Harvard scientists have used light and genetic trickery to trace out neurons’ abilityto excite or inhibit one another, literally shedding new light on the questionof how neurons interact with one another in live animals.The work is described in the current issue of thejournal Nature Methods. It buildsupon scientists’ understanding of the neural circuitry of the nematode worm Caenorhabditiselegans, frequently used as a modelin biological research. While the detailed physical structure of C. elegans scant 302 neurons is well documented, the newresearch helps measure how neurons in this organism affect each others’activity, and could ultimately help researchers map out in detail how neuralimpulses flow throughout the organism.“This approach gives us apowerful new tool for analyzing small neural circuits, and directly measuringhow neurons talk to each other,” says Sharad Ramanathan, an assistantprofessor of molecular and cellular biology(MCB) and of applied physics at Harvard.“While we’ve only mapped out the interplay of four neurons, it’s the first timescientists have determined the ability of multiple neurons in a circuit toexcite or inhibit their neighbors.”Zengcai Guo and Ramanathan combined genetically encodedcalcium sensors and light-activated ion channels with optics. The scientists useda mirror array to excite individual neurons – each just two to three millionthsof a meter wide – while simultaneously measuring calcium activity in multipleother neurons. This calcium activity serves to indicate whether these otherneurons were activated or inhibited by the neuron that was primed with a burstof light.“Using this technique, for the first time, we couldexcite both a sensory neuron and an interneuron and monitor how activity propagates,”says Guo, a research assistant in the FAS Center for Systems Biology, MCB, and School of Engineering and Applied Sciences. “Weexpect that our technique can eventually be used more broadly to measure howactivity propagates through neural circuits.”Manipulating neurons with light, Guo and Ramanathanwere able to evoke an avoidance response – causing the worm to back away fromlight – that is normally prompted only when the organism is touched. With a compact nervous system consisting of only 302neurons linked by some 7,000 synapses, the nematode C. elegans is anideal system for studying the interplay between neural circuits and behavior.While the physical connectivity of the neurons in this nematode is well known, scientistsknow very little about which of these connections are excitatory and which are inhibitory.Because of the smallsizes of the neurons and a tough cuticle surrounding the worm,electrophysiological recordings can be made from only one neuron at a time, precludingthe possibility of any circuit-level analysis of neural activity. By establishing thisfirst fully genetically encoded light-based electrophysiology, the authors havedeveloped a way to overcome this limitation.Guo and Ramanathan’s Nature Methods paper was co-authored by Anne C. Hart ofMassachusetts General Hospital and Harvard Medical School. Their work wasfunded by the National Institute of General Medical Sciences.
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