Sitting at the desk in his lower-campus office at Cold Spring Harbor Laboratory, the neuroscientist Tony Zador turned his computer monitor toward me to show off a complicated matrix-style graph. Imagine something that looks like a spreadsheet but instead of numbers it’s filled with colors of varying hues and gradations. Casually, he said: “When I tell people I figured out the connectivity of tens of thousands of neurons and show them this, they just go ‘huh?’ But when I show this to people …” He clicked a button onscreen and a transparent 3-D model of the brain popped up, spinning on its axis, filled with nodes and lines too numerous to count. “They go ‘What the _____!’”

What Zador showed me was a map of 50,000 neurons in the cerebral cortex of a mouse. It indicated where the cell bodies of every neuron sat and where they sent their long axon branches. A neural map of this size and detail has never been made before. Forgoing the traditional method of brain mapping that involves marking neurons with fluorescence, Zador had taken an unusual approach that drew on the long tradition of molecular biology research at Cold Spring Harbor, on Long Island. He used bits of genomic information to imbue a unique RNA sequence or “bar code” into each individual neuron. He then dissected the brain into cubes like a sheet cake and fed the pieces into a DNA sequencer. The result: a 3-D rendering of 50,000 neurons in the mouse cortex (with as many more to be added soon) mapped with single cell resolution.

This work, Zador’s magnum opus, is still being refined for publication. But in a paper recently published by Nature, he and his colleagues showed that the technique, called MAPseq (Multiplexed Analysis of Projections by Sequencing), can be used to find new cell types and projection patterns never before observed. The paper also demonstrated that this new high-throughput mapping method is strongly competitive in accuracy with the fluorescent technique, which is the current gold standard but works best with small numbers of neurons.

Tony Zador, a neurophysiologist at Cold Spring Harbor Laboratory, realized that genome sequencing techniques could scale up to tame the astronomical numbers of neurons and interconnections in the brain. jeansweep /Quanta Magazine

The project was born from Zador’s frustration during his “day job” as a neurophysiologist, as he wryly referred to it. He studies auditory decision-making in rodents: how their brain hears sounds, processes the audio information and determines a behavioral output or action. Electrophysiological recordings and the other traditional tools for addressing such questions left the mathematically inclined scientist unsatisfied. The problem, according to Zador, is that we don’t understand enough about the circuitry of the neurons, which is the reason he pursues his “second job” creating tools for imaging the brain.