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Worms surprise scientists with hints that stress can guard nerves


For release: Friday, May 16, 2014

Buckle up, make a turn
Buckle up, make a turn

Springs inside the touch-sensing neuron lacking spectrin (glowing ribbon along worm’s right side) have lost their tautness, causing the cell to buckle when compressed as the animal turns right. Credit: M. Goodman, Stanford University.

Taut springs guard worm’s sensory neurons during flexing and help respond to touch, an NIH-funded study reports

Stress is our life’s new norm. Is it any wonder then that nerve cells inside our bodies are also feeling the daily crunch? A recent study, published in Nature Cell Biology, reports that certain neurons – those activated specifically by mechanical stimuli, such as touch to the skin or dilation of blood vessels - are under chronic physical strain.

”With every heartbeat,” says Miriam Goodman, Ph.D., Associate Professor of Molecular and Cellular Physiology at Stanford University School of Medicine, the study’s senior author, “these cells experience and sense mechanical stress.”

How do they cope? With built-in shock absorbers, the study’s findings suggest. Inside these cells, stretched out springs, made from the protein called spectrin, stand ready to rebound:  whenever the cell is squeezed or pulled, they literally spring into action and swiftly neutralize the insult.

Focusing specifically on sensory neurons that respond to touch, the study finds that inner stress also helps them to do better their job of detecting tactile stimuli. “Imagine two cans with a string looped between them,” explains Dr. Goodman, comparing the sense of touch with the sound. “If the string is taut, the sound can travel; if the string is slack, it cannot.”

“Touch is a vital part of the human experience,” says Jim Gnadt, Ph.D., Program Director at the National Institute of Neurological Disorders and Stroke, part of the NIH. “This study helps us better understand how touch works, how it can go wrong and, perhaps, how to capture its eloquence in order to develop more sensitive prostheses.”

Mechanical engineering behind worm’s buckling nerves

To understand how mechanosensory neurons deal with stress, Michael Krieg, Ph.D., the study’s lead author, turned to roundworms - primitive organisms that have only 302 nerve cells and can grow in the laboratory on a petri dish.

Worm’s touch sensing cells, called touch receptor neurons, or TRNs, extend sprouts, called axons, alongside the worm’s body. Because these cells are so long, they bend – either stretch or compress - every time the animal turns its head, which makes them perfect test subjects for exploring mechanical stress.

Luckily, these cells have the same properties in worms as in humans. “In a simple system like worms, you can figure out how things work at a level of detail that is difficult to achieve in rodents or humans,” explains Dr. Gnadt.

Blood cells are known to be highly resistant to mechanical stress. What gives them strength is the internal meshwork of molecules called spectrin. Can spectrin make nerve cells stronger too?

To find out, Dr. Krieg studied TRNs from the strain of worms that lack spectrin. He observed that they looked fine when stretched, but “buckled” when compressed like strings of worn out elastic.

What exactly is buckling? Dr. Krieg found clues in an unexpected place – in a Mechanics textbook, where a sophisticated mathematical model called “constrained Euler buckling,” is used to describe a flexible rod being squeezed at the ends. The model predicts that when pushed beyond a certain level of strain, the rod “loses its spine” - collapses into striking squiggles - much like the buckling nerve.

Buckling of TRNs lacking spectrin is likely also due to a critical loss of resistance to compression.

Dr. Gnadt commends the authors for making sense of math in the context of biology: “Not only do they give us the equations, but also talk about their limits. These limits are likely programmed into the worm’s behavior so that the animal knows how far it can bend.”

To understand what caused the loss of resistence, Dr. Krieg used several engineering techniques. In one experiment, he gently pulled on individual cells with microscopic tweezers. Healthy TRNs recoiled readily, while TRNs lacking spectrin offered almost no opposition to the offense. Similarly, when the body of the TRN was cut with a scalpel-like laser beam, the axon recoiled instantly like a snapped rubber band. Axons devoid of spectrin, however, hung sluggishly back. Thus, it looked as if TRNs carry in them some kind of a spring that fails if spectrin is absent. Loosening of this spring was the likely explanation of why TRNs lacking spectrin buckle when bent.

Spectrin relay lights up with tension

Could the spectrin molecule itself be this spring?

To check, Dr. Krieg used a small fragment of an elastic protein found in spider’s capture web silk, a material known for its exceptional elasticity. When inserted into spectrin, it springs or coils along with it, reading out the tension spectrin is experiencing.

To measure tension, Dr. Krieg used the method called FRET, or fluorescent resonance energy transfer. He placed a yellow-glowing molecule (FRET donor) on one end of the spring and a blue-glowing molecule (FRET acceptor) on the other end. He then made the donor glow by shining a laser beam on it.

If two ends of the spring are close enough, he surmised, some energy of donor’s glow will be transferred to the acceptor, causing it to start glowing in turn (with blue colored light).

Dr. Krieg observed that the blue glow of the inserted spring was dimmer than that of the free-floating spring, suggesting that the ends of the inserted spring are further apart. Hence, the spectrin molecule must be stretched. When the axon was cut with laser, the glow grew stronger, confirming this conclusion.

Thus, spectrin molecules themselves are the TRN springs. Surprisingly, they appear to be stretched all the time, even when the cell is not being pressed or pulled.

Mechanical stress in health and disease

TRNs sense touch. Do tensed springs help them do so more efficiently?

To find out, Dr. Krieg repeatedly touched worms with an eyebrow hair. Animals lacking spectrin turned away from this irritant less often than healthy worms, suggesting that they were not able to feel being touched.

The problem was likely with tactile sensation itself. When TRNs were activated in a way that did not involve physically touching the animal, worms lacking spectrin showed a normal response.

In addition to being useful for detection of tactile stimuli, mechanical stress is also surprisingly common in biology. The folds of our brains, for example, are shaped, well before birth by tensions that build up within growing tissue, which is sharply stretched as it expands. Tension sensors developed by Dr. Goodman and colleagues to probe spectrin springs can be retooled to generate some powerful insights into the mechanics of these “growing pains.”

Lack of resistance to stress may also lead to disease. Defects in spectrin family proteins have been observed in anemia, cardiovascular disease, and spinocerebellar ataxia type 5. If failing springs prove to be at fault in these conditions, this will greatly influence their diagnosis and treatment.

Biologists have not always used physics and math to elucidate basic mechanisms. But, thanks to studies like this one -- a collaboration between a neurobiologist and a chemical engineer -- they are beginning to appreciate that the same physical forces that stretch an elastic band or make cords resonate also shape our organs and senses.

Reference

Mechanical control of the sense of touch by β-spectrin. Krieg M, Dunn AR, Goodman MB. Nat Cell Biol. 2014 Mar;16(3):224-233.

Last Modified May 19, 2014