on how your brain cells respond to stress,” explains Chen. . “Just as it is important to employ the most sensitive research methods even when research does not specifically focus on male-female differences, it is important to employ female animals in research, especially in the neurosciences and behavioral sciences. “It is essential to include this information so that we can obtain the most complete picture possible of brain activity,” Brivio added.
Reference: “Sex of stress exposure shapes cell type-specific transcriptional signatures in the mouse hypothalamus” Elena Brivio, Aron Kos, Alessandro Francesco Ulivi, Stoyo Karamihalev, Andrea Ressle, Rainer Stoffel, Dana Hirsch, Gil Stelzer, Mathias By V. Schmidt, Juan Pablo López and Aron Chen, July 29, 2023. cell report.
DOI: 10.1016/j.celrep.2023.112874
The study also included Dr. Aaron Koss, Dr. Stoyo Karamikhalev, Dr. Andrea Ressl, Dr. Rainer Stoffel, and Dr. Matthias V. Schmidt from the Max Planck Institute for Psychiatry in Munich. Dr. Alessandro Francesco Ulivi, Leibniz Institute of Neurobiology, Magdeburg, Germany; Dana Hirsch of the Weitzman Veterinary Resources Department. and Dr. Gil Stelzer of Weizmann’s Life Sciences Core Facilities Division.
Professor Aron Chen’s research is supported by the Luhmann Family Institute for the Study of the Neurobiology of Stress. He is from the Richt family. Irving B. Harris New Directions Fund for Brain Research. Professor Chen is the current holder of the Vera and John Schwartz Professorship in Neurobiology.