Scientists Provide New Grasp of Soft Touch

A study led by scientists at The Scripps Research Institute (TSRI) has helped solve a long-standing mystery about the sense of touch.

The “gentle touch” sensations that convey the stroke of a finger, the fine texture of something grasped and the light pressure of a breeze on the skin are brought to us by nerves that often terminate against special skin cells called Merkel cells. These skin cells’ role in touch sensation has long been debated in the scientific community. The new study, however, suggests a dual-sensor system involving the Merkel cell and an associated nerve end in touch sensation.

“In this long debate over the role of Merkel cells, it appears that both camps were right,” said the study’s senior author Ardem Patapoutian, a Howard Hughes Medical Institute (HHMI) Investigator and professor at TSRI’s Dorris Neuroscience Center and Department of Molecular & Cellular Neuroscience. “The nerve ends respond to touch, but so do the adjacent Merkel cells.”

The report appears in an Advance Online Publication of Nature on April 6, 2014.

In addition to elucidating the mammalian sense of touch, whose mechanisms until recently have been obscure, the findings could have relevance for certain pain syndromes in which touch sensations trigger pain—even the light pressure of a shirt on the skin or a breeze against the skin.

“Touch and pain are very closely related,” said Patapoutian, “and thus the characterization of these mechanisms of touch should help us to understand pain better too.”

Opening the Flow

The discovery comes four years after the Patapoutian laboratory identified a protein called Piezo2 as a mechanically activated “ion channel” protein with a likely role in touch sensation.

Ion channels are embedded in the outer membranes of various cell types and nerve fibers throughout the body. Piezo2 ion channels have been thought to respond to the stretching of the nerve membrane where they are embedded—a stretching caused by something that presses against the skin, for example.

When activated in this way, the ion channels open to allow an inflow of sodium or other positively charged ions. Such a surge of electrical charge into a nerve can initiate a signal that travels up the nerve and to the brain via a relay of neurons along the spine.

In the earlier study, Patapoutian’s team found evidence that Piezo2 proteins are made within touch-sensing neurons, including gentle-touch neurons that extend their nerves into the skin and against the mysterious Merkel cells.

In the new study, Patapoutian and his colleagues set out to learn more.

In Pursuit of Answers

The team began by creating a line of mice in which the activity of the Piezo2 gene also causes the production of a fluorescing protein called GFP. Guided by these fluorescent beacons as well as other markers, they found a high concentration of Piezo2 in Merkel cells in the skin of the mice.

“You can easily miss Piezo2 expression in the skin, because it’s not highly expressed there, aside from the tiny population of Merkel cells,” said first author Seung-Hyun Woo, a postdoctoral fellow in the Patapoutian laboratory.

Next the researchers sought proof of Piezo2’s role in Merkel cells, essentially by subtracting the protein from those cells and observing the result. To do this—a particularly challenging feat—they created a new line of mice in which the Piezo2 gene is specifically “knocked out” of all skin cells, including Merkel cells, but left intact everywhere else where it is ordinarily produced.

Piezo2 skin-knockout mice and their Merkel cells appeared normal. The mice also responded normally on most standard tests of touch and pain sensitivity. But on the so-called von Frey test, in which thin, bendable fibers are pressed against the mice’s paws with varying force, the effect of the loss of Piezo2 became apparent. “The mice whose Merkel cells lacked Piezo2 didn’t respond to the gentler forces as much as the control mice did,” said Woo.

Examining this change in responsiveness in more detail, Woo and her colleagues isolated Merkel cells from the two groups of mice. They found that those Merkel cells lacking Piezo2 failed to show the usual current flows when gently pushed with a probe.

Collaborating researchers in the laboratory of Cheryl L. Stucky at the Medical College of Wisconsin showed that gentle touch-sensing nerves known as slowly adapting (SA) Aβ fibers generally responded with a lower frequency of signaling in the mice lacking Piezo2 in Merkel cells. Another collaborating laboratory, led by Ellen A. Lumpkin at Columbia University, showed that Merkel cell-associated nerves also responded less durably to test stimuli on skin in these same mice.

