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)

Scientists Identify Key Cells in Touch Sensation

In a study published online today in the journal Nature, a team of Columbia University Medical Center researchers led by Ellen Lumpkin, PhD, associate professor of somatosensory biology, solve an age-old mystery of touch: how cells just beneath the skin surface enable us to feel fine details and textures.

Touch is the last frontier of sensory neuroscience. The cells and molecules that initiate vision—rod and cone cells and light-sensitive receptors—have been known since the early 20th century, and the senses of smell, taste, and hearing are increasingly understood. But almost nothing is known about the cells and molecules responsible for initiating our sense of touch.

This study is the first to use optogenetics—a new method that uses light as a signaling system to turn neurons on and off on demand—on skin cells to determine how they function and communicate.

The team showed that skin cells called Merkel cells can sense touch and that they work virtually hand in glove with the skin’s neurons to create what we perceive as fine details and textures.

“These experiments are the first direct proof that Merkel cells can encode touch into neural signals that transmit information to the brain about the objects in the world around us,” Dr. Lumpkin said.

The findings not only describe a key advance in our understanding of touch sensation, but may stimulate research into loss of sensitive-touch perception.

Several conditions—including diabetes and some cancer chemotherapy treatments, as well as normal aging—are known to reduce sensitive touch. Merkel cells begin to disappear in one’s early 20s, at the same time that tactile acuity starts to decline. “No one has tested whether the loss of Merkel cells causes loss of function with aging—it could be a coincidence—but it’s a question we’re interested in pursuing,” Dr. Lumpkin said.

In the future, these findings could inform the design of new “smart” prosthetics that restore touch sensation to limb amputees, as well as introduce new targets for treating skin diseases such as chronic itch.

The study was published in conjunction with a second study by the team done in collaboration with the Scripps Research Institute. The companion study identifies a touch-activated molecule in skin cells, a gene called Piezo2, whose discovery has the potential to significantly advance the field of touch perception.

“The new findings should open up the field of skin biology and reveal how sensations are initiated,” Dr. Lumpkin said. Other types of skin cells may also play a role in sensations of touch, as well as less pleasurable skin sensations, such as itch. The same optogenetics techniques that Dr. Lumpkin’s team applied to Merkel cells can now be applied to other skin cells to answer these questions.

“It’s an exciting time in our field because there are still big questions to answer, and the tools of modern neuroscience give us a way to tackle them,” she said.

Researchers find hand to mouth movement in humans likely hard-wired

A team of researchers in France has found evidence that suggests that human hand-to-mouth actions are hard-wired into the brain. In their paper published in Proceedings of the National Academy of Sciences, the researchers describe an experiment they conducted on adults undergoing brain surgery and why what they found could have profound implications on human brain development theories.

Read more

The Best Longreads on Autism

Autism rates have skyrocketed in recent years, according to recent data from the Centers for Disease Control. Much of that has to do with our growing awareness of the disorder. But despite what we are learning about the possible origins and causes of autism, which has no cure, it continues to frustrate and perplex.

In honor of Autism Awareness Month, we’ve compiled a list of longform journalism pieces that give glimpses into the world of those diagnosed with the disorder, and the struggle of those who love and care for them. In one, a father figures out the secret to connecting with his autistic son. In another, we meet the first person ever diagnosed with the disorder. Bookmark these four deep dives into the world of autism, and take your time to read them throughout the month.

“Reaching My Autistic Son Through Disney,” The New York Times Magazine

“Catch Me If You Can,” Outside

“Navigating Love and Autism,” The New York Times

“Autism’s First Child,” The Atlantic

Toward a clearer diagnosis of chronic fatigue syndrome

Great minds think alike

Study finds pigeons and other animals, like humans, can place everyday things in categories

Pinecone or pine nut? Friend or foe? Distinguishing between the two requires that we pay special attention to the telltale characteristics of each. And as it turns out, us humans aren’t the only ones up to the task.

According to researchers at the University of Iowa, pigeons share our ability to place everyday things in categories. And, like people, they can hone in on visual information that is new or important and dismiss what is not.

