Scientists at the Francis Crick Institute say they have devised a novel method that maps electrical circuits in the brain far more comprehensively than ever before. Their approach overcomes previous limitations and has enabled them to map out all 250 cells that make up a microcircuit in part of a mouse brain that processes smell, something that has never been achieved before, according to the research team who believe their technique can be used by scientists to reveal the architecture of different parts of the brain.

The study (“Architecture of a Mammalian Glomerular Domain Revealed by Novel Volume Electroporation Using Nanoengineered Microelectrodes”) is published in Nature Communications

Dedicated groups of neurons that connect up in microcircuits help process information about things we see, smell, and taste. Knowing how many and what type of cells make up these microcircuits would give scientists a deeper understanding of how the brain computes complex information about the world around us. 

“Dense microcircuit reconstruction techniques have begun to provide ultrafine insight into the architecture of small-scale networks. However, identifying the totality of cells belonging to such neuronal modules, the “inputs” and “outputs,” remains a major challenge. Here, we present the development of nanoengineered electroporation microelectrodes (NEMs) for comprehensive manipulation of a substantial volume of neuronal tissue. Combining finite element modeling and focused ion beam milling, NEMs permit substantially higher stimulation intensities compared to conventional glass capillaries, allowing for larger volumes configurable to the geometry of the target circuit., “write the investigators.

“We apply NEMs to achieve near-complete labeling of the neuronal network associated with a genetically identified olfactory glomerulus. This allows us to detect sparse higher-order features of the wiring architecture that are inaccessible to statistical labeling approaches. Thus, NEM labeling provides crucial complementary information to dense circuit reconstruction techniques. Relying solely on targeting an electrode to the region of interest and passive biophysical properties largely common across cell types, this can easily be employed anywhere in the CNS.”

“Traditionally, scientists have either used color-tagged viruses or charged dyes with an applied electric current to stain brain cells, but these approaches either don't label all cells or they damage the surrounding tissue,” said Andreas Schaefer, Ph.D., group leader at the Crick who led the research. 

By creating a series of tiny holes near the end of a micropipette using nanoengineering tools, the team found that they could use charged dyes but distribute the electrical current over a wider area, to stain cells without damaging them. And unlike methods that use viral vectors, they could stain up to 100% of the cells in the microcircuit they were investigating. They also managed to work out the proportions of different cell types in this circuit, which may give clues into the function of this part of the brain.

“We're obviously working at a really small scale, but as the brain is made up of repeating units, we can learn a lot about how the brain works as a computational machine by studying it at this level,“ continued Dr. Schaefer. “Now that we have a tool of mapping these tiny units, we can start to interfere with specific cell types to see how they directly control behavior and sensory processing.”

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