Anterior Cingulate Cortex Astrocytes Regulate Chronic Itch and Comorbid Negative Emotional Disorders in Mice.

AIMS: The anterior cingulate cortex (ACC) is widely recognized as a key brain region in modulating itch and itch-associated behaviors. Though neuronal mechanisms are increasingly clarified, the role of ACC astrocytes remains poorly understood. METHODS: By employing a diphenylcyclopropenone (DCP)-induced chronic itch mouse model, we assessed scratching behavior and negative emotions via behavioral tests. Astrocytic morphology was examined through immunofluorescence staining and sholl analysis. Fiber photometry was used to record calcium signals of ACC astrocytes and CaMKII-positive neurons. Chemogenetic manipulation was applied to modulate astrocyte activity. Gliotransmitter quantification was implemented to detect the gliotransmitter release in the ACC. RESULTS: DCP induced robust scratching responses and concomitant anxiety- and depression-like behaviors. ACC astrocytes exhibited morphological activation and elevated calcium responses. Chemogenetic activation of ACC astrocytes alleviated DCP-induced scratching behavior and negative emotions, and enhanced calcium activity of local CaMKII-positive neurons. Conversely, chemogenetic inhibition of ACC astrocytes reduced such neuronal calcium activity. D-serine and ATP levels were reduced in DCP-induced chronic itch, while chemogenetic activation of astrocytes significantly elevated them. CONCLUSIONS: ACC astrocytes play a critical role in regulating chronic itch and comorbid anxiety-depression by modulating CaMKII-positive neuronal activity, providing a potential therapeutic target for intractable chronic itch in clinical settings.