Summary: Researchers shed light on the mechanism that drives the uncontrollable urge to scratch an itch.
Source: Cell Press.
It’s a maddening cycle that has affected us all: it starts with an itch that triggers scratching, but scratching only makes the itchiness worse. Now, researchers have revealed the brain mechanism driving this uncontrollable itch-scratching feedback loop. In a study publishing on December 13 in the journal Neuron, the researchers showed that the activity of a small subset of neurons, located in a deep brain region called the periaqueductal gray, tracks itch-evoked scratching behavior in mice.
“Effective treatment for chronic itch is still lacking, which is largely due to our limited knowledge about the neural mechanism of itch,” says senior study author Yan-Gang Sun of the Chinese Academy of Sciences. “Our study provides the starting point to further decipher how itch is processed and modulated in the brain. Eventually this might lead to the identification of new therapeutic targets.”
Itching can be triggered by a wide range of causes, including allergic reactions, skin conditions, irritating chemicals, parasites, diseases, pregnancy, and cancer treatments. The itch-scratching cycle can significantly impair quality of life and lead to serious skin and tissue damage. Recent studies have identified specific subtypes of neurons in the spinal itch circuit, including cells that express the gastrin-releasing peptide receptor (GRPR). But relatively little is known about the brain regions involved in itch processing. Sun and his team suspected that the periaqueductal gray could be involved, in part due to its critical and well-known role in processing related sensory information such as pain.
In the new study, the researchers first recorded from periaqueductal gray neurons in freely moving mice that were induced to scratch through injections with either histamine or an antimalarial drug called chloroquine. Itch-induced scratching behavior tracked the activity of a specific set of neurons that produce a neurotransmitter called glutamate and a neuropeptide called tachykinin 1 (Tac1). When the researchers ablated the Tac1-expressing neurons, itch-induced scratching decreased significantly. By contrast, stimulation of these neurons triggered spontaneous scratching behavior, even without histamine or chloroquine, by activating GRPR-expressing neurons in the spinal itch circuit.
Sun says little is known about how the itch circuit evolved, despite its importance for the survival of animals. “Itch sensation plays a key role in detecting harmful substances, especially those that have attached to the skin,” Sun says. “As itch leads to scratching behavior, this allows the animal to get rid of the harmful substances. In some cases, the lesion caused by scratching can evoke strong immune responses, which might help to combat the invaded substances.”
In future studies, Sun and his team plan to investigate which molecules in the Tac1-expressing periaqueductal gray neurons can be targeted by drugs. They will also search for other nodes in the brain’s itch network. “These studies will help us design new approaches or develop new drugs for the treatment of patients with chronic itch,” Sun says.
Funding: This research was supported by the National Natural Science Foundation of China and the Strategic Priority Research Program of the Chinese Academy of Sciences.
Source: Carly Britton – Cell Press
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is credited to Jing-Tao Miao.
Original Research: Open access research for “Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation” by Zheng-Run Gao, Wen-Zhen Chen, Ming-Zhe Liu, Xiao-Jun Chen, Li Wan, Xin-Yan Zhang, Lei Yuan, Jun-Kai Lin, Meng Wang, Li Zhou, Xiao-Hong Xu, and Yan-Gang Sun in Neuron. Published December 13 2018.
Tac1-Expressing Neurons in the Periaqueductal Gray Facilitate the Itch-Scratching Cycle via Descending Regulation
Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.