Neurons that respond to touch are less picky than expected

Researchers used to believe that individual primary touch-sensitive neatly responded to specific types of touch. Now a Northwestern University study finds that touch-sensitive neurons communicate touch in a much messier and jumbled manner.

In the study, the team developed a new technique to stimulate rats’ whiskers in three dimensions while simultaneously recording first-stage touch-sensitive neurons in the rats’ brains. The researchers discovered that, instead of responding to distinct types of touch, these neurons — which are the first to receive early touch signals — responded to many types of touch and to varying degrees.

The research was published online in the Proceedings of the National Academy of Sciences.

“Many people used to think that each neuron was very precisely tuned for some aspect of the touch stimulus,” said Northwestern’s Mitra Hartmann, one of the study’s senior authors. “We didn’t find that at all. Some neurons respond more than others to some features of the stimulus, so there is some degree of tuning. But these neurons respond to many combinations of different forces and torques applied to the whisker.”

“When we compared all the recorded neurons, we found that the stimuli they responded to overlapped with each other but not perfectly,” added Nicholas Bush, the paper’s first author. “It’s similar to a painter’s palette: We expected to find a handful of ‘primary colors,’ where a neuron could be one of a few different types. But we found the ‘palette’ had already been mixed. Each neuron was a little different from all the others, but together they covered an entire spectrum.”

Hartmann is a professor of biomedical and mechanical engineering at Northwestern’s McCormick School of Engineering, where she is a member of the Center for Robotics and Biosystems. A former Ph.D. candidate in Hartmann’s laboratory, Bush now is a postdoctoral fellow at the Seattle Children’s Research Institute. Sara Solla, a professor of physiology at Northwestern University Feinberg School of Medicine and of physics and astronomy in the Weinberg College of Arts and Sciences, is the other senior author of the study.

Previous studies ‘too restricted, simplified’

With just a brush of their whiskers, rats can extract detailed information from their environments, including an object’s distance, orientation, shape and texture. This keen ability makes the rat’s sensory system ideal for studying the relationship between mechanics (the moving whisker) and sensory input (touch signals sent to the brain). But despite the popularity of using the whisker system to explore the mystery of touch, many long-standing questions remain.

Although large regions of the brain are dedicated to processing touch signals, the number of primary sensory neurons that first acquire tactile information is relatively small and little understood. “There is an ‘information bottleneck,’” Bush said. “We wanted to know how the neurons that sense touch are capable of acquiring and representing complex information despite this bottleneck.”

While previous studies have explored how neurons respond to a stimulated whisker, those studies were unable to realistically replicate natural touch. In many studies, for example, researchers clipped an anesthetized rat’s whisker to about a centimeter in length and then precisely moved the whisker back and forth, micrometers at a time.

“This doesn’t at all capture the full flexibility of the whisker,” Hartmann said. “It’s not how a rat would move in a natural environment. It’s a precise stimulation, which gives a precise response, but it’s too restricted and simplified.”

New comprehensive technique

In Northwestern’s study, however, the researchers left the whisker intact and manually stimulated it through a comprehensive range of motions, directions, speeds and forces, up and down the full length of the whisker. Using implanted electrodes to measure the electrical activity of neurons that received the touch signals, the researchers quantified how these neurons responded to a broad range of mechanical signals, much closer to what a real rat would experience in its natural environment. Ultimately, they found that all neurons responded — albeit some more than others — to all different types of stimuli.

“This finding suggests that the sense of touch may be capable of very complex tactile feats because it doesn’t throw away or filter much information at that first stage of sensory acquisition before information gets to higher processing centers in the brain,” Bush said. “Rather, these early sensory neurons are relaying a high-fidelity — but ‘jumbled’ or ‘messy’ — representation. The brain has to be, and clearly is, capable of sorting through the jumble and reconciling it with all the other information available to interpret the sense of touch.”

Next, Hartmann and her team plan to combine this new finding with WHISKiT, the first 3D simulation of a rat’s whisker system, which was recently developed in her laboratory.

“We can use the WHISKiT model to simulate the mechanical signals that will occur during natural whisking behavior, and then simulate how a population of first-stage touch neurons would respond to those mechanical signals,” Hartmann said. “Simulation scenarios will be based on the results we uncovered in this latest study.”

Unraveling the Mystery of Touch

Some parts of the body—our hands and lips, for example—are more sensitive than others, making them essential tools in our ability to discern the most intricate details of the world around us.

This ability is key to our survival, enabling us to safely navigate our surroundings and quickly understand and respond to new situations.

It is perhaps unsurprising that the brain devotes considerable space to these sensitive skin surfaces that are specialized for fine, discriminative touch and which are continually gathering detailed information via the sensory neurons that innervate them.

But how does the connection between sensory neurons and the brain result in such exquisitely sensitive skin?

