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In the current issue of The Journal of Neuroscience, Dr. Teresa Milner, Professor of Neuroscience at Weill Cornell Medical College, presents new evidence supporting the importance of estrogen in brain function. In close collaboration with Drs. Keith Akama and Bruce McEwen at The Rockefeller University, Dr. Milner elucidates how estrogen is regulating the ability of the brain to learn and encode memories. The research suggests that some form of estrogen replacement therapy might counteract the effects of aging and delay the onset of Alzheimer's disease.

My colleagues and I are telling two stories in parallel, using two different approaches, says Dr. Milner, a member of the Division of Neurobiology at Weill Cornell. We conducted these studies simultaneously but independently, to serve as sort of 'blind controls' in support of each other. Drs. Akama and McEwen were looking at isolated neurons while my lab was looking at animal tissue to explore the same idea namely, how does estrogen signaling affect the condition of a neuron?

Previous research has shown that high levels of estrogen are important for maintaining the plasticity of a neuron, or nerve cell, which is important for learning and memory processes. This plasticity decreases with aging, and is directly affected in neurological diseases such as Alzheimer's disease. In fact, almost twice as many women as men develop Alzheimer's after menopause, during which estrogen levels fall off dramatically, while men, though they have a lower level of estrogen overall, maintain those levels throughout life.

Estrogen was previously thought to be able only to signal through the nucleus of a cell, but studies from Drs. Milner and McEwen's laboratories, examining the neurons at the subcellular level under the electron microscope, revealed a new mechanism of estrogen signaling. Estrogen receptors were found, far from the nucleus, on dendritic spines, which look like small thorns extending from the branches of the nerve cells.

The number of spines on a neuron's dendrite is a direct indication of that neuron's degree of plasticity. The more spines present, the more sensitive the neuron is to input, indicating a heightened ability to learn and remember. When the number of spines decrease, the nerve cell becomes more susceptible to damage induced by stroke or disease. The number of spines directly correlates with the amount of estrogen; higher levels of estrogen induce an increased number of spines.

In the current research, Dr. Milner, with Vladimir Znamensky, examined the effects of estrogen levels on signaling events at the level of a spine, using tissue samples from female rats at various stages of their estrous cycle. Male rats, which have an overall lower, constant level of estrogen, were also examined for comparison. Studies at the subcellular level revealed that as levels of estrogen increase in female rats during their estrous cycle, there is an increase in activation of a molecule called AKT. This molecule is known to play a significant role in neuroprotection, cell proliferation, and protein translation.

Upon AKT activation, there is a flurry of local activity at the spine. Proteins are translated and actin is rearranged, resulting in the formation and maturation of a new spine. All of this occurs without any input from the nucleus, demonstrating that all of these events are poised to happen; they just need a push from estrogen signaling.
As levels of estrogen decline, so does the amount of dendritic spines. Looking at female rats at different points of their estrous cycle supports this observation. Stress also causes a decrease in the amount of spines. The molecules that are released when a person is under stress counteract the estrogen and cause the spines to collapse. This may explain the detrimental effects of stress on learning and concentration.

This study demonstrates the positive effects of estrogen, and its important role in learning and memory processes, states Dr. Milner. It argues that, fundamentally, some type of estrogen replacement therapy, specifically targeting its beneficial effects, may be advantageous for women after menopause. The replacement therapy could help to counteract the effects of aging and delay the onset of Alzheimer's disease.

Dr. Bruce McEwen, and his postdoctoral fellow Dr. Keith Akama, are close collaborators from the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at The Rockefeller University. First author Vladimir Znamensky is currently in his first year of medical school.

The group's research was funded by the National Institutes of Health and the Ares-Serono Foundation.
For the McEwen-Akama Rockefeller University study in the same issue of The Journal of Neuroscience, visit http://newswire.rockefeller.edu/2003/03/14/link-found-between-estrogen-changes-in-brain-structure-and-learning-and-memory/.