Highly synchronized cortical circuit dynamics mediate spontaneous pain

Ding, W.; Fischer, L.; Chen, Q.; Li, Z.; Yang, L.; You, Z.; Hu, K.; Wu, X.; Zhou, X.; Chao, W.; Hu, P.; Dagnew, T. M.; DuBreuil, D.; Wang, S.; Xia, S.; Bao, C.; Zhu, S.; Chen, L.; Wang, C.; Wainger, B. M.; Jin, P.; Mao, J.; Feng, G.; Harnett, M.; Shen, S.

doi:10.1101/2022.10.04.510722

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bioRxiv · 10.1101/2022.10.04.510722

Highly synchronized cortical circuit dynamics mediate spontaneous pain

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Abstract

Cortical neural dynamics mediate information processing for the cerebral cortex, 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 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 robust 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 importantly, restoring a normal range of neural dynamics, through attenuating pain-induced S1 synchronization, alleviated pain-like behavior. These results suggest spontaneous pain pushes S1 regional network into a synchronized state, whereas reversal of this synchronization alleviates pain.

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Ding, W., Fischer, L., Chen, Q., Li, Z., Yang, L., You, Z., Hu, K., Wu, X., Zhou, X., Chao, W., Hu, P., Dagnew, T. M., DuBreuil, D., Wang, S., Xia, S., Bao, C., Zhu, S., Chen, L., Wang, C., Wainger, B. M., Jin, P., Mao, J., Feng, G., Harnett, M., Shen, S.. 2022-10-04. Highly synchronized cortical circuit dynamics mediate spontaneous pain. https://doi.org/10.1101/2022.10.04.510722

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