Studies suggest that a single stressful event can sharpen how the male brain learns to associate environmental cues with rewards, creating the essential motivational building blocks to master new skills. On the other hand, more prolonged stress can be a deterrent to learning.
After testing this pattern, a research team at The University of Texas at San Antonio decided to investigate a new question: Does the female brain respond the same way to stress, and do fluctuations in hormones affect these reactions?
How hormones can flip the script
In the preclinical study recently published in Neuropsychopharmacology – Nature, the team found that the effect of stress on reward learning in females is “gated” by their reproductive cycle. Depending on the stage of the hormone cycle, a single exposure to stress can either enhance or suppress the ability to learn new cue-reward associations.
The powerful effect of hormones was not immediately obvious to the team because over time, the two possible outcomes balance out.
“It’s very enlightening to see that when we looked at all the females put together, it looks like stress isn’t having an impact,” explained Morgan P. Johnston ’25, the lead author on the study. “But when you look closer, and specifically you look at hormone changes, you see these opposing effects happening at different points in the cycle. In one stage we have enhanced learning, and in one stage, we have weakened learning.”
Johnston, who earned her PhD in neuroscience and now serves as a lecturer at the University of Oklahoma, was driven to study the issue to address a glaring gap in existing scientific literature: females are often excluded from preclinical research.
“One of my big passions for a long time has been the fact that females are not often included in research. So most studies, including in neuroscience, really under-research females,” she said.
A clearer picture of stress disorders
These findings provide a useful piece of the puzzle in understanding why stress-related disorders, such as depression and anxiety, often manifest differently and more frequently in women than in men. Because women exhibit greater activation of the stress-response system — fight-or-flight mode — and a higher incidence of these disorders, understanding the biological interaction between hormones and stress is crucial.
“If you put a male and a female in the same scenario, the female is more likely to report it as stressful,” Johnston explained. “Women will release more cortisol on average, and it is harder to shut that response down. There is a feedback loop where the stress response simply lasts longer.”
The study has the potential to help medical professionals explore new treatments or better anticipate how different patients will respond to different drugs and therapeutics.
“Hormones could potentially be administered exogenously to nullify the effects of stress,” said Matthew J. Wanat, an associate professor in the Department of Neuroscience, Developmental and Regenerative Biology, who supervised the study in the Wanat Lab. “But the important thing is that you need to know the state of the individual. These hormones under one circumstance might be good. But if the individual is in a different stage of the reproductive cycle and you give them that same drug, it might actually exacerbate the symptoms,” he added.
Chronic stress and brain priming
The research also touched on the long-term impacts of stress. While a single stressor produced cycle-dependent results, repeated stress exposure led to an increase in reward-driven behavior regardless of the cycle stage, suggesting that chronic stress may “prime” the brain to be more sensitive to rewards over time.
These “mechanistic insights” gained from preclinical models are a cornerstone of the research taking place in the Wanat Lab. By identifying how specific circuits in the brain, such as the dopamine system, are altered by stress and hormones, the team hopes to pave the way for more personalized treatments.
“We’re taking advantage of the natural biology of cycling hormones and seeing these interesting effects on behavior,” Wanat said. “This maybe indicates that steroidal hormones could be given as a treatment to blunt the effect of stress.”
Johnston also noted that while estrogen’s effect on the female brain is often a focus for researchers, male brains are also influenced by shifts in hormones, including estrogen and testosterone, but those impacts remain poorly understood.
“People often assume if you’re looking at females, you’re only looking at hormones. But when you look at males, no one asks whether you’re looking at testosterone,” Johnston said. “I think one of the most fascinating next steps is going to be exploring what we see in males regarding hormones.”
Building a “bench-to-bedside” pipeline
The study is part of a broader effort at UT San Antonio to establish a “bench-to-bedside” pipeline for treating stress-induced brain changes.
Wanat and his colleagues are currently working toward establishing a dedicated research center to explore how treatments like MDMA and Transcranial Magnetic Stimulation (TMS) can restore normal brain activity in individuals suffering from PTSD.
The research was a collaborative effort with co-authors Brandon I. Garcia-Castañeda, Leonor G. Cedillo, Sachi K. Patel and Victoria S. Vargas and was supported by grants from the National Institutes of Health and the National Science Foundation.
