Both clinical and animal studies showed that the impaired functions of the orbitofrontal cortex (OFC) underlie the compulsive drug-seeking behavior of drug addiction. However, the functional changes of the microcircuit in the OFC and the underlying molecular mechanisms in drug addiction remain elusive, and little is known for whether microcircuits in the OFC contributed to drug addiction-related behaviors. Utilizing the cocaine-induced conditioned-place preference model, we found that the malfunction of the microcircuit led to disinhibition in the OFC after cocaine withdrawal. We further showed that enhanced Somatostatin-Parvalbumin (SST-PV) inhibitory synapse strength changed microcircuit function, and SST and PV inhibitory neurons showed opposite contributions to the drug addiction-related behavior of mice. Brevican of the perineuronal nets of PV neurons regulated SST-PV synapse strength, and the knockdown of Brevican alleviated cocaine preference. These results reveal a novel molecular mechanism of the regulation of microcircuit function and a novel circuit mechanism of the OFC in gating cocaine preference.

临床和动物研究均表明，眶额皮质（OFC）功能受损是吸毒成瘾的强迫性寻药行为的基础。然而，OFC中微电路的功能变化以及药物成瘾的潜在分子机制仍然难以捉摸，并且对于OFC中的微电路是否有助于药物成瘾相关行为知之甚少。利用可卡因诱导的条件性位置偏好模型，我们发现微电路故障导致可卡因戒断后 OFC 的去抑制。我们进一步表明，增强的生长抑素-小白蛋白（SST-PV）抑制性突触强度改变了微电路功能，并且SST和PV抑制性神经元对小鼠药物成瘾相关行为表现出相反的贡献。 PV 神经元神经周围网络的 Brevican 调节 SST-PV 突触强度，并且 Brevican 的敲低减轻了可卡因偏好。这些结果揭示了微电路功能调节的新分子机制和 OFC 控制可卡因偏好的新电路机制。