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Thalamocortical Circuit Controls Neuropathic Pain via Up-regulation of HCN2 in the Ventral Posterolateral Thalamus

 Yi Yan1,2,3  · Mengye Zhu1,2,3 · Xuezhong Cao1,2,3 · Gang Xu1,2,3 · Wei Shen1,2,3 · Fan Li1,2,3 · Jinjin Zhang1,2,3 · Lingyun Luo1,2,3 · Xuexue Zhang1,2,3 · Daying Zhang1,2,3 · Tao Liu4
1 Department of Pain Medicine, The First Afliated Hospital of Nanchang University, Nanchang 330006, China 
2 Institute of Pain Medicine, Jiangxi Academy of Clinical and Medical Sciences, Nanchang 330006, China 
3 Key Laboratory of Neuropathic Pain, Healthcare Commission of Jiangxi Province, Nanchang 330006, China 
4 Center for Experimental Medicine, the First Afliated Hospital of Nanchang University, Nanchang 330006, China

Abstract

The thalamocortical (TC) circuit is closely associated with pain processing. The hyperpolarization-activated cyclic nucleotide-gated (HCN) 2 channel is predominantly expressed in the ventral posterolateral thalamus (VPL) that has been shown to mediate neuropathic pain. However, the role of VPL HCN2 in modulating TC circuit activity is largely unknown. Here, by using optogenetics, neuronal tracing, electrophysiological recordings, and virus knockdown strategies, we showed that the activation of VPL TC neurons potentiates excitatory synaptic transmission to the hindlimb region of the primary somatosensory cortex (S1HL) as well as mechanical hypersensitivity following spared nerve injury (SNI)-induced neuropathic pain in mice. Either pharmacological blockade or virus knockdown of HCN2 (shRNA-Hcn2) in the VPL was sufficient to alleviate SNI-induced hyperalgesia. Moreover, shRNA-Hcn2 decreased the excitability of TC neurons and synaptic transmission of the VPL–S1HL circuit. Together, our studies provide a novel mechanism by which HCN2 enhances the excitability of the TC circuit to facilitate neuropathic pain.


Keywords
Neuropathic pain; Thalamocortical circuit; HCN2 channel; Optogenetics; Electrophysiology