As you read this article, your brain has begun a series of complicated chemical steps in order to form a memory. How long you keep this memory may well depend on whether you are a man or a woman.  

Some scientists think that the reason for this difference may be estrogens. Women are disproportionately affected by Alzheimer’s disease, dementia and memory loss. In fact, almost two thirds of Americans living with Alzheimer’s are women. While researchers across the globe are still working to uncover the basic mechanisms of learning and memory, it is now known that estrogens help to regulate memory formation in both males and females. From a cultural and societal standpoint, when people think of estrogen they probably imagine pregnancy, periods and woman-fueled rage. Most people probably don’t consider memory; but maybe it’s time we all start thinking about estrogens’ role in memory a little more.  

Karyn Frick, a professor of psychology at the University of Wisconsin-Milwaukee, studies the connection between estrogens and memory. She and her students are among the scientists working to uncover the basic cellular and molecular mechanisms underlying memory formation. Part of Frick’s research focuses on how estrogens enhance memory, particularly through their action in the hippocampus.

The hippocampus is a small, curved region in the brain that plays an important role in the formation of memories. But it wasn’t always known for this role. In fact, so little was known about the brain and memory that, when a young man named Henry Molaison laid down on the surgical table in 1953 in a quest to cure his epilepsy, a skilled surgeon named William Beecher Scoville removed several structures from his brain, including a large portion of his hippocampus.

Molaison, although almost entirely cured of his seizures, immediately developed severe amnesia that persisted for the rest of his life; in short, he was unable to form new memories. However, the work surrounding Molaison and his memory impairments set the stage for decades of research into how the hippocampus is able to transform a short-term memory into a long-lasting and persistent one.

But what does this have to do with estrogens? Estrogens, particularly the most potent estrogen, called estradiol, latch onto structures called estrogen receptors, kind of like a key fitting into a lock. These receptors are abundant in the brain regions that support memory formation, particularly in the hippocampus. Now, brain cells have branch-like extensions (dendrites) that are necessary to communicate with other brain cells. On these dendrites are short protrusions called spines.

These spines are where the communication between brain cells really happens.

Importantly, these spines change with learning experiences. They grow. They shrink. They change shape. And research shows that estradiol can even increase the number of spines within the hippocampus. Thanks to researchers like Frick, we are beginning to understand the basic molecular mechanisms by which this process happens and how it relates to memory loss in aging women.

Frick has been studying rodents for nearly 30 years. Believe it or not, most of what we now know about memory comes from research in mice and rats. Early in her career, she characterized both male and female lab mice in regard to their memory function, as there were shockingly little data on memory in female mice at that time. She tested young, middle-aged and old male and female mice on a number of tasks, including a water maze that forces mice to use their hippocampus. She found that all the young mice performed well on these tasks, and all of the old mice were terrible, but it was in the middle-aged group she observed a striking effect.

While the middle-aged males performed like young mice, the middle-aged females performed like the old mice in the water maze. Frick and her colleagues attributed this effect to “estropause,” which, while not identical to menopause, is similar in many respects. Estropause refers to when the rodent estrous cycle (which is kind of like a woman’s menstrual cycle) starts to become irregular and essentially falls apart in middle-aged female rodents.

“These [middle-aged] females are going through a premature memory decline. The males got there eventually, but it happened earlier in females and it seemed to be associated with a loss of [estrous] cycling,” she says. “Over the last decade, or more, we have focused on trying to figure out exactly how, on a molecular level, estradiol enhances memory.”

Frick does this by using two tests called the “object recognition” and “object placement” tasks. Essentially, mice love new things, and they can recognize when a new object has been placed in their environment, as well as if a familiar object has been moved. Frick and her students found that when they infuse estradiol into the hippocampus immediately after the mice first encounter the objects, the mice better remember the identity and location of objects later. This allows them to use these tests as tools for figuring out the molecular mechanisms that create memory enhancements.

Recently they have started looking at another brain region, the prefrontal cortex, in addition to the hippocampus. The prefrontal cortex is the front-most part of your brain that is important for planning, complex thinking, and personality. Like the hippocampus, estrogen receptors are found in great number here. Importantly, Frick and her students have shown that infusions of estradiol into the hippocampus affect the dendritic spines in the prefrontal cortex.

“Clearly these two brain regions were communicating together in some meaningful way, but we didn’t know whether those two brain regions both had to be active simultaneously in order for the [hippocampus] infusion to enhance memory. All our interpretations of the hippocampal infusions [were] that it was a hippocampus effect, but maybe not, maybe it’s a circuit effect,” says Frick. The idea of circuits, or the connections between two or more brain regions, has been of great interest to neuroscientists in recent years, particularly among memory researchers. Understanding how infusions of estradiol are helping memory at the level of the circuit is an important next step in the basic research that drives science forward. Even Frick says, “What I’m excited about is the concept of trying to figure out what’s going on in the circuit.”

But she also has another reason to be excited these days. 

A team of Wisconsin researchers, including Frick, William Donaldson (a synthetic chemist from Marquette University) and Daniel Sem (a pharmacologist from Concordia University) are working together to create a drug that sticks to a special kind of estrogen receptor for the treatment of menopausal memory dysfunction. By designing the drug in this way, the researchers can avoid the negative consequences of estrogen replacement therapy, such as increased risk for cardiovascular diseases and breast cancer. Last summer, this group even formed a company called Estrigenix Therapeutics to facilitate the research and development of this drug.

Around that same time, as part of a four week long intensive program, they went out and talked to people, mostly menopausal women, physicians, and people from the pharmaceutical industry, and through that process they discovered that most patients and physicians aren’t really concerned about memory dysfunction or their potential increased risk of Alzheimer’s disease.

“Many of them weren’t even aware they were at an increased risk of Alzheimer’s disease. What they were most concerned with were hot flashes, depression and anxiety,” says Frick. So how can we make people, particularly women, more aware of the risk of memory loss as result of menopause?

“People don’t typically like to talk about menopause. It’s one of these things that women don’t like to admit that they’re going through,” says Frick. She goes on to explain that perhaps if women talk more about menopause and the symptoms of menopause, it can help make this period of a woman’s life more socially acceptable and something we can openly talk about. “Female gender, aside from age, is the greatest risk factor for Alzheimer’s disease, and most women don’t realize that,” says Frick.

As the basic science moves forward, not every step will be huge. First, we need to change the conversation so that women are aware of the risk their very gender poses.