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The hippocampus, the brain’s hub for memory, both generates and reacts to estrogen. This phenomenon is observed in both male and female brains. (Image credit: BSIP via Getty Images)Share this article 0Join the conversationFollow usAdd us as a preferred source on GoogleSubscribe to our newsletter
Elevated estrogen levels within the brain’s memory center might diminish one’s capacity to withstand traumatic experiences, thereby increasing the likelihood of developing memory impairments or post-traumatic stress in the aftermath, according to a recent investigation in mice.
The research, which appeared in April in the journal Neuron, scrutinized the impact of estrogen on the mouse brain. It specifically focused on the hippocampus, a crucial region involved in cognition and recollection. Both male and female mammals exhibit substantial estrogen production in the hippocampus, contrary to its common perception as a “female” hormone.
The study indicates that these localized estrogen concentrations could influence susceptibility to memory deficits following significant acute stress. Although the investigation was conducted on mice, the authors believe it likely holds relevance for humans.
“I believe this is highly applicable,” Dr. Tallie Z. Baram, a professor, developmental neuroscientist, and child neurologist at the University of California, Irvine, and senior author of the study, told Live Science.
Estrogen is not always beneficial for memory
Traumatic incidents can lead to memory disturbances, such as difficulty recalling specific personal events and experiencing fear in previously secure environments. When these issues persist and are accompanied by intrusive recollections of the traumatic event, they are categorized as post-traumatic stress disorder (PTSD).
Approximately 10% to 12% of women encounter PTSD in their lifetime, compared to 5% to 6% of men. Part of this disparity might be attributed to variations in the lived experiences of men and women; for instance, women report higher incidences of sexual assault at younger ages than men do. Biological distinctions between the sexes are another possible factor, but their contribution to the phenomenon is not well understood.
The recent study highlights hippocampal estrogen as one potential biological difference. “This research has opened up significant new avenues for PTSD investigation,” Victoria Luine, a professor emerita of psychology at Hunter College in New York City who was not involved in the study, shared with Live Science via email.
In the course of the study, researchers replicated acute traumatic events by subjecting laboratory mice to concurrent stressors, including intense illumination, loud sounds, and the scent of other distressed mice. The mice underwent various memory assessments before and after the stressful exposure, and their performance was contrasted with that of a control group that did not endure such stressors.
In comparison to mice that were not stressed, the stressed male mice exhibited diminished performance on the memory tests, with these deficits persisting for several weeks. “Even after a month, they still had a memory impairment — indicating a very persistent effect,” Heller remarked.
The hormonal cycles of female mice and humans share similarities, but they operate on vastly different timelines, with the mouse cycle being approximately one-seventh the duration of the human cycle.
(Image credit: dra_schwartz via Getty Images)
A comparable pattern was observed in female mice subjected to stress during proestrus, the phase of their hormonal cycle characterized by peak estrogen levels and preparation for ovulation. Both groups of mice learned to associate specific cues with the stressful experience and subsequently avoided them, with females demonstrating greater sensitivity to these cues than males.
However, it was noteworthy that female mice stressed during estrus, when estrogen levels drop and ovulation occurs, exhibited resilience. Their behavior and memory remained on par with those of unstressed mice. “The female mice experiencing low estrogen levels seemed unaffected — they were entirely protected,” Baram stated.
Studies suggest that hippocampal estrogen levels are comparable in males and proestrus females, while estrus females have lower concentrations. The researchers substantiated this finding through mass spectrometry, discovering that estrus mice possessed half the amount of hippocampal estrogen compared to males and proestrus females.
In this context, the absence of estrogen in the hippocampus appeared to shield against the detrimental effects of stress. Baram pointed out that this discovery was unexpected, given that estrogen is generally considered to enhance memory function in both sexes, and declines in estrogen, such as those occurring during menopause, are linked to memory issues. It should be noted, however, that menopause unfolds over a significantly longer period than the female mouse hormonal cycle, which lasts only four to five days.
A link to DNA
The significance of estrogen levels for memory is explained by the fact that “estrogen receptors directly regulate gene expression,” according to Heller. By attaching to its receptors, estrogen modulates the activity of specific genes, either increasing or decreasing it.
Heller’s laboratory investigates the mechanisms governing gene activity in the context of psychiatric conditions. One such mechanism involves chromatin remodeling, which refers to alterations in the way DNA is organized within a cell that can affect which genes are accessible for activation at any given time. A section of chromatin can be in an “open” state, making genes accessible to the machinery that turns them on, or in a “closed” state, which typically deactivates genes.
It appears that high hippocampal estrogen levels in male mice and proestrus female mice lead to an “opening” of their chromatin, potentially rendering them susceptible to memory problems induced by severe stress. In contrast, female mice in estrus exhibit a distinctly different chromatin profile that seems to offer protection.
What is it about women at that stage in life that makes them more vulnerable to memory loss with aging?
Tallie Z. Baram, professor, developmental neuroscientist and child neurologist at the University of California, Irvine
“We can observe that the function of many of these [open] genes is related to synapse biology,” Heller explained. Synapses are the junctions where different neurons connect and transmit electrical signals, and they are fundamental to the physical structure of memories within the brain.
Under most circumstances, it is likely advantageous to have elevated hippocampal estrogen levels because they facilitate chromatin “opening,” enabling the hippocampus to rapidly form new memories in response to novel experiences, Baram suggested. However, when these experiences involve severe acute stress, “that same plasticity, that same capacity of the brain to learn, becomes detrimental,” she stated. If these findings translate to humans, women might be particularly susceptible to such memory effects during specific phases of their menstrual cycles or at points in their lives when estrogen levels are high.
In both males and females, different types of estrogen receptors were implicated in the stress-induced memory impairments. The underlying reasons for this distinction will be a subject of future research, Baram noted. Furthermore, upcoming studies could aim to precisely identify the locations of these various estrogen receptors throughout the hippocampus, Heller added.
The research provides a “compelling demonstration that estrogens drive sex-specific, stress-induced alterations in chromatin networks that can profoundly affect neural functions such as memory,” Luine commented. Moreover, “these findings present strong evidence that sex is a significant biological variable.”
Historically, female laboratory animals were excluded from studies due to the perceived complexity of their hormonal cycles, which was thought to potentially confound results. The field of neuroscience exemplified this practice. In recent years, the U.S. National Institutes of Health (NIH) has mandated that scientists consider sex differences when designing human and animal studies funded by the NIH, yet progress has been gradual on both fronts, and current federal leadership has indicated a lack of support for this initiative.
It is crucial to include both sexes in research to achieve a comprehensive understanding of brain function and its response to external stimuli, such as stress, Luine emphasized. “A vital objective of this and other studies is to safeguard individuals against PTSD,” she added, and this research strongly suggests that preventive treatments for PTSD may require sex-specific tailoring.
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Beyond PTSD, Baram anticipates that this research could have implications for women’s risk of age-related memory decline and dementia.
While the reduction in estrogen during menopause is believed to increase this risk, the period preceding menopause, known as perimenopause, is characterized by substantial estrogen surges. The study’s findings suggest that if stress occurs during perimenopause, the combination of stress and elevated estrogen levels might contribute to memory difficulties. Consequently, perimenopause could represent another period during which women are particularly susceptible to memory disturbances, Baram proposed.
“We need to adopt a slightly different perspective,” she urged. “What is it about women at that phase of life that makes them more susceptible to memory impairment with aging?”