Circular RNA signatures in vestibular migraine and migraine from cold regions: Preliminary mechanistic insights

Background: Vestibular migraine (VM) is a common disorder characterized by recurrent dizziness or vertigo, often aggravated by cold exposure. This study aimed to identify differentially expressed circular RNAs (circRNAs) in cold-region VM and explore the underlying molecular mechanisms. Methods: Peripheral blood samples from long-term residents of Heilongjiang Province profiled by circRNA microarray, and differentially expressed circRNAs were validated by quantitative reverse transcription polymerase chain reaction (qRTPCR). A competing endogenous RNA (ceRNA) network and enriched pathways were inferred by bioinformatics. A VM-like mouse model was established using nitroglycerin (NTG) and kainic acid (KA) and confirmed by behavioral testing and western blot. The hsa_circ_0003201/miR-31-5p/triggering receptor expressed on myeloid cells 2 (TREM2) axis and related pathways were examined in clinical samples and in the trigeminal nucleus caudalis (TNC) and vestibular nuclei (VN) of mice using qRTPCR, enzyme-linked immunosorbent assay (ELISA), and western blot. CircRNA microarray profiling also compared expression patterns between VM and migraine patients. Results: Hsa_circ_0003201 was significantly upregulated in cold-region VM patients. Bioinformatic analyses revealed that hsa_circ_0003201 may regulate the miR-31-5p/TREM2 axis and be associated with phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling, pyruvate metabolism, and transient receptor potential (TRP) pathways. Clinical validation confirmed increased hsa_circ_0003201 and TREM2 and decreased miR-31-5p. VM-like mice exhibited central sensitization and vestibular dysfunction, with increased TREM2, decreased miR-31-5p, and PI3K/AKT activation in the TNC and VN. Comparative circRNA analysis between VM and migraine patients indicated distinct expression patterns. Conclusion: Hsa_circ_0003201 shows potential as a diagnostic biomarker for cold-region VM, and the hsa_circ_0003201/miR-31-5p/TREM2 axis may contribute to pathogenesis through PI3K/AKT signaling, pyruvate metabolism, and TRP-related pathways.