Neuroimmune dysregulation and comorbidity mechanisms of major depressive disorder and migraine.

BACKGROUND: Although major depressive disorder (MDD) and migraine often present together, their comorbidity mechanisms are complex. This study aims to identify potential biomarkers and common mechanisms of MDD-migraine through neuroimmune microenvironment and transcriptome data, which is crucial for understanding its pathogenesis and developing diagnostic and treatment strategies. METHODS: We constructed a dynamic atlas of neural-peripheral immune cells in patients experiencing a MDD-migraine comorbidity. Differentially expressed genes (DEGs) were identified and performed functional enrichment and metabolic analyses of cell types involved in MDD and migraine. Multiple classification models were built by combining single-nucleus RNA sequencing and transcriptome data from patients with MDD to screen hub genes. In addition, cluster, cell communication, and trajectory analyses of major cell types in migraine were performed. Finally, common pathways in MDD-migraine comorbidity were identified. RESULTS: We identified 60,982 and 22, 523 cells in patients with MDD and migraine, respectively. The proportions of oligodendrocytes and excitatory neurons were increased in the MDD group, while that of T cells was significantly increased in the migraine group. DEGs in the MDD and migraine cell types were associated with Rap1 signaling. Metabolic reprogramming was found to involve in the pathological processes of MDD and migraine. Six hub genes were screened using the optimal model: AHI1, NRCAM, PTMA, RABGAP1L, RPL15, and RPL41. T cells were the major cell subpopulation in migraine, and Naive T cells were the starting point of differentiation. Finally, eight common pathways were identified between MDD and migraine. CONCLUSION: This study provides new insights into the pathogenesis of MDD-migraine comorbidity suggesting that the identified key genes and signaling pathways may provide potential targets for the early diagnosis and treatment of the disease.