Story Summary: Of the billions of neurons in the human brain, only a thousand or so might be coordinating each of these tasks at a given time. Loogers group has created a molecule that can be manufactured inside an animals nerve cells so that those cells light up under a microscope whenever they fire. The protein works by signaling the presence of calcium ions, a sure-fire way of knowing that a neuron is active. The new genetically-encoded calcium indicator molecule is far more powerful than earlier-generation tools for imaging neural activity in worms, fruit flies, and mice. The number of tools currently available to track activity in neural circuits is limited, and this new molecule, Looger says, is a game-changer for the study of what neurons are doing in awake, behaving animals, and how and why brains get wired up the way they do. Looger and his colleagues, including Karel Svoboda, Vivek Jayaraman, and others at Janelia Farm, HHMI investigator Cornelia Bargmann at The Rockefeller University, and collaborators at the University of Puerto Rico, published their research on November 8, 2009, in the journal Nature Methods. Magnetic resonance imaging (MRI) can show activity in large regions of the brain and is one of the few techniques amenable to routine use on humans, but is not detailed enough to reveal which neurons are firing. More recent tools take advantage of the chemical changes that occur inside neurons as those cells switch between active and passive states. When a neuron receives a message from another neuron, its chemistry changes, triggering a brief period of positive charge before returning to its inactive, negatively charged state. Such dyes typically produce strong signals in the presence of calcium, but have a short useful lifespan. In the late 1990s, researchers genetically modified animals so that their neurons contained genes capable of generating calcium indicators. When the calcium level inside a neuron rises due to neural signaling, these indicator molecules bind to the calcium and start glowing. Looger likens the chatter between neurons in the brain to the hum of conversation at a party: With the constant conversation going on, it is hard to figure out who said what. But last year, when Looger and a team of colleagues determined the molecular structure of an indicator known as GCaMP2 (the predecessor of GCaMP3)- both alone and bound to calcium – it became clear to them that some chemical tinkering could make it more useful. It did not take long before he and his team roughed out ideas for making modifications to the molecule that would make it grab calcium more tightly. Jayaraman says his research group uses the tool for their studies of the neural circuitry that guides visual processing. Cornelia Bargmanns lab at Rockefeller genetically engineered worms that expressed the new calcium indicator in a neuron known to detect odors, and watched that neuron light up as certain smells were presented and taken away. Looger also collaborated with Janelia group leader Karel Svoboda to use GCaMP3 for imaging brain activity in the mouse. The new indicator for the first time allows us to image activity in large populations of neurons in the intact brain, and to track the same neurons over time, Svoboda says. We hope to be able to relate the dynamics of large neuronal ensembles to neural computation and learning. For instance, we dont know which cell does what precisely, or which ones responds when the whisker hit something or at what angle. The Svoboda lab hopes that GCaMP3 will now let them get to the business of deciphering exactly what information this brain region is receiving, and how it quickly processes this information into a decision about what to do next. Looger believes that GCaMP3 will be useful in finding answers to fundamental questions about the neural circuits that guide behavior. For example, he says, tracking neural activity with GCaMP3 in the brains of living mice will allow scientists to ask: When the mouse looked left, which 1,000 neurons were used?…Read the Full Story

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