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"They're just smarter"
Genetically altered mice with improved learning ability attract world-wide attention
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At a September 1 press conference, Assistant Professor of Molecular Biology Joe Tsien announced that he has created genetically altered mice with improved learning and memory, marking a breakthrough in memory research.
The report created a media sensation: pictures of Tsien's mice appeared in newspapers and magazines around the world, from England and Germany to India and Brazil; the New York Times ran three major stories and an editorial; ABC News and the BBC featured the research on their national news programs; and calls are still coming in.
Working with collaborators at MIT and Washington University, Tsein found that adding a single gene to mice significantly boosted the animals' ability to solve maze tasks and to 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 believed to be better than adults at grasping large amounts of new information.
September 2 in Nature
The work, which Tsein published in the September 2 issue of Nature, is an important advance in memory research in part because it reveals a common biochemical mechanism at the root of 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. This confirms a longstanding theory about how we learn and remember, an idea posited in 1949 by Donald Hebb that has been central to memory research.
The finding also shows that genetic improvement of intelligence and memory in mammals is now feasible. According to Ira Black, chair of neuroscience and cell biology at Rutgers University, "This approach holds the hope of not only making animals smarter, but ultimately of having a (human) gene therapy for use in areas such as dementia."
NR2B a key switch
Tsien's research proves that the gene he used, called NR2B, is a key switch that controls the brain's ability to associate one event with another. He 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, was 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. (The corresponding gene exists in humans, but its enhancing effect in humans is not known.)
Developing a drug or gene therapy from Tsien's discovery would take many years of testing in animals and humans, but his results tell researchers that the NR2B gene is a good place to start. According to Jonathan Cohen, professor of psychology, Tsien's work assures scientists that the process NR2B controls is not merely an indirect part of learning and memory. "Now we're able to say that it's not just shadowing another area, 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."
Blueprint for NMDA
The NR2B gene is the blueprint for part of a protein complex 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. 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 (for example, one results from seeing a lit match and another from a sensation of pain), then the receptor is triggered, and a memory is formed.
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 a decline in NR2B activity makes the receptor less responsive, which makes learning more difficult. This phenomenon of declining memory has persisted throughout evolution and has been observed in species ranging from songbirds to primates.
In Tsien's experiments, he not only gave mice extra copies of the NR2B gene, he set up those copies so that their activity increases as the mice age, counteracting the decline of the natural gene. 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 research group named the new strain of mice Doogie, after the precocious character on the television show "Doogie Howser, MD."
Collaborators
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 he 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 test that was the first of its kind, 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."
Experiments
Tsien's group tested the performance of the transgenic mice in a variety of situations that addressed different aspects of learning and memory.
First, they tested 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 control mice spent an equal amount of time exploring both objects, indicating that the old object was no more familiar than the new. By repeating the test, 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. The mice were put in a chamber where they received mild shocks to their feet. When they were put back in the chamber an hour, a 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 of an audible tone rather than a physical space; this was a significant observation because hearing employs a different type of brain circuitry.
The third test was designed to determine whether the gene modification helped mice learn more effectively. The researchers repeated the process of conditioning the mice with either a shock chamber or a tone, then returned the animals to the fear-causing environment without the shocks. While the transgenic mice initially became more fearful, they were also much quicker to resume normal behavior once the shocks were removed; in other words, 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.
First positive effect
The conclusion, Tsien said, can only be that the NMDA receptor is a keystone for learning and memory. "The transgenic mice learn things much better and remember longer. They're just 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, said Stevens, "is one of the best pieces of evidence so far" in favor of the LTP model, 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.