An Anterior Cingulate Cortex-to-Midbrain Projection Controls Chronic Itch in Mice
Ting‑Ting Zhang1 · Su‑Shan Guo2 · Hui‑Ying Wang1 · Qi Jing1 · Xin Yi2 · Zi‑Han Hu1 · Xin‑Ren Yu1 · Tian‑Le Xu2,3 · Ming‑Gang Liu2,3 · Xuan Zhao11 Department of Anesthesiology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai 200072, China
2 Department of Anatomy and Physiology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
3 Center for Brain Science of Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
Abstract
Itch is an unpleasant sensation that provokes the desire to scratch. While acute itch serves as a protective system to warn the body of external irritating agents, chronic itch is a debilitating but poorly-treated clinical disease leading to repetitive scratching and skin lesions. However, the neural mechanisms underlying the pathophysiology of chronic itch remain mysterious. Here, we identified a cell type-dependent role of the anterior cingulate cortex (ACC) in controlling chronic itch-related excessive scratching behaviors in mice. Moreover, we delineated a neural circuit originating from excitatory neurons of the ACC to the ventral tegmental area (VTA) that was critically involved in chronic itch. Furthermore, we demonstrate that the ACC→VTA circuit also selectively modulated histaminergic acute itch. Finally, the ACC neurons were shown to predominantly innervate the non-dopaminergic neurons of the VTA. Taken together, our findings uncover a cortex–midbrain circuit for chronic itch-evoked scratching behaviors and shed novel insights on therapeutic intervention.
Keywords
Anterior cingulate cortex; Chronic itch; Ventral tegmental area; Chemogenetics; Neural circuit
