Researchers at the University of Michigan have illuminated a complete sensory pathway showing how the skin communicates the temperature of its surroundings to the brain.
This discovery, believed to be the first of its kind, reveals that cool temperatures get their own pathway, indicating that evolution has created different circuits for hot and cold temperatures. This creates an elegant solution for ensuring precise thermal perception and appropriate behavioral responses to environmental changes, said Bo Duan , senior author of the new study.
"The skin is the body's largest organ. It helps us detect our environment and separate, distinguish different stimuli," said Duan, a U-M associate professor of molecular, cellular, and developmental biology. "There are still many interesting questions about how it does this, but we now have one pathway for how it senses cool temperatures. This is the first neural circuit for temperature sensation in which the full pathway from the skin to the brain has been clearly identified."
This work deepens our understanding of fundamental biology and brings us closer to an explanation for how we evolved to inhabit safe temperatures and avoid dangerous extremes, Duan said. But it also has medical implications that can be explored to help improve the quality of life for people in the future.
For example, more than 70% of people who have undergone chemotherapy experience pain caused by cool temperatures, Duan said. The new study found that the neural circuit responsible for sensing innocuous cool does not mediate this type of cold pain. But, in understanding how the cool-sensing circuitry works when it's functioning properly under normal conditions, researchers now have a better chance of discovering what goes wrong in disease or injury. It could also help develop targeted therapies that restore healthy sensation without impairing normal temperature perception.
This research was funded by the National Institutes of Health and performed in collaboration with Shawn Xu and his research team in the U-M Life Sciences Institute.
A cool amplifier discovery
In their study, published in the journal Nature Communications, Duan and his team used sophisticated imaging techniques and electrophysiology to observe how mice transmitted the sensation of cool temperatures from their skin to the brain.
It's an approach the team has applied to other sensations in the past. Headed by postdoctoral research fellow Hankyu Lee and doctoral students Chia Chun Hor and Lorraine Horwitz , the team turned its focus to temperature in this work.
"These tools have allowed us to identify the neural pathways for chemical itch and mechanical itch previously," Duan said. "Working together, the team identified this very interesting, very dedicated pathway for cool sensation."
The cool signal starts at the skin, which is home to molecule sensors that can detect a specific range of temperatures between about 15 and 25 degrees Celsius—equivalent to 59 and 77 degrees Fahrenheit. When those sensors engage, they excite primary sensory neurons, which send the cool signal to the spinal cord. Here, the team found that the signal is amplified by specialized interneurons, which then activate projection neurons that connect to the brain.
Researchers had previously known about the skin's molecular thermometers—they, in part, earned researchers in California the 2021 Nobel Prize in Physiology or Medicine—but the spinal cord's amplifier was an unknown key ingredient. With the amplifier disabled, the cool signal becomes lost in the noise, the team found.
Although the study was performed in mice, each component of the circuit has been shown to be in humans through genetic sequencing, Duan said. So it's likely that we have the same pathway to thank for the refreshing sensation of stepping into an air-conditioned room on a hot summer day.
Moving forward, the team is looking to identify the pathway or pathways involved in acute cold pain.
"I think the painful sensations are going to be more complicated," Duan said. "When we're in riskier situations, there could be multiple pathways involved."
His team is also interested in how the brain processes these various skin signals and how we've evolved not only to differentiate between them, but also connect emotions with them to help protect ourselves. In fact, it's the curiosity around those sorts of questions that originally motivated Duan's work, which he is perpetually reminded of working in Michigan.
"In summer, I love walking along Lake Michigan and having a gentle breeze hit my face. I feel very cool, very comfortable," Duan said. "But the winter is really terrible for me."
