#EBSstories Making sense of the brain’s circuits

09-03-2021

EBS is enabling research that was previously impossible. Users from the Francis Crick Institute in London have spent a week on ID16A imaging complete mammalian neuronal circuits whose functional activity had been previously recorded.

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“The brain is one of the most intricate machines that exist, and we still don’t know how it works”, says Carles Bosch Piñol, senior neuroscientist at the Francis Crick Institute in London. His research focuses on understanding how neuronal circuits receive, process and propagate information to drive behaviour. This information is encoded by hierarchical structures of sizes ranging from millimetres (neural circuits) and hundreds of microns (neuronal dendritic trees) to few nanometres (synapses). “We came to the ESRF’s ID16A beamline to find out how these circuits work”, he explains.

Bosch and his colleagues just finished a successful remote experiment. Previous experiments with the same sample provided information on how the neurons in that circuit responded to stimuli, and synchrotron imaging with full-field tomography revealed sub-µm detail on the circuit’s structure. At ESRF they wanted to obtain an even more detailed insight of the structure using X-ray holotomography, which would allow to resolve a very important subset of neuronal cables.

EBS enables neuroscientists to image a whole circuitry in one go, and not just a tiny piece of it, which is what happened in the past. “We can now have a complete picture of what goes on so it is easier to make sense of it and this is unique”, he explains.

The ID16A beamline is also enabling them to go further in their research: “X-ray holotomography has shown unique potential to non-destructively resolve key neuronal processes in tissue. This is fantastic for us because we can go elsewhere with our sample and do complementary experiments, using, for example, volume electron microscopy, to provide detail of narrower regions of interest”, he explains.

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Planned acquisition of a neural circuit with holotomography. Diagram showing a top view of the specimen (edges in navy blue) and its regions of interest (in vivo recorded cell bodies in brown, genetically-tagged glomerulus in white). Tiles were planned and priority-ranked (a) with enough overlap so they can be all stitched into a single continuous volume dataset (b). (c-d) Lateral dendrites (green, nucleus in brown) are resolved (c) and can be followed until exiting the tile (d).

The research is very fundamental for the moment, being the goal to provide a mechanistic understanding of how a small part of the brain functions. However, “in the future, this knowledge could help us to understand cases of malfunction of a certain circuit”, concludes Bosch.

Top image: Scientists resolved lateral dendrites of projection neurons (dendrite in green, nucleus in brown) using synchrotron X-ray holotomography in heavy metal-stained mammalian brain tissue. Credits: C. Bosch