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Confirmation of human protein interaction data by human expression data

As the brain develops, neurons reach out helter-skelter forming new connections, only a small number of which take hold. How the brain chooses which connections to keep and which to prune back appears to be governed by which branches have the most electrical activity—a finding that could help to explain how early experiences guide brain development.

The work, published in the April 21 issue of Nature, takes advantage of tiny, see-through zebrafish. Stephen Smith, PhD, professor of molecular and cellular physiology at the Stanford University School of Medicine, and his graduate student Jackie Hua immersed 3-day-old fish in a breathable, Jell-O-like substance that kept the fish alive but immobile. The researchers could then focus video cameras on the fish’s developing brain to watch how the branches of individual neurons grew and shrank over time.

It turns out that determining which of the branches will grow follows an age-old axiom: The squeaky neuron gets the grease. “Louder neurons drown out their quieter neighbors,?Smith said.

Working out this seemingly simple rule took some technical finesse. Hua created zebrafish with a few brain cells that made a protein that prevented them from firing their normal electrical signals. These cells were also engineered to produce a protein that glowed green under the appropriate light.

Hua looked for green neurons in her immobilized fish to see how their branches fared compared with neighboring neurons that fired normally. The green neurons didn’t compete well.

Although the poorly-firing green neurons still formed extensive branching structures, which the researchers call the neuron’s arbor, most of those branches eventually receded while neighboring neurons formed a large number of stable connections. When the fish were five days old, the green neurons had a smaller, less complex arbor than those of neighboring neurons.

“We know that the arbor should occupy a certain amount of space , and in these fish it doesn’t take up that much space,?Hua said.

Hua gave those losing neurons a fighting chance through another molecular twist. She managed to silence some neurons near the green, quietly-firing cells. When she did that, the green cells were able to compete successfully and formed longer, more complex arbors.

Although this work specifically examined the brains of fish, Smith said the same rules likely apply to all neurons, including those in the human brain. “Probably these same things are happening all the time,?he said.

Neurons that fire regularly while learning to recognize a new person’s face, for example, will form larger arbors with more connections that help retain that memory for the future. Likewise, neurons stimulated by engaging toys or experiences will probably create larger arbors than similar neurons in less exciting conditions.

“We are looking at a dynamic part of development,?Smith said. “These are the connections that let us think and fight and love.?/p>
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