“It all shows that the Merkel cells play an important role in touch sensing and that they need Piezo2 to do so,” Woo said.

The findings were bolstered by a separate study from Lumpkin’s laboratory—of which Patapoutian is a co-author—that is reported in the same issue of Nature. In that study, mice engineered to lack Merkel cells exhibited touch-sensing deficits very similar to those described in the Patapoutian group’s study.

(Image: iStockphoto)

Short circuit in molecular switch intensifies pain

Pain functions as an important alarm signal. It alerts us to potential bodily harm – a hot or sharp object, for example – and motivates us to withdraw from damaging situations. At the cellular level, pain involves the stimulation of a network of pain nerves spread through the skin, mucosa and bodily organs.

Embedded in the cell wall surrounding these nerves are ion channels. These tiny, microscopic pathways respond to stimuli such as extreme cold or heat, mechanical pressure or harmful chemicals. When ion channels open, an electrical signal is created, transmitted to the brain, and interpreted as pain.

In previous research, the team of KU Leuven researchers led by Professor Thomas Voets (Laboratory of Ion Channel Research) and Professor Joris Vriens (Laboratory of Obstetrics and Experimental Gynaecology) discovered that a particular ion channel – TRPM3 – acts as a molecular fire detector: the ion channel detects heat and the hormone pregnenolone sulfate, a precursor to the sex hormones estrogen and testosterone and a trigger for pain and inflammation. In the present study, the researchers were looking for TRPM3 inhibitors that could potentially be used as painkillers.

Short circuit

Surprisingly, their results show that a number of drugs meant as painkillers actually increased pain in mice tested in the study, says Professor Voets: “Normally, when the ion channel is closed, no electrical signal is sent to the brain and therefore no pain is detected. But we found that pain can indeed occur despite a closed ion channel. How? A short circuit in the ion channel. When short-circuiting occurs, the electrical signal effected by a stimulus does not follow the normal pathway through the central pore of the ion channel. Instead, it navigates an alternative path through the surrounding material. This ‘electrical leak’ activates the pain nerves, thus increasing the sensation of pain. This may explain the pain-enhancing side effects of some drugs – such as clotrimazole, a common remedy for yeast infections that often causes unpleasant side effects such as irritation and burning sensations.”

“It is striking that short circuits in the ion channel only occur at high hormone levels. This could explain why some patients experience these side effects while others do not,” says Professor Voets. The researchers hope this new knowledge about TRPM3-dependent pain will contribute to the development of new painkillers with fewer painful side effects.

Crossing the channel: Surprising new findings in the neurology of sleep and vigilance

A recent neurological addressing one of the most fundamental issues in sleep rhythm generation study underscores an inconvenient truth—namely, that established scientific facts have and will continue to change. Researchers at Institute for Basic Science (Daejeon), Korea Institute of Science and Technology (Seoul) and Yonsei University (Seoul) have demonstrated significant exceptions to the theory, long accepted as dogma, that low-threshold burst firing mediated by T-type Ca²⁺channels in thalamocortical neurons is the key component for sleep spindles. (A T-type Ca²⁺channel is a type of voltage-gated ion channel that displays selective permeability to calcium ions with a transient length of activation. Burst firing refers to periods of rapid neural spiking followed by quiescent, silent, periods. Sleep spindles are bursts of oscillatory brain activity visible on an EEG that occurs during non-rapid eye movement stage 2, or NREM-2, sleep, during which no eye movement occurs, and dreaming is very rare.) The scientists presented both in vivo and in vitro evidence that sleep spindles are generated normally in the absence of T-type channels and burst firing (periods of rapid neural spiking followed by quiescent, silent, periods) in thalamocortical neurons. Moreover, their results show what they describe as a potentially important role of tonic (constant) firing in this rhythm generation. They conclude that future studies should be aimed at investigating the detailed mechanism through which each type of thalamocortical oscillation is generated.

