Making a Smarter Rat

The bumper sticker reads “My rat is smarter than YOU.” Transgenically-enhanced Hobbie-J –- named after a clever rat in a Chinese cartoon book – may not be smarter than you, but she appears to be smarter than the smartest known breeds of rat.

According to Science Daily, Hobbie-J was able to remember novel objects, such as a toy she played with, three times longer than the average Long Evans female rat, the smartest rat strain. Hobbie-J was also better at remembering which path she last traveled to find a chocolate treat.

Researchers from the Medical College of Georgia and East China Normal University developed Hobbie-J ‘s superior brainpower by transgenic over-expression of the NR2B gene, which in turn increased communication between NMDA receptor sites maybe a hundred milliseconds longer than normal, just enough to enhance learning and memory. NMDA receptors (and their NR2B subunits) are the controlling molecular structures for synaptic plasticity and memory.

"This adds to the notion that NR2B is a universal switch for memory formation," says Dr. Joe Z. Tsien, co-director of the MCG Brain & Behavior Discovery Institute and co-corresponding author with Dr. Xiaohua Cao of a paper called “Genetic Enhancement of Memory” published recently in PLoS One.

Gene expression is translation of information encoded in a gene into protein or RNA. When done to a very high level, it is known as over-expression. The researchers wanted to determine whether the NR2B gene is “a universal genetic factor that acts as a rate-limiting molecule” across species. Here’s a short video showing the process of gene expression:

Previous studies of mice suggest a common biochemical mechanism at the root of nearly all learning. Tsien and Cao wanted to show that the brain uses the same basic mechanism in rats when it forms associations. Their research supports the hypothesis that NR2B is a key switch that controls the brain’s ability to associate one event with another, critical to learning. Tsien had previously created mice that lacked the gene in a tiny region of the brain and showed that they had impaired learning and memory. Adding new or improved ability, however, is a harder task requiring a more rigorous test of the gene’s function.

Charles Stevens, a neuroscientist at the Salk Institute who works on the mechanisms responsible for synaptic transmission, said that Tsien’s earlier work with mice helped to answer a hotly debated question in memory research. Many scientists argue that memories are created when two neurons form a strong connection, called long-term potentiation or LTP. Others believe LTP is not necessary for learning. Tsien’s work "is one of the best pieces of evidence so far" in favor of the LTP model, Stevens said, because activating the NMDA receptor clearly leads to LTP.

In his earlier research, Tsien developed Doogie –- a “smart” mouse named after the precocious TV character Doogie Howser, M.D. (with a genius intellect and eidetic memory) – by over-expressing the NR2B gene in his hippocampus, a learning and memory center affected in diseases such as Alzheimer’s. Hobbie-J-the-rat’s memory improvements were very similar to Doogie-the-mouse’s. Subsequent testing has demonstrated that Doogie has maintained superior memory as he aged.

Dr. Tsien’s work with rats confirms his earlier findings with mice. "We want to make sure this is a real phenomenon," Dr. Tsien says of the connection between higher levels of NR2B and better memory. "You should never assume that discovery you made in a cell line or a mouse can be translated to other species or systems unless you do the experiments." In one intelligence test, Hobbie-J had to learn to alternate between right and left paths to get a chocolate reward. Both Hobbie-J and a non-enhanced rat did well when they only had to wait a minute to repeat the task. After three minutes only Hobbie-J could remember the path. After five minutes, she forgot as well.

Enhanced intelligence followed by subsequent forgetfulness is the theme of the famous short story, “Flowers for Algernon,” by Daniel Keyes – adapted numerous times for the television and also as the Academy-award winning 1969 film, Charly. In the short story, researchers Nemur and Strauss develop a surgical procedure to enhance intelligence. The laboratory mouse Algernon is able to beat the mentally-challenged human, Charlie Gordon, at solving simple mazes. Charlie decides to become the first human to undergo the surgery and ends up with a genius-level IQ – but only temporarily.

Charlie discovers a flaw in Nemur and Strauss’ intelligence-enhancing procedure. Algernon starts behaving erratically, loses his new intelligence, and dies. As Charlie does further research, he determines that he too is at risk. He ends up losing his mental acuity and returning to his former life in a special needs home. In a final postscript, he asks that someone put flowers on Algernon’s grave.

This moving little allegory is perhaps a warning to both researchers and potential test subjects to be rigorous in experimental procedures, as it appears that Dr. Tsien is attempting to be with his rat studies. This is not to say that Hobbie-J-the-rat is at risk of dying from NR2B gene over-expression –- it bodes well that Doogie-the-mouse maintained superior memory into old age.

There may not be the need for such caution with nootropics (smart drugs) such as vasopressin, oxiracetam, and Ginko biloba that are being used a memory aids (see the h+ article "Tweaking Your Neurons") – the risks are low, although the scientific data to support their effectiveness is largely anecdotal at present. Interestingly, Tsien’s work suggests that magnesium – a mineral found in nuts, legumes and green vegetables such as spinach – may be as effective a memory enhancer as genetic manipulation. The magnesium ion blocks entry to the NMDA receptor so more magnesium forces brain cells to increase expression levels of the more efficient NR2B to compensate. This is similar to how statin drugs help reduce cholesterol levels in the blood by inhibiting its synthesis in the liver.

So perhaps you should listen to your mother and eat your spinach. Whether it’s magnesium biochemical pathways or NR2B gene over-expression in mice and rats, it’s clear that further research is warranted with the NR2B gene as a drug target for improving memory in healthy individuals as well as those coping with Alzheimer’s or mild dementia.

Hobbie-J may not be smarter than you, but you might be smart to pay attention to Hobbie-J.