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The Chemical Secrets of Memory
This is your brain on estrogen.
March/April 2009
by Elizabeth Svoboda '03
Elizabeth Svoboda '03, a contributing editor at Popular
Science, writes for Fast Company and Discover.
Some labs are as white and sterile as hospital rooms, but Karyn Frick’s looks more like the inside of FAO Schwarz. Everywhere you
look, there are buckets crammed with plastic toys in rainbow colors,
transforming the lab into one big amusement park for the dozens of female mice
in residence. But Frick’s not out just to keep her rodent charges occupied; she
uses the toys to glean insight into how they learn and remember. She picks up
two identical multicolored prisms and puts them in a large white box, a kind of
murine playpen. "We put two of these objects in," she explains, "and let the
mice explore for 30 seconds." Next comes the crucial step: injecting the mice
with estrogen.
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36% of people 85 and older report moderate or severe memory problems.
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Scientists have long known that estrogen is
responsible for female sex development in mammals. Frick, a Yale associate professor
of psychology, is one of a growing number of researchers who have done
experiments showing that the hormone also aids memory in females. (Estrogen is
also important for males. Many of the effects of testosterone on memory in
males are due to its conversion to estrogen.) If Frick can help to find out how
and why estrogen has these effects, her work may lead to new drug therapies for
people suffering from Alzheimer’s and other memory disorders. "All of us are
going to get old someday," she says. "The question is, Is there a type and
duration of estrogen treatment that can enhance memory function or reduce its
decline?”
Drugs like these could be a particular boon for women
who experience memory problems after menopause or later in life and find themselves
forgetting not just their keys, but their grandchildren’s names—or their
children's. Memory loss increases precipitously with advancing age: only 4
percent of people aged 65 to 69 report moderate or severe memory problems, but
36 percent of people 85 and older do. Like nuclear fallout, the impact of
memory loss on individuals and families is widespread and seemingly
irreversible. Frick has made it her mission to give memory-loss sufferers some
hope—to isolate the pathways that govern memory retrieval in order to fortify
them against the assaults of age and disease.
To gauge estrogen’s effect on her mouse subjects'
memory retention, Frick rounded up mice that had looked at the prisms two days
before and put them back in the playpen with one of the prisms and a novel
toy—a water spigot. "The longer they explore the new object, the more we know
they remember the old one," Frick says. "Since they already know about it,
they're not that interested in it. But if they don’t remember the old object, they’ll explore
both objects about equally." In a recent study published in the Journal of
Neuroscience, Frick
demonstrated that mice receiving estrogen injections remembered objects better
than did the control group of mice, which had gotten a placebo injection.
Frick’s study was one of many that present
tantalizing evidence that estrogen can indeed serve as a memory aid. As far
back as 1992, Bruce McEwen and colleagues at Rockefeller University found that
the number of synapses, or nerve connections, in female rats' brains rise and
fall with their estrous cycle. McEwen’s studies focused on the hippocampus, a
part of the brain that is needed for the formation of many kinds of memories
and that is exceptionally vulnerable to aging and Alzheimer’s disease. Since
then, researchers have probed, and confirmed, the link between estrogen and
memory from many different angles.
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Estrogen acts differently on mice of different ages.
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Yet as promising as the research is, its proponents
keep bumping up against formidable obstacles. In 2004, the National Institutes
of Health called a halt to its large-scale study of estrogen-replacement
therapy because participants had a slightly higher than average risk of
stroke—eight extra strokes per year for every 10,000 women—as well as more
cases of breast and uterine cancer. Thousands of women flushed their estrogen
pills down the toilet, literally or figuratively, when they and their doctors
heard the news. The findings were also discouraging for estrogen-based memory
therapy. Analysis of the NIH data found no discernible memory improvement. In
some women, estrogen use even seemed to carry an increased risk of dementia.
What lies behind this apparent contradiction? Part of
the answer may be the age of the NIH subjects. "The population in this study
was older—they had all been off natural estrogen for many years before they
started the therapy," says Christina L. Williams, a behavioral neuroscientist
at Duke. "More-current studies have suggested that when estrogen is replaced
right after menopause, it can be very good for cognitive function over the long
term.”
Frick concurs. "The mean age of the women in this
study was mid-sixties, but estrogen may work much better when women are in
their fifties. The NIH data support the critical-period theory that suggests
there’s a limited window in which estrogen therapy can be beneficial.”
