A new study led by researchers at UF Health has uncovered why males and females may experience stress differently, providing crucial insights into how the brain's molecular mechanisms adapt to acute challenges.
The brain produces a neurosteroid called allopregnanolone, or AP, in response to acute stress — a brief but intense reaction to a sudden challenge or threat. Elevated levels are a key part of the body's initial stress response, helping individuals quickly adapt and regulate their reactions. For example, when facing stressful events such as an imminent danger, elevated AP levels boost focus and energy by helping individuals stay on track and respond effectively.
The production of AP relies on an enzyme called 5α-reductase, or 5αR, which exists in two main forms: 5αR1 and 5αR2. UF College of Pharmacy researchers used animal studies to reveal how these enzymes function, highlighting biological differences in stress responses between men and women.
"Men, in general, tend to have a greater propensity to display outward, aggressive reactions to acute stress, whereas women have a much greater tendency to internalize their responses. This distinction is believed to contribute to the higher female prevalence of anxiety and depression," said Marco Bortolato , M.D., Ph.D., a professor of pharmacodynamics in the University of Florida College of Pharmacy and senior author of the study published Jan. 22 in Science Advances.
The study revealed that acute stress raises levels of 5αR2 — but not 5αR1 — in the front region of the brain of male laboratory 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 critical neurosteroid.
When the researchers reduced 5αR2 in male rats, these animals were less engaged and slower to respond to both acute stress and rewarding stimuli. However, administering AP restored this ability, underscoring the enzyme's importance. Analysis showed that during stress, 5αR2 stimulates protein production in the animals' neurons and support cells in the brain helping it adapt more effectively.
"Our research sits at the intersection of stress response and sex differences, which have major potential implications for personalized medicine," Bortolato said. "For instance, understanding why women are more susceptible to depression than men allows us to tailor more targeted treatments. Ultimately, these findings could help guide the development of drugs that specifically modulate stress responses."
Bortolato is excited about the potential to translate these findings into new medicines, noting that they may eventually pave the way for a novel class of steroid-based compounds. These compounds could play a crucial role in treating forms of depression that are resistant to current therapies.
"Depression is the leading cause of disability worldwide, largely due to increasing levels of chronic stress," Bortolato said. "Conventional antidepressants often take two to four weeks to show initial results. Conversely, AP-based treatments could have much faster effects. Enhancing our ability to produce AP could transform the way we approach depression and other stress-related disorders."
The study featured contributions from Giulia Braccagni , Ph.D., co-first author of the article and a postdoctoral fellow in the UF College of Pharmacy, and Caterina Branca , Ph.D., a research assistant professor in the UF College of Pharmacy.
