Perineuronal nets in the insular cortex shape salience-related behaviour in diabetes

Diabetes is associated with behavioural abnormalities that reflects changes in functional connectivity in the Central Nervous System (CNS). Brain network activity is shaped by perineuronal nets (PNN), which are condensed structures of extracellular matrix surrounding parvalbumin-positive interneurons. We found that PNN density was reduced in the somatosensory cortex and medial prefrontal cortex, and increased in the insular cortex, amygdala and reticular thalamic nucleus of diabetic mice. Enzymatic degradation of PNNs in the insular cortex did not affect mechanical pain thresholds, or risk-taking behaviour, but corrected abnormalities in the social interaction test and in the Place Escape/Avoidance Paradigm test in diabetic mice. Our findings suggest that diabetes switches salience attribution towards negative values and this is causally related to increases in PNNs in the insular cortex.