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

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 6

Clinically effective treatments alleviate S1 synchronization and pain-like behavior.

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Clinically effective treatments alleviate S1 synchronization and pain-li...
(A) Diagram depicting the carbamazepine (Carba.) experiment. Excitatory neuron imaging and behavioral testing were carried out on separate groups of animals. (B and C) Two-photon calcium imaging 14 days after FLIT surgery. Animals (n = 4) received normal saline followed by carbamazepine 60 mg/kg with a 12-hour interval. (B) Left: Sample calcium transient traces of neurons. Middle: Heatmaps of neuronal activity. Right: Correlation coefficient matrices of the neurons shown in the left panels. (C) Pairwise correlation for each treatment for all 4 animals (gray circles). Data indicate the mean ± SEM. *P < 0.05, by paired t test. (D–F) Fourteen days after FLIT surgery, animals received normal saline followed by carbamazepine with a 12-hour interval (n = 10). (D) Mechanical withdrawal threshold for von Frey filament tests (mean ± SEM). **P < 0.01, by 2-way ANOVA; a post hoc Bonferroni’s test was performed to determine significant differences at the indicated time points for saline versus carbamazepine treatment. (E) Facial grooming counts. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA; a post hoc Bonferroni’s test was performed to determine the P value for saline versus carbamazepine treatment. (F) Percentage of mice with asymmetrical facial grimacing. No statistical significance (NS) was found between the groups (Fisher’s exact test). (G) Flowchart of the experiment for S1 calcium imaging (n = 4) and behavioral tests (n = 10 per group) for decompression (removal of Surgifoam) of the trigeminal nerve root in FLIT mice. (H) Representative neuronal activity heatmaps and correlation coefficient matrices. (I) Pairwise correlation coefficient before and after decompression (individual animals are indicated in gray and the mean ± SEM in red). **P < 0.01, by 1-way ANOVA, with a Tukey-Kramer comparison. (J–L) Behavioral testing of mice subjected to decompression 14 days after FLIT surgery. (J) Asymmetrical facial grimacing. *P < 0.05, by Fisher’s exact test. (K) Wood-chewing assay. *P < 0.05, by 2-way ANOVA; a post hoc Bonferroni’s test was performed to determine the P value for FLIT versus FLIT plus decompression. (L) Composite z scores for behaviors were computed for all groups. ***P < 0.001, by 2-way ANOVA; a post hoc Bonferroni’s test was performed to determine the P value for FLIT versus FLIT plus decompression.