“The basic concept at play is selective attention. That is, in a complex world, with its booming, buzzing confusion, we don’t attend to all properties of our environment. We attend to those that are novel or relevant,” says Ed Wasserman, UI psychology professor and secondary author on the paper, published in the Journal of Experimental Psychology: Animal Learning and Cognition.

Selective attention has traditionally been viewed as unique to humans. But as UI research scientist and lead author of the study Leyre Castro explains, scientists now know that discerning one category from another is vital to survival.

“All animals in the wild need to distinguish what might be food from what might be poison, and, of course be able to single out predators from harmless creatures,” she says.

More than that, other creatures seem to follow the same thought process humans do when it comes to making these distinctions. Castro and Wasserman’s study reveals that learning about an object’s relevant characteristics and using those characteristics to categorize it go hand-in-hand.

When observing pigeons, “We thought they would learn what was relevant (step one) and then learn the appropriate response (step two),” Wasserman explains. But instead, the researchers found that learning and categorization seemed to occur simultaneously in the brain.

To test how, and indeed whether, animals like pigeons use selective attention, Wasserman and Castro presented the birds with a touchscreen containing two sets of four computer-generated images—such as stars, spirals, and bubbles.

The pigeons had to determine what distinguished one set from the other. For example, did one set contain a star while the other contained bubbles?

By monitoring what images the pigeons pecked on the touchscreen, Wasserman and Castro were able to determine what the birds were looking at. Were they pecking at the relevant, distinguishing characteristics of each set—in this case the stars and the bubbles?

The answer was yes, suggesting that pigeons—like humans—use selective attention to place objects in appropriate categories. And according to the researchers, the finding can be extended to other animals like lizards and goldfish.

“Because a pigeon’s beak is midway between its eyes, we have a pretty good idea that where it is looking is where it is pecking,” Wasserman says. “This could be true of any bird or fish or reptile.

“However, we can’t assume our findings would hold true in an animal with appendages—such as arms—because their eyes can look somewhere other than where their hand or paw is touching,” he explains.

Moonwalker Flies Backing Up

Most land animals walk forward by default, but can switch to backward walking when they sense an obstacle or danger in the path ahead. The impulse to change walking direction is likely to be transmitted by descending neurons of the brain that control local motor circuits within the central nervous system. This neuronal input can change walking direction by adjusting the order or timing of individual leg movements.

Screening for flies with altered walking patterns

In the current study, Dickson and his team aimed to understand the fly’s change in walking direction at the cellular level. Using a novel technology known as thermogenetics, they were able to identify the neurons in the brain that cause a change in locomotion. Their studies involved screening large numbers of flies with it which specific neurons were activated by heat, producing certain behaviors only when warmed to 30°C, but not at 24°C . Analysing several thousand flies, the researchers looked for strains that exhibited altered walking patterns compared to control animals.

Moonwalker-neurons control backward walking

Using the thermogenetic screen, the IMP-researchers isolated four lines of flies that walked backward on heat activation. They were able to track down these changes to specific nerve cells in the fly brain which they dubbed “moonwalker neurons”. They could also show that silencing the activity of these neurons using tetanus toxin rendered the flies unable to walk backward.

Among the moonwalker neurons, the activity of descending MDN-neurons is required for flies to walk backward when they encounter an obstacle. Input from MDN brain cells is sufficient to induce backward walking in flies that would otherwise walk forward. Ascending moonwalker neurons (MAN) promote persistent backward walking, possibly by inhibiting forward walking.

“This is the first identification of specific neurons that carry the command for the switch in walking direction of an insect”, says Salil Bidaye, lead author of the study. “Our findings provide a great entry point into the entire walking circuit of the fly. “
Although there are obvious differences in how insects and humans walk, it is likely that there are functional analogies at a neural circuit level. Insights into the neural basis of insect walking could also generate applications in the field of robotics. To date, none of the engineered robots that are used for rescue or exploration missions can walk as robustly as animals. Understanding how insects change their walking direction at a neuronal level would reveal the mechanistic basis of achieving such robust walking behavior.

(Image credit)