The seemingly complex phenomenon by which fruit flies (Drosophila) learn from bad experiences has been reduced to the actions of a mere 12 neurons, according to research by a team of UK- and US-based scientists. Manipulating this cluster of cells with a laser, the scientists were able to trick the flies into having associative memories of events they had not actually experienced.

Flies learn from smells and other signals in their environment. Conditioning by, for example, electric shocks, can teach them to avoid certain odours.

Previous experiments had shown that a structure in the fly brain called the mushroom body was essential for storing those memories, but the mechanism by which those memories get stored has not been well understood.

To examine the mechanism, a team led by the University of Oxford's Gero Miesenböck took advantage of "optogenetics", a technique in which they use light to activate particular cell types that have been genetically engineered to express a light-responsive protein. When laser pulses hit the brain, cells expressing the light-sensitive protein activate. "It's like sending a radio signal to a city but only those houses with a radios set to the right frequency will get the signal," says Miesenböck.

Light work

Previous research showed that dopamine was involved in making negative associations, for example with smells to be avoided, so Miesenböck's team made different clusters of dopaminergic cells light-sensitive. Then the flies were trained: when they crossed into a certain gas stream -- methylcyclohexanol (MCH) -- a laser was flipped on and the dopaminergic cells were activated.

The experiment was as effective as electric shock treatment -- the flies learned to avoid MCH. The memory was written directly into the brain without the sensory input. Although it is impossible to know, Miesenböck doubts the flies experience pain, like a shock. "I think it's probably more abstract than that," he says.

The surprise, reported today in Cell1, came when they cut open the fly brains and found -- in all of the several dozen flies analyzed -- that only 12 neurons were responsible for the training effect. "These 12 neurons point to presumed memory storage sites in the mushroom body," says Miesenböck.

"It's a landmark study, and very clever," says Ann-Shyn Chiang, a Drosophila neuroscientist at National Tsing Hua University in Hsinchu, Taiwan. "We have known that dopaminergic cells act as stimuli for forming memories, but we have been waiting for a long time to know which ones."

What's more, some of those neurons point directly to the central complex, a brain region implicated in visual memory. Miesenböck says the same group of neurons might account for the formation of negative visual associations too. "It would make sense. When your brain tells you that you're doing something wrong, that you should change your actions, it shouldn't matter which sense it uses to get that information."

Love it or hate it

Miesenböck's next target is to find out what lies upstream from that message, to see how that signal gets to the 12 neurons. This pathway could be used by researchers to make predictions of impending reward or punishment.

Chiang agrees that that is the next step, and he says better imaging techniques could get there. Figures in the Cell paper show how the neurons cluster around the mushroom body, but it's not possible to see individual neurons, says Chiang. "What I'd really like to know is which of these neurons is involved. It might be a smaller subset of the 12. I'd also like to see the specific morphology of the connections -- where the dendrites go," he says. This kind of precision, says Chiang, would help in efforts to reconstruct the whole circuit of how memories are formed.

Miesenböck says it is unlikely that this degree of resolution will be possible in mice or other animals because the brains of larger animals have more neurons and the genetics of the Drosophila brain has been mapped in greater detail. "Numerically the odds are stacked against you," he says.

But the study does parallel a report earlier this year in which scientists used optogenetic techniques to train mice. Mice, unlike fruit flies, respond positively to released dopamine, so instead of teaching them to dislike something (negative reinforcement), as with the flies, the mice were taught to prefer something (positive reinforcement) -- in this case, a certain location.

Despite the differences, Miesenböck says many aspects of the basic pathway are probably conserved evolutionarily so that the fly studies will teach us much about how the human brain learns.