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 5

Dampening S1 synchronization through interneuron activation alleviates pain-like behavior.

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Dampening S1 synchronization through interneuron activation alleviates p...
(A–C) Interneuron calcium imaging. The S1ULp–S1J region was injected with AAV-Dlx-GCaMP6f on day –28, followed by FLIT or sham surgery on day 0. Calcium imaging was performed at the indicated time points (n = 4 per group). (A) Diagram of S1 injection. Lower panel shows representative GCaMP6f expression. Scale bar: 50 μm. (B) Representative single neuron calcium dynamics tracing. (C) Total integrated calcium signals. *P < 0.05, by 2-way ANOVA with a post hoc Tukey-Kramer test shows significant difference between the FLIT and sham groups. (D) Comparison of GABAergic interneuron–related gene transcripts. **P < 0.01 and ***P < 0.001, by unpaired t test. (E–K) Chemogenetic activation of interneurons dampened the synchronization of c-Fos–induced pain-related neurons (sham n = 6, FLIT n = 5). (E) Diagram and flowchart of the experimental design. (F) Representative brain slice showing expression of dTomato and GCaMP6f within the S1ULp–S1J region. (G–I) Chemogenetic activation of interneurons decreased the synchronization of c-Fos–induced pain-related neurons. (G) Representative calcium dynamics tracing at day 7 after FLIT surgery. (H) Representative heatmaps and fraction of active neuron plots. (I) Representative correlation matrix plots. (J) Mean pairwise correlation at different time points after FLIT surgery. (K) Fraction of global transients among total transients at different time points after FLIT surgery. *P < 0.05 and **P < 0.01, by 2-way ANOVA; a post hoc Tukey-Kramer test was performed to determine the P value for vector/FLIT versus Gq-DREADD/FLIT. (L–O) Chemogenetic activation of interneurons alleviated pain-like behavior (n = 7 sham, n = 8 for the other groups; data indicate the mean ± SEM). (L) Flowchart of the experimental design. (M) Mechanical withdrawal threshold. (N) Solid food preference. (O) Composite z scores (mechanical withdrawal; grooming; body weight; incisor length; wood weight changes; and solid food preference) were computed for all groups. (M–O) *P < 0.05 and **P < 0.01, by 2-way ANOVA; a post hoc Bonferroni test was performed to determine the P value of vector/FLIT versus Gq-DREADD/FLIT.