Whole brain calcium imaging in freely behaving nematodes

How does the collective activity of individual neurons in the brain generate actions? This most fundamental question in neuroscience remains unanswered in part because we lack methods to record from every neuron simultaneously in an animal that is allowed to move about freely. We propose to start small by developing a new instrument that will allow us to record from every neuron in a microscopic worm’s brain as it freely moves about. This worm, known as C. elegans, only has 125 neurons in its head. This is opposed to rodents or humans, which have millions or billions of neurons, respectively. To record from the worm’s brain, its neurons will be genetically engineered so that they emit flashes of light every time they are active. We are developing a new kind of instrument—a sophisticated microscope—that can both record the activity of every neuron as well as track the animal’s movements in real-time. Developing this microscope will require a multidisciplinary effort that draws upon techniques from physics, electrical engineering, computer science, and molecular biology. Our technology will lead to the first brain-wide models of how neural activity leads to actions. We are starting small, but the work here in C. elegans will serve as a launching pad for further investigations into the mammalian brain, and, one day, this tiny worm may even shed light on how the human brain works as well.