Transcriptomic signatures of the insular cortex in a mouse model of neuropathic pain.

BACKGROUND

Neuropathic pain (NP) remains poorly managed by current therapies. Although the insular cortex (IC) is critical for cortical pain processing, a comprehensive spatiotemporal molecular characterization of the IC in NP is lacking.

METHODS

We employed RNA sequencing of the anterior (aIC) and posterior (pIC) insular cortices at 2 and 4 weeks following spared nerve injury in mice. Integrative bioinformatics analyses-including differential expression, functional enrichment, weighted gene co-expression network analysis, and protein-protein interaction (PPI) network construction-were used to delineate the molecular landscape.

RESULTS

Widespread transcriptional dysregulation in the IC was observed, with the number of differentially expressed genes increasing over time. Functional analyses reaffirmed involvement of neuroinflammation and synaptic plasticity-related pathways and further identified dysregulation of mitochondrial pathways-mechanisms commonly implicated in neurodegenerative disorders. Subregion analysis revealed that the aIC exhibited broader and more persistent pathway alterations than the pIC, including programmed cell death (early phase), mitochondrial dysfunction/neurodegeneration (late phase), indicating a progressive stress response unique to the aIC. PPI network analysis identified stage-specific hub genes: early-phase interferon-stimulated genes predominated in both subregions; late-phase hub genes included circadian rhythm regulators, ER stress markers and inflammatory mediators.

CONCLUSION

This study presents a detailed transcriptomic profile of the IC in NP, revealing region- and time-dependent remodeling. Our results confirm known mechanisms and uncover dysregulation reminiscent of neurodegenerative disorders-predominantly in the aIC, suggesting its heightened susceptibility to pain-induced pathology. These findings expand our understanding of IC-mediated pathophysiological processes in NP and may provide a framework for identifying novel therapeutic targets for chronic pain.