Oxytocin inhibits methamphetamine-associated learning and memory alterations by regulating DNA methylation at the Synaptophysin promoter
Oxytocin inhibits methamphetamine-associated learning and memory alterations by regulating DNA methylation at the Synaptophysin promoter
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DOI：
10.1111/adb.12697
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发表时间：
2020-01-01
影响因子：
3.4
通讯作者：
Wu, Chun-Fu
中科院分区：
文献类型：
--
作者：
Fan, Xin-Yu;Yang, Jing-Yu;Wu, Chun-Fu
甲基苯丙胺（METH）导致记忆改变，但其潜在机制知之甚少。表观遗传机制，包括DNA甲基化，可能会导致大脑中的突触变化。催产素（OT）在学习和记忆中起着重要作用，但OT对MET相关记忆变化的影响知之甚少。在这里，我们探讨了OT在MET诱导的表观遗传改变中的作用，这些表观遗传改变是空间和认知记忆变化的基础。METH（2.0 mg/kg，i.p.）对雄性C57 BL/6小鼠每隔一天施用一次，持续8天。OT（2.5 μ g，i.c.v.）或在METH之前给予aCSF。空间和认知记忆进行了评估。在髋关节和PFC，突触结构和蛋白质进行了检查，DNA甲基转移酶（DNMTs）和甲基CpG结合蛋白2（MECP 2）的水平进行了测定，并在突触素（Syn）启动子的DNA甲基化状态进行了评估。METH增强空间记忆，减少突触长度，下调DNMT 1，DNMT 3A，DNMT 3B和MECP 2，并诱导Hip中Syn启动子的DNA低甲基化。相比之下，METH降低认知记忆，增加突触厚度，上调DNMT 1，DNMT 3A和MECP 2，并诱导PFC中Syn启动子的DNA超甲基化。OT预处理特异性改善了METH诱导的学习和记忆改变，使突触结构正常化，并通过调控DNMT和MECP 2来逆转Hip和PFC中Syn启动子DNA甲基化状态的改变，DNA甲基化是一个重要的基因甲基苯丙胺诱导的学习和记忆改变的调节机制。OT可能被用来专门操纵与METH相关的记忆变化。
Methamphetamine (METH) causes memory changes, but the underlying mechanisms are poorly understood. Epigenetic mechanisms, including DNA methylation, can potentially cause synaptic changes in the brain. Oxytocin (OT) plays a central role in learning and memory, but little is known of the impact of OT on METH-associated memory changes. Here, we explored the role of OT in METH-induced epigenetic alterations that underlie spatial and cognitive memory changes. METH (2.0 mg/kg, i.p.) was administered to male C57BL/6 mice once every other day for 8 days. OT (2.5 mu g, i.c.v.) or aCSF was given prior to METH. Spatial and cognitive memory were assessed. In Hip and PFC, synaptic structures and proteins were examined, levels of DNA methyltransferases (DNMTs) and methyl CpG binding protein 2 (MECP2) were determined, and the DNA methylation status at the Synaptophysin (Syn) promoter was assessed. METH enhanced spatial memory, decreased synapse length, downregulated DNMT1, DNMT3A, DNMT3B, and MECP2, and induced DNA hypomethylation at the Syn promoter in Hip. In contrast, METH reduced cognitive memory, increased synapse thickness, upregulated DNMT1, DNMT3A, and MECP2, and induced DNA hypermethylation at the Syn promoter in PFC. OT pretreatment specifically ameliorated METH-induced learning and memory alterations, normalized synapse structures, and regulated DNMTs and MECP2 to reverse the DNA methylation status changes at the Syn promoter in Hip and PFC. DNA methylation is an important gene regulatory mechanism underlying METH-induced learning and memory alterations. OT can potentially be used to specifically manipulate METH-related memory changes.