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Contact: Mark Shwartz
Scientists use gene therapy to improve memory and learning in animals
Stanford University neuroscientists have designed a gene that enhances memory and learning ability in animals under stress. Writing in the Nov. 8 issue of the Journal of Neuroscience, the Stanford team says that the experimental technique might one day lead to new forms of gene therapy that can reduce the severe neurological side effects of steroids, which are prescribed to millions of patients with arthritis, asthma and other illnesses.
"Steroids can mess up the part of the brain involved in judgment and cognition," said neuroendocrinologist Robert Sapolsky, co-author of the study. "In extreme cases it's called steroid dementia. Ideally, if you could deliver this gene safely, it would protect the person from some of these cognitive side effects, while allowing the steroid to do whatever helpful thing it should be doing elsewhere in the body."
Sapolsky, the John A. and Cynthia Fry Gunn Professor of Biological Sciences and a professor of neurology and neurological sciences at Stanford, has conducted numerous experiments on the damaging physiological effects of stress and has written extensively on the subject, including a 1995 book, "Why Zebras Don't Get Ulcers."
In the Journal of Neuroscience study, Sapolsky and his colleagues focused on the effect of stress on the hippocampus, a part of the brain that's important for learning and memory. Nerve cells throughout the hippocampus contain numerous receptors that respond to a group of steroid hormone called glucocorticoids, which are secreted from the adrenal glands in male and female rats during times of stress. When high levels of these corticoids bind to the hippocampal receptors, they can trigger a destructive biochemical cascade that damages nerve cells in the hippocampus and ultimately impairs memory and learning.
But not all hormones are bad. Estrogen, the primary female sex hormone, enhances memory and can therefore block the negative cognitive effects of the corticoids.
"Estrogen protects memory against stress," said former Stanford postdoctoral fellow Andrea Nicholas, lead author of the study, who was recently named an adjunct professor at St. Mary's College. "In women, there are long-term protective effects of estrogen in the brain. As people age, females often fare better than males cognitively, in part because they have that estrogenic protection."
In a 2004 study, Sapolsky and his co-workers showed that gene therapy could be used to neutralize the deleterious effects of stress in laboratory rats. The idea behind gene therapy is eventually to cure a disease or repair an injury by injecting a beneficial gene into the patient's DNA. For the experiment, Sapolsky and his team created what geneticists call a chimera--an experimental strand of DNA made with two genes stitched together, in this case a glucocorticoid-receptor gene from a rat combined with an estrogen-receptor gene from a human.
When this new chimeric gene was injected into the hippocampus of a rat, the result was dramatic. The gene produced new protein receptors that quickly converted stress-inducing glucocorticoids into beneficial estrogen signals.