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DNA甲基化在阿片类药物调控情绪环路功能中的作用及其神经机制
Project Number91332115
隋南
Subtype一般项目
Project Source国家自然科学基金
Project Level国家级项目
2013-12-31
End Date2016-12-30
Abstract

成瘾药物导致脑内情绪环路的功能异常是复吸行为反复发作的核心机制之一。新近的研究证据表明,环境事件刺激诱导的DNA甲基化可造成神经元功能和学习记忆等行为的长期改变,提示阿片类药物反复刺激诱导的DNA甲基化可能是导致情绪环路功能异常的重要机制。本课题拟以正性情绪调控通路腹侧被盖区-伏隔核和负性情绪调控通路杏仁核-岛叶为目标,用自身给药(SA)和位置厌恶(CPA)等情绪行为范式,结合DNA甲基化检测、脑片膜片钳、HPLC以及小动物光纤式共聚焦显微成像等方法,探索反复使用阿片类药物对核团DNA甲基化的影响、情绪通路功能的继发性改变以及相应的行为输出效应,并进一步了解其神经递质活动和突触可塑性机制。该项目研究结果将增加环境刺激与DNA甲基化对脑功能影响的认识,增进对情绪环路功能和调控机制的理解。

Other Abstract

Repeated exposure to abusive drugs cause long-term alterations in the affective circuits, which is one of the key drives of relapse. Recently environmental events change neuronal plasticity and learning and memory behaviors via inducing DNA methylation, suggesting that DNA methylation may play a critical role in opiates-induced long-term dysfunction of the affective system. The present study proposes to investigate this hypothesis by examining the effects of repeated morphine-induced self-administration on the levels of DNA methylation in key nuclei of the affective regulation and how the latter affects subsequential behavioral reactions of drug and non-drug stimuli in conditioned place preference or aversion. Further, microdialysis-HPLC study will explore the neurotransmitters mediating the morphine-induced alteration of DNA methylation. In vitro electrophysiological recording of slice and behavior-coupled in vivo fluorescent imaging in awake animals will examine the effect of DNA methylation on plasticity and activation of the nuclei. The present proposal will greatly advance the understanding of the mechanisms of environmentally-induced DNA methylation and its effects on brain function.

 

Keyword吗啡 Dna甲基化 海马 前边缘皮层 成瘾记忆
Other KeywordMorphine ; DNA methylation ; Hippocampus ; Prelimbic cortex ; Addiction related memory
Project Funding70
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Project Intro.

成瘾药物导致脑内情绪环路的功能异常是复吸行为反复发作的核心机制之一。阿片类药物反复刺激诱导的DNA甲基化可能是导致情绪环路功能异常的重要机制。本课题以正性情绪记忆通路海马-伏隔核和负性情绪调控通路杏仁核-岛叶为目标,用自身给药(SA)和位置厌恶(CPA)等情绪行为范式,结合行为药理、免疫组化、DNA甲基化检测以及小动物光纤式共聚焦显微成像等方法,探索反复使用阿片类药物对情绪加工脑区的DNA甲基化的影响,及其在成瘾记忆中的调控机制。研究结果发现:(1)单独吗啡多次暴露不能诱导伏隔核或海马中发生DNA甲基化,吗啡相关的记忆的形成会诱导海马CA1而非伏隔核中发生DNA甲基化的显著上调;(2)海马中的DNA甲基化在吗啡成瘾记忆的获得和巩固中发挥重要作用,前边缘皮层中的DNA甲基化在提取中发挥重要作用,蛋白磷酸酶PP1可能是DNA甲基化调控的关键靶点;(3)基底外侧杏仁核(而非中央杏仁核,或伏隔核)中的DNA甲基化是吗啡成瘾记忆再巩固所必须,DNMT3a和DNMT3b是关键酶,Sox10、GNAS和PIK3R1可能是关键靶基因;(4)吗啡戒断相关负性情绪记忆再巩固阶段,岛叶中AI亚区的DNA甲基化和基底外侧杏仁核都发挥关键作用。以上结果提示,海马CA1、前边缘皮层和基底外侧杏仁核中的DNA甲基化分别调控吗啡相关的奖赏记忆的获得与巩固、提取和再巩固过程,岛叶AI和基底外侧杏仁核共同调控吗啡戒断相关负性情绪记忆的再巩固。DNA甲基化可能是阿片类药物成瘾记忆加工的关键机制。

Document Type项目
Identifierhttp://ir.psych.ac.cn/handle/311026/27177
Collection健康与遗传心理学研究室
Affiliation中国科学院心理研究所
First Author AffilicationInstitute of Psychology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
隋南.DNA甲基化在阿片类药物调控情绪环路功能中的作用及其神经机制.2013.
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