Dr. Hee-Sup Shin and Prof. Eunji Cheong discussed the paper that they recently published in Proceedings of the National Academy of Sciences. “The previous theory implicated thalamocortical TC burst firing in all sleep waves which appear in different sleep stages,” Cheong tells Medical Xpress. “However, we’ve long questioned the extent to which thalamocortical T-type Ca²⁺ channels and the resulting burst firing contribute to the heterogeneity of thalamocortical oscillations during non-rapid eye movement sleep consisting of multiple brain waves.” A T-type Ca²⁺channel is a type of voltage-gated ion channel which displays selective permeability to calcium ions, in this case with a transient length of activation.

Shin notes that the scientists faced a number of issues in designing and interpreting the results of the in vivo and in vitro experiments to test their hypothesis. “Since we observed the quite intact sleep spindles in Ca_V3.1 knockout mice, we tried to figure out how the sleep spindles are generated in the absence of a thalamocortical burst.” (A gene knockout, or KO, is a genetic technique in which one of an organism’s genes is made inoperative to learn about its function from the difference between the knockout organism and normal individuals. Ca_V3.1 is a T-type calcium channel found in neurons, cells that have pacemaker activity.) “The issues were if the spindles are generated within the thalamocortical circuit as previously known, and how thalamocortical neurons generate spikes during spindles in the presence or absence of a thalamocortical burst.” All of the researchers’ the experiments were designed to investigate these questions.

"The purpose of in vitro thalamocortical-thalamic reticular nucleus,” or TC-TRN, “network oscillations was to show if thalamocortical oscillations observed in Ca_V3.1 knockout mice could be generated either within an intrathalamic network or if they were cortical driven oscillations,” Cheong points out. “Another difference between in vivo and in vitro networks is that compared to in vivo network all the afferent inputs into TC or TRN are not intact in an in vitro TC-TRN network.” The results showed that spindle-like oscillations were generated even in the absence of cortex.

The study shows that these differences also relate to In vivo data suggesting that TRN neurons are spindle pacemakers. “There have been debates on the leading role of TRN versus cortex in pacing the sleep spindles. In an in vitro TC-TRN network, both the afferent inputs and corticothalamic inputs onto TC neurons are not intact,” Shin explains. “Therefore, major inputs onto TC neurons in those experiments come from TRN neurons. The generation of intrathalamic oscillations under this condition indicates that the reciprocal connection between TRN and TC could generate the oscillations, which adds weight to the TRN neurons as spindle pacemakers. The generation of Ca_V3.1 knockout mice which lack T-type Ca²⁺ channels in TC neurons was the key to address this issue.”

Cheong emphasizes that the study’s major findings call into question the essential role of low-threshold burst firings in thalamocortical neurons. “It’s noteworthy that tonic spikes were more abundant than burst spikes during spindles even in wild Type thalamocortical neurons – not only in Ca_V3.1^-/- TC neurons – whereas no difference in tonic and burst spike frequency was seen during non-spindle periods. Moreover,” he continues, “the tonic spike frequency increases significantly during cortical spindle events compared to non-spindle periods even in wild-type TC neurons. This is clearly different from that seen for burst spike frequency in wild-type TC neurons, which occurred with almost equal incidence during both the spindle and non-spindle periods.” Therefore, Cheong points out, the scientists concluded that TC burst firing is not required for the generation in spindle generation.

The researchers also found that the peak frequency of sleep spindles was not different between wild and Ca_V3.1 KO mice, which suggested that TC spikes are not critical in determining the spindle frequency. However, Shin notes, the question of what drives TC neurons to fire during spindles remains to be further investigated, although they think that TC firing during spindles indicates that the TC-TRN network is not as simple as previously believed.

Moving forward, Cheong tells Medical Xpress, the researchers would like to further investigate the firing pattern of TC neurons during natural NREM sleep, including spindle, delta and slow waves. and also elucidate the detailed ensemble behavior of neuron within thalamocortical network during sleep. Moreover, TC burst firing has long been implicated in both physiological thalamocortical oscillations during both sleep and pathological thalamocortical oscillations, such as spike-wave-discharges appearing in absence epilepsy. “Our current study clearly showed that TC burst are not essential for sleep spindles, which would be helpful information to develop the anti-epileptic agents,” Shin concludes.

