Center for Alcohol Research in Epigenetics, Department of Psychiatry, University of Illinois at Chicago, Chicago, Illinois, USA.
Addict Biol. 2020 Nov;25(6):e12821. doi: 10.1111/adb.12821. Epub 2019 Aug 21.
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.
酒精使用障碍最恶劣的特征之一是尽管有负面后果仍强迫性饮酒。脑岛控制着风险或冲突条件下的决策。皮质活动受到抑制性中间神经元的严格控制，这些神经元通常被称为周围神经网 (PNN) 的特殊细胞外基质结构包围，它们调节神经元兴奋性和可塑性。重复狂饮后，脑岛中的 PNN 密度增加，这表明它们可能在从社交性到强迫性或厌恶抵抗性饮酒的转变中发挥作用。在这里，我们使用一种将苦味剂奎宁掺入乙醇的小鼠模型，研究了脑岛 PNN 是否在厌恶抵抗性饮酒中发挥作用。破坏脑岛中的 PNN 使小鼠对奎宁掺假的乙醇更敏感，但对单独的乙醇不敏感。在厌恶抵抗性饮酒期间，通过 c-fos 表达测量到脑岛的激活，并且通过消除 PNN 进一步增强。这些结果表明，PNN 控制着厌恶抵抗性饮酒期间脑岛的激活，并表明在冲突条件下适当的兴奋/抑制平衡对于决策很重要。破坏脑岛中的 PNN 或优化脑岛激活可能是减少厌恶抵抗性饮酒的一种新策略。
