November 07, 2006
Gene Therapy Enhances Learning Of Rats Under Stress

A gene therapy that converts glucocorticoid stress hormones into estrogen enhances the cognitive performance of male rats under stress.

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."

The gene therapy combines two receptors into a single gene and a single gene product.

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.

The gene therapy was injected into the hippocampus region of the brain in male rats.

Once injected, individual copies of the virus penetrate the hippocampal neurons, thereby delivering the chimeric gene and activating it in the rat's brain. The new gene then transforms harmful corticoids into helpful estrogens--a process that should hypothetically block the animal's negative behavioral response to stress.

To make sure that natural estrogen wasn't a factor, the experiment was restricted to male rats only. Every rat was trained to find the hidden platform. To raise corticoid levels in the animal's bloodstream, the rats were subjected to a variety of stresses, such as immobilization or cold temperature, then released into the water, where observers counted how quickly and how often they swam to the area above the missing platform.

Stress tests were conducted before the animal received training, immediately after training and 24 hours later. "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. The results were clear: When stress was applied 24 hours after training, the rats infected with the chimeric gene swam to the area of the missing platform faster, and spent significantly more time looking for it, than the normal rats did.

"These results are pretty fantastic, " Nicholas said. "They suggest that this gene therapy not only blocks the deleterious effects of glucocorticoids but actually enhances spatial memory and learning through estrogen-controlled events, even in the presence of stress. Seeing this enhancement effect was pretty exciting. It's the best we could have hoped for."

What I wonder: Does the estrogen created from the glucocorticoids increase female behavior in the male rats?

Also, suppose the hippocampus was genetically engineered to simply have fewer glucocorticoid receptors. That might make it less susceptible to damage from stress. But would some advantage be lost?

We need better methods for consciously controlling stress reponses. In modern environments stress responses often serve no useful function. The environmental cues that cause stress responses are often not associated with the kinds of natural dangers that stress responses were designed to handle. So the body's response to stresses has become very maladaptive in industrial societies. We aren't evolved to handle modern society. So our reactions to it have become too often problematic.

We need genetic engineering to adapt our bodies to our technologies and the environments we have created with our technologies.

Share |      Randall Parker, 2006 November 07 10:59 PM  Brain Enhancement


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