Contagious itch serves an important purpose, explains Zhou-Feng Chen, who studies itch at Washington University School of Medicine in St. Louis. Mice have notoriously bad eyesight, he says, and therefore “they cannot see mosquitos; they cannot see insects. But if other mice are scratching, you better scratch.”
In a study published October 4 in Cell Reports, Chen and his colleagues probed the neural circuitry driving contagious itch in mice, which he says likely differs from that of humans due to the comparative complexity of our brains. The team found a previously unreported visual circuit in the brain that appears to be responsible for detecting certain types of movement (in this case, a fellow mouse scratching), starting in the retina and ending in a brain region that plays an important role in guiding several autonomic processes. Unlike nearly all other known pathways involved in visual processing, the newly discovered circuit bypasses the visual cortex.
This wasn’t the lab’s first foray into uncovering the neural basis for contagious itch behaviors. In a Science study from 2017, the team tracked these behaviors to the suprachiasmatic nucleus (SCN), a cluster of neurons in the hypothalamus that are activated when mice watch other mice scratch themselves. The new study was meant to piece together how visual input triggers that activation.
To identify the brain areas activated by seeing scratching, the researchers injected an immunostaining virus into the SCN of live mice, which allowed them to track the structure and activity of the region’s upstream and downstream projections using in vivo calcium imaging. They then played the mice one of two videos: one showed a mouse walking around, and the other showed a mouse scratching itself.
Both videos, Chen emphasizes, showed a mouse as it would be seen from the perspective of another, allowing the team to observe the lab mice behaving as they would around actual itchy mice. “I think that we need to imagine what an animal can see,” he says. “And play some real [things] they actually care about. . . . We have to understand mouse visual systems from the rodent’s perspective.”
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The results showed that intrinsically photosensitive retina ganglion cells (ipRGCs) in the eye detect the motion of a fellow rodent scratching itself and pass along the signal to the SCN. The team found in their 2017 study that some SCN neurons trigger the release of gastrin-releasing peptide (GRP), which has long been associated with itching, and that activates other SCN neurons carrying GRP receptors, which then propagate the signal to the ending of the pathway: the paraventricular nucleus of the thalamus (PVT), which seems to trigger the itching behavior itself.
In the new study, the team also tested mice that were injected with an engineered virus that modified their genomes to inhibit the ipRGCs that projected to their SCNs. When these mice viewed the scratching video, they did not show any contagious itch behaviors despite otherwise behaving the same as mice with active ipRGCs—demonstrating that these cells and the SCN are indeed required for contagious itching, the authors write in their paper. Similar inhibition of cells in the visual cortex and other brain regions commonly associated with vision had no effect on contagious itch, which suggests that they’re not involved in the pathway.
These experiments showed that the newly discovered pathway “is required and enough to mediate contagious itch behavior,” Parisa Gazerani, who studies pain and contagious itch at Aalborg University in Denmark but didn’t work on the new study, tells The Scientist over email. “I think the researchers have provided a piece of groundbreaking evidence (at behavioral, and cellular-molecular levels) on the pathway involved in the contagious itch.”
Chen says he’s received criticism from other researchers who find it hard to believe that the visual cortex isn’t involved in the contagious itch pathway, given that it begins with a visual stimulus. He explains that the contagious itch visual pathway likely evolved before the emergence of a cortex. The brain regions it involves, such as the thalamus and hypothalamus, are far more ancient. He adds that humans have a lower percentage of ipRGCs in our eyes than mice do, indicating that human photoreceptors changed as our visual cortex evolved.
Gazerani notes that the finding highlights the difficulty of determining how contagious itch is triggered across species. In humans, itch can be set off by sight, sound, conversation, or even thought, she says, indicating that more-complicated neural pathways are at play than the one Chen and his colleagues found. That illustrates that we can’t necessarily draw conclusions about human itch based on mouse studies—or vice versa.
“Some of those pathways can be tested in animal models if [studies] are designed to address the nonvisual pathways, such as auditory,” Gazerani says. “However, the higher cognitive aspects are challenging to test in rodents—for example . . . the conversation about itch between two or more humans cannot be modeled. . . . Animal models can certainly help us understand some mechanistic aspects in detail that might not be possible to study in humans due to ethical and practical limitations.”