How Our Nerves Keep Firing

University of Utah and German biologists discovered how nerve cells recycle tiny bubbles or “vesicles” that send chemical nerve signals from one cell to the next. The process is much faster and different than two previously proposed mechanisms for recycling the bubbles.

Researchers photographed mouse brain cells using an electron microscope after flash-freezing the cells in the act of firing nerve signals. That showed the tiny vesicles are recycled to form new bubbles only one-tenth of a second after they dump their cargo of neurotransmitters into the gap or “synapse” between two nerve cells or neurons.

“Without recycling these containers or ‘synaptic vesicles’ filled with neurotransmitters, you could move once and stop, think one thought and stop, take one step and stop, and speak one word and stop,” says University of Utah biologist Erik Jorgensen, senior author of the study in the Dec. 4 issue of the journal Nature.

“A fast nervous system allows you to think and move. Recycling synaptic vesicles allows your brain and muscles to keep working longer than a couple of seconds,” says Jorgensen, a distinguished professor of biology. “This process also may protect neurons from neurodegenerative diseases like Lou Gehrig’s disease and Alzheimer’s. So understanding the process may give us insights into treatments someday.”

A brain cell maintains a supply of 300 to 400 vesicles to send chemical nerve signals, using up to several hundred per second to release neurotransmitters, says the study’s first author, postdoctoral fellow Shigeki Watanabe.

Recycling vesicles is called “endocytosis.” Jorgensen and Watanabe named the process they observed “ultrafast endocytosis.” They showed it takes one-tenth of a second for a vesicle to be recycled, and such recycling occurs on the edge of “active zone” – the place on the end of the nerve cell where the vesicles first unload neurotransmitters into the synapse between brain cells.

“It’s like Whac-A-Mole: one vesicle goes down (fuses and unloads) and another pops up someplace else,” Jorgensen says.

Jorgensen believes ultrafast endocytosis is the most common way of recycling vesicles, but says the study doesn’t disprove two other, long-debated hypotheses:

– “Kiss-and-run endocytosis,” which supposedly takes one second, with a vesicle just “kissing” the inside of its nerve cell, dumping its neurotransmitters outside and “running” by detaching to reform a recycled vesicle in the same part of the active zone.

– Clathrin-mediated endocytosis,” which purportedly takes 20 seconds and occurs away from the active zone, at a point where a protein named clathrin assembles itself into a soccer-ball-shaped scaffold that forms a new vesicle or bubble.

Earlier this year, Jorgensen, Watanabe and colleagues published a related study in the journal eLife revealing that ultrafast endocytosis occurs in nematode worms. The new study of hippocampal brain cells from mice “tells us that mammals – and thus humans – do it the same way,” Jorgensen says. “The two papers together identify a process never previously seen – much faster than has been measured before.”

Jorgensen and Watanabe conducted the study with M. Wayne Davis, a University of Utah research assistant professor of biology; and technician Berit Söhl-Kielczynski and neuroscientists Christian Rosenmund, Benjamin Rost and Marcial Camacho-Pérez, all of Germany’s Charity University Medicine Berlin.

The study was funded by the National Institutes of Health, the European Research Council and the German Research Council. Jorgensen also is funded by his status as a Howard Hughes Medical Institute investigator and an Alexander von Humboldt Scholar.

Machine Gun Analogy for Vesicle Recycling

The process of a vesicle fusing to the nerve cell’s wall from the inside, then releasing neurotransmitters into the synapse is known as “exocytosis.” An analogy might be a bubble rising from boiling soup and releasing steam. The liquid part of the bubble fuses with the liquid in the soup, sooner or later to arise in another bubble.

The 2013 Nobel Prize in Physiology or Medicine went to three scientists who discovered key aspects of vesicle transport of cargo and exocytosis in nerve and other cells: which genes are required for vesicle transport, how vesicles deliver cargo to the correct locations, and how vesicles in brain cells release neurotransmitters to send a signal to the next brain neuron.