A new study led by researchers at Harvard Medical School has unveiled a mechanism that may underlie the greater sensitivity of certain skin regions. The research, conducted in mice and published Oct. 11 in Cell, shows that the overrepresentation of sensitive skin surfaces in the brain develops in early adolescence and can be pinpointed to the brain stem.

Moreover, the sensory neurons that populate the more sensitive parts of the skin and relay information to the brain stem form more connections and stronger ones than neurons in less sensitive parts of the body.

Sensitive skin regions

“This study provides a mechanistic understanding of why more brain real estate is devoted to surfaces of the skin with high touch acuity,” said senior author David Ginty, the Edward R. and Anne G. Lefler Professor of Neurobiology at Harvard Medical School. “Basically, it’s a mechanism that helps explain why one has greater sensory acuity in the parts of the body that require it.”

While the study was done in mice, the overrepresentation of sensitive skin regions in the brain is seen across mammals—suggesting that the mechanism may be generalizable to other species.

From an evolutionary perspective, mammals have dramatically varied body forms, which translates into sensitivity in different skin surfaces. For example, humans have highly sensitive hands and lips, while pigs explore the world using highly sensitive snouts. Thus, Ginty said this mechanism could provide the developmental flexibility for different species to develop sensitivity in different areas.

Moreover, the findings, while fundamental, could someday help illuminate the touch abnormalities seen in certain neurodevelopmental disorders in humans.

Scientists have long known that certain body parts are overrepresented in the brain—as depicted by the brain’s sensory map, called the somatosensory homunculus, a schematic of human body parts and the corresponding areas in the brain where signals from these body parts are processed. The striking illustration includes cartoonishly oversized hands and lips.

Previously, it was thought that the overrepresentation of sensitive skin regions in the brain could be attributed to a higher density of neurons innervating those skin areas. However, earlier work by the Ginty lab revealed that while sensitive skin does contain more neurons, these extra neurons are not sufficient to account for the additional brain space.

“We noticed that there was a rather meager number of neurons that were innervating the sensitive skin compared to what we’d expect,” said co-first author Brendan Lehnert, a research fellow in neurobiology, who led the study with Celine Santiago, also a research fellow in the Ginty lab.

“It just wasn’t adding up,” Ginty added.

To investigate this contradiction, the researchers conducted a series of experiments in mice that involved imaging the brain and neurons as neurons were stimulated in different ways.

First, they examined how different skin regions were represented in the brain throughout development. Early in development, the sensitive, hairless skin on a mouse’s paw was represented in proportion to the density of sensory neurons.

However, between adolescence and adulthood, this sensitive skin became increasingly overrepresented in the brain, even though the density of neurons remained stable—a shift that was not seen in less sensitive, hairy paw skin.

“This immediately told us that there’s something more going on than just the density of innervation of nerve cells in the skin to account for this overrepresentation in the brain,” Ginty said. 

“It was really unexpected to see changes over these postnatal developmental timepoints,” Lehnert added. “This might be just one of many changes over postnatal development that are important for allowing us to represent the tactile world around us, and helping us gain the ability to manipulate objects in the world through the sensory motor loop that touch is such a special part of.”

Sensory and brain stem neurons

Next, the team determined that the brain stem—the region at the base of the brain that relays information from sensory neurons to more sophisticated, higher-order brain regions—is the location where the enlarged representation of sensitive skin surfaces occurs.

This finding led the researchers to a realization: The overrepresentation of sensitive skin must emerge from the connections between sensory neurons and brain stem neurons. 

To probe even further, the scientists compared the connections between sensory neurons and brain stem neurons for different types of paw skin. They found that these connections between neurons were stronger and more numerous for sensitive, hairless skin than for less sensitive, hairy skin. Thus, the team concluded, the strength and number of connections between neurons play a key role in driving overrepresentation of sensitive skin in the brain.

Finally, even when sensory neurons in sensitive skin weren’t stimulated, mice still developed expanded representation in the brain—suggesting that skin type, rather than stimulation by touch over time, causes these brain changes.

“We think we’ve uncovered a component of this magnification that accounts for the disproportionate central representation of sensory space.” Ginty said. “This is a new way of thinking about how this magnification comes about.”

Next, the researchers want to investigate how different skin regions tell the neurons that innervate them to take on different properties, such as forming more and stronger connections when they innervate sensitive skin.

“What are the signals?” Ginty asked. “That’s a big, big mechanistic question.”

And while Lehnert described the study as purely curiosity-driven, he noted that there is a prevalent class of neurodevelopmental disorders in humans called developmental coordination disorders that affect the connection between touch receptors and the brain—and thus might benefit from elucidating further the interplay between the two.

“This is one of what I hope will be many studies that explore on a mechanistic level changes in how the body is represented over development,” Lehnert said. “Celine and I both think this might lead, at some point in the future, to a better understanding of certain neurodevelopmental disorders.”