[September 06, 2008]

Estrogen's pathway to memory identified

(New Haven Register (New Haven, CT) (KRT) Via Acquire Media NewsEdge) Sep. 6--Yale scientists have identified a molecular pathway in the brain that estrogen uses to improve memory, suggesting the possibility of designing hormone-free drugs to bolster learning and thinking in postmenopausal women.

Menopausal women could take such medications to preserve cognition without facing side effects that accompany hormone replacement therapy.

The research, published in the Journal of Neuroscience, pinpointed one of a probable array of chemical links that allow estrogen to protect and enhance the function of a center in the brain crucial to learning and memory.

"We're trying to figure out how estrogen works in the brain to effect cognitive function," said Karyn M. Frick, associate professor of psychology ay Yale and senior author of the study.

"If we can identify specific molecules critical to this process, then drugs could be developed for these 'targets' that reduce age-related memory decline, but do not affect other tissues like the breast and heart," Frick said.

Contrary to previous clinical studies, research from the Women's Health Initiative studies published in 2002 and 2003 found that estrogen therapy increases the risk of cognitive impairment and dementia in post-menopausal women.

The study also found that hormone replacement therapy increased the risk of heart attack, stroke, breast cancer, and colorectal cancer.

However, more recent analysis of the Women's Health Initiative data suggests that estrogen improves cognition in younger menopausal women, younger than 65.

Frick said that estradiol, the most potent form of estrogen, has been shown to modify parts of the brain involved in cognitive function, such as learning and memory.

However, this research on animals did not directly link alterations in the brain produced by estradiol with improved memory.

Frick's research on rodents demonstrated the positive cognitive effect of estradiol, and also revealed a specific molecular pathway that estradiol uses to communicate with the nerve cells.

Estradiol also promotes the health of neurons in part of the brain called the hippocampus. The hippocampus is involved in the formation of many types of memories, and is one of the first brain structures to be damaged by Alzheimer's disease.

Previous studies at Yale by Frick and colleagues showed that mice treated with estradiol had enhanced spatial memory for the identity of objects.

Frickandcolleaguesdesigned an experiment to determine whether estradiol acts through a complex pathway of enzymes and other proteins.

One molecule of this system, called extracellular signal-regulation kinase, or ERK, is necessary for long-term memory. Without activation of the ERK pathway, animals cannot form long-term memories, she said.

Researchers first showed that estradiol increased ERK activation in the hippocampus. Next, to confirm that ERK activation in the hippocampus is necessary for estradiol to enhance memory, the scientists blocked another enzyme "up stream" from ERK. With ERK out of the loop, estradiol had no effect on memory.

Consequently, ERK is an example of an important molecule that estrogen uses to form memories. There are probably many other pathways, Frick said.

"We found one of probably many critical molecules like ERK that estrogen uses to affect cognition. This isn't the end of the story, it's the beginning of the story," she said.

In the future, treatments may be developed to stimulate ERK directly, without triggering estrogen receptors on the surface of neurons, Frick said.

The study was funded by the National Institute on Aging.

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