Liu Guan-Xi, Wei Jia-You, Liu Meng, Shi Wen-Jing, Song Liang-Huan, Li Shang, Zhu Shi-Qi, Xin Wen-Jun, Zhang Xue-Qin
The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), Guangzhou 510370, China; School of Health Management, Guangzhou Medical University, Guangzhou 510182, China.
The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China.
Brain Behav Immun. 2020 Feb;84:72-79. doi: 10.1016/j.bbi.2019.11.009. Epub 2019 Nov 18.
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.
条件性位置偏爱（CPP）是一种习得行为，在此行为中动物学会将环境背景与奖赏效应联系起来。CPP的形成是多个学习过程的综合结果。尽管已经提出了这种背景学习的多种解剖学基质，但CA1区内特定的分子信号通路是否介导与吗啡条件作用相关的背景学习仍不清楚。在这里，我们表明与吗啡条件作用相关的重复背景学习显著增加了海马CA1神经元中CXCL12的水平，并且抑制CXCL12的表达改善了在与吗啡条件作用相关的背景暴露后的CPP行为。此外，与吗啡条件作用相关的重复背景暴露增加了CA1区表达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，与吗啡条件作用相关的重复背景暴露增加了STAT3与CXCL12基因启动子的结合以及STAT3与p300之间的相互作用，这通过增加CXCL12基因启动子中组蛋白H4的乙酰化促进了CXCL12的转录增强。鞘内注射S3I-201抑制STAT3可抑制组蛋白H4的乙酰化。这些数据证明了与吗啡条件作用相关的重复背景暴露后CXCL12的表观遗传上调，这可能有助于与吗啡条件作用诱导的条件性位置偏爱相关的空间记忆巩固。
