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Wiring diagrams might let biologists ‘rewire’ brains

A new way to visualize connections between cells in animal brains could lead to wiring diagrams that show how neurons are linked.

“To understand how the brain works we need to know how neurons are wired to each other,” says Carlos Lois, research professor in biology and biological engineering at Caltech. “This is similar to understanding how a computer works by looking at how transistors are connected.”

In the current study, published in the journal Development, Lois and colleagues focused on the cells in the brain of the fruit fly Drosophila melanogaster. They say the system also could be applied to image networks of cells in organs other than the brain.

fly larval brain
Microscopy image of a fly larval brain and nerve cord shows how a class of glial cells (red) are connected to a subset of neurons (green). The red spindly chords are nerves wrapped by glial cells. (Credit: Lois Laboratory/Caltech)

The technique depends on two groups of cells: the emitters, which are those that give off a signal, and the receivers, which are those that register the signal. Emitters glow red, while any cell they are in contact with (receivers) glow green. The researchers take pictures of the red and green cells through a microscope, and the resulting patterns reveal how cells in the brain “talk” to each other.

“It’s like the six degrees of separation game, where you can find a connection between anybody and a celebrity in six steps or less. But we start with one degree at a time,” says Lois. “First we look at one type of emitter cell and figure out which cells it is connected to. Then we go to those cells that were connected to the initial emitter cells and, in turn, find out which cells they are connected to.”

Trace cancer’s path

The system works through genetic manipulations of cells. The researchers genetically alter emitter cells in fly brains—various neurons or glial cells in this case—to express two independent proteins.

First, the emitter cells are made to express a red fluorescent protein, which allows the researchers to identify the cells’ location. Next, the emitter cells express a molecule called a ligand that can activate receptors on receiver cells. All of the cells in the fly brain have the potential to become receiver cells: they are engineered to express a green fluorescent protein but only when activated by emitter cells. In other words, the red, ligand-producing cells make any cell they are in contact with turn green.

Brain’s tricky wiring surprises scientists

Among other applications, the system could be used to trace the path of cancer cells as they migrate through an animal’s body.

“You could see how a cancer cell left a tumor from its site of origin and how it entered a particular organ,” says Lois.

In addition, the cells can be genetically manipulated in such a way to reveal not just the connections between cells but also their functions. For example, by rewiring the neurons in an animal’s brain, researchers could use the new system to study the role of those neurons.

“We can understand how a computer works by changing the way that the transistors are connected in a circuit, and observing how the output of the computer changes,” says Lois. “With the system that we have designed, we can modify how cells interact with each other in an animal, essentially rewire them, and examine how behaviors change as a result.”

Lois and his colleagues ultimately would like to use their new tool to create wiring diagrams of fly and mouse brains on a neuron-to-neuron basis. That goal may be years off but would provide clues to the complex workings of human brains and the diseases, such as cancer, that result when cell communication breaks down.

The National Institutes of Health funded the study.

Source: Caltech

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