Around midterm season, students know all too well how stress can impede their abilities to learn and remember. Stanford scientists, however, have taken this fact of life to the next level. They have engineered a gene that can restore cognitive function in stressed-out rats. The finding may eventually prove useful in combating the neurological side effects of steroids, a common treatment for asthma and auto-inflammatory diseases such as arthritis.

The study, which appeared in the November issue of the Journal of Neuroscience, showed that a man-made gene referred to as “ER/GR” can improve learning and memory in rats that have been subjected to stress. “ER” and “GR” stand for “estrogen-receptor” and “glucocorticoid-receptor,” respectively. Just as its name indicates, the new gene is a fusion, or “chimera,” of existing genes that naturally code for each of these two receptors.

Glucocorticoids are known as “stress hormones.” Under conditions of stress, these molecules are secreted by the body and land in a certain region of the brain called the hippocampus. The hippocampus is a key player in memory consolidation, which is how glucocorticoids can have such cognitively detrimental effects. In contrast, estrogen — better known for its role as a sex hormone — has been shown to enhance spatial memory.

Cells in the hippocampus have receptors for each of these two types of signals, glucocorticoids and estrogen. Each receptor has a region that senses the presence of the signal and a region that affects changes in the cell. ER/GR encodes a receptor with the glucocorticoid “sensor” region and the estrogen “effector” region.

“Basically, we can turn the “bad” effects of glucocorticoids into the “good” effects of estrogen signals,” said Andrea Nicholas, the first author of the study and adjunct professor at St. Mary’s College. She has been collaborating with Biological Sciences Prof. Robert Sapolsky, a co-author of the paper.

Members of the Sapolsky lab previously used the ER/GR gene to protect neurons against the effects of chemically-induced brain damage. The current study grew out of this research, published in 2004.

“The logical next step was do behavioral studies,” Nicholas said. “We wanted to find out something more about spatial memory, and about the effects of stress on memory.”

In order to test this, Nicholas and colleagues used the Morris Water Maze paradigm: rats are placed in a pool of water with a “hidden island” beneath the water’s surface. During training, the rats become quicker and quicker at finding this platform, onto which they can climb aboard to rest. Then, the platform is removed and scientists record how long it takes the rat to remember the spot where the platform once was and the number of times rats swim across the it-a measure of the rats’ memory.

“The Morris Water Maze is the gold standard for tests of rats being able to remember,” Nicholas said.

First, Nicholas measured the rats’ performance on the test both in the presence and absence of stress. Nicholas and colleagues varied acuteness of the stressors and time over which stress was administered; the types of stressors included everything from simply handling the rats to constraining their movement or exposing to cold. More importantly, the researchers had groups of rats subjected to stress either before, immediately after or 24 hours after training on the Morris Water Maze.

“This taps into three different domains and three different timings-the effects of stress on learning, on storing learned information as memory and on retrieving that memory,” Sapolsky explained in a press release.

The scientists found that stress impaired memory most when it occurred 24 hours after training. The clincher of the study, however, was that when ER/GR was delivered to the hippocampus — by injection of a virus with ER/GR incorporated into its genome — it had a “rescue” effect. Rats given the chimeric gene looked sooner and longer for the missing platform, presumably because in spite of the stress they had undergone, they had effective cognitive function.

Researchers emphasize the applications of this research, particularly its potential for gene therapies. Patients of multiple sclerosis and rheumatoid arthritis, for example, take corticoids in the long term to treat their diseases.

“People who take high doses of these steroids can also get clinically depressed,” Sapolsky said in a press release. “In principle, you could use gene therapy to protect them as well.”

In recent years, delivery of such therapies has been an obstacle in science and medicine. Practically speaking, it is difficult to deliver gene therapy at the present time. However, Nicholas argued that when a method of delivery has been found, developments such as the ER/GR gene will prove valuable.

“There been a lot of complications with people trying to use gene therapy in humans, especially with going into brain, because of the blood-brain barrier,” Nicholas said. “But we can’t stop developing ideas for treatments. When we are ready to deliver we have to have these things ready to go.”

For now, however, gene therapies in the lab can still be scientifically interesting, according to Nicholas. In the future, Nicholas hopes to continue using these constructs to untangle more subtle mechanisms behind stress and cognitive ability.

“Gene therapy for the moment I think is important, because we can use these as tools,” Nicholas said. “It’s not just an endpoint in treatment for a disease. We have something that lets us see the mechanism of how something works.”

Nicholas described the situation as one of “gene therapy tomorrow and good research tools today.”