Estrogen in both the male and female brain shapes responses to trauma, study suggests
High estrogen in the memory center of the brain may worsen resilience to traumatic events, influencing the tendency to develop memory problems or post-traumatic stress later, a new study in mice suggests.
The research, published in April in the journal Neuronexplored the effects of estrogen on the mouse brain. He zoomed in seahorsea key part of the brain involved in learning and memory. Both male and female mammals produce significant amounts of estrogen in the hippocampus, although it is often presented as a “female” hormone.
The study suggests that these local estrogen concentrations may influence vulnerability to memory problems following major acute stress. Although the research was conducted on mice, the authors believe it is likely relevant to humans.
“I think it’s highly translatable,” study lead author Dr. Tallie Z. Baramprofessor, developmental neuroscientist and child neurologist at the University of California, Irvine, told Live Science.
Estrogen is not always a memory booster
Traumatic experiences can cause memory problems, including difficulty remembering specific personal experiences and have fearful reactions to once safe and familiar situations. When these problems persist and are accompanied by intrusive memories of the traumatic event, they are classified as post-traumatic stress disorder (PTSD).
About 10 to 12% of women suffer from PTSD during their lifetime, compared to 5-6% of men. Part of this difference may come from differences in the experiences men and women have; for example, women have higher rates of sexual assault at a young age than men. Biological differences between women and men are another potential factor, but their contribution to the phenomenon is poorly understood.
The new study highlights hippocampal estrogen as a difference that might matter. “The research has uncovered important new avenues for PTSD research,” Victoria Luinéprofessor emeritus of psychology at Hunter College in New York who was not involved in the work, told Live Science in an email.
In the study, researchers simulated acute traumatic events by exposing laboratory mice to multiple stressors at the same time, including bright lights, loud music, and the odors of other stressed mice. They subjected the mice to various memory tests before and after the stressful experience and compared these rodents to a group that had not experienced such stressors.
Compared to unstressed mice, stressed male mice performed worse on different memory tests, and these deficits persisted for weeks. “Even a month later, they had a memory deficit, so it’s a really perseverative effect,” Heller said.
The hormonal cycles of female mice and humans are similar, but they occur on very different time scales, with the mouse cycle being about one-seventh the length of the human cycle.
(Image credit: dra_schwartz via Getty Images)
A similar pattern was observed in stressed female mice during proestrus, the phase of their hormonal cycle where estrogen peaks and the body prepares for ovulation. Both groups of mice learned to associate certain cues with the stressful experience and avoid them, with females being more sensitive to these cues than males.
But interestingly, female mice stressed during estrus, when estrogen drops and ovulation occurs, showed resilience. Their behavior and memory remained comparable to those of unstressed mice. “The female mice that had low estrogen levels laughed it off – they were completely protected,” Baram said.
Studies suggest that estrogen levels in the hippocampus are similar in proestrus male and female mice, while estrus females have lower levels. The researchers confirmed this using a technique called mass spectrometry, revealing that estrus mice had half the amount of hippocampal estrogen as proestrus males and females.
In this context, this lack of estrogen in the hippocampus seems to protect against the negative effects of stress. This finding is surprising, Baram noted, because estrogen is generally thought to promote memory function in both sexes and decrease estrogen. as seen during menopauseare linked to memory problems. That said, menopause takes place over a much longer period than the female mouse’s hormonal cycle, which only takes four or five days.
A link with DNA
Why are estrogen levels important for memory? “Estrogen receptors directly control gene expression,” Heller said. By binding to its receptors, estrogens increase or decrease the activity of certain genes.
Heller’s lab studies the mechanisms that control gene activity in the context of psychiatric disorders. One such mechanism is chromatin remodeling, or changes in the way DNA is packaged in a cell, which can alter which genes can be turned on at any given time. Part of the chromatin can be “open,” exposing genes to machines that turn them on, or “closed,” which generally turns genes off.
It turns out that elevated estrogen in the hippocampus of proestrus male and female mice opens their chromatin in a way that could make them vulnerable to memory problems brought on by severe stress. Female mice in estrus, on the other hand, have a completely distinct chromatin profile that appears protective.
What is it about women at this stage of life that makes them more vulnerable to memory loss as they age?
Tallie Z. Baram, professor, developmental neuroscientist and pediatric neurologist at the University of California, Irvine
“We can see that the function of many of these [open] Genes are related to the biology of synapses,” Heller said. Synapses are the points where different neurons meet and exchange electrical signals, and they are central to the physical structure of memories in the brain.
It may be that in most cases it helps to have high levels of estrogen in the hippocampus because it “opens” the chromatin, allowing the hippocampus to quickly form new memories in response to new experiences, Baram noted. But when those experiences consist of severe acute stress, “that same plasticity, that same ability of the brain to learn, becomes problematic,” she said. If the findings translate to humans, women could be particularly vulnerable to these memory impacts in certain phases of their menstrual cycle or at certain times of their lives when estrogen is high.
In men and women, different flavors of estrogen receptors were responsible for stress-induced memory problems. The reasons for this difference will be the subject of future study, Baram said. Additionally, future research could try to determine exactly where different estrogen receptors are located in the hippocampus, Heller said.
The study provides a “strong demonstration that estrogen leads to sex-dependent and stress-induced changes in chromatin networks, which can significantly impair neuronal functions like memory,” Luine said. Additionally, “these results present compelling evidence that sex is a powerful biological variable.”
Historically, laboratory females were excluded from studies because it was thought that their hormonal cycles were too complex and would skew the results. The field of neuroscience illustrates this trend. In recent years, the The United States National Institutes of Health (NIH) required that scientists take gender differences into account when designing NIH-funded human and animal studies, but progress has been made been slow on both fronts — and the current federal leadership has reported lack of support for the initiative.
It’s important to include both sexes in research to truly understand how the brain works and responds to external factors, like stress, Luine said. “An important goal of this and other studies is to protect humans from PTSD,” she added, and this study strongly suggests that preventive treatments for PTSD may need to be tailored based on gender.
Beyond PTSD, Baram thinks the research could have implications for the risk of aging-related memory problems and dementia in women.
The decline in estrogen at menopause is thought to increase this risk, but before menopause comes perimenopause — a period with massive surges in estrogen. The study results suggest that if stress occurs during perimenopause, the combination of stress and high estrogen levels may contribute to memory problems. So perimenopause could represent another time when women are particularly vulnerable to memory problems, Baram suggested.
“We need to start thinking a little differently,” she said. “What is it about women at this stage of life that makes them more vulnerable to memory loss as they age?”
This article is for informational purposes only and is not intended to offer medical advice.
Find out everything you know about the most complex organ in the human body with our brain quiz!
