Recent research suggests that axons, traditionally thought of as smooth structures, may have a “string of pearls” shape, with small protrusions that influence the speed and accuracy of electrical signals. This shape, possibly conserved throughout evolution, has been observed in different species and may be caused by physical instabilities in membranes under tension. Although there is controversy over whether these “pearls” reflect the natural state of axons or are effects of sample preparation, studies indicate that this morphology may play an important functional role in the conduction of nerve signals and brain plasticity.
When you imagine a neuron, you probably think of something like the classic drawing from biology textbooks: a cell with a rounded body and long branches, including a main structure called an axon.
The axon is responsible for conducting electrical signals, connecting neurons so that they can communicate. Traditionally, axons are thought to have a smooth tubular shape.
But new research suggests something surprising: Instead of being smooth, axons may look like a string of pearls.
This study, published in the renowned journal Nature Genetics, led by Shigeki Watanabe of Johns Hopkins University, used an advanced technique called high-pressure freezing to preserve the structure of rat neurons and examine them under an electron microscope.
The technique revealed that axons have tiny, regularly spaced “pearls,” each about 200 nanometers in diameter. According to the researchers, these “pearls” are not caused by damage or stress, but may be a natural state of axons.
The scientists discovered that these bumps play an important role: They influence the speed at which electrical signals travel along axons. When the “pearls” are closer together, the signal travels slower. When they are farther apart, the signal travels faster.
This suggests that the shape of axons can dynamically change to adjust communication between neurons, especially when the brain is processing a large amount of information.
Microscopic images of mouse neurons preserved using a technique called high-pressure freezing have revealed a string-of-pearls structure that researchers believe may be the cells’ natural shape. Source: Griswold et al.
The discovery is a revolution in how we understand neurons and how they work. For decades, scientists have known that axons can develop temporary “bulges” called “stress beads” under conditions of disease or cellular stress.
These beads may prevent damage from spreading down the neuron. But Watanabe’s study suggests that the newly observed “pearls” are something else entirely: a natural feature that helps axons perform their role in the brain more efficiently.
Not all experts agree with this interpretation; a paper published in another renowned journal, Science, brings some of the doubters to task. Some question whether the "pearls" seen in the study are a side effect of the preservation technique used, although Watanabe's team also observed similar structures in living neurons, without using chemical or freezing methods.
Other researchers argue that axons are not completely smooth, but they also disagree with the “string of pearls” idea. “I think it’s true that [the axon] is not a perfect tube, but it’s not just this kind of accordion that they show,” says neuroscientist Christophe Leterrier of Aix-Marseille University, who calls the study “a controversial addition to the literature.”
While there are doubts, similar studies have observed similar structures in other animals, such as worms and jellyfish. This suggests that the formation of “pearls” in axons may be a phenomenon that has been widely conserved throughout evolution, possibly playing an important functional role.
“The beaded shape itself is not surprising,” explains Pramod Pullarkat, a biophysicist at the Raman Research Institute. He has been investigating the physical forces involved in this phenomenon and notes that a growing body of research suggests that these “pearls” may arise due to so-called “pearl instability”, a physical phenomenon in which a structure The cylindrical structure under tension develops ridges or bulges.
Pullarkat admits that it is “quite possible” that this pattern is the normal state of axons, although he emphasizes that more research is needed to confirm this hypothesis.
Axons are extremely thin and flexible structures, and their shape is influenced by physical forces, such as the tension of the cell membrane and the rigidity of the cell’s internal skeleton (cytoplasm). Previous studies have shown that changes in the shape of axons, even small ones, can significantly affect the speed of electrical signals. For example, when the membrane is pulled or stretched, axons can form bulges like “pearls.”
The research also revealed that changes in membrane components, such as cholesterol, can change the size and shape of the “pearls.” This raises a fascinating question: does the brain intentionally adjust the shape of axons to optimize their communication?
While there is still debate about what these “pearls” actually mean, scientists agree that they open a new window into understanding how neurons work. The next step will be to study these structures in living human brains, which is currently a technological challenge.
However, the current work already offers important clues about how the shape of axons can influence the way we think, feel, and process information.
Ultimately, this research shows that even after decades of study, the brain still holds many secrets that could transform our understanding of life.
a) Representative electron micrographs of acutely extracted mouse brain tissue (left), organotypic slice cultures of mouse hippocampus (middle), and dissociated neuronal culture of mouse hippocampus after high-pressure freezing. b) High-magnification images of axons representative of each condition. c) A schematic showing two NSVs flanked by a connector. Inflection points define the boundary between these two features. d) Graphs showing the dimensions of NSVs (left) and connectors (right) of the indicated tissue types. Dimensions are measured from three independent samples for acutely extracted brain tissue and dissociated neuronal culture and one for organotypic slices; n = 30 axons from each acutely extracted sample, n = 133 axons from the organotypic sample, and n = 100 axons from each dissociated sample.
READ MORE:
Study 1:
Science, Vol 386, Issue 6726.
Study 2:
Membrane mechanics dictate axonal pearls-on-a-string morphology and function
Jacqueline M. Griswold, Mayte Bonilla-Quintana, Renee Pepper, Christopher T. Lee, Sumana Raychaudhuri, Siyi Ma, Quan Gan, Sarah Syed, Cuncheng Zhu, Miriam Bell, Mitsuo Suga, Yuuki Yamaguchi, Ronan Chéreau, U. Valentin Nägerl, Graham Knott, Padmini Rangamani & Shigeki Watanabe
Nature Neuroscience (2024)
Abstract:
Axons are ultrathin membrane cables that are specialized for the conduction of action potentials. Although their diameter is variable along their length, how their morphology is determined is unclear. Here, we demonstrate that unmyelinated axons of the mouse central nervous system have nonsynaptic, nanoscopic varicosities ~200 nm in diameter repeatedly along their length interspersed with a thin cable ~60 nm in diameter like pearls-on-a-string. In silico modeling suggests that this axon nanopearling can be explained by membrane mechanical properties. Treatments disrupting membrane properties, such as hyper- or hypotonic solutions, cholesterol removal and nonmuscle myosin II inhibition, alter axon nanopearling, confirming the role of membrane mechanics in determining axon morphology. Furthermore, neuronal activity modulates plasma membrane cholesterol concentration, leading to changes in axon nanopearls and causing slowing of action potential conduction velocity. These data reveal that biophysical forces dictate axon morphology and function, and modulation of membrane mechanics likely underlies unmyelinated axonal plasticity.
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