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 1

FLIT model of TN leads to robust c-Fos activation in the S1ULp–S1J region.

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FLIT model of TN leads to robust c-Fos activation in the S1ULp–S1J regio...
(A) Diagram of trigeminal nerve root impingement to recapitulate human TN. Yellow structure depicts the trigeminal anatomy including the trigeminal nerve root, the trigeminal ganglion (TG), and peripheral branches; red represents the Surgifoam impingement site at the trigeminal nerve root. (B–D) Behavioral testing for the FLIT model. Mice underwent sham (n = 18) or FLIT (n = 18) surgery, followed by behavioral testing at the indicated time points. (B) Mechanical withdrawal threshold for von Frey filament testing (data indicate the mean ± SEM). **P < 0.01 and ***P < 0.001, by 2-way ANOVA with Bonferroni’s post hoc test for differences between groups. (C) Percentage of mice with asymmetrical facial grimacing behavior. Mice in the FLIT group displayed paroxysmal asymmetrical facial grimacing. ***P < 0.001, by Fisher’s exact test. (D) Summary quantification of behavioral tests quantified as a composite z score (mechanical withdrawal; grooming; body weight; length of incisors; wood weight changes; percentage of time spent eating solid chew), computed over 28 days. ***P < 0.001, by 2-way ANOVA with Bonferroni’s post hoc test differences between groups. (E) c-Fos activation in the S1ULp–S1J region after surgery. Representative tangential slices of c-Fos staining of FLIT-operated mice (original magnification, ×4 and ×10). Sequential slices from left to right represent coronal sections covering S1J (bregma 1.2 mm), S1ULp (bregma 0.5 mm), anterior S1BF (bregma –0.8 mm), and posterior S1BF (bregma –1.8 mm) cortex regions. Slices between bregma –0.8 mm and –1.8 mm were costained with VGLUT2 (red) to visualize barrels. Lower panels represent boxed regions of the corresponding upper panels. Scale bars: 500 μm (top row) and 20 μm (bottom row). (F) Quantification of c-Fos+ cells in the S1J, S1ULp, and S1BF cortex regions (n = 4 per group). **P < 0.01, ****P < 0.0001, by 2-way ANOVA with Bonferroni’s post hoc test to determine significant differences between groups.