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 2

Highly synchronized S1 neural dynamics in FLIT mice.

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Highly synchronized S1 neural dynamics in FLIT mice. (A–H) Two-photon im...
(A–H) Two-photon imaging of the anterolateral S1 cortex in awake mice (n = 7 sham, n = 5 FLIT). Images were acquired in the same field of view across all days. (A) Left: Schematic of AAV injection into the S1 cortex contralateral to the FLIT surgery side. Right: Representative image of GCaMP6 expression in the S1 cortex. Scale bar: 100 μm. (B) Robust neuronal activities in the S1ULp–S1J regions captured by wide-field two-photon calcium imaging in large cortical areas. Heatmap shows calcium activity in the imaging field 7 days after FLIT surgery. M, middle; L, lateral. Scale bar: 1 mm. (C) Representative heatmaps and the corresponding fraction of simultaneously active neurons for each group at days 0 and 7. Orange triangles indicate global events. (D) Sample neuron calcium transients from S1 of a FLIT-operated mouse at days 0 and 7. Gold traces indicate global synchronized events. (E) Mean pairwise correlation coefficient across days and groups. The FLIT group exhibited a significantly higher correlation. P < 0.001, by 2-way ANOVA versus the sham group; *P < 0.05 and ***P < 0.001, by Bonferroni’s post hoc test for pairwise comparison. (F) Fraction global transients across days and groups. P < 0.001 versus the sham group, by 2-way ANOVA; *P < 0.05 and ***P < 0.001 for comparison of global transients, by Bonferroni’s post hoc test. (G) Fraction of global transients per neuron (normalized to each animal). Each circle indicates 1 neuron, and each line represents the fit for 1 animal from the FLIT group. (H) Left and middle panels: Representative plots of neuronal trajectories using the first 3 coefficients of PCA in FLIT model mice at days 0 and 7. Activity during the global events is highlighted in gold. Right panel: Euclidean distance between the mean of the first 3 coefficients and global events (gold) versus nonglobal events (gray). ***P < 0.001, by Wilcoxon rank-sum test. (I) Correlation between the z score and the synchronization index in the FLIT model. There was a positive correlation between the z score and the synchronization index at the indicated time points. The solid line represents linear regression, and the dashed line represents 95% CI.