Does biological sex impact how our brains handle chronic stress?

A new study reveals sex differences in how stress remodels our brains and behavior.

Photo by Vera Arsic from Pexels

Reference: Gaspar, R., Soares-Cunha, C., Domingues, A. V., Coimbra, B., Baptista, F. I., Pinto, L., Ambrósio, A. F., Rodrigues, A. J., & Gomes, C. A. (2022). The duration of stress determines sex specificities in the vulnerability to depression and in the morphologic remodeling of neurons and microglia. Frontiers in Behavioral Neuroscience, 16.

For ages, science has told us that stress wreaks havoc on the body and mind. Chronic stress can lead to digestive issues, high blood pressure, and mental health concerns and place one at greater risk for life-threatening conditions like heart disease (Mayo Foundation, 2021). Research has recently begun to shed light on how stress impacts men and women individually. Life stress can result in anxiety and depression — often appearing in different ways for men and women. For example, when depressed, anger and isolation behaviors are more common in men than in women (U.S. Department of Health, 2017). Neuroscientists think that stress can impact even the biological pathways in the brain by which we process emotional regulation. The specific mechanism of this phenomenon remains uncertain— prompting researchers to investigate the brain cells that comprise and govern these pathways for answers.

The messenger and the defender

Our brains are made up of specialized cells that convey messages, respond to damage, clean up waste, and much more (Penttila, 2019). Neurons are the cells responsible for transmitting information back and forth throughout the brain. They can send messages to a neighboring cell and create networks that span across several brain regions. Immune cells are also needed in the brain to respond to infection and cell damage— that is where microglial cells come into play. Microglial cells act as the brain’s immune system, releasing inflammatory factors to fight infection and repair damage to neurons. This partnership plays a vital role in maintaining balance in the brain and supporting overall health.

Mental health challenges in response to length of chronic stress exposure

A team of Portugal researchers recently set out to investigate how chronic stress impacts brain cells and behavior differently for men and women. The researchers used an unpredictable chronic stress protocol that involved exposing experimental mice to a variety of mild stressors every week for up to 2 weeks (short-term) or 6 weeks (long-term). Mild stressors included depriving the mice of either food or water for 15 hours and then exposing them to inaccessible food or an empty water bottle for 1 hour, among other techniques. Mice underwent behavioral testing afterward to probe for possible anxiety and depression symptoms.

Created by Caleigh Findley in BioRender

Short-term chronic stress led to increased stress hormone levels and anxiety for male and female mice. Interestingly, anxiety persisted with long-term chronic stress, but only male mice began to show depressive symptoms. The research team investigated further to uncover what might cause sex differences in these stress-induced behaviors. They extracted neurons and microglia from the dorsal hippocampus and nucleus accumbens— depression centers of the brain— and looked for any structural changes that may uncover clues.

Chronic stress produces sex-specific changes to brain cell biology

Researchers found that brain cells are fundamentally impacted by chronic stress in different ways for males and females. Short-term chronic stress weakened microglial cells in the nucleus accumbens of female mice and activated these cells in the hippocampus long-term. On the other hand, male mice saw negative effects on their neurons in both depression centers regardless of the length of chronic stress exposure. Also, males only saw an impact on their microglia in the nucleus accumbens during short-term chronic stress — with these cells appearing activated instead of weakened like the female mice. Findings from the brains of stressed male and female mice tell a different story that may contribute to their divergence in behavioral symptoms.

This study highlights the important role of sex in mediating the brain’s response to chronic stress and provides interesting avenues for future investigation. Conducting chronic stress research in experimental mice facilitated the examination of behavior, sex, and biological effects on the brain to better inform our knowledge of the interactions between these factors. The structural changes to brain cells observed possibly point to a stress-induced toxic environment that can drive anxiety and depressive-like symptoms and cause long-term health issues if left unchecked. Future research efforts toward unpacking the ramifications of chronic stress for men and women could better tailor mental health treatment to the individual and ultimately improve patient care.  

Additional References

Mayo Foundation for Medical Education and Research. (2021, July 8). Chronic stress puts your health at risk. Mayo Clinic. Retrieved from

Penttila, N. (2019, September 19). Cells of the brain. Retrieved from,necessary%20for%20proper%20brain%20function

U.S. Department of Health and Human Services. (2017, January). Men and depression. National Institute of Mental Health. Retrieved from