In a recent study published in Neuron, Dr. SUN Yangang’s lab at the Institute of Neuroscience of the Chinese Academy of Sciences demonstrated that tachykinin 1 (Tac1)-expressing neurons in the periaqueductal gray (PAG) facilitate the itch-scratching cycle via descending regulation. 

By using extracellular recording, fiber photometry, pharmacogenetic and optogenetic approaches, the study showed that Tac1-expressing neurons in the PAG promote scratching behavior via descending modulation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch sensation. It revealed the cellular and circuit mechanisms underlying descending modulation of itch, which brings new insight to treatment of chronic itch. 

Itch is an unpleasant sensation, which leads to scratching behavior. Itch sensation is critical for the survival of animals. Therapeutic approaches for chronic itch treatment have developed slowly due to the lack of knowledge about the neural mechanism underlying itch processing. 

A lot of effort has been devoted to understanding the mechanism of itch signal transduction and transmission in the peripheral nervous system and at the spinal level. In contrast, little was known before about how itch information is processed in the brain and how the brain can dynamically modulate the processing of itch. 

Previous functional imaging studies revealed changes in the activity of the PAG during itch signal processing. In addition, the PAG is well known for its critical role in modulating pain processing at the spinal level via a descending pathway. However, the functional role of the PAG in itch modulation remained unknown. 

In this study, researchers investigated the cellular and circuit mechanisms underlying the top-down modulation of itch by the PAG through examining the neural dynamics of PAG neurons and the behavioral responses after pharmacogenetic and optogenetic manipulation of different subtypes of PAG neurons. 

They explored the activity of PAG neurons during itch-induced scratching behavior, and found that some PAG neurons exhibited scratching behavior-related neural activity. 

The results further showed that Tac1-expressing glutamatergic neurons in the PAG exhibited itch-selective activity, and that ablating or suppressing the activity of these Tac1-expressing neurons decreased itch-induced scratching behavior. 

Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching behavior, which was suppressed by ablation of spinal GRPR neurons, the key relay neurons for itch. 

The findings revealed the cellular and circuit mechanisms underlying descending modulation of itch and found a group of Tac1-expressing neurons in the brain that is critical for promoting the itch-scratching cycle. These Tac1-expressing neurons in the brain can be a potential central therapeutic target for breaking the vicious itch-scratching cycle associated with chronic itch. 

It raised the possibility that targeting the brain cells involved in itch processing could be a way to design new therapeutic methods for treatment of chronic itch.