Mice may hold the key to understanding cognitive deficits during menopause

A UCLA Health study is the first ever to look at menopause in mice.

Researchers at UCLA Health are optimistic about the results of a study conducted on female mice that explores menopausal-related memory and cognitive deficits. They say the findings could lead to a better understanding of neurological and psychiatric changes experienced by some women during menopause.

The study — the first to look at menopause in mice — was authored by Istvan Mody, PhD, a professor of Neurology and Physiology at the David Geffen School of Medicine at UCLA and a researcher with the UCLA Brain Research Institute. Dr. Mody and his team observed the mice for 33 weeks, during which they measured brain oscillations, phase-amplitude coupling (the coordination of slow and fast brain rhythms), sleep- and vigilance-state patterns, running-wheel use and other behaviors.

The study also measured bone loss, similar to a scan for osteoporosis in menopausal women.

“We started examining these animals at multiple levels,” Dr. Mody says. “It was a comprehensive study, but by no means all-inclusive.”

Brain waves altered

Menopause is the stage in a woman’s life when the ovaries stop producing reproductive hormones and there are no monthly periods for 12 consecutive months. Because mice do not have menopause as humans do, Dr. Mody’s team needed to simulate it chemically. Half of the study mice were injected with 4-vinylcyclohexene-diepoxide, a chemical that replicates menopause in mice by killing the ovarian follicles. The control group received saline solution.

After 15 days of daily injections, electrodes were attached to monitor the animals’ brains 24 hours a day for six weeks. An infrared camera tracked the mice’s activities day and night.

The results showed significant alterations in brain rhythms and oscillations in the menopausal mice that could affect cognition, Dr. Mody says.

Dr. Istvan Mody

He explains that the brain is characterized by a variety of oscillatory activity brain waves that come at various frequencies generated by assemblies of neural cells involved in certain tasks. The slower rhythms are coupled with the faster rhythms in what’s called phase-amplitude coupling.

But in the menopausal mice, the brain waves were not acting as they used to.

“In other words, these cognitive wheels no longer fit together,” Dr. Mody explains. What does it mean? “Perhaps cognitive impairment, problem-solving and memory impairments — all these could result from such a finding.”

Calming effect

After two weeks, the researchers introduced running wheels in the mice’s cages and recorded their brain activity. An infrared camera monitored their movement and wheel-running activity.

Dr. Mody notes that infrared cameras in the wild have shown that mice will line up and try to get on the wheel and run as fast as they can, averaging up to 2 miles a day.

In the study, the menopausal mice got on the wheel much sooner than the control mice, and they ran for a lot longer, Dr. Mody says. The team also recorded slower brain-wave activity during wheel-running, almost like sleeping, he added.

“It remains to be replicated and further analyzed if this rhythm-inducing effect of the wheel-running is something calming for the animals, perhaps like sleep is,” Dr. Mody says.

In addition to these findings, the team scanned the mice’s bones and found osteoporosis, or bone loss, often found in menopausal women. He notes that they did not find major anxiety in the mice.

Further studies needed

The National Institutes of Health did not require the use of females — including animals — in research studies until 2016, which may explain the lack of studies on women’s health issues. However, Dr. Mody says his interest in hormonal changes in the female brain goes back more than 10 years, when he became interested in excitability changes in the brain during the ovarian cycles of mice.

"I can only hope that, based on our studies, more experimental neuroscientists will pick up on this very interesting topic and pursue some of our findings."

Istvan Mody, PhD, a researcher with the UCLA Brain Research Institute

That interest prompted studies on pregnancy and the mechanisms of postpartum depression.

“We started using pregnant animals’ brains and we discovered major alterations that were trying to defend against enormous hormonal changes,” Dr. Mody says. “This is how we arrived at the mechanisms of postpartum depression that were used to develop a synthetic derivative of the ovarian hormone to treat postpartum depression.”

That drug, brexanolone, was approved by the U.S. Food and Drug Administration in 2019.

Dr. Mody next set out to study menopause and the brain. He notes that women are twice as likely as men to develop depression, and after menopause, the likelihood increases four-fold.

“Those are staggering numbers,” Dr. Mody says, and they illustrate the need for more studies on menopausal women.

His next step will be to look into the correlation between Alzheimer’s disease and menopause.

Dr. Mody adds that new technologies such as magnetoencephalography, which can record faster brain activities than electrodes placed on the skull, will help advance the field.

“I can only hope that, based on our studies, more experimental neuroscientists will pick up on this very interesting topic and pursue some of our findings.”

Jennifer Karmarkar is the author of this article.