A new study reveals that male and female mice respond differently to stress at a cellular level, indicating the importance of diversity in scientific research to better understand and treat stress-related conditions. The research used advanced methods to analyze gene expression in individual brain cells and could pave the way for personalized treatments for conditions such as anxiety, depression and obesity.

A recent study in mice could pave the way for personalized treatments for depression, anxiety and other stress-related conditions, which are known to affect men and women differently.

Scientific excellence 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 apply to the design of scientific experiments. Despite this, a large proportion of life sciences research relies solely on male rats, which can skew results and limit the applicability of results to humans.

A new study by researchers from the Weizmann Institute of Science addresses this challenge, revealing in unprecedented detail how the brains of male and female mice respond differently to stress.

In the study published in Cell ReportsResearchers from Professor Alon Chen’s joint lab at the Weizmann Institute and the Max Planck Institute for Psychiatry in Munich have discovered that a subclass of brain cells respond to stress in a very different way in males and females. The findings could lead to a better understanding of health conditions affected by chronic stress, such as anxiety, depression, and even obesity and diabetes, and could pave the way toward personalized treatments for these disorders.

Mental and physical disorders caused by chronic stress are constantly on the rise, putting great pressure on society. It affects both men and women, though not necessarily in the same way. Although much evidence suggests that men and women deal with stress differently, the reasons for these differences are not yet fully understood, and in any case, personalized treatments for men and women remain beyond the reach of medicine.

However, researchers from Chen’s lab, which specializes in studying the stress response, hypothesized that innovative research methods could help change the picture.

Previous studies in other laboratories have found specific gender differences in stress response, but these results were obtained using research methods that can mask significant differences in the responses of specific cells or even completely erase the roles that relatively rare cells play. In contrast, Chen’s lab uses advanced methods that allow scientists to analyze brain activity with unprecedented precision—at the individual cell level—and may thus shed new light on differences between the sexes.

“We aimed the most sensitive research lens as possible at the brain region that serves as a central hub for stress response in mammals, the paraventricular nucleus (PVN) in the hypothalamus,” says Dr. Elena Brivio, who led the study. through the sequence RNA Molecules in that part of the brain At the individual cell level, we were able to map the stress response of male and female mice along three main axes: how each type of cell in that part of the brain responds to stress, and how each cell responds to stress. A species previously exposed to chronic stress responds to a new stress experience and how these responses differ between males and females.

The researchers mapped gene expression in more than 35,000 individual cells, generating a massive amount of data that provides a picture of stress response unprecedented in its scope and in highlighting differences between how males and females perceive and process stress. As part of the study, and in keeping with the principles of open access science, the researchers decided to make the fully detailed maps publicly available on a dedicated interactive website, which was published at the same time as the study, providing other researchers with convenient, user-friendly access to the data. “The site will allow, for example, researchers who focus on a specific gene to see how the expression of that gene changes in a particular cell type in response to stress, in both males and females,” Brivio explains.

Comprehensive mapping has already allowed the researchers to identify a long list of differences in gene expression — between males and females, and between chronic and acute stress. The data showed, among other things, that some brain cells respond differently to stress in males and females: some cells are more susceptible to stress in females and some are more susceptible to stress in males.

The most significant difference was found in a type of brain cell called oligodendrocytes, a subtype of glial cells that provide support for neurons and play an important role in regulating brain activity. In males, exposure to stressful conditions, particularly chronic stress, altered not only gene expression in these cells and their interactions with surrounding neurons, but also their structure themselves. As for females, no significant change was observed in these cells, and they were not subject to stress.

Neurons attract the most scientific interest, but they only make up about a third of all cells in the brain. The method we implemented allows us to see A richer and more complete picture, including all cell types and their interactions in the part of the brain under study.” Head of a research group at the Department of Neuroscience at Karolinska Institutet in Sweden.

Basic diversity

Until the 1980s, clinical trials of new drugs were conducted only on men. The accepted view was that including women was unnecessary, and that it would only complicate the research, introducing new variables such as the menstrual cycle and hormonal changes. For the same reasons, preclinical studies avoided the use of female animals until very recently.

But it is now known that variance between male animals, both at the molecular and behavioral level, is usually greater than between females, so there is no reason to suppose that females may complicate experiments more than males. However, in basic research, it is still common to only conduct experiments on males.

“Our findings show that when it comes to stress-related health conditions, from depression to diabetes, it is very important to take the gender variable into account, as it has a significant impact on how different brain cells respond to stress,” Chen explains. . “Even if a study does not focus specifically on differences between males and females, it is imperative that female animals be included in research, especially in neuroscience and the behavioral sciences, just as it is important to implement the most sensitive research methods, in order to get a complete picture,” Brevio adds. brain activity as possible.

Reference: “Sex shapes cell-type-specific transcriptional signatures of stress exposure in the mouse hypothalamus” by Elena Brivio, Aaron Koss, Alessandro Francesco Olivi, Stoyo Karamehalev, Andrea Rissell, Rainer Stoffel, Dana Hirsch, Jill Stelzer, Matthias F. Schmidt, Juan Pablo Lopez and Alon Chen, July 29, 2023, Available Here. Cell Reports.
doi: 10.1016/j.celrep.2023.112874

Also participating in the study were Dr. Aaron Koss, Stoyo Karamehalev, Andrea Rissell, Rainer Stoffel, Dr. Matthias F. Schmidt of the Max Planck Institute of Psychiatry in Munich; Dr. Alessandro Francesco Olivi of the Leibniz Institute for Neurobiology in Magdeburg, Germany; Dana Hirsch of the Weizmann Veterinary Resources Department; and Dr. Jill Stelzer of the Life Sciences Core Facilities Division at Weizmann.

Professor Alun Chen’s research is supported by the Rahman Family Research Laboratory in the Neurobiology of Stress. Licht family. and the Irving P. Harris Fund for New Directions in Brain Research. Professor Chen holds the Vera and John Schwartz Chair in Neurobiology.

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