The interplay of convergent and divergent networks has emerged as one of the organizational principles of information processing in the brain. In the brain, dedicated groups of neurons that connect up in microcircuits help us 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 circuit reconstruction techniques have begun to provide an unprecedented amount of anatomical detail regarding local circuit architecture and synaptic anatomy for spatially limited neuronal modules.
These techniques, however, still rely predominantly on pre-selection of target structures, because the volumes that can be analyzed are generally small when compared to brain structures of interest (see, however, recent advances in whole-brain staining), or remain confined to simpler model organisms.
But now, by combining finite element modeling and focused ion beam milling, scientists at the Francis Crick Institute have developed Nanoengineered Electroporation Microelectrodes (NEMs) for comprehensive manipulation of a substantial volume of neuronal tissue.
They have been able 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.
“Traditionally, scientists have either used colour-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, Group Leader at the Crick who led the research.
The team worked this out by creating a series of tiny holes near the end of a micropipette using nano-engineering tools, through which they 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.
Andreas added: “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. 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 behaviour and sensory processing.“
