A groundbreaking investigation, spearheaded by esteemed researchers from the University of Pennsylvania, the Karolinska Institute, and Linköping University, has meticulously mapped the intricate landscape of human tactile perception.
The diverse nature of bodily sensations stems from a variety of dorsal root ganglion (DRG) neurons. However, obtaining detailed transcriptional profiles from individual human (h)DRG neurons—essential for fully understanding their roles—has been hampered by technical challenges. In their recent work, Yu and colleagues successfully isolated the cell bodies from individual hDRG neurons and performed extensive RNA sequencing (RNA-seq). This process revealed, on average, the expression of over 9,000 distinct genes within each neuron, leading to the identification of 16 unique neuronal subtypes.
The human capacity for perceiving touch, thermal changes, and pain is mediated by the somatosensory system.
A prevailing hypothesis suggested that distinct neuronal populations are exclusively dedicated to processing specific sensations, such as nociception (pain), affective touch, or thermal perception.
However, the findings from this recent investigation challenge this long-held belief, indicating that the mechanisms underlying bodily sensations are considerably more multifaceted.
“A substantial portion of our current understanding regarding the nervous system’s operations originates from studies conducted on animal models,” stated Dr. Wenqin Luo from the University of Pennsylvania, alongside her collaborative team.
“Yet, the extent of congruence between, for instance, a murine subject and a human remains a critical question.”
“Numerous discoveries reported in animal research have not found corroboration in human studies.”
“One significant contributing factor to this disparity might be the insufficiency of our comprehension of human neural mechanisms.”
“Our objective was to construct a comprehensive cartography of the diverse neuronal subtypes engaged in human somatosensation and subsequently juxtapose this with data from mice and macaques, a primate species.”
Within the scope of this research, detailed analyses were performed on the genetic materials utilized by individual neurons, employing a sophisticated technique known as deep RNA sequencing.
Neurons exhibiting analogous gene expression patterns were systematically categorized into distinct sensory neuron types.
Through this rigorous methodology, the investigators successfully delineated 16 neuronal types that are specific to humans.
This study represents a pioneering effort to correlate gene expression profiles within various neuronal categories with their actual functional responses.
To elucidate the functional roles of these neurons, the scientists employed a microneurography technique, enabling them to monitor the electrophysiological activity of individual neurons in real-time.
This advanced method allows researchers to expose cutaneous neurons in conscious participants to varying thermal stimuli, tactile inputs, or specific chemical agents, while simultaneously recording the signaling output of a single neuron to ascertain its responsiveness and its transmission of neural impulses to the brain.
During these experimental procedures, the researchers made serendipitous discoveries that would likely have remained elusive without the foundational insights provided by the comprehensive mapping of the molecular machinery within different neuronal subtypes, which inspired novel avenues of inquiry.
One such significant revelation pertained to a specific neuronal type identified as responding to pleasant tactile sensations.
These investigators observed that this particular neuronal population also exhibited reactivity to thermal stimuli (heating) and capsaicin, the compound responsible for the pungency of chili peppers, a response that was previously unexpected.
A reaction to capsaicin is typically indicative of nociceptors, leading to surprise among the scientists that neurons associated with touch perception would exhibit sensitivity to such a stimulus.
Furthermore, this neuronal subtype demonstrated a response to cooling, despite not producing the sole known protein currently identified as a mediator of cold perception.
This observation cannot be adequately explained by existing knowledge of the cell’s molecular mechanisms and suggests the existence of an as-yet-undiscovered pathway for cold detection.
The authors propose that these neurons may contribute to an integrated sensory pathway responsible for conveying pleasant sensations.
“For a decade, we have been analyzing the neural signals originating from these neurons, but we lacked insight into their molecular makeup,” remarked Dr. Håkan Olausson from Linköping University.
“This study provides clarity on the types of proteins these neurons express and the stimuli to which they can respond, thereby establishing a crucial link. This represents a monumental advancement.”
Another notable finding involved a class of high-conduction-velocity pain-sensing neurons that were observed to respond to non-painful cooling stimuli and menthol.
“There is a widespread assumption that neurons operate with high specificity—that one neuronal type exclusively detects cold, another senses a particular vibrational frequency, and a third reacts to pressure, and so forth,” explained Dr. Saad Nagi, also affiliated with Linköping University.
“This is how the subject is frequently discussed. However, our findings reveal a far more intricate reality.”
Regarding the comparative analysis between mice, macaques, and humans, the degree of relatedness observed was substantial. Many of the 16 neuronal types identified in this study exhibited considerable similarity across the species.
The most pronounced divergence was identified in the fast-conducting pain-sensing neurons that are activated by stimuli capable of inducing tissue damage.
In comparison to their murine counterparts, humans possess a significantly greater abundance of pain neurons that rapidly transmit nociceptive signals to the brain.
“While our study cannot definitively explain the underlying reasons for this disparity, we have formulated a hypothesis,” stated Dr. Olausson.
“The enhanced velocity of pain signaling in humans relative to mice is likely a direct consequence of body size differences.”
“A mouse does not necessitate such rapid neural communication. However, in humans, the greater distances involved require signals to be transmitted to the brain with increased speed; otherwise, individuals would be susceptible to injury prior to initiating a protective withdrawal reflex.”
The comprehensive details of this research are disseminated in a publication featured in the esteemed journal Nature Neuroscience.
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H. Yu et al. Leveraging deep single-soma RNA sequencing to explore the neural basis of human somatosensation. Nat Neurosci, published online November 4, 2024; doi: 10.1038/s41593-024-01794-1
