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A new strain of genetically engineered mice has allowed researchers to pinpoint, for the first time, the precise cellular connections that form as a memory is created. By tracing a protein tagged to glow fluorescent green as it migrates through individual neurons, from the cell body out through the branching dendrites, the researchers could see exactly which synapses–connections to other neurons–were involved when the mice learned to fear an electric shock.

“It’s a first step in visualizing the synapses that encode memories,” says Stephen Maren, director of the neuroscience graduate program at the University of Michigan, who was not involved with the research. “We really haven’t had a tool like this to see memory encoding at a synaptic level. It’s an exciting paper.”

“We are developing techniques that allow us to focus on the actual physical sites that are changing in the brain with learning, at finer and finer resolution,” says the study’s lead investigator, Mark Mayford, associate professor of cell biology at the Scripps Research Institute.

Neuroscientists believe that in order for a memory to form, individual synaptic connections must be strengthened in response to a memory-generating stimulus. This strengthening is likely the result of a specific set of proteins migrating to synapses in a precisely choreographed pattern, but it remains a mystery which proteins are involved and how they are targeted to their destinations. The new study, which appears in today’s issue of Science, is the first to trace a particular protein as it makes its way to particular synapses.

The studied protein is a receptor for glutamate, a neurotransmitter previously implicated in memory formation. The researchers engineered a strain of mice so that the glutamate receptor would glow green under extremely specific, manipulable circumstances.

The genetically modified mice were then trained to expect an electric shock to their feet whenever they were placed in a certain box. The resulting fear is “a very long-lasting, very robust memory,” says Mayford. Presumably, he says, the neurons activated as the mice learned to fear the box were those responsible for forming the aversive memory.

The fluorescently tagged glutamate receptor was modified so that neurons would only manufacture it when they became active. This allowed the group to identify which neurons contributed to the memory formation by following the green glow.

In addition, the researchers could completely turn off the entire tagged protein system by administering the drug doxycycline. The mice were fed doxycycline throughout their lives–right up until the learning task, and again when the task was over. In this way, the tagged protein was manufactured only during the formation of this particular memory.

“You’re capturing only the events surrounding the learning episode,” says Craig Powell, assistant professor of neurology and psychiatry at University of Texas Southwestern Medical Center, who was not involved with the research.

Mayford’s group followed the glowing glutamate receptor as it migrated through neurons in a region called the hippocampus by examining brain slices at several time points after the learning task. They found that after the protein was manufactured in the nucleus, it traveled outward through the cell’s many branching dendrites and eventually settled in far-flung synapses.

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Credit: Mark Mayford and Naoki Matsuo, Scripps Research Institute

Tagged: Biomedicine, neuroscience, memory

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