Jorgensen, Shigeki and colleagues studied the next step, endocytosis: how the membrane that forms vesicles (and nerve cell walls) is recycled to form new vesicles.

To illustrate the three possible mechanisms for recycling vesicles, Jorgensen compares vesicles with machine gun shells.

“You are fusing vesicles to the nerve cell membrane and expelling the neurotransmitter contents at extremely high rates,” he says. “The synapse will use up its ‘ammo’ very quickly at these rates, so the cell needs to refill the empty shells.”

Clathrin-mediated vesicle recycling is like “remaking the shell from scratch,” he says, while kiss-and-run endocytosis is like picking up every empty shell casing and refilling them one at a time.

“Ultrafast endocytosis allows the synapse to whip up all of the empty shells by the handful, fill them, and put them back in line at incredibly fast rates so the machine gun never runs out of ammo,” Jorgensen says.

Flash and Freeze for Nerve Cells in Action

Shigeki, Jorgensen and colleagues developed a method to photograph the tiny vesicles inside a nerve cell as the bubbles moved to the end of the cell, fused with the cell membrane, dumped their load of neurotransmitters into the gap or “synapse” between nerve cells, and then were recycled to reappear as new bubbles inside the nerve cell.

“We found a way to look at this process on a timescale that no one ever looked at before,” Watanabe says.

First, the researchers grew hundreds of brain cells from the mouse hippocampus – the often-studied part of the brain required for memory formation – on quarter-inch-wide sapphire disks placed in petri dishes with growth medium.

They added an algae gene to mouse brain cells that made the neurons produce an “ion channel” – basically a switch – that is stimulated by light instead of electricity. Then the brain cells were placed in a super-cold, high-pressure chamber, at 310 degrees below zero Fahrenheit and pressure 2,000 times greater than Earth’s atmosphere at sea level.

A wire cannot be routed into the chamber, which is why the cells were genetically programmed to be stimulated by light. The researchers flashed blue light on the mouse brain cells, making them “fire” neurotransmitter nerve signals. At the same time, the firing neurons were frozen with a blast of liquid nitrogen. To catch neurons in all stages of firing, the nerve cells were frozen at various times after the flash of blue light: 15, 30 and 100 milliseconds and one, three and 10 seconds.

“We built a new device to capture neurons performing fast behaviors,” Jorgensen says. “It stops all motion in the cell – even membranes in the act of fusing.

“We call it flash and freeze,” Watanabe says.

Next, the sapphire disks with neurons were put into liquid epoxy, which hardened and then were thin-sliced so the neurons could be photographed under an electron microscope. The ultrafast formation of recycled vesicles was visible.

“You see the outline of the membrane,” Jorgensen says. “You see the bubbles or vesicles in different stages of formation.”

Watanabe says about 3,000 mouse brain cell synapses were flashed, frozen and analyzed during the study. About 20 percent of the nerve cells had been fired and showed signs that nerve vesicles were being recycled.

Multibeam femtosecond optical transfection for the ultimate brain interface

The robotic brain surgeon, featured in the 2013 movie “Enders Game” is no fictional brain-fixing machine. The open-source surgical platform, known as Raven II, has already starred in several brain procedures to date. It is not too hard now to imagine machines like this eventually installing brain controlled interfaces (BCIs). What is missing from this futuristic vision, is what happens at the business end, where the bots meet the brain. This unfolding drama, which began with crude electrode array stimulation, now parlays a combination of optical technologies that permits both transfection of neurons with interface machinery, and their subsequent control. A huge advance in automating the transfection part, and reducing the time it takes by orders of magnitude, has been reported today in Nature’s Scientific Reports by a Scottish group from the University of Saint Andrews. Their new technology delivers DNA plasmids containing optical indicators and ion channels to individual neurons using arrays of femtosecond laser beams—and they can do this as fast as they can reach out and touch the neuron profiles on the screen in front of them.

