Hyperactive lateral habenula mediates the comorbidity between rheumatoid arthritis and depression-like behaviors

Objective: The aim of this study was to identify the neural and molecular mechanisms underlying the comorbidity of rheumatoid arthritis (RA) and depression. Methods: A cohort of 200 RA patients were recruited to quantitatively assess the association between depressive symptoms and RA disease activity, as well as quality of life. The collagen antibody-induced arthritis (CAIA) mouse model of RA was used to screen for brain regions that showed changes in c-FOS expression, an indicator of alteration in brain activity, accompanying the appearance of depression-like behaviors. RNA sequencing, immunostaining, AAV-mediated expression, micro-CT, plasma cytokines/chemokines measurements and histological analyses were applied to evaluate the contribution of the identified brain region in the disease progression of RA and depression-like symptoms. Results: In this study, we showed that in RA patients, the depression scores were significantly correlated with the severity and quality of life of the patients. The CAIA mice developed RA symptoms, together with depression-like behaviors accompanied by hyperactivity and alterations in gene expression reflecting cerebrovascular disruption in the lateral habenula (LHb), a brain region processing negative valence. Importantly, inhibition of the LHb outputs not only alleviated depression-like behaviors, but also resulted in rapid remission of RA symptoms and reduction in sympathetic nerve fibers in the synovial joints of the CAIA mice.Conclusion: Our study highlights a critical but previously overlooked contribution of hyperactive LHb to the comorbidity between RA and depression, suggesting that targeting LHb in conjunction with RA treatments may be a promising strategy for RA patients comorbid with depression.