Conditioned place preference (CPP) is a learned behavior, in which animals learn to associate environmental contexts with rewarding effects. The formation of CPP is an integrated outcome of multiple learning processes. Although multiple anatomical substrates underlying this contextual learning have been proposed, it remains unknown whether a specific molecular signaling pathway within CA1 mediates context learning associated with morphine conditioning. Here, we showed that repeated context learning associated with morphine conditioning significantly increased CXCL12 levels in hippocampal CA1 neurons, and the inhibition of CXCL12 expression ameliorated the CPP behavior following context exposure with morphine conditioning. Additionally, repeated context exposure with morphine conditioning increased the phosphorylation of STAT3 and the acetylation of histone H4 in CXCL12-expressing neurons in CA1. Immunoprecipitation and chromatin immunoprecipitation assays demonstrated that repeated context exposure with morphine conditioning increased the binding of STAT3 to the CXCL12 gene promoter and the interaction between STAT3 and p300, which contributed to the enhanced transcription of CXCL12 by increasing the acetylation of histone H4 in the CXCL12 gene promoter. The inhibition of STAT3 by intrathecal injection of S3I-201 suppressed the acetylation of histone H4. These data demonstrated the epigenetic upregulation of CXCL12 following repeated context exposure with morphine conditioning, which potentially contributed to the spatial memory consolidation associated with conditioned place preference induced by morphine conditioning.

中文翻译：

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海马 CXCL12 的表观遗传上调有助于背景空间记忆相关的吗啡条件反射

条件性位置偏好 (CPP) 是一种学习行为，其中动物学会将环境背景与奖励效果联系起来。CPP的形成是多种学习过程的综合结果。尽管已经提出了这种情境学习背后的多种解剖学底物，但 CA1 内的特定分子信号通路是否介导与吗啡条件反射相关的情境学习仍然未知。在这里，我们表明与吗啡条件反射相关的重复上下文学习显着增加了海马 CA1 神经元中的 CXCL12 水平，并且抑制 CXCL12 表达改善了在吗啡条件化的上下文暴露后的 CPP 行为。此外，重复环境暴露与吗啡条件作用增加了 CA1 中表达 CXCL12 的神经元中 STAT3 的磷酸化和组蛋白 H4 的乙酰化。免疫沉淀和染色质免疫沉淀分析表明，重复环境暴露与吗啡条件化增加了 STAT3 与 CXCL12 基因启动子的结合以及 STAT3 和 p300 之间的相互作用，这通过增加 CXCL12 基因中组蛋白 H4 的乙酰化促进了 CXCL12 的转录发起人。通过鞘内注射 S3I-201 抑制 STAT3 抑制了组蛋白 H4 的乙酰化。这些数据证明了 CXCL12 在重复环境暴露与吗啡条件作用后的表观遗传上调，