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可卡因环境相关奖赏记忆提取激活伏隔核中央核和杏仁核基底外侧核神经元

王隽, 姚文青, 陈跃军, 马兰, 陶冶铮^*

复旦大学上海医学院医学神经生物学国家重点实验室，药理研究中心，脑科学研究院，上海 200032

摘要

奖赏刺激和伴药环境之间的强烈关联记忆，使得成瘾者在戒除药物数月或数年后暴露于类似环境即可诱发复吸。研究成瘾记忆的神经生物学基础有重要意义。本研究以可卡因条件位置偏爱(conditioned place preference, CPP)实验为行为学模型模拟分析药物与环境之间关联的建立。c-Fos、Zif268是常用的反映神经元活动增加的即早基因标记物。本文旨在通过采用免疫组织荧光染色方法，对可卡因环境相关的奖赏记忆提取后小鼠各脑区c-Fos、Zif268表达进行定量，比较分析它们的表达差异，以此来观察环境相关奖赏记忆提取时不同脑区神经元的激活情况。C57BL/6小鼠分为三组：生理盐水提取组、可卡因环境相关奖赏记忆提取组以及可卡因未提取组。后两组均接受CPP训练(一侧为伴可卡因侧，另一侧为伴生理盐水侧)，训练结束后可卡因环境相关奖赏记忆提取组提取相关记忆，可卡因未提取组不提取。生理盐水提取组在放入CPP箱两侧前均腹腔注射生理盐水。结果显示，在药物成瘾相关脑区伏隔核核部，可卡因环境相关奖赏记忆提取组c-Fos、Zif268蛋白表达量显著高于生理盐水提取组。可卡因环境相关奖赏记忆提取组杏仁核基底外侧核Zif268蛋白表达量显著高于生理盐水提取组。在中脑边缘多巴胺系统的其他相关脑区如前额叶皮层、海马等，各组间c-Fos、Zif268蛋白表达量并未观察到明显的差异。以上结果表明伏隔核中央核和杏仁核基底外侧核在可卡因环境相关奖赏记忆提取过程中被激活，这提示伏隔核中央核和杏仁核基底外侧核脑区内激活的神经元是可卡因环境相关奖赏记忆的重要神经基础，为进一步解析药物成瘾记忆机制打下了基础。

关键词： 环境相关奖赏记忆; c-Fos; Zif268; 伏隔核核部; 杏仁核基底外侧核

分类号：R964

[Neurons in NAc core and BLA are activated during cocaine context-associated reward memory retrieval in mice.] [Article in Chinese]

WANG Jun-Jun, YAO Wen-Qing, CHEN Yue-Jun, MA Lan, TAO Ye-Zheng^*

The State Key Laboratory of Medical Neurobiology and Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China

Abstract

The intense associative memories that develop between cocaine-paired contexts and rewarding stimuli make addiction hard to cure by contributing to cocaine seeking and relapse. So it’s of great importance to examine the neurobiological basis of addiction memory. Cocaine conditioned place preference (CPP) used in this study is a form of Pavlovian conditioning which can establish associations between drug and contextual factors. c-Fos and Zif268 are commonly used immediate early gene (IEG) makers to identify neurons that are activated after a stimulus or behavioral conditioning. This study was designed to reveal neuronal c-Fos, Zif268 expression pattern in 10 brain regions following cocaine context-associated reward memory retrieval in mice, combining animal behavioral study and immunofluorescence method. C57BL/6 mice were randomly divided into 3 groups: Saline retrieval, Cocaine retrieval, and No retrieval of cocaine groups. Cocaine retrieval and No retrieval of cocaine underwent CPP training (one side paired with cocaine, and the other side with saline) except that No retrieval of cocaine group didn’t undergo CPP test. Saline retrieval group received saline injections (i.p) on both sides. The results showed that: Neuronal c-Fos, Zif268 protein expression levels in nucleus accumbens (NAc) core both were elevated in Cocaine retrieval group compared with those in Saline retrieval (Control) group during cocaine context-associated reward memory retrieval. Zif268 protein expression level in basolateral amygdala (BLA) was also elevated in Cocaine retrieval group compared with that in control mice. Elevation was not seen in other regions such as hippocampus, prefrontal cortex (PFC). Thus, NAc core and BLA were activated during cocaine context-associated reward memory retrieval. The results suggest that neurons that are activated in NAc core and BLA are crucial basis of cocaine context-associated reward memory.

Key words: context-associated reward memory; c-Fos; Zif268; NAc core; BLA

收稿日期：2014-04-11　　录用日期：2014-05-14

通讯作者：陶冶铮　　E-mail: 071101066@fudan.edu.cn

引用本文：

王隽, 姚文青, 陈跃军, 马兰, 陶冶铮. 可卡因环境相关奖赏记忆提取激活伏隔核中央核和杏仁核基底外侧核神经元[J]. 生理学报 2014; 66 (5): 545-558.

WANG Jun-Jun, YAO Wen-Qing, CHEN Yue-Jun, MA Lan, TAO Ye-Zheng. [Neurons in NAc core and BLA are activated during cocaine context-associated reward memory retrieval in mice.] [Article in Chinese]. Acta Physiol Sin 2014; 66 (5): 545-558 (in Chinese with English abstract).