Background
Neurons are shaped like trees. Their branching dendrites receive signals from other cells, while the nucleus in the cell body holds the genetic instructions that keep these branches supplied. Changes to both dendrites and the nucleus have been reported in brain disorders such as epilepsy. However, no existing method could measure both in the same intact neuron. Seeing the nucleus in detail usually means cutting tissue into thin slices, which severs the dendrites. Tissue-clearing methods keep the dendrites intact but shrink or swell the tissue, distorting measurements.
Research
The team turned a 150-year-old staining quirk into a new measurement tool. Golgi-Cox staining, a classic method for visualising neurons, never stains the nucleus, which has long been treated as an artefact. Using 3D X-ray microscopy on whole, unsliced mouse brain tissue, the researchers showed that this unstained nucleus appears as a sharp, measurable gap inside the brightly stained cell. This allowed them to reconstruct the nucleus and dendrites of the same neurons at the same time. In 26 neurons from the hippocampus, measurements of the nucleus were consistent across two independent scans. In four of five fully reconstructed neurons, the nucleus sat slightly closer to the basal dendrites, an early finding that now needs testing in larger studies. A scan of a whole brain hemisphere also detected around 86,000 neurons, showing the approach can scale up.
Potential Impact
Because the method doesn’t destroy the tissue, the same sample can be studied again afterwards with other techniques. The workflow gives scientists a new way to ask whether the position and shape of a neuron’s nucleus change in disease. For example, it can measure the space surrounding the nucleus, the route molecules travel between the nucleus and the rest of the cell, which is disrupted in some neurodegenerative conditions. In the longer term, the approach could help detect subtle structural changes in epilepsy and neurodegenerative diseases, and could even be extended to human brain tissue.