Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B-/- mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.

中文翻译：

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表达 D1 的细胞类型中 GluN2B 的遗传缺失增强了长期可卡因奖赏和丘脑伏隔突触的增强。


伏隔核 (NAc) 中含有 GluN2B 的 NMDA 受体 (R) 的瞬时上调被认为是与持续性可卡因相关行为相关的中长期 AMPAR 可塑性。然而，GluN2B 对可卡因持久作用的细胞类型和输入特异性贡献仍有待阐明。我们利用 GluN2B 细胞类型特异性敲除和光遗传学来解构 GluN2B 在可卡因诱导的 NAc 突触和行为可塑性中的作用。虽然奖励学习不受影响，但 D1 多巴胺受体表达细胞 (D1) 中 GluN2B 的缺失导致奖励记忆的保留时间延长。在对照小鼠中，前额皮质（PFC）-D1（+）NAc AMPAR功能不受可卡因暴露的影响，而中线丘脑（mThal）-D1（+）NAc AMPAR功能增强，但在戒断后减弱。在 D1-GluN2B-/- 小鼠中，mThal-D1(+) NAc AMPAR 功能的增强在戒断后持续存在，这与可卡因奖赏行为的持续表达相对应。这些数据表明，含有 NAc GluN2B 的 NMDAR 具有反馈作用，可能会削弱与奖励相关的记忆。