Femtosecond laser pulses, by concentrating optical power into a short interval, combine exacting control with a minimum use of power. By implication, there is also a minimum of damage to surrounding tissue due to errant or otherwise prolonged irradiation. One difficulty with femtosecond lasers has been that an exotic system of free-space beam delivery optics is often called for. This is because the short pulses are significantly transformed by passage through standard fiber optics. As the authors now show, off-the-shelf instruments, like two-photon scanning or uncaging microscopes can be readily modified to perform fast, automated laser persuasion of cell membranes to allow DNA to slip inside.

In order to deliver various molecular constructs to single cells, protocols including manual injection, modified patch-clamping, lipofection, and electroporation have been developed. Unfortunately, these methods do not scale well if you want to hotwire a bunch of cells in a short time. Transfecting neighboring cells with different reporters or channels, or alternatively the same cell but sequentially with different elements, would be off the table with these methods. Trying to transfect neurons in the brain rather than large egg cells, and using naked DNA rather vector-based DNA, or RNA, involves additional considerations.

Using their custom-developed touchscreen, and image-guided femtobeam, the researchers were able to target up to 100 cells per minute. At a maximum recommended beam power of 77 milliWatts, they could also target a 4x4 array of points (on a 4um grid) to deliver 12-200 femtosecond pulses over 60 ms metapulse intervals. Depending on the specifics of the protocol, transfection yields from 50-100 percent could be obtained. These numbers were for dividing cells in which the nuclear membrane is transiently dispersed and therefore doesn’t present an additional barier to the DNA. For neurons, the researchers added a nuclear membrane-targeted peptide (Nupherin), that binds with the plasmid DNA and enhances transport. In further experiments with these neurons, they successfully activated the transfected channel rhodopsin protein using blue light, and recorded subsequently evoked spikes via patch clamp.

To really squeeze the technique into greater productivity, the researchers hope to implement spatial light modulators for precise and independent control of multiple beams. For an vivo or behaving scenario, the researchers point to fairly recent work where fiber based femotosecond transfection has been made to work in CHO-K1 cells at efficiencies of 74 percent. Using a compact, endoscope-like system with 6000 individual cores, this “nanosurgical instrument” was also used for simultaneous microfluidic delivery of drug to localized areas under direct imaging.

I asked lead author Maciej Antokowiak whether he thought there would be significant distortion in migrating to fiber-based delivery. He said that at 200fs, pulse stretching is much less of a concern than for the shorter 12-20 fs pulses. He also mentioned that in the high repetition regime (76MHz) femtosecond transfection appears to involve cumulative biochemical changes in the cell membrane.

Astounding reports of so-called glowing memories have also been trickling in this week along with the larger wake from the recent Society for Neuroscience meeting. This kind of selective optical interrogation of complete circuits in the brain will take mere connectomics into full-blown activity maps, and then, to control. As it has become apparent through omni-labelling techniques like Brainbow I and II, total label of the synaptic jungle is hardly better than no label. The ability to pick and choose multiple combinatorial activators or other modifiers, by finger or algorithm, as a prelude to thought itself, will be the quickest path to workable BCIs and our subsequent understanding of the brain.

Listen to this: Research upends understanding of how humans perceive sound

A key piece of the scientific model used for the past 30 years to help explain how humans perceive sound is wrong, according to a new study by researchers at the Stanford University School of Medicine.

The long-held theory helped to explain a part of the hearing process called “adaptation,” or how humans can hear everything from the drop of a pin to a jet engine blast with high acuity, without pain or damage to the ear. Its overturning could have significant impact on future research for treating hearing loss, said Anthony Ricci, PhD, the Edward C. and Amy H. Sewall Professor of Otolaryngology and senior author of the study.

“I would argue that adaptation is probably the most important step in the hearing process, and this study shows we have no idea how it works,” Ricci said. “Hearing damage caused by noise and by aging can target this particular molecular process. We need to know how it works if we are going to be able to fix it.”

The study was published Nov. 20 in Neuron. The lead author is postdoctoral scholar Anthony Peng, PhD.

Deep inside the ear, specialized cells called hair cells detect vibrations caused by air pressure differences and convert them into electrochemical signals that the brain interprets as sound. Adaptation is the part of this process that enables these sensory hair cells to regulate the decibel range over which they operate. The process helps protect the ear against sounds that are too loud by adjusting the ears’ sensitivity to match the noise level of the environment.

