Temporal Transcriptomic Changes in the Cingulate Cortex of Neuropathic Pain Mice

Background: Neuropathic pain (NP), a debilitating condition resulting from nervous system lesions, is poorly managed by current therapies. The cingulate cortex is crucial for affective pain processing, yet a comprehensive spatiotemporal understanding of its molecular changes in NP is lacking. Methods: We performed RNA sequencing to profile transcriptomic alterations in the anterior cingulate (ACC) and midcingulate (MCC) cortices of mice at two and four weeks after spared nerve injury. Bioinformatics analyses, including differential expression, functional enrichment, weighted gene co-expression network analysis, and protein-protein interaction (PPI) network construction, were employed. Results: We identified widespread, time-dependent transcriptional dysregulation in both regions, with differentially expressed genes increasing over time. Functional analyses confirmed central roles for synaptic plasticity and neuroinflammatory pathways, and further identified pathways related with neurodegeneration and mitochondrial dysregulationin NP pathogenesis. Subregion analysis revealed that the ACC exhibited broader pathway alterations than the MCC, including neuroinflammation (early phase) and mitochondrial dysfunction/neurodegeneration (late phase), indicating a progressive stress response unique to the ACC. PPI analysis identified stage-specific hub genes (e.g., early interferon-stimulated genes and late ribosomal proteins in ACC; persistent extracellular matrix components in MCC). Conclusions: This study provides a detailed transcriptomic atlas of the cingulate cortex in NP, reinforcing known synaptic and neuroinflammatory mechanisms, and suggests a possible role of mitochondrial dysregulation in NP pathogenesis. The findings provide a basis for further mechanistic studies.