Insects, Rachel Wilson says, may be closer cousins than we imagine, at least in terms of their brain power. "Of course they're not terribly smart. But unlike simpler invertebrates like slugs or worms, the way they interact with the world is relatively flexible. They can play a lot of games with only about a hundred thousand brain cells." This balance between simplicity and complexity is what attracted Wilson to studying the fruit fly Drosophila as a model for investigating neural circuit function.
When Wilson was a doctoral student, she began studying neural circuits with conventional methods, using slices of mouse and rat brain tissue. She learned to make recordings from individual brain cells while visualizing them under a microscope. She came to love the technique and its power. "Poke a neuron with an electrode and you can watch it behave in real time. It's like playing a videogame," she says. However, she started to wonder whether she could extend this approach to live brains. "I thought this would be easiest in a small brain—something we could put under a microscope," she recalls. "The fruit fly seemed like a natural choice, given the genetic tools that were available."
As a postdoctoral fellow at the California Institute of Technology, Wilson set out to develop techniques for making intracellular recordings from individual neurons in the living Drosophila brain, in collaboration with fellow postdoc Glenn Turner and their adviser Gilles Laurent. Turner (now at Cold Spring Harbor Laboratory) had nursed the same secret dream. He and Wilson decided to join forces on the project, which was a tricky one because the fly brain is no bigger than a poppy seed. They worked sitting next to each other at dissection microscopes, terrified the project would be a bust. "The first day we opened the fly head, we couldn't actually find the brain. It turns out that it looks a lot like fat!" she laughs. But after three months of frenzied work, they knew they could do it. "The experience really taught me that if you are going to do something risky, it's way more fun to do it with someone else," says Wilson.
Now at Harvard Medical School, Wilson is using these methods to decipher how the brain decodes sensory information to direct behavioral choices. In particular, she has been focusing on how the brain processes information about odors. "How do animals find their way to an odor source without explicit spatial information, such as visual cues?" she asks. A fly seeking out rotting fruit in a dumpster and a human drawn to the smell of freshly baked bread from a bakery are probably not using vastly different sensory strategies, she notes. Both the fly brain and human brain must process a "noisy" mix of odor information to successfully guide the fly toward the fruit or the person toward the bakery.
To begin to understand how this process works in the fly, Wilson labels individual neurons or groups of neurons with genetically encoded fluorescent markers. This allows her to direct her electrodes to specific genetically defined groups of cells, or even to identifiable individual neurons. She is then able to build up a cumulative picture of how a particular neuron is connected to the rest of the circuit as well as how it responds to olfactory stimuli. In a typical experiment, Wilson tracks the activity from a neuron while she presents various olfactory stimuli to a living fly and records the neuron's responses to each stimulus. In this way, she generates a picture of how each odor stimulus is encoded in the brain. She can manipulate different cells in the circuit by mutating the genes they express, by killing them with toxins targeted to particular cells, or by causing them to express novel genes. By studying how each manipulation changes the odor responses of identified neurons, she can infer the functional connectivity of the circuit.
Other experiments involve monitoring the behavioral responses of flies to odors. By comparing neural and behavioral responses to the same stimulus, Wilson aims to understand the relationship between neural activity and sensory perception. Specific hypotheses about the function of these circuits can be tested by comparing the behavioral responses of normal and genetically modified flies.
By combining the results from such experiments, Wilson hopes to reveal fundamental principles about how circuits in the brain's olfactory region are organized and how they process incoming signals and control behavior. Some aspects of these circuits are likely to translate to other brain areas, helping elucidate how the brain processes different kinds of information.
Wilson sets a high bar when it comes to deciding on big goals, but she's able to break those goals down into smaller pieces that make the project seem more manageable. "If we can use a simple system to work out the fundamental principles of processing and then identify the architecture that is responsible for it, then the task of understanding how the whole brain functions might be easier."
