No less than 16 different types of nerve cells have been identified by scientists in a new study on the human sense of touch. Comparisons between humans, mice and macaques show both similarities and significant differences. The study, a collaboration between researchers at Linköping University and Karolinska Institutet in Sweden and the University of Pennsylvania in the USA, has been published in Nature Neuroscience.

“Our study provides a landscape 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 somatic sensation system. A common understanding is that there is a specific type of nerve cell for each type of feeling, such as pain, pleasant touch, or cold. But the findings from the current study challenge that notion and show that bodily sensations are probably much more complicated than that.

Much of the knowledge we have today about how the nervous system works comes from research on animals. But how big are the similarities between, for example, 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 inadequate. The researchers behind the current study, therefore, wanted to create a detailed atlas of different types of nerve cells involved in human somatosensation and compare it with those of mice and macaques, a primate species.

In the study, a research group at the University of Pennsylvania, led by Associate Professor Wenqin Luo, made detailed analyses 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 one sensory nerve cell type. In this way, they identified 16 distinct types of nerve cells in humans. As the researchers analyse more cells, they will likely discover even more distinct types of sensory nerve cells.
The nerve cell gene expression analyses provide a picture of what the cellular machinery looks like in the different cell types. The next question was how this relates to nerve cell function. If a nerve cell produces a protein that can detect heat, does that mean that the nerve cell responds to heat?

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

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

“For ten years, we’ve 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 type of proteins these nerve cells express as well as what kind of stimulation they can respond to, and now we can link it. It’s a huge step forward”, says Håkan Olausson.

Another example is a type of very rapidly conducting pain-sensing nerve cell, which was found to respond to non-painful cooling and menthol.

“There’s a common perception that nerve cells are very specific – that one type of nerve cell detects cold, another senses a certain vibration frequency, and a third reacts to pressure, and so on. It’s often talked about in those terms. But we see that it’s a lot 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 that the researchers identified in the study are roughly similar between the species. The biggest difference the researchers found was in very rapidly conducting pain-sensing nerve cells that react to stimulation that can cause injury. These were first discovered in humans in 2019 by the same group at Linköping using microneurography. Compared to the mouse, humans have many more pain nerve cells of the type that send pain signals to the brain at high speed. Why this is so, the study cannot answer, but the researchers have a theory:

“The fact that pain is signalled at a much higher velocity in humans compared to mice is probably just a reflection of body size. A mouse doesn’t require such rapid nerve signalling. But in humans, the distances are greater, and the signals need to be sent to the brain more rapidly; otherwise, you’d be injured before you even react and withdraw,” says Håkan Olausson.

The study is a collaboration between Patrik Ernfors’ research group at Karolinska Institutet, Wenqin Luo’s research group at the University of Pennsylvania and Håkan Olausson and Saad Nagi’s research group 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.

Article: Leveraging Deep Single-soma RNA Sequencing to Explore the Neural Basis of Human Somatosensation, Huasheng Yu, Saad S. Nagi, Dmitry Usoskin et al. (2024). Nature Neuroscience, published online November 4 2024, doi:10.1038/s41593-024-01794-1