A microglial activation cascade across cortical regions underlies secondary mechanical hypersensitivity to amputation.

Feb 19, 2024

Experts: Hong-Rui Wei, Lan Tang, Xin-Lu Yang, Chang-Mao Chen, Le-Xian Li, Yu Mao, Di Wang, Fang Kang, Sen Qun, Zhi Zhang, Peng Cao, Yan Jin

Neural mechanisms underlying amputation-related secondary pain are unclear. Using in vivo two-photon imaging, three-dimensional reconstruction, and fiber photometry recording, we show that a microglial activation cascade from the primary somatosensory cortex of forelimb (S1FL) to the primary somatosensory cortex of hindlimb (S1HL) mediates the disinhibition and subsequent hyperexcitation of glutamatergic neurons in the S1HL (S1HL), which then drives secondary mechanical hypersensitivity development in ipsilateral hindpaws of mice with forepaw amputation. Forepaw amputation induces rapid S1FL microglial activation that further activates S1HL microglia via the CCL2-CCR2 signaling pathway. Increased engulfment of GABAergic presynapses by activated microglia stimulates S1HL neuronal activity, ultimately leading to secondary mechanical hypersensitivity of hindpaws. It is widely believed direct neuronal projection drives interactions between distinct brain regions to prime specific behaviors. Our study reveals microglial interactions spanning different subregions of the somatosensory cortex to drive a maladaptive neuronal response underlying secondary mechanical hypersensitivity at non-injured sites.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

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ABOUT THE EXPERTS

Hong-Rui Wei, Lan Tang, Xin-Lu Yang, Chang-Mao Chen, Le-Xian Li, Yu Mao, Di Wang, Fang Kang, Sen Qun, Zhi Zhang, Peng Cao, Yan Jin

Hong-Rui Wei

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Lan Tang

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Xin-Lu Yang

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Department of Anesthesiology, The First Affiliated Hospital of Wannan Medical College, Wuhu, Anhui 241000, China.

Chang-Mao Chen

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Le-Xian Li

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Yu Mao

Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.

Di Wang

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Fang Kang

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Sen Qun

Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.

Zhi Zhang

Department of Anesthesiology, The First Affiliated Hospital of USTC, Hefei National Laboratory for Physical Sciences at the Microscale, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China; Center for Advanced Interdisciplinary Science and Biomedicine, Institute of Health and Medicine, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. Electronic address: zhizhang@ustc.edu.cn.

Peng Cao

Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. Electronic address: pengcao@ustc.edu.cn.

Yan Jin

Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China. Electronic address: jinyan@ustc.edu.cn.