Recent research identifies 16 human nerve cell types, revealing complex sensory responses and challenging traditional views on nerve specificity.
In a new study published in Nature Neuroscience, scientists have identified 16 distinct types of nerve cells related to the human sense of touch. The research, conducted by Linköping University, Karolinska Institutet, and the University of Pennsylvania, not only challenges the traditional notion that specific nerve cells are dedicated to specific sensations like pain or temperature but also reveals significant similarities and differences across humans, mice, and macaques.
“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.
Challenging Established Notions of Sensation
Humans perceive touch, temperature, and pain through the somatic sensation system. It’s widely believed that distinct types of nerve cells correspond to specific sensations like pain, pleasant touch, or cold. However, the findings from the current study challenge that notion and show that bodily sensations are likely much more complicated.
Our current understanding of the nervous system largely stems from animal research. 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 them with those of mice and macaques, a primate species.
Advances in Nerve Cell Classification
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 with 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 analyze 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?
Linking Gene Expression to Function
The 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 signaling 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 determine 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 the 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.
Surprising Findings in Nerve Response
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.
Comparative Analysis Across Species
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 signaled 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 signaling. 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.
Reference: “Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation” by Huasheng Yu, Saad S. Nagi, Dmitry Usoskin, Yizhou Hu, Jussi Kupari, Otmane Bouchatta, Hanying Yan, Suna Li Cranfill, Mayank Gautam, Yijing Su, You Lu, James Wymer, Max Glanz, Phillip Albrecht, Hongjun Song, Guo-Li Ming, Stephen Prouty, John Seykora, Hao Wu, Minghong Ma, Andrew Marshall, Frank L. Rice, Mingyao Li, Håkan Olausson, Patrik Ernfors and Wenqin Luo, 4 November 2024, Nature Neuroscience.
DOI: 10.1038/s41593-024-01794-1
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.
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