Up-regulation of HCN2 channels in a thalamocortical circuit mediates allodynia in mice

Jun-Ma Yu; Rui Hu; Yu Mao; Yingju Tai; Sen Qun; Zhi Zhang; Danyang Chen; Yan Jin

doi:10.1093/nsr/nwac275

Up-regulation of HCN2 channels in a thalamocortical circuit mediates allodynia in mice

Natl Sci Rev. 2022 Nov 30;10(2):nwac275. doi: 10.1093/nsr/nwac275. eCollection 2023 Feb.

Authors

Jun-Ma Yu¹, Rui Hu¹, Yu Mao^{2

3}, Yingju Tai³, Sen Qun⁴, Zhi Zhang³, Danyang Chen³, Yan Jin⁴

Affiliations

¹ Department of Anesthesiology, The Third Affiliated Hospital of Anhui Medical University (The First People's Hospital of Hefei), Hefei 230061, China.
² Department of Anesthesiology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
³ Department of Biophysics and Neurobiology, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China.
⁴ Stroke Center and Department of Neurology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China.

Abstract

Chronic pain is a significant problem that afflicts individuals and society, and for which the current clinical treatment is inadequate. In addition, the neural circuit and molecular mechanisms subserving chronic pain remain largely uncharacterized. Herein we identified enhanced activity of a glutamatergic neuronal circuit that encompasses projections from the ventral posterolateral nucleus (VPL^Glu) to the glutamatergic neurons of the hindlimb primary somatosensory cortex (S1HL^Glu), driving allodynia in mouse models of chronic pain. Optogenetic inhibition of this VPL^Glu→S1HL^Glu circuit reversed allodynia, whereas the enhancement of its activity provoked hyperalgesia in control mice. In addition, we found that the expression and function of the HCN2 (hyperpolarization-activated cyclic nucleotide-gated channel 2) were increased in VPL^Glu neurons under conditions of chronic pain. Using in vivo calcium imaging, we demonstrated that downregulation of HCN2 channels in the VPL^Glu neurons abrogated the rise in S1HL^Glu neuronal activity while alleviating allodynia in mice with chronic pain. With these data, we propose that dysfunction in HCN2 channels in the VPL^Glu→S1HL^Glu thalamocortical circuit and their upregulation occupy essential roles in the development of chronic pain.

Keywords: HCN2 channels; chronic pain; in vivo recordings; neural circuit.