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Background <p>Chronic migraine is a disabling neurological disorder with complex mechanisms. The trigeminal nucleus caudalis (TNC) is a critical relay in migraine pathogenesis, yet its cellular and molecular underpinnings remain unclear.</p> Methods <p>We applied single-nucleus RNA sequencing (snRNA-seq) to the TNC of a nitroglycerin (NTG)-induced chronic migraine mouse model and controls. Major neuronal classes were annotated, followed by subclustering of GABAergic neurons. We assessed cell-type abundance changes, reconstructed transcriptional trajectories, and applied network- and pathway-level analyses including high-dimensional weighted gene co-expression network analysis (hdWGCNA), pseudotime modeling, and CellChat-based intercellular communication profiling.</p> Results <p>We identified a previously unrecognized GABAergic subpopulation characterized by high Nox4 expression (GABA_Nox4). This subpopulation was significantly reduced in NTG-treated mice compared with controls (<i>p</i> = 0.018), a finding further validated by immunofluorescence staining. hdWGCNA identified a migraine-associated co-expression module enriched in GABA_Nox4 neurons, which was further supported by disease enrichment analysis. Pseudotime analysis showed that GABA_Nox4 neurons diverged into distinct transcriptional states under NTG treatment. Intercellular communication analysis revealed enhanced crosstalk of GABA_Nox4 neurons with astrocytes, endothelial cells, and OPCs in the NTG group, mediated by NTG-enriched ligand–receptor pairs such as Agrn–Dag1, Ncam1–Ncam2, and endothelial-derived Ncam1–L1cam, whereas VEH-specific interactions such as Pdgfa–Pdgfra and Pdgfa–Pdgfrb were diminished.</p> Conclusions <p>Our integrative single-cell analysis identifies GABA_Nox4 neurons as a vulnerable and communication-active GABAergic subpopulation in the TNC that is selectively reduced and transcriptionally reprogrammed in chronic migraine. The disruption of inhibitory signaling and rewiring of ligand–receptor networks highlight this population as a potential cellular driver of migraine pathophysiology and a candidate target for therapeutic intervention.</p>

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Selective loss and transcriptional reprogramming of Nox4+ GABAergic neurons in the trigeminal nucleus caudalis of NTG-induced chronic migraine model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Yunhao Xu,
  • Yiping Deng,
  • Peiyu Wu,
  • Mengke Tian,
  • Chen Liu,
  • Xuyang Liu,
  • Danhua Liu,
  • Yinan Guo,
  • Pengfei Wang,
  • Yuming Xu,
  • Yonggang Wang,
  • Yusheng Li

摘要

Background

Chronic migraine is a disabling neurological disorder with complex mechanisms. The trigeminal nucleus caudalis (TNC) is a critical relay in migraine pathogenesis, yet its cellular and molecular underpinnings remain unclear.

Methods

We applied single-nucleus RNA sequencing (snRNA-seq) to the TNC of a nitroglycerin (NTG)-induced chronic migraine mouse model and controls. Major neuronal classes were annotated, followed by subclustering of GABAergic neurons. We assessed cell-type abundance changes, reconstructed transcriptional trajectories, and applied network- and pathway-level analyses including high-dimensional weighted gene co-expression network analysis (hdWGCNA), pseudotime modeling, and CellChat-based intercellular communication profiling.

Results

We identified a previously unrecognized GABAergic subpopulation characterized by high Nox4 expression (GABA_Nox4). This subpopulation was significantly reduced in NTG-treated mice compared with controls (p = 0.018), a finding further validated by immunofluorescence staining. hdWGCNA identified a migraine-associated co-expression module enriched in GABA_Nox4 neurons, which was further supported by disease enrichment analysis. Pseudotime analysis showed that GABA_Nox4 neurons diverged into distinct transcriptional states under NTG treatment. Intercellular communication analysis revealed enhanced crosstalk of GABA_Nox4 neurons with astrocytes, endothelial cells, and OPCs in the NTG group, mediated by NTG-enriched ligand–receptor pairs such as Agrn–Dag1, Ncam1–Ncam2, and endothelial-derived Ncam1–L1cam, whereas VEH-specific interactions such as Pdgfa–Pdgfra and Pdgfa–Pdgfrb were diminished.

Conclusions

Our integrative single-cell analysis identifies GABA_Nox4 neurons as a vulnerable and communication-active GABAergic subpopulation in the TNC that is selectively reduced and transcriptionally reprogrammed in chronic migraine. The disruption of inhibitory signaling and rewiring of ligand–receptor networks highlight this population as a potential cellular driver of migraine pathophysiology and a candidate target for therapeutic intervention.