Chronic environmental cold stress increases migraine susceptibility associated with regional dysregulation of RBFOX1 and PTPRD in the somatosensory network

Introduction Environmental stressors influence migraine chronification, yet mechanisms linking chronic cold exposure to central sensitization remain unclear. Methods Utilizing a Mendelian randomization framework, we identified genetic associations between occupational cold exposure and increased migraine susceptibility, prioritizing gut microbiota and functional somatosensory brain imaging phenotypes as potential mediators. To explore these in silico predictions in a parallel in vivo context, we evaluated a mouse model subjected to combined physical cold stress and an acute nitroglycerin (NTG) trigger. Results Behaviorally, this dual exposure exacerbated migraine-like mechanical allodynia and spontaneous pain compared to NTG alone. Morphological and molecular analyses revealed significant upregulation of the pain-related neuropeptide CGRP in the trigeminocervical complex of cold-stressed mice. Furthermore, immunofluorescence and biochemical expression profiling demonstrated a selective regional depletion of the RNA-splicing factor RBFOX1 and a distinct overexpression of the synaptic receptor PTPRD within the examined brain parenchyma across the somatosensory network. Discussion Collectively, these translational observations suggest that environmental cold stress alters the regional molecular baseline of sensory networks, potentially lowering the neurological threshold for migraine and highlighting RBFOX1 and PTPRD as specific neurobiological signatures of this susceptibility.