Ronald Davis: In Search of Memory

By Eric Sauter

The journal Neuron recently asked Ron Davis, chair of The Scripps Research Institute's Department of Neuroscience, to write a review of the literature of memory and learning in Drosophila melanogaster, the common fruit fly. Since much of the important research in the last decade or so was done by Davis and his lab members, he was an inspired choice.

Davis's review, which weighs in at nearly 10,000 words, covers what is currently known about the organization and logic of memory traces—changes in the Drosophila brain when memory is formed. These traces occur in various (but distinct) parts of the insect's nervous system, with the different temporal phases of memory spaced across different windows of time after learning and registering as increased calcium flow into the neurons or as release of neurotransmitters.

Thanks to Davis, these neurological changes, which have most often been studied in response to a particular odor, can be seen as bright green fluorescent explosions on a computer screen (and measured in accompanying graphic charts). The decade's worth of breakthrough work by Davis and members of his laboratory on this vivid imaging technique has helped reveal the mechanisms underpinning memory and learning.

For Davis, the Neuron review not only gave him a chance to share his knowledge about this area of neuroscience, it also prompted him to rethink what he has done and where he might go next.

"New questions came up and questions I've forgotten about came up again," he said. "I got to think about them from a different perspective."

Visualizing Memory

Davis first started thinking about how you might image the formation of memory in the early 1990s. At that time, when it came to learning and memory, the only real measure was behavior. What was needed was an independent assay to determine whether learning had actually occurred.

"I had this fantasy that maybe we could see the brain changes that reflect learning, because there's nothing more powerful than an image," Davis said. "In humans, imaging is often performed that measures blood flow, but does that really represent neural activity? With our work, you can see the calcium influx into the neuron; you can see when the neurotransmitters are released."

Davis's search for the right functional optical imaging technique in the fly brain turned serious in 1999. One postdoctoral fellow in his lab spent nearly three years on the project with little to show for it. In that initial process, the team used hundreds of different kinds of transgenic flies, none of which worked well.

As it turned out, the scientists were looking in the wrong place in the fly brain—the mushroom bodies, a pair of oversized lobes that are known to mediate learning and memory, particularly the memories of smell.

"We looked for memory trace in the flies right after conditioning and didn't see it—because the memory trace in the mushroom bodies comes later. So we went back to the antennal lobe—which gets olfactory input from the antenna. As it turns out, the memory trace forms there fairly early."

Since 2004, when they solved the problem, Davis's imaging work with Drosophila has provided an intriguing portrait of how the brain may store temporal memory. "We know memory traces seem to form in different places in the olfactory nervous system," Davis said. "But that raises questions. Are they dependent? Do the later traces form independently of the early traces? Do they form in parallel or in a series? What is the molecular mechanism for these memory traces? Why, after the fly learns and the trace is formed, do you see more calcium influx into a particular neuron in response to a learned odor than another odor?"

They do not know the mechanism, although Davis is clearly eager to find out.

"We've had that question on our 'to do' list for many years," he said.

The Lure of Mutations

Davis grew up in Pueblo, Colorado, then earned his undergraduate degree at Brigham Young University in Utah, for the most part more interested in math and engineering than biology. Right up to the second semester of his junior year, he thought he would end up an engineer.

"I was rooming with some pre-meds who complained that this genetics course was the most difficult course they had ever taken," he said. "I took it as a challenge. The guy who taught the course was outstanding and he turned me on to the whole thing."

What intrigued Davis most was how mutations could cause such severe phenotypes (observable traits). It was a mystery, he said, like engineering, basic problem solving. Studying genetics in graduate school was another turning point, one that would, in the roundabout way of learning and discovery, cement his relationship with Drosophila.

The lab he had joined was studying a small molecule called cyclic AMP—a second messenger that relays cell surface signals to inside the cell—and its role in development. The study was being done on flies. His lab created a mutant without an enzyme that controlled cyclic AMO levels in the fly, mapping the mutation to one end of the X chromosome.

At the same time, another lab had discovered a way to study learning and memory in flies using an odor cue and isolated a mutant they called dunce that also happened to be out on the end of the X chromosome.

"I read about it and wondered if we were working with the same gene," Davis said. "It turned out we were."

That discovery became the first learning mutant ever isolated in any organism, a single gene mutation that caused a learning defect. That was in 1981 and Davis has continued down this path ever since.

A Window into the Brain

When he was an undergraduate, Davis thought flies were fairly repugnant and when he went to graduate school, he hoped never to work with them again. But then something happened.

"I started working with human cells, then took a few courses and learned what you can do with flies to answer questions about people, and the flies seduced me into working with them."

The human brain has a hundred billion neurons, and each neuron makes perhaps 10,000 connections, a complexity beyond the scope of even the most extravagant imaginations. So researchers have used model systems, such as the fly, to uncover the brain's organizational logic. Many of the genes involved in learning and memory in the fly are also involved in learning and memory in the mouse and several have already been implicated in human psychiatric disorders.

This approach also fits with Davis's strong belief in basic research, which he believes is the foundation upon which everything else rests.

"If you look back on the major biological discoveries, they're usually built on basic research and model systems," he said. "We probably know more about how the cell works from studies of yeast than any other organism. Molecular biology has its roots in basic research with bacteria like E. coli and bacteriophage. For instance, the discovery of enzymes that clip DNA at specific sequences, which lie at the heart of current molecular biology, were discovered by researchers who just wanted to know about these enzymes. No one at the time predicted how important these enzymes would prove to modern molecular biology."

But his basic research with Drosophila, summed up in his Neuron review, has led him to expand into translational research.

"We have all these genes in flies that are involved in learning and memory and that cause memory problems when mutated," Davis said. "What is the probability the same genes are involved in human psychiatric disorders? I would say it's 100 percent. Not every gene, but a large number."

Send comments to: mikaono[at]scripps.edu

Ronald Davis's work has included developing a technique to image brain changes related to learning and memory.