The traditional explanation for how adaptation works, based on earlier research on frogs and turtles, is that it is controlled by at least two complex cellular mechanisms both requiring calcium entry through a specific, mechanically sensitive ion channel in auditory hair cells. The new study, however, finds that calcium is not required for adaptation in mammalian auditory hair cells and posits that one of the two previously described mechanisms is absent in auditory cochlear hair cells.

Experimenting mostly on rats, the Stanford scientists used ultrafast mechanical stimulation to elicit responses from hair cells as well as high-speed, high-resolution imaging to track calcium signals quickly before they had time to diffuse. After manipulating intracellular calcium in various ways, the scientists were surprised to find that calcium was not necessary for adaptation to occur, thus challenging the 30-year-old hypothesis and opening the door to new models of mechanotransduction (the conversion of mechanical signals into electrical signals) and adaptation.

“This somewhat heretical finding suggests that at least some of the underlying molecular mechanisms for adaptation must be different in mammalian cochlear hair cells as compared to that of frog or turtle hair cells, where adaptation was first described,” Ricci said.

The study was conducted to better understand how the adaptation process works by studying the machinery of the inner ear that converts sound waves into electrical signals.

“To me this is really a landmark study,” said Ulrich Mueller, PhD, professor and chair of molecular and cellular neuroscience at the Scripps Research Institute in La Jolla, who was not involved with the study. “It really shifts our understanding. The hearing field has such precise models — models that everyone uses. When one of the models tumbles, it’s monumental.”

Humans are born with 30,000 cochlear and vestibular hair cells per ear. When a significant number of these cells are lost or damaged, hearing or balance disorders occur. Hair cell loss occurs for multiple reasons, including aging and damage to the ear from loud sounds. Damage or impairment to the process of adaptation may lead to the further loss of hair cells and, therefore, hearing. Unlike many other species, including birds, humans and other mammals are unable to spontaneously regenerate these hearing cells.

As the U.S. population has aged and noise pollution has grown more severe, health experts now estimate that one in three adults over the age of 65 has developed at least some degree of hearing disability because of the destruction of these limited number of hair cells.

“It’s by understanding just how the inner machinery of the ear works that scientists hope to eventually find ways to fix the parts that break,” Ricci said. “So when a key piece of the puzzle is shown to be wrong, it’s of extreme importance to scientists working to cure hearing loss.”

Pulse propagation and signal transduction in the hydraulic brain

When Descartes turned his critical eye to the nervous system, he reasoned that the nerves must transduce hydraulic power to control the musculature. In the circulatory system, blood is pushed comparatively slowly through the aorta, perhaps around 0.3 meters per second. Superimposed on that flow, however, is an arterial pulse wave which propagates much faster, both through the blood and the walls of the vessel. For compliant and healthy vessels that speed might be around 10 meters per second, while for more hardened arteries, it could be 15 or higher. Modern day electrophysiologists have since replaced the hydraulic model with the idea that nerves really only transmit information—electrical information no less. Yet when looking at the power supply to the leg, for example, it is still hard to ignore the fact that the main femoral artery, at a diameter scarcely a half of an inch, looks rather meager next to the “information-supplying” sciatic nerve, which may actually be more like three-quarters of an inch. A conflux of ideas from a variety of disciplines has recently led to a critical re-emergence of the more mechanical side of the nervous system. To that point, two German scientists have just published a paper in the journal, Medical Hypotheses, where they suggest that the pulse wave is the main event in nervous conduction, while the electrical show is mere epiphenomenon.

We recently discussed the increasingly popular idea that action potentials may actually be soliton waves which propagate in the membranes of axons as phase transitions with minimal loss in energy. Convincing biologists that these subtle creatures could exist in the chaotic and varied conditions inside neurons has been a challenge. However, it is harder to argue against the fact that any kind of electrochemical spike based on the rapid influx of ions will be accompanied by a significant pressure pulse. The idea that the German researchers have supported, is that these as the pressure pulses naturally decay in the viscoelastic medium of the nerve, they are refreshed by ionic input at the nodes between myelinated axon segments, or continuously in unmyelinated axons.

