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.

Migraine is a common primary headache which seriously affects the quality of patients' life due to the high prevalence and disability rate. Recent years a large number of studies have found that temperature is directly bound to migraine and migraine patients in cold regions have higher prevalence, different manifestations and poor response to the conventional therapy. We propose in this review article a new concept of migraine in cold regions on the basis of geography and summarize the research advances on the pathogenesis of migraine in cold regions to provide conceptual basis for the clinical diagnosis and treatment of this disease entity.