Brain Function Activity Changes and Contribution of Neuroinflammatory Factors in Insular Cortex of Mice with Dry Eye-Related Chronic Corneal Pain

Purpose：Chronic corneal pain is the most common symptom of dry eye disease (DED), while the central sensitization mechanisms underlying remain unclear. Methods：Excision of extra orbital lacrimal glands was used to establish dry eye (DE) model. Tear volume measurements, corneal fluorescein staining, corneal hypersensitivity and anxiety behavior were tested after surgery. The amplitude of low-frequency fluctuation (ALFF) by fMRI was used for determining brain functional activity. C-Fos, Brain-derived neurotrophic factor (BDNF), and cytokine levels in corresponding brain regions were tested. Results：Compared to the Sham group, the ALFF signals in the supplemental somatosensory area, secondary auditory cortex, agranular insular cortex, temporal association areas, and ectorhinal cortex brain areas were enhanced in DE group. ALFF signal in the insular cortex was related to corneal hypersensitivity (p < 0.01). C-Fos (P < 0.001), BDNF (P < 0.01), TNF-α, IL-6 and IL-1β (P < 0.05) increased, while IL-10 levels (P < 0.05) decreased in the insular cortex in the DE group. Surgery-induced corneal hypersensitivity and upregulation of inflammatory cytokines, but not anxiety, could be blocked by insular cortex injection of Tyrosine Kinase receptor B (TrkB) agonist cyclotraxin-B (P< 0.01). Conclusions ：This research presents the map of functional brain by ALFF through rs-fMRI associated with chronic corneal pain. BDNF-TrkB signaling-related neuroinflammation in the insular cortex might contribute to dry eye-related chronic corneal pain. This measure could potentially help clinicians improve therapeutic approach to pain control and development of diagnostic approach.