Role of the anterior agranular insular cortex in the modulation of fear and anxiety

The insular cortex, anatomically close to amygdala, is also an integrative hub for sensory, emotional and cognitive function. Growing body of evidences suggest that alterations in insular structure and function have also been implicated in anxiety disorders. However, the reciprocal connections and precise subdivision of insular cortex involved in anxiety activities remains mechanistically unclear. In the present study, using anterograde and retrograde tracing methods, we verified that the anterior (AIa) but not posterior (AIp) agranular insular cortex is a major source of projections to the amygdala. Consistently, excitotoxic lesions only in AIa induced the anxiolytic behaviors and impaired fear memory. Using optogenetics methods, we found that selectively photoactivation of AIa GABAergic neurons remarkably promoted cued fear extinction and relieved anxiety in PSTD mice model. Finally, the participation of Ala in the storage of learned fear is also supported by the abolished LTP after fear conditioning and decreased the cued freezing using protein synthesis inhibitor immediately following training. Our results underscore the importance of AIa in fear and anxiety behavior and suggest that the Ala might share functions and interaction with amygdala in in anxiety related disorders.