For more than half a century, researchers have studied how nerve fibers in the skin represent—how they “code”—the full range of temperatures, from searing heat to freezing cold. But much less is known about the neural code for temperature at the next stage of information processing, in the spinal cord.
Now, Chen Ran and Xiaoke Chen at Stanford University, US, along with Mark Hoon at the National Institutes of Health, Bethesda, US, have shown that neurons in the spinal cord of mice represent heat and cold in different ways. With heat, neurons carry information about the absolute temperature, but with cold, neurons instead track the change in temperature.
“It’s very striking to me that these coding properties are so diametrically different,” says Michael Caterina at Johns Hopkins University, Baltimore, US, who was not involved in the study. “[The study] adds a nice dimension to our understanding of innocuous and noxious information processing.”
The research was published online July 25 in the journal Nature Neuroscience.
Hot versus cold
A given temperature is first sensed by nerve endings in the skin, which send electrical signals to a group of neurons in an area called the dorsal root ganglion, which is located near the spinal cord. These signals in turn are routed to the spinal cord. But there, the code for temperature has remained more of a mystery. “The spinal cord has long been regarded as a black box,” says Ran, the lead author of the study.
To peer inside, Ran and colleagues knew they needed a new approach. Earlier studies used a technique called electrophysiology to measure nerve cell electrical activity in the spinal cord, but these studies could only eavesdrop on a tiny number of neurons, making it difficult to identify general patterns of activity. So, in the new study, the investigators devised a way to study a larger swath of neurons.
First, the researchers injected a fluorescent dye into the spinal cord of anesthetized mice; the dye only fluoresces when cells are active. Then, they bathed one hind limb, stripped of its hair, with water of an exact temperature. Finally, through a sophisticated microscope enabling them to see the florescent activity, they watched precisely when and how neurons responded when the water bathing the hind limb was either heated or cooled.
As they cooled the skin, the researchers found that neurons in the spinal cord responded vigorously. When they dropped the temperature by different amounts, but always to the same target temperature, they found that greater amounts of cooling activated more neurons and to a larger degree than smaller amounts of cooling did. Furthermore, the neurons stayed silent once the temperature had stabilized, regardless of the absolute temperature of the skin. These results showed that the neurons only coded the change in temperature during cooling conditions, rather than the absolute temperature.
With heat, neurons appeared to code temperature in an opposite way. More neurons responded to more intense heating, but these cells stayed active once the temperature became stable. Furthermore, when the researchers raised the temperature of the skin to the same target temperature, from different starting temperatures, neurons responded similarly. In contrast, when they changed the temperature by the same amount, but from different starting temperatures, the researchers found stronger responses for higher target temperatures. Together, the findings showed that when it comes to heat, neurons only encode the absolute temperature, and not the change in temperature.
Overall, the study reveals that spinal neurons use different codes for heat versus cold. But why the difference? Ran thinks it may have to do with the risk of injury from high temperatures. “Heat is more dangerous for an animal than cold,” says Ran. “If a temperature can damage a tissue, you want neurons to provide a very constant warning signal.” The neural code identified for heat, but not cold, may be that kind of signal.
The authors also found that spinal cord neurons synthesize information about temperature from many types of dorsal root ganglia neurons (the ones that send information into the spinal cord). And, some spinal neurons responded to both heat and cold, especially at more extreme temperatures.
What do the results mean for pain? Caterina thinks it’s too early to know. “It’s difficult to assign the phenomena that were being measured to painful versus non-painful sensations. That’s something that will play out over time.” – Matthew Soleiman
To read about the research in more detail, see the related Pain Research Forum news story here.
Matthew Soleiman is a science writer residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman