Wu Manqing, Lai Miaojun, Zhou Yiyin, Cheng Yingjie, Shi Sai, Wang Fangmin, Liu Huizhen, Zhao Min, Zhou Wenhua
Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Zhejiang Provincial Key Laboratory of Addiction Research, The affiliated Kangning Hospital of, Ningbo University, Ningbo, P.R. China.
Nat Commun. 2025 Jul 25;16(1):6871. doi: 10.1038/s41467-025-62188-w.
Methamphetamine (METH) addiction involves escalating intake with strong cue reactivity, and high relapse risk, yet its neural mechanism remains unclear. Using c-Fos mapping and machine learning, we identified the claustrum (CLA), a subcortical region reciprocally connected with the anterior cingulate cortex (ACC), as key mediators of both METH taking and seeking in self-administering male rats. Chemogenetic inhibition of CLA suppressed both drug consumption and cue-induced reinstatement, while ACC inhibition selectively reduced drug-seeking. Circuit tracing and manipulation revealed that the CLA-ACC circuit supported drug-taking, whereas the ACC-CLA circuit was specifically recruited during drug-seeking. Activity-dependent labeling showed that ACC ensembles activated by cues overlapped with those engaged during prior drug use. These findings suggest that CLA drives METH reward through the ACC, while the ACC gains cue salience and feeds back to CLA, reinforcing relapse. Targeting this bidirectional CLA-ACC circuit may provide novel therapeutic strategies for treating METH addiction.
甲基苯丙胺（METH）成瘾涉及摄入量不断增加、强烈的线索反应性和高复发风险，但其神经机制仍不清楚。我们通过c-Fos图谱和机器学习，确定了与前扣带回皮质（ACC）相互连接的皮质下区域屏状核（CLA），它是自我给药雄性大鼠中甲基苯丙胺摄取和觅药行为的关键调节因子。对屏状核进行化学遗传学抑制可同时抑制药物消耗和线索诱导的复吸，而抑制前扣带回皮质则选择性地减少觅药行为。神经回路追踪和操控显示，屏状核-前扣带回皮质回路支持药物摄取，而前扣带回皮质-屏状核回路则在觅药过程中被特异性激活。活动依赖标记显示，由线索激活的前扣带回皮质神经元集群与先前药物使用期间参与活动的神经元集群重叠。这些发现表明，屏状核通过前扣带回皮质驱动甲基苯丙胺奖赏，而前扣带回皮质获得线索显著性并反馈到屏状核，增强复发。针对这一双向屏状核-前扣带回皮质回路可能为治疗甲基苯丙胺成瘾提供新的治疗策略。
