Scientists discover key differences in male and female responses to stress in the brain

The research team led by prof. Marco Bortolato, University of Florida, in collaboration with prof. Simona Scheggi, University of Siena, has recently provided crucial insights into how brain’s molecular mechanisms adapt to acute challenges, and highlights why males and females may experience stress differently. Men tend to have more aggressive responses to acute stress, while women have a greater tendency to internalize their responses, which may underlie the higher prevalence of depression in women. Understanding why women are more susceptible to developing anxiety and depression is critical to identifying targeted therapies. This study may help identify new drugs that specifically modulate stress responses.

The brain produces a neurosteroid called allopregnanolone, or AP, in response to acute stress; its production relies on an enzyme called 5α-reductase, or 5αR, which exists in two main forms: 5αR1 and 5αR2. Using animal studies, the researchers showed how these enzymes act, highlighting biological differences in stress responses between men and women. The study revealed that acute stress raises levels of 5αR2 — but not 5αR1 — in the prefrontal cortex of the brain of male rats. Female rats, however, showed no such change, highlighting a significant sex-specific difference in how stress may be managed at the molecular level.

The researchers found that 5αR2 is essential for producing AP during stress, while 5αR1 helps maintain baseline levels of this neurosteroid. When 5αR2 was reduced in male rats, these animals were less engaged and slower to respond to both acute stressors and rewarding stimuli. However, administering AP restored this ability, underscoring the enzyme’s importance. Transcriptomic analysis showed that, during stress, 5αR2 stimulates protein production in the animals’ neurons and support cells in the brain helping it adapt more effectively.

In the figure: Acute stress induces the enzyme 5αR2 in male rat prefrontal cortex

Cadeddu, R., Braccagni, G., Floris, G., Branca, C., Corridori, E., Salviati, S., Sánchez, P., Santovito, L. S., Torres, J. M., Ortega, E., Pinna, G., Moos, P. J., Scheggi, S., & Bortolato, M. (2025). Prefrontal 5α-reductase 2 mediates male-specific acute stress response. Science advances, 11(4), eadr0563. https://doi.org/10.1126/sciadv.adr0563