Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice
Weihua Ding, … , Mark T. Harnett, Shiqian Shen
Weihua Ding, … , Mark T. Harnett, Shiqian Shen
Published January 5, 2023
Citation Information: J Clin Invest. 2023;133(5):e166408. https://doi.org/10.1172/JCI166408.
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Research Article Neuroscience Therapeutics

Highly synchronized cortical circuit dynamics mediate spontaneous pain in mice

Abstract

Cortical neural dynamics mediate information processing for the cerebral cortex, which is implicated in fundamental biological processes such as vision and olfaction, in addition to neurological and psychiatric diseases. Spontaneous pain is a key feature of human neuropathic pain. Whether spontaneous pain pushes the cortical network into an aberrant state and, if so, whether it can be brought back to a “normal” operating range to ameliorate pain are unknown. Using a clinically relevant mouse model of neuropathic pain with spontaneous pain–like behavior, we report that orofacial spontaneous pain activated a specific area within the primary somatosensory cortex (S1), displaying synchronized neural dynamics revealed by intravital two-photon calcium imaging. This synchronization was underpinned by local GABAergic interneuron hypoactivity. Pain-induced cortical synchronization could be attenuated by manipulating local S1 networks or clinically effective pain therapies. Specifically, both chemogenetic inhibition of pain-related c-Fos–expressing neurons and selective activation of GABAergic interneurons significantly attenuated S1 synchronization. Clinically effective pain therapies including carbamazepine and nerve root decompression could also dampen S1 synchronization. More important, restoring a “normal” range of neural dynamics through attenuation of pain-induced S1 synchronization alleviated pain-like behavior. These results suggest that spontaneous pain pushed the S1 regional network into a synchronized state, whereas reversal of this synchronization alleviated pain.

Authors

Weihua Ding, Lukas Fischer, Qian Chen, Ziyi Li, Liuyue Yang, Zerong You, Kun Hu, Xinbo Wu, Xue Zhou, Wei Chao, Peter Hu, Tewodros Mulugeta Dagnew, Daniel M. Dubreuil, Shiyu Wang, Suyun Xia, Caroline Bao, Shengmei Zhu, Lucy Chen, Changning Wang, Brian Wainger, Peng Jin, Jianren Mao, Guoping Feng, Mark T. Harnett, Shiqian Shen

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Figure 3

Pain-related c-Fos–expressing neurons drive S1 synchronization.

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Pain-related c-Fos–expressing neurons drive S1 synchronization. (A–D) Ne...
(A–D) Neuronal synchronization captured in the S1ULp–S1J regions of a TRAP2 mouse 7 days after FLIT surgery. (A) Diagram and flowchart of two-photon imaging of a TRAP2 mouse (n = 3). (B) Representative heatmaps with the corresponding fraction of simultaneously active neurons and correlation matrices at days 7 and 14. Global synchronized neuron activity (>50% neurons active simultaneously) was present in TRAP2 mice that underwent FLIT surgery. (C) Sample neuron calcium transient traces. Gold arrowhead indicates global synchronized events. (D) Representative plots of neuronal trajectories using the first 3 coefficients of PCA in FLIT mice at days 7 and 14. Activity during global events is highlighted in gold. Euclidean distance between the mean of the first 3 coefficients and global events (golden) versus nonglobal events (gray). ***P < 0.001, by Wilcoxon rank-sum test. (E–H) S1ULp-S1J neuronal synchronization was subdued by inhibition of c-Fos–induced Gi-DREADD–expressing neurons in TRAP2 mice with TN. (E) Diagram and flowchart of inhibition of c-Fos–induced Gi-DREADD–expressing neurons in S1ULp–S1J regions of a TRAP2 mouse (n = 3). (F) Representative heatmap and correlation matrix showing neuronal synchronization present from day 7 after FLIT and tamoxifen administration. C21 administration in mice injected with a vector virus did not alter synchronization. (G) Representative heatmap and correlation matrix showing neuronal synchronization presented since day 7 after FLIT and tamoxifen. C21 administration to mice injected with Gi-DREADD virus suppressed neuronal synchronization. (H) Mean pairwise correlation coefficient across days and groups. Both groups of mice injected with vector or Gi-DREADD virus exhibited a significant correlation from day 7 after FLIT surgery, whereas C21 administration decreased the correlation in mice injected with Gi-DREADD compared with mice injected with vector virus. ***P < 0.001, by 2-way ANOVA with Bonferroni’s post hoc test for differences between vector control and Gi-DREADD. corr., correlation.