Sep. 2, 1999 PRINCETON, N.J. -- In an achievement that one day may give scientists the ability to boost human intelligence, Princeton University researchers reported today (Sept. 1) that they have genetically modified mice to have improved learning and memory.
Neurobiologist Joe Tsien, with collaborators at MIT and Washington University, found that adding a single gene to mice significantly boosted the animals’ ability to solve maze tasks, learn from objects and sounds in their environment and to retain that knowledge. This strain of mice, named Doogie, also retained into adulthood certain brain features of juvenile mice, which, like young humans, are widely believed to be better than adults at grasping large amounts of new information.
The work, reported in the September 2 issue of Nature, is a breakthrough in memory research and reveals a common biochemical mechanism at the root of nearly all learning. It shows that the brain uses the same basic tool when it forms associations, even though parts of the brain work in specialized ways and deal with diverse types of information, such as sights, sounds and touch. The result gives scientists confirmation of a long-standing theory about how we learn and remember, an idea posed in 1949 by Donald O. Hebb that had been central to memory research.
The finding also shows that genetic improvement of intelligence and memory in mammals is now feasible, thus offering a striking example of how genetic technology may affect mankind and society in the next century.
"Joe is doing some really interesting and fundamental work," said Ira Black, chairman of neuroscience and cell biology at Rutgers University. "It’s a novel approach. It's very exciting and holds the hope of not only making animals smarter, but also, ultimately of having a (human) gene therapy for use in areas such as dementia."
The research proves that the gene Tsien used, called NR2B, is a key switch that controls the brain’s ability to associate one event with another, the core feature of 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 function, however, is a harder task and a more rigorous test of the gene's function.
Taken together, these results could be of major interest to researchers trying to understand and treat human disorders that involve the loss of learning and memory. In particular, the NR2B gene could be a target for drug makers, who could try to design medicines that boost its effects. In the long-term, the results may promote further discussions on ethical and social issues regarding whether and how genetic technology should be used to modify or enhance mental and cognitive attributes in people. At this point, it has been shown that the corresponding gene exists in humans, but its enhancing effect in humans is not known.
Indeed, developing a drug or gene therapy from Tsien's discovery would take many years of testing in animals and humans. "This is far in the future and is certainly not something we could bring to the bedside tomorrow," said Black.
Nonetheless, the results tell researchers that the NR2B gene is good place to start. Jonathan Cohen, a Princeton professor of psychology, said Tsien's work assures scientists that NR2B is not merely an indirect player in learning and memory. "Now we are able to say that it's not just shadowing another area; now we can say that it's having an effect on its own," said Cohen. "The ability to get in there and change things at a genetic level gives us a level of specificity that is unsurpassed. And that's really exciting."
A double-keyed lock for learning and memory
The NR2B gene is the blueprint for a protein that spans the surface of neurons and serves as a docking point, or receptor, for certain chemical signals. This receptor, called NMDA, is like a double lock on a door; it needs two keys -- or two signals -- before it opens. As such, it is an excellent tool for creating memory, a process that fundamentally consists of associating two events. If two signals arrive at the same time -- maybe one results from seeing a lit match and the other results from a sensation of pain -- then the receptor is triggered and a memory is formed.
Studies have shown that in young animals the NMDA receptor responds even when the two signals are relatively far apart, so it's easy to make connections between events and to learn. After adolescence, the receptor becomes less responsive, making learning more difficult. This phenomenon of declining memory has persisted throughout evolution and has been observed in species ranging from songbirds to primates.
In his experiments, Tsien not only gave mice extra copies of the NR2B gene, he set up the extra copies so that their activity increases as the mice age, counteracting the decline of the natural gene. The experiment showed that under identical conditions, mice with the extra gene had a much greater learning response than normal mice. And, as adults, their brains retained physical features that usually characterize juvenile animals; in particular, they had a high level of plasticity, the ability to form long-term connections between neurons. Tsien's group named the new strain of mice "Doogie" after the precocious character on the television show "Doogie Howser, MD."
In studying the brains of these transgenic mice, Tsien collaborated with Guosong Liu, assistant professor in MIT's Department of Brain and Cognitive Sciences, and Min Zhuo, assistant professor of neurobiology at Washington University. At Princeton, Tsien worked with postdoctoral researchers Ya-Ping Tang, Eiji Shimizu and Claire Rampon.
The MIT work centered on ensuring, on a cellular level, that altering the gene actually led to enhanced NMDA receptor activity. Using a first-of-its-kind test, MIT researchers directly measured the number and function of NMDA receptors at individual synapses -- the locus where interneural communication occurs.
"Measuring the receptor cell's response at an individual synapse is extremely difficult, but without this assurance there would be no way to know whether the altered gene led to increased NMDA receptor activity," said Liu. "With this test, the whole hypothesis becomes very solid."
High test scores
Tsien's research group tested the performance of the transgenic mice in a variety of situations that addressed different aspects of learning and memory. First, they tested one of the most basic aspects of memory, the ability to recognize an object. They put the mice into a space and let them explore two objects for five minutes. Several days later, one object was replaced with a new one and the mice were returned to the space. The gene-modified mice remembered the old object, and devoted their time to exploring the new one. The normal, or control, mice, however, spent an equal amount of time exploring both objects, indicating that the old object was no more familiar to them than the new. By repeating the test at different intervals, the researchers found that the gene-modified mice remembered objects four to five times longer than their normal counterparts.
Second, the researchers tested emotional memory in the mice. The animals were put in a chamber where they received mild shocks to their feet. When the mice were put back in the chamber one hour, one day, or 10 days later, the transgenic mice had a much more pronounced fear response than the control mice. The same pattern held true when the mice were taught to be fearful to an audible tone rather than a physical space -- a significant observation because hearing employs a different type of brain circuitry.
The third test asked whether the gene modification helped mice learn more effectively, in addition to just having improved memory. The researchers repeated the process of conditioning the mice with either a shock chamber or tone, then placed the animals back into the fear-causing environment, but without the shocks. While the transgenic mice became more fearful initially, they also were much quicker to resume normal behavior once the shocks were removed -- they learned faster.
The final experiment tested spatial learning. The mice were put into a pool of water that had a hidden platform where they could climb out of the water. The transgenic mice learned to find the platform after three sessions, while the control mice required six.
The conclusion, Tsien said, can only be that the NMDA receptor is a keystone for learning and memory. "They're learning things much better and remembering longer," Tsien said. "They're smarter."
Charles Stevens, a neuroscientist at the Salk Institute and an expert in the biological underpinnings of memory, said Tsien's work helps 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. Many scientists have disrupted LTP and shown that learning and memory suffered, but it's hard to say whether there was direct cause-and-effect. "Joe's is the first study to produce a positive effect, and that's why it's so good," Stevens said.
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