If you have ever been absent-minded enough to grab a live wire, or even brush up strongly against one, the sensation is unforgettable. It is not such a stretch to acknowledge that when you slam your funny bone, or more precisely the Ulnar nerve (largest unprotected nerve in your body), the resultant vibe and decay feels almost identical to a real electrical assault. Similarly, the so-called “stingers” that run down the limbs after a sharp blow to the head are familiar to most footballers, and can give one quite a shock. Unfortunately these (albeit very simplistic) macroscopic intuitions don’t hold up so well when extended to the microscopic domain. Granted, when the electrochemical mechanisms that are assumed to underlie nervous conduction are looked at in detail, it becomes more difficult to disentangle the mechanical from the electric. However, as the authors observe, at some point, an attentive electrophysiologist must ask his or herself, “why are so many ion channels mechanosensitive” ?

One unexpected finding of the patch clamp recording technique was that the dilation of the membrane caused by local tension leads to considerable increase in transmembrane ion flow. Impulse waves causing short extensions in the membrane can directly induce opening and closing of both voltage and ligand gated channels. The idea that the pore in these channels is a rigid tube isolated from larger membrane events is difficult to support in this context. According to the authors, it is quite likely that common mechanoreceptor devices, like the pressure- or vibration-sensitive Vater-Pacinian corpuscles of the skin, conduct signals to initiate high-speed polysynaptic muscle reflex circuits without any classical intermediary electrical conversion.

The exact conduction velocity of mechanical impulses in nerve fibers remains unknown. It is estimated that under physiologic conditions, an unamplified axoplasmic pressure pulse would decay over roughly 1 mm due to viscosity, depending on the distensibility of the axon wall. When compared to the theoretical case of an absolutely rigid wall, a typical myelin sheath may be rigid enough to support pulse speeds up to one-fifth of the estimated maximum. That speed is not to shabby when compared with some rough estimates from previous authors, which put the maximum pulse velocity under an indistensible membrane somewhere upwards of 1500 meters per second. Suddenly, the quicker than life eyeblink response, or speed of the tenderfoot stepping on a sharp shard, become a little more comprehensible.

The theory as it stands is incomplete and needs to be adapted for specific cases with real biology in mind. In different animals, and in different regions of their brains, conduction in neurons goes by different names. For example, in the cerebellum, the unmyelinated parallel fibers pack to extreme densities in a regular crystalline lattice whose reason to be defies physiologic explanation to this day. Just as we currently have no good explanation for how signals could be properly isolated in nerve bundles where seemingly random nodes of Ranvier overlap in extent and influence, it is hard to imagine parallel fibers could maintain their electrochemical, or even mechanical, autonomy within this geometry.

The pressure wave theory wields considerable predictive power when it comes to explaining some of the unique synaptic specializations found throughout the brain. When considered only from an electrochemical point of view, the huge structural synaptic investments, like those found at the neuromuscular junction (NMJ), can hardly be imagined to be driven by local, and weak, current or field effects. One might need look no further than simple-to-recreate Chaldni patterns set up in two dimensions on the surface of a taunt drum, to make the imaginative leap to a three dimensional system, with multiple vibrating players, where more extreme patterns might easily be set up to provide authorship to repeatable complex structure. For the NMJ in particular, the case has been made that at the end-plate, the comparatively enormous efflux of acetylcholine to the deeply-guttered cleft, and propagation of excitation through the transverse tubule system, are all components of a continuous mechanical amplifier.

The apparent ease with which evolving organisms manage to cobble together all manner of sensitive hearing devices becomes infinitely more explicable once we see that nature has apparently been doing this kind of thing all alone inside of neurons. The amplification and transduction through liquid channels, of barely noticeable vibrations against a background of thermal noise much greater in magnitude, is in this light, no evolutionary stumble-upon, but rather the bread and butter of neural systems, and perhaps many aspects of life in general.