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For more than a century, illustrations of brain cells have typically shown axons as smooth, narrow tubes carrying electrical signals from one neuron to another. New research suggests that picture may be missing an important detail. Some axons appear to contain a repeating series of tiny bulges that resemble a string of pearls, and their shape may influence how quickly signals travel.
Researchers at Johns Hopkins Medicine identified these structures in mouse neurons and found evidence that they are a normal feature of some axons rather than a sign of cellular damage. The findings were published in Nature Neuroscience.
The structures, which researchers call “non-synaptic varicosities,” are different from the larger swellings associated with synapses, where neurons communicate with other cells. They are also distinct from the pronounced beading often observed when neurons are damaged by disease or degeneration.
The discovery began with observations of repeated swellings in the axons of worms. Johns Hopkins researcher Shigeki Watanabe and colleagues initially suspected the pattern might be controlled by the axon’s internal skeleton. However, experiments showed that disrupting this structural framework did not eliminate the pearling.
The researchers then turned their attention to the axon’s membrane. Working with theoretical biophysicist Padmini Rangamani, they developed mathematical models showing that relatively simple physical forces within the membrane could produce the repeating pattern.
To study the structures in detail, the team used high-pressure freezing electron microscopy. Unlike conventional preparation methods that chemically fix and dehydrate tissue, rapid freezing can preserve delicate cellular structures closer to their natural state.
Across tens of thousands of images of mouse neurons, the researchers repeatedly observed the pearled structure. High-resolution imaging of living neurons also showed similar patterns, suggesting the structures were not simply artifacts created during sample preparation.
The team found that changes to membrane properties could affect both the shape of the pearls and electrical signaling. Removing cholesterol, for example, made the membrane more fluid and altered the axon’s structure while reducing the speed of signal transmission.
Neural activity also appeared to reshape the axons. After high-frequency electrical stimulation, the structures became about 8% longer and 17% wider, with the changes lasting at least 30 minutes. Electrical signaling slowed afterward, with the effect persisting for at least an hour.
Subsequent research has extended observations of pearled axons to human cortical tissue obtained during epilepsy surgery. However, researchers caution that this does not establish that every human axon has the same architecture or that pearling affects signaling identically throughout the brain.
The findings could eventually help scientists better understand how axon structure influences communication between neurons and distinguish normal structural changes from the damaging beading associated with neurological disease. For now, they suggest that one of the brain’s most familiar microscopic structures may be considerably more complex than textbook illustrations have shown.
