The three scientists are recognized for elucidating basic neuronal mechanisms underlying perception and decision.

The Norwegian Academy of Sciences and Letters has awarded the 2012 Kavli Prize in Neuroscience to Cornelia Bargmann, a Howard Hughes Medical Institute investigator at Rockefeller University, Winfried Denk, a senior fellow at the Janelia Farm Research Campus who is also at the Max Planck Institute for Medical Research, and Ann M. Graybiel of the Massachusetts Institute of Technology. The three scientists, who are recognized for elucidating basic neuronal mechanisms underlying perception and decision, will share an award of one million dollars.

The Kavli Prizes, which have been awarded biennially since 2008, recognize scientists for seminal advances in astrophysics, nanoscience, and neuroscience. They are awarded through a partnership between the Norwegian Academy of Science and Letters, the Kavli Foundation and the Norwegian Ministry of Education and Research. Past recipients of the neuroscience prize include HHMI investigators Thomas M. Jessell of Columbia University and Thomas Südhof of Stanford University School of Medicine.

Cornelia Bargmann investigates how the wiring of the brain is organized and influences behavior, using the transparent, millimeter-long worm C. elegans. The worm's keen sense of smell has provided a unique opportunity for Bargmann to learn about the interface between genetics and experience. Many responses to odors are genetically determined, like the favorable response by human infants to the smell of vanilla, but a bad experience, like getting sick after eating a particular food, can create a lifetime aversion to its smell.

While the human brain has billions of neurons, the C. elegans brain has only 302, of which 32 are dedicated to smell, making it an ideal model for studying the relationship among genes, neural circuits, and behavior. Yet, the brains of worms and humans share many of the same features of wiring and function, and many of the genes found in C. elegans are also in humans. "When we understand the worm's brain, we'll be in a much better position to understand the complex functions of the human brain," Bargmann noted.

In 2003, her lab discovered a "matchmaker" signaling molecule, known as SYG-1, which directs neurons to form connections with each other during early development. The finding was a major advance in scientists' understanding of the formation of nerve fibers and is relevant to brain diseases such as epilepsy, where the correct nerve cell connections either do not form at all or form abnormally.

In other studies, Bargmann's lab pinpointed a gene called npr-1 that determines whether worms prefer to eat alone or in social groups and is closely related to a human protein involved in regulating appetite and anxiety. And by studying mutant worms that can detect odors but can't tell them apart, she discovered a gene responsible for odor discrimination and determined how worms can recognize and distinguish among thousands of odors in their environment.

Winfried Denk developed two-photon microscopy, a technique that has revolutionized how cells inside tissues are visualized. Before this advance, biologists primarily had used the confocal microscope for imaging - an instrument that scans a focused beam of light across a sample containing some molecules labeled with a fluorescent dye. When a dye molecule absorbs a photon of light, it becomes excited and then emits light of a different wavelength that passes through a pinhole and is then measured by a detector. However, small structures can be difficult to visualize because so much of the sample fluoresces at the same time and light from the structure is scattered and lost at the pinhole. Also, the short-wavelength light used by the microscope can damage cells and tissues.

The idea behind two-photon microscopy is that two, instead of one, photons of long wavelength are needed to excite fluorescence. A dye molecule absorbs the two photons at almost the same time, kicking the molecule into an excited state, which then emits light. Because the probability of a near-simultaneous hit by two photons is low, except near the beam focus, there is little or no excitation outside the focus or by scattered light.

Two-photon microscopy is a powerful technique for imaging molecules, typically far outperforming other techniques at depths greater than 100 microns below the surface of a tissue sample. "This is critical when you are working with brain tissue, because if you cut the tissue to make the specimen thinner and increase resolution, you lose the connectivity between nerve cells," explains Denk. He later showed that two-photon microscopy is also ideal for imaging tissues, such as the retina, that are sensitive to light.

Because the resolution of traditional confocal microscopy and two-photon microscopy was not sufficient for following the network of connections, or wires, among neurons, Denk later turned to the scanning electron microscope - a powerful microscope that scans a beam of electrons on the surface of a specimen and then measures the electrons that are scattered back to produce an image. Denk equipped this microscope with a tool for cutting thin slices of tissue. As each slice is cut away and discarded, the electron beam is scanned over the remaining block face to build three-dimensional images. "We think it is possible to use this technique to track neuronal processes across large distances," he says.

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