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Cold Spring Harbor, NY--Scientists at Cold Spring Harbor Laboratory have used a genetic strategy in fruit flies to switch electrical activity in the insect brain on and off at will. In doing so, they have made the surprising discovery that switching off electrical activity in the brain blocks memory recall, but not initial formation of memory.
"The brain of the fly works very much like the brain of other animals, including humans. Flies are capable of learning just like Pavlov's dogs," says Dr. Tim Tully, one of the authors of the study, which appears in this week's issue of Nature. [May 24].
After ringing the dinner bell and presenting his dogs with food several times over a few days, the Russian physiologist Ivan Pavlov found that eventually, his dogs would display dinnertime behavior (drooling, excitement) on just the sound of the bell.
Today, all dog and cat owners are familiar with this form of "associative learning." They see it in action each time the sound of the can opener sends their furry friends running to the kitchen in anticipation of their supper.
What pet owners are actually seeing, however, is the retrieval of the "can opener:food" memory that has already been acquired and stored in the animal's brain. Now, the Cold Spring Harbor Laboratory researchers have found that memories based on associative learning can be formed in the absence of electrical activity in the fruit fly brain, but cannot be recalled.
Memory has three components: acquisition (learning), storage, and retrieval (recall). By training flies to avoid an odor--and by switching off electrical activity in the brain at different times during or after training--the researchers could test whether electrical activity in the insect brain is necessary for the acquisition, storage, or retrieval phases of memory.
The scientists used a new genetic strategy to answer an age-old question in neurobiology: Is persistent electrical activity necessary for memory formation? "The surprising answer is no!" says Tully.
"A simple form of memory can be acquired and stored normally in the absence of electrical activity, but recall is blocked. This suggests that these memories are happening as a chemical process and that electrical activity is necessary only to recall these memories."
The key to the study was expressing a mutant form of a gene called Shibire ("sha-beer-ee") in the flies' brain. Normally, the gene is involved in neurotransmitter release. However, the mutant form of the gene encodes a protein that works at low temperature (20ºC) but which blocks neurotransmitter release at high temperature (30ºC). This property allowed the scientists to switch Shibire activity in the brain on and off at will by shifting the flies from high to low or low to high temperature.
"When this gene does not function, neurons run out of neurotransmitter and this paralyzes that part of the brain," says Dr. Josh Dubnau, the lead author of the study. "By raising the temperature of the animal slightly we shut off a part of the brain involved in learning this simple task. When we shift the temperature back down, normal electrical function is restored."
Dubnau, Tully and their colleagues trained flies to avoid an odor and later tested the flies' recall by exposing them to the same odor and measuring their avoidance response. The scientists discovered that the flies' ability to recall memories could be switched on, off, and back on again by simply shifting the animals to different temperatures.
"In most other studies, scientists have typically had to cause permanent structural damage to study brain function. In this study, the flies can develop and learn normally and then brain activity can be shut down in a reversible way to test memory. It is a very elegant approach," says Steven de Belle, a neuroscientist at the University of Nevada, Las Vegas.
When the researchers switched electrical function off in part of the brain during or just after training flies, the flies avoided the odor upon subsequent testing. In contrast, when the scientists switched electrical function off in part of the brain during the recall period, the flies did not avoid the odor. "These findings mean that different parts of the brain do not have to communicate with each other to store memory, but they do need to communicate to recall memory," says Dubnau.
When it comes to learning and memory, "The brain must function electrically to recall what is stored chemically," says Tully. (Color illustrations available on request)