They didn't mean to create smart mice, but that's what happened when brain scientists genetically altered mice to lack a certain brain protein. As this ScienCentral News story explains, the chance discovery could lead to new drugs to treat learning and memory disorders.
In a laboratory at the University of Texas Southwestern Medical Center in Dallas, researchers study a mouse swimming in a pool of milky water. While it looks like any other mouse, something is quite different about this mouse's genetically-modified brain. It finds a hidden platform in the water much faster than the other mice. This smart mouse is giving brain researchers new insights into intelligence.
"Most people think of intelligence, they think learning and remembering," brain researcher James Bibb says. "However, flexibility in the face of changing situations may be a more important feat of intelligence."
By turning off a certain gene, James Bibb (left) and his team found that the mice became smarter.
James Bibb and his team didn't set out to make mice smarter. They simply wanted to study the function of a gene nobody knew much about. "We wanted to understand features of the brain's function and we didn't expect the animals to end up showing improved or enhanced performance in anything," he says. "We expected deficiencies to appear and for that to tell us what the role of this gene for Cdk5 was."
When scientists want to study a gene's function, they create mice that lack it-- so-called "knockout mice." But that wasn't possible with Cdk5. "When you knock out this particular gene for Cdk5, the animals don't survive the developmental process," Bibb says. "They have a lot of abnormalities, and they aren't born. If they're born, they don't survive."
In this intelligence test, mice have to find a hidden platform under milky water.
So Bibb and his team used a new technique, called "conditional knockout." They gave mice a version of Cdk5 that they altered in a way that would allow them to switch it off after the mice reached adulthood by simply giving them a particular drug. Bibb says that his team is the first to successfully use this technique in animals. "That's allowed us to make some discoveries that previously were not possible," he says.
As they wrote in the journal Nature Neuroscience, when they turned off the gene in the brains of adult mice, the mice did better on tests such as finding a hidden platform in a pool of milky water or learning which box in a maze will produce a mild shock.
"The way they were different in the learning wasn't just that they had better memory, and improved ability to learn," he says, "what was more remarkable was the improved flexibility that the mice showed in solving problems, finding out that the situation had changed and adjusting to that situation."
Bibb says that learning how Cdk5 works could lead to new drugs that treat learning and memory disorders. For example, this research could shed some light on post-traumatic stress disorder, which is marked by increased anxiety that develops after a stressful event. "In PTSD, people often gain memories to adverse events and those memories get reconsolidated to such a strong level and to such a dominant level within the neuronal circuitry that it interferes with their ability to function," he says. "Perhaps by targeting these mechanisms that are involved in flexibility, more so than just enhanced learning, we can develop treatments that will allow people to break that cycle."
Bibb says the research could also help find ways to "un-learn" things like drug addiction. "People learn that they want these drugs and that these drugs are rewarding and we may be able to disrupt those memories and replace them with new learning processes," he says.