Rewriting Life

New Brain-Mapping Technique Captures Every Connection Between Neurons

A new technique called MAP-seq uses RNA bar codes to quickly and cheaply chart connections between brain cells.

The human brain is among the universe’s greatest remaining uncharted territories. And as with any mysterious land, the secret to understanding it begins with a good map.

Neuroscientists have now taken a huge step toward the goal of mapping the connections between neurons in the brain using bits of genetic material to bar-code each individual brain cell. The technique, called MAP-seq, could help researchers study disorders like autism and schizophrenia in unprecedented detail.

“We’ve got the basis for a whole new technology with a gazillion applications,” says Anthony Zador, a neuroscientist at Cold Spring Harbor Laboratory who came up with the technique.

Current methods for mapping neuronal connections, known as the brain’s connectome, commonly rely on fluorescent proteins and microscopes to visualize cells, but they are laborious and have difficultly following the connections of many neurons at once.

MAP-seq works by first creating a library of viruses that contain randomized RNA sequences. This mixture is then injected into the brain, and approximately one virus enters each neuron in the injection area, granting each cell a unique RNA bar code. The brain is then sliced and diced into orderly sections for processing. A DNA sequencer reads the RNA bar codes, and researchers create a connectivity matrix that displays how individual neurons connect to other regions of the brain.

The newly published study, which appears Thursday in the journal Neuron, follows the sprawling outbound connections from 1,000 mouse neurons in a brain region called the locus coeruleus to show that the technique works. But Zador says the results actually reconcile previously conflicting findings about how those neurons connect across the brain.

Justus Kebschull, who worked with Zador in developing MAP-seq, says the technique is getting better. “We’re now mapping out 100,000 cells at a time, in one week, in one experiment,” he says. “That was previously only possible if you put a ton of work in.”

Both autism and schizophrenia are viewed as disorders that may arise from dysfunctional brain connectivity. There are perhaps hundreds of genetic mutations that may slightly alter the brain’s wiring as it develops. “We are looking at mouse models where something is mucked up. And now that the method is so fast, we can look at many mouse models,” Kebschull says. By comparing  the brain circuitry in mice with different candidate genes for autism, researchers expect, they’ll get new insight into the condition.

“I think it is a great method that has a lot of room to grow,” says Je Hyuk Lee, a molecular biologist at Cold Spring Harbor Laboratory, who was not part of the MAP-seq study. Although other groups have used similar bar-coding to study individual differences between cells, no one knew if the bar codes would be able to travel along the neuronal connections across the brain. “That had been conjectured but never shown, especially not at this scale,” Lee says.

Zador says that as of now, his lab is the only one bar-coding the brain, but he hopes others will start using MAP-seq to chart the brain’s circuitry. “Because the cost of sequencing is continuing to plummet, we can envision doing this quickly and cheaply,” he said. It may not be long, then, before a complete map of the brain is ready for its first explorer to use.

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