Thalamo-cortical Circuit Controls Neuropathic Pain Via HCN2 In The Ventral Posterolateral Thalamus

Neuropathic pain(NP)is a type of pain caused by injury or disease to the somatosensory nervous system.Its key symptoms include allodynia,hyperalgesia,spontaneous pain,and paresthesia.As China has become an aging society,the prevalence of NP increases steadily year by year.According to foreign epidemiological data,the number of NP sufferers in China has already surpassed 100 million.Currently,medications dominate the clinical therapy of NP,although the therapeutic impact is limited,and drug side effects frequently accompany it.Many patients are unable to acquire satisfactory curative results at the tolerable dose.The current treatment of NP is not promising.The main reason for NP dilemma is that the pathophysiology has not been fully elucidated.As a result,a better knowledge of NP’s pathophysiology is critical for improving the clinical therapeutic effectiveness.The thalamus is an important relay station in the brain for spinal dorsal horn.It takes pain signals from the peripheral nervous system and transfers them to the cortex,where it participates in pain coding in different dimensions.Previous studies have shown that the abnormal excitability of thalamocortical(TC)neurons in the ventral posterolateral thalamic nucleus(VPL)is involved in the development of NP.However,how the TC neurons and thalamocortical circuit participate in the pathophysiology of NP remains largely unknown.Previous studies have confirmed that hyperpolarization-activated-cyclic-nucleotide-gated(HCN)channels(especially HCN2 channel).HCN2 channel is mainly expressed in VPL TC neurons.Therefore,we want to know if the aberrant expression and function of the HCN2 channel in VPL TC neurons affects the excitability of TC neurons and the synaptic transmission of thalamocortical circuit in the NP?In order to further explore the above questions,this study used sciatic nerve injury(SNI)as the NP model,and combined behavioral,electrophysiological,optogenetic,molecular biological,immunofluorescence staining,pharmacological block,and virus-mediated knockdown techniques to observe the excitability of VPL TC neurons,and the synaptic transmission of VPL-the hindlimb region of the primary somatosensory cortex(S1HL)circuit in NP.Revealing the molecular and circuit mechanisms of NP,for improving the clinical efficacy of NP has important significance.We found that the excitability of TC neurons was increased after SNI.Optogenetic inhibition of VPL TC neurons was sufficient to reverse SNI-induced mechanical allodynia.In contrast,optogenetic activation of TC neurons exacerbated pain sensitivity in SNI mice.Furthermore,we anatomically confirmed the synaptic transmission of the VPL-S1 HL circuit by the anterograde and retrograde tracer.We used electrophysiology to determine the excitatory monosynaptic transmission of VPL-S1 HL circuit.Besides,the synaptic transmission from VPL to S1 HL was increased in SNI mice.Furthermore,we found that HCN2 channel expression was up-regulated and the hyperpolarization-activated cation current(Ih)amplitude was increased in the VPL after SNI.Pharmacological block as well as virus knockdown of HCN2 channel in VPL TC neurons could alleviate the excitability of TC neurons and SNI-induced hyperalgesia.Importantly,silencing the HCN2 channel in VPL TC neurons decreased their excitability of TC neurons and ectopic synaptic transmission of VPL-S1 HL circuit,and reversed SNI-induced hyperalgesia.Together,our findings unveil the unknown role of HCN2 channel in the thalamocortical circuit and NP from molecular and circuit perspective.This has important implications for understanding the pathophysiology and therapeutic targets of NP.