Plasticity of neurons in the ventral tegmental area (VTA) is critical for establishment of drug dependence. However, the remodeling of the circuits mediating the transition between positive and negative effect remains unclear. Here, we used neuronal activity-dependent labeling technique to characterize and temporarily control the VTA neuronal ensembles recruited by the initial morphine exposure (morphine-positive ensembles, Mor-Ens). Mor-Ens preferentially projected to NAc, and induced dopamine-dependent positive reinforcement. Electrophysiology and rabies viral tracing revealed the preferential connections between the VTA-projective corticotrophin-releasing hormone (CRH) neurons of central amygdala (CRH^CeA→VTA) and Mor-Ens, which was enhanced after escalating morphine exposure and mediated the negative effect during opiate withdrawal. Pharmacologic intervention or CRISPR-mediated repression of CRHR1 in Mor-Ens weakened the inhibitory CRH^CeA→VTA inputs, and alleviated the negative effect during opiate withdrawal. These data suggest that neurons encoding opioid reward experience are inhibited by enhanced CRH^CeA→VTA inputs induced by chronic morphine exposure, leading to negative effect during opiate withdrawal, and provide new insight into the pathological changes in VTA plasticity after drug abuse and mechanism of opiate dependence.

腹侧被盖区 (VTA) 神经元的可塑性对于建立药物依赖性至关重要。然而，介导正效应和负效应之间转换的回路重塑仍不清楚。在这里，我们使用神经元活动依赖性标记技术来表征和临时控制由初始吗啡暴露（吗啡阳性合奏，Mor-Ens）招募的 VTA 神经元合奏。Mor-Ens 优先投射到 NAc，并诱导多巴胺依赖性正强化。电生理学和狂犬病病毒追踪揭示了中央杏仁核 (CRH ^{CeA→VTA ) 的 VTA 投射促肾上腺皮质激素释放激素 (CRH) 神经元之间的优先联系}) 和 Mor-Ens，它在吗啡暴露增加后得到增强，并在阿片戒断期间介导了负面影响。Mor-Ens 中 CRHR1 的药物干预或 CRISPR 介导的抑制削弱了抑制性 CRH ^CeA→VTA输入，并减轻了阿片戒断期间的负面影响。这些数据表明，编码阿片类药物奖赏体验的神经元受到慢性吗啡暴露诱导的增强 CRH ^CeA→VTA输入的抑制，导致阿片戒断期间的负面影响，并为药物滥用后 VTA 可塑性的病理变化和阿片类药物机制提供了新的见解依赖。