Perineuronal nets in the insula regulate aversion‐resistant alcohol drinking

One of the most pernicious characteristics of alcohol use disorder is the compulsion to drink despite negative consequences. The insular cortex controls decision making under conditions of risk or conflict. Cortical activity is tightly controlled by inhibitory interneurons that are often enclosed by specialized extracellular matrix structures known as perineuronal nets (PNNs), which regulate neuronal excitability and plasticity. The density of PNNs in the insula increases after repeated bouts of binge drinking, suggesting that they may play a role in the transition from social to compulsive, or aversion‐resistant, drinking. Here, we investigated whether insular PNNs play a role in aversion‐resistant alcohol drinking using a mouse model in which ethanol was adulterated with the bitter tastant quinine. Disrupting PNNs in the insula rendered mice more sensitive to quinine‐adulterated ethanol but not ethanol alone. Activation of the insula, as measured by c‐fos expression, occurred during aversion‐resistant drinking and was further enhanced by elimination of PNNs. These results demonstrate that PNNs control the activation of the insula during aversion‐resistant drinking and suggest that proper excitatory/inhibitory balance is important for decision making under conditions of conflict. Disrupting PNNs in the insula or optimizing insula activation may be a novel strategy to reduce aversion‐resistant drinking