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Reducing memory to a molecule: A researcher explores the molecular essence of memory

June 2009--When Mollie Meffert was only 7 or 8 years old, she spent an afternoon mulling over the fleeting nature of certain memories. Why was it that she could remember a new phone number long enough to dial it but then forget the number as soon as she hung up the phone? Where did the memory go? “It’s the first time that I remember thinking about memory,” says Meffert.

Whether that initial intellectual curiosity is what inspired her to choose her current career, Meffert can’t say. Nevertheless, she went on to study neuroscience, and now, as an assistant professor in biological chemistry, she focuses on understanding the molecular events required to lay down enduring memories.

“One theory says memory is divided into two phases,” says Meffert. In an initial phase, the brain retains information for only a brief period of time—long enough to dial a new phone number, for instance.

On a molecular level, this sort of memory probably involves neurons making transient changes to proteins that already exist. These changes don’t last—the protein is recycled or degraded—and the memory vanishes.

Meffert is more interested in the second phase of memory, in which memories are embroidered into the neural fabric for longer periods of time. This process, she says, involves not just alterations to existing proteins. It also entails changes in gene expression (the “turning on” or “turning off” of particular genes) that induce neurons to make altogether new proteins, or to stop the production of certain proteins, or even to crank up or muffle the production of yet other proteins.

These events, says Meffert, “can regulate the strength of connections between neurons, the number of connections, and the partners to which neurons are connected.” According to this model, such adjustments in neural communication lay down enduring memories.

Meffert has focused much of her research on a molecule called NF-kappaB. It is a transcription factor, a protein that binds to DNA and controls the activity of the genes at those binding sites. NF-kappaB was particularly intriguing because of its location in the neuron. Unlike most transcription factors, it is also present at the neuron’s synapses, far from the nucleus.

That observation, says Meffert, suggested that NF-kappaB might act as a sort of messenger; it might somehow receive incoming information at the synapse (from a neurotransmitter, for example) and then travel to the nucleus to deliver that information to the genes. That communication process might be integral to learning and memory.

As a postdoc, Meffert used genetically engineered mice to test this hypothesis. The mice produced were lacking a particular version of NF-kappaB. She then put the mice through a series of standard learning and memory tests.

The mice performed miserably compared to their siblings that were not lacking in NF-kappaB, especially on tests of spatial memory such as navigating a maze. These results  indicated that NF-kappaB is critical to memory.

At Hopkins, Meffert has continued her research on NF-kappaB. Recently, she has explored the details of how the transcription factor makes the long journey from the synapse to the nucleus.

For this journey to begin, the transcription factor must first be activated. Researchers have elucidated many of the biochemical steps that appear to be involved in activating NF-kappaB. But until recently, it was not clear how the factor travels the long distance to the nucleus.

The answer, says Meffert, appears to be by motor.

In research she recently reported in the Proceedings of the National Academy of Sciences, Meffert has shown that a molecular motor called dynein shuttles NF-kappaB  along a series of microtubules stretching from the synapse to the nucleus, similar to the way a motorized ski lift would transport a skier from the bottom of the hill to the top.

Her studies to date have shown that NF-kappaB is essential to learning and memory. But Meffert now wants to dig even deeper into the role this molecule plays in memory. “What changes in the neuron’s function does the NF-kappaB pathway regulate?”

Specifically, which genes is the factor turning on or turning off, and how do these changes in gene expression alter the connections among neurons? Her studies suggest that NF-kappaB affects the number and strength of those connections. “We can see it does that,” she says, “but we don’t yet know how.”

–Melissa Hendricks

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