But most importantly, the seeming conflict between
the NIH study and other research merely underlines what scientists already
know: that memory is extraordinarily complicated. In 2002, Frick herself had
published a paper noting that there were "inconsistencies regarding the ability
of estrogen to improve memory in menopausal women." She has probed estrogen's
inconsistencies in her research with mice. The range of results she has
produced shows, among other things, that estrogen acts differently on mice of
different ages; that progesterone can block estrogen’s effects but can also
have memory-boosting effects of its own; and that mice experiencing different
levels and lengths of environmental enrichment (more toys, more places to
explore) respond differently to estrogen.
To understand these varied effects, scientists need
to find out how estrogen works at the level of the brain cells that encode and
retain the information we call memory. As Frick pointed out in her 2002 paper,
the inconsistencies make it all the more important to find out what’s really
going on.
How are memories made and kept? The process is mostly
uncharted territory. "The human brain contains 100 million neurons, but not all
of them are involved in encoding any one memory," says Sheena Josselyn, a
neuroscientist at the University of Toronto. "Each memory is encoded by a
different network of individual cells. So the next important areas to look at
will be: which cells? How do these cells communicate with their neighbors, and
how is this network hooked up?”
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Dendritic spines are now a central focus of brain research.
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Some of the basics are clear. To store information,
the brain forms networks of nerve cells, joined by the flow of signals through
synapses. New experiences may change the strength or weakness of the synapses,
eliminate them entirely, or build new ones. This changing flow of signals
changes the shape and chemistry of the networks, and therefore the information
they store.
In this process, the synapses are central. Signals
pass through a synapse from the axon of one cell to the dendrite of another.
The receiving end of most synapses is a structure called a dendritic spine—a
tiny filament that grows on the dendrite like a thorn on a blackberry stem. But
unlike thorns, the spines change shape, grow larger or smaller, and disappear
or multiply. Very broadly speaking, the hypothesis goes like this: more spines
mean more memories; larger spines mean more-durable memories.
And so dendritic spines are now a central focus of
brain research. Biologists have been chipping away at the mysteries of their
formation, literally molecule by molecule, identifying essential chemicals and
their functions. An enzyme called MAP kinase activates the mechanism that makes
proteins for building new spines. CREB and MKK1 together regulate spine shape,
so that spines are smaller when there are many and larger when there are few.
MMP-9 drives the enlargement of spines. And the list goes on. So many chemicals
play essential parts that scientists speak of these cellular processes as
"cascades" of molecules.
Frick doesn’t usually work at the molecular level. But one of the studies she published in 2008 was a breakthrough involving a
type of MAP kinase. Other scientists had shown that the molecule—known as ERK,
for extracellular signal-regulated kinase—is crucial to consolidating memories.
Among other things, it initiates the formation of proteins that reshape spines
for long-term memory.
Frick wondered if estrogen might play some role in
activating ERK. To test the theory, she and the students in her lab first did
chemical analyses showing that female mice injected with estrogen experience a
surge in ERK activation in the hippocampus. Then they tested for long-term
memories. They gave one group of mice estrogen injections, and another group estrogen
plus a drug known to block ERK’s activation in the hippocampus. The first group
of mice performed well at remembering toys they had seen two days earlier. The
second group—the one that received the ERK inhibitor—did not.
This result shows that estrogen’s power to enhance
memory depends on whether or not it is able to activate ERK. The study is the
first to link estrogen to one of the chemical processes that create memories:
as Duke University’s Williams puts it, Frick has "been able to pinpoint a specific
pathway in the brain.”
Identifying such pathways is the first step in
finding ways to target them that can improve memory with minimal side effects,
says Bruce McEwen of Rockefeller. Ordinarily, estrogen acts on many different
tissues in the body—breast and uterine tissue, among others. The real question
is, says McEwen, "Could you develop an estrogen-like compound that would do all
the good things and none of the bad things? That’s the holy grail for this line
of research." A precisely targeted drug, Williams adds, might benefit men as
well as women.
Such a drug may, of course, be decades away, if it
ever materializes at all. Frick sees the ERK study as "just the beginning of
the story." She’s planning to redo the study in middle-aged mice, to better simulate
the critical period of life when estrogen supplements may have the most
pronounced effects on memory. More broadly, she hopes to assemble, over time, a
detailed road map of how estrogen acts on the brain: "There are probably heaps
of molecules that play a role in how estrogen affects memory, so we're going to
continue to look at other aspects of cell signaling. What genes is estrogen
changing? What are the important proteins that neurons are using under
estrogen’s influence?”
The research is key to unraveling the supremely
mysterious mechanism the brain uses to make memories. And one day, it may lead
to that powerful memory aid. Says Frick, "The women I talk to tell me, 'Work
faster—we need this!'” 
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