Genetic Tags Reveal Secrets of Memories' Staying Power in Mice

A better understanding of how memory works is emerging from a newfound ability to link a learning experience in a mouse to consequent changes in the inner workings of its neurons.

Researchers, supported in part by the National Institutes of Health's National Institute of Mental Health (NIMH), have developed a way to pinpoint the specific cellular components that sustain a specific memory in genetically-engineered mice.

"Remarkably, this research demonstrates a way to untangle precisely which cells and connections are activated by a particular memory," said NIMH Director Thomas Insel, M.D. "We are actually learning the molecular basis of learning and memory."

For a memory to last long-term, the neural connections holding it need to be strengthened by incorporating new proteins triggered by the learning. Yet, it's been a mystery how these new proteins -- born deep inside a neuron -- end up becoming part of the specific connections in far-off neuronal extensions that encode that memory.

By tracing the destinations of such migrating proteins, the researchers located the neural connections, called synapses, holding a specific fear memory. In the process, they discovered these synapses are distinguished by telltale molecular tags that enable them to capture the memory-sustaining proteins.

Mark Mayford, Ph.D., and Naoki Matsuo, Ph.D., of the Scripps Research Institute, report on their findings in the February 22, 2008 issue of the journal Science.

The Scripps researchers have been applying their new technique in a series of studies that focus on progressively finer details of the molecular machinery of memory.

"Inside neurons involved in a specific memory, we're tracing molecules activated by that learning to see how it ultimately changes neural connections," explained Mayford.

In a study published in the August 31, 2007 Science, Mayford and colleagues showed the same neurons activated by a learning experience are also activated when that memory is retrieved. The more neurons involved in the learning, the stronger the memory.

The researchers determined this by genetically engineering a strain of mice with traceable neurons in the brain's fear center, called the amygdala. Inserted genes caused activated neurons to glow red when the animals learned to fear situations where they received shocks, in a process known as fear conditioning -- and to glow green when the memory was later retrieved.

The researchers then chemically prevented further expression of those neurons, so that resulting neural and behavioral changes could be confidently attributed to that learning experience at a later time. The study revealed which circuits and neurons were involved in the specific learning experience.

In the new study, Mayford and Matsuo adapted this approach to discover how fear learning works at a deeper level -- inside neurons of the brain's memory hub, called the hippocampus.