A new set of methods allows experimental interaction with biological systems composed of many interacting cell types, such as neural circuits in the brain. Researchers at the University of Oxford have used light to manipulate the memories of fruit flies, allowing them to learn from mistakes they never made and to pinpoint the nerve cells that make them do so. “Remote-controlling these cells and turning them on using light creates an illusion in the brain of the fly that it is experiencing something bad. The fly learns from the ‘mistake’ it never really made and improves its actions the next time,” explains Professor Gero Miesenböck of the department of physiology, anatomy and genetics, who led the work. Researchers at Oxford University in the UK used lasers to manipulate fruit fly memories, allowing them to learn from mistakes they never made and permitting scientists to pinpoint the nerve cells that regulate such actions. Miesenböck is one of the key players in the field of optogenetics, which develops genetic strategies for observing and controlling brain circuits using light. He uses optical approaches for genetic engineering to remote control the action of specific cells within tissues, or whole organisms like worms, fruit flies, fish and mice; he focuses on the structure and dynamics of circuits involved in processing and memorizing sensory information and on how actions are selected or patterns are generated in the brain. In his paper “The Optogenetic Catechism,” published in the Oct. 16, 2009, issue of Science (Vol. 326, p. 395), he outlines how two kinds of devices perform complementary functions: While light-driven actuators control electrochemical signals, light-emitting sensors report them. The actuators pose questions by delivering targeted perturbations, and the sensors (in combination with other measurements) signal the answers. He says that these catechisms are beginning to yield previously unattainable insight into the organization of neural circuits, the regulation of their collective dynamics, and the causal relationships between cellular activity patterns and organism behavior. This is accomplished by encoding proteins in DNA. DNA molecules act as pieces of code that are packaged into different kinds of delivery vehicles before being integrated into the genome of organisms. Once a piece of DNA has been introduced into a cell, the cell’s machinery is directed to produce the required protein. This solves the problem of delivering experimental agents deep into the tissues of intact organisms. That is, after genetic modification, the organism itself generates the mechanisms necessary for the light interaction: Light-driven actuator proteins, used to control genetically targeted cells in a circuit, convert optical commands into de- or hyperpolarizing currents, whereas light-emitting sensor proteins report changes in membrane potential, intracellular calcium concentration or synaptic transmission. In a recent experiment funded by the UK’s Medical Research Council and reported in the journal Cell (Oct. 16, p. 405), Miesenböck’s team genetically engineered fruit flies so that a small set of nerve cells in the flies’ brains would “fire” in response to a flash of laser light. This showed the investigators which cells are involved in how a fruit fly learns and remembers what to avoid – research offering an opportunity to investigate how memories are formed. Fruit flies are attracted by some odors and repelled by others. “We tracked the flies using a video camera as they moved around a small chamber while two different odors were fed into the chamber from either end. We found that we could implant a lasting preference for one odor over the other by remotely activating a specific set of brain cells each time a fly strayed into a particular odor,” says researcher Dr. Adam Claridge-Chang, who is now at the Wellcome Trust Centre for Human Genetics at Oxford University. Using this method, the researchers were able to pinpoint the precise nerve cells that are responsible for telling the flies that they’ve done wrong, narrowing down the search from the 100,000 cells in the brain of a fruit fly to a set of just 12 neurons, implying that aversive memories are dependent on just a small cluster of neurons.