Scientists identify 16 types of nerve cells in the human sense of touch

At least 16 different types of nerve cells have been identified by scientists in a new study of the human sense of touch. Comparisons between humans, mice and macaques show both similarities and important differences. The study, a collaboration between researchers at Linköping University and the Karolinska Institute in Sweden and the University of Pennsylvania in the US, was published in Nature Neuroscience.

“Our study provides a cross-sectional view of the human sense of touch. As a next step, we want to make portraits of the different types of nerve cells we have identified,” says Håkan Olausson, professor at Linköping University, about the study published in Nature Neuroscience.

We perceive touch, temperature and pain through the somatosensory system. A common understanding is that there is a specific type of nerve cell for each type of emotion, such as pain, pleasant touch or cold. But findings from the current study challenge that idea and show that bodily sensations are probably much more complex than that.

Much of the knowledge we have today about how the nervous system works comes from animal research. But how great are the similarities between, say, a mouse and a human? Many findings in animal studies have not been confirmed in human research. One reason for this may be that our understanding of how it works in humans is insufficient. The researchers behind the current study, then, wanted to create a detailed atlas of different types of nerve cells involved in human somatosensation and compare it to those of mice and macaques, a species of primate.

In the study, a research team at the University of Pennsylvania, led by associate professor Wenqin Luo, made detailed analyzes of the genes used by individual nerve cells, so-called deep RNA sequencing. Nerve cells that had similar gene expression profiles were grouped together as a type of sensory nerve cell. In doing so, they identified 16 different types of nerve cells in humans. As researchers analyze more cells, they will likely discover even more different types of sensory nerve cells.

Gene expression analyzes of neural cells provide insight into what cellular machinery looks like in different cell types. The next question was how this relates to nerve cell function. If a nerve cell makes a protein that can detect heat, does that mean the nerve cell responds to heat?

The current study is the first to link gene expression in different types of nerve cells to their actual function. To investigate the function of nerve cells, a research team at Linköping University, led by Saad Nagi and Håkan Olausson, used a method that allows researchers to listen to nerve signaling in one nerve cell at a time. Using this method, called microneurography, researchers can subject nerve cells in the skin of awake participants to temperature, touch, or certain chemicals and “listen” to a single nerve cell to find out whether that particular nerve cell is responding and sending signals to the brain.

During these experiments, the researchers made discoveries that would not have been possible if mapping the cellular machinery of different types of nerve cells had not given them new ideas to test. One such discovery involves a type of nerve cell that responds to pleasant touch. The researchers found that this type of cell unexpectedly also reacts to heat and to capsaicin, the substance that gives chili its heat. The response to capsaicin is characteristic of pain-sensing nerve cells, so it surprised the researchers that touch-sensing nerve cells responded to such stimulation. Furthermore, this type of nerve cell also responded to cooling, even though it does not produce the only protein so far known to signal the perception of cold. This finding cannot be explained by what is known about the cell’s mechanism and suggests that there is another cold-sensing mechanism that has yet to be discovered. The authors speculate that these nerve cells form an integrated sensory pathway for pleasurable sensations.

“For ten years, we have been listening to the nerve signals from these nerve cells, but we had no idea about their molecular characteristics. In this study, we see what kind of proteins these nerve cells express as well as what kind of stimulation they can respond to, and now we can connect it is a huge step forward,” says Håkan Olausson.

Another example is a type of nerve cell that detects pain very quickly, which was found to respond to non-painful cooling and menthol.

“There is a common perception that nerve cells are very specific – that one type of nerve cell detects cold, another senses a certain frequency of vibration, and a third reacts to pressure and so on. It is often spoken in these terms. But we see that it is much more complicated than that,” says Saad Nagi, Associate Professor at Linköping University.

And what about the comparison between mice, macaques and humans? How similar are we? Many of the 16 types of nerve cells the researchers identified in the study are roughly similar across species. The biggest difference the researchers found was in the very fast conduction of pain-sensing nerve cells that react to stimulation that can cause injury. These were first discovered in humans in 2019 by the same group in Linköping using microneurography. Compared to mice, humans have many more pain nerve cells of the type that send pain signals to the brain at high speed. Why this happens, the study can’t answer, but the researchers have a theory:

“The fact that pain is signaled with much greater speed in humans compared to mice is probably just a reflection of body size. A mouse doesn’t need as fast nerve signaling. But in humans, the distances are longer and the signals need to be sent to the brain faster, otherwise, you’ll injure yourself before you even react and withdraw,” says Håkan Olausson.

The study is a collaboration between the research group of Patrik Ernfors at Karolinska Institutet, the research group of Wenqin Luo at the University of Pennsylvania, and the research group of Håkan Olausson and Saad Nagi at Linköping University. Financial support for the study was provided by the National Institutes of Health, the Swedish Research Council, ALF Grants Region Östergötland and the Knut and Alice Wallenberg Foundation.