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伏隔核-腹侧苍白球功能去抑制介导戒断后觅药动机的机制
Alternative TitleNucleus accumbens-ventral pallidum dis-inhibition mediate the enhancement of drug-seeking motivation after withdrawal
蒙怡铭
Contributor隋南
2021-06
Abstract研究目的:觅药动机是产生复吸的重要内在原因之一。在一定的戒断时间内,觅药动机随戒断时间延长而持续增强。腹侧苍白球(Ventral Pallidum, VP)负责奖赏动机的编码和转化。但是,VP介导戒断后觅药动机异常强化的作用机制及其亚区的功能特异性尚不明确。戒断后伏隔核(Nucleus Accumbens, NAc)内多巴胺(Dopamine, DA)递质水平下降,继而发生NAc-VP的GABA能通路功能减弱,这可能导致VP神经元功能亢进,从而介导觅药动机增强。因此,本课题建立大鼠可卡因自身给药(Self Administration, SA)模型,并利用断点(Break Point,BP)测试评估觅药动机。在此基础上,采用免疫组织化学方法和在体钙成像技术,比较研究VP的三个功能亚区在戒断后觅药动机增强中的作用,并结合逆向示踪技术进一步明确NAc对VP关键亚区活性的调节功能。然后,化学遗传技术探索NAc-VP投射功能对戒断后觅药动机的影响。该课题的开展有助于深入理解戒断后觅药动机异常的调控机制,为干预复吸提供新的思路。 研究方案:本研究采用大鼠可卡因SA训练模型,进行了如下实验:1)在戒断后的不同时间点,检测觅药动机水平;2)采用免疫组化方法检测VP亚区的c-Fos阳性细胞表达水平,并利用钙成像技术进一步明确VP的关键亚区及其神经元激活状态;3)钙成像和逆向示踪技术明确NAc-VP投射在戒断后的功能改变;4)化学遗传技术验证NAc-VP神经投射功能减弱介导觅药动机的增强。 研究结果: 1)在戒断第14天,大鼠可卡因觅药动机显著增强;2)腹内侧VP(Ventromedial VP, VPvm)和腹外侧VP(ventral lateral VP, VPvl)亚区c-Fos阳性细胞表达水平在戒断后显著增强,钙成像实验表明VPvm神经元在戒断后显著激活;3)钙成像和逆向示踪实验表明NAc-VP神经投射在戒断后功能减弱;4)化学遗传实验表明在戒断前特异性减弱NAc-VP神经投射,觅药动机增强。 实验结论:本研究阐明 VP参与戒断后觅药动机增强具有亚区特异性,NAc-VP投射的功能减弱介导了戒断后觅药动机的强化,并且可能以去抑制的方式发挥调控作用。
Other AbstractObjectives: The drug seeking motivation is one of the most important internal reasons of relapse. During a certain period of withdrawal, drug seeking motivation increases over time. The ventral pallidum (VP) is responsible for the coding and transforming of the reward motivation. However, the mechanisms of how VP-mediated abnormal enhancement of drug seeking motivation after withdrawal and the functional specificity of its subregions are still unclear. After withdrawal, the level of the transmitter-dopamine (DA) in the nucleus accumbens (NAc) decreases, which results to the weakened projection of GABAergic pathway of NAc-VP, and the latter may lead to the hyperfunction of VP neurons, and cause the enhancement of drug-seeking motivation eventually. In this study, we established the cocaine self-administration(SA) model in rats, and used the break point (BP) test to evaluate drug seeking motivation. On the basis of this animal model, we then used immunohistochemical method and in-vivo fiber photometry to detect the roles of the three functional sub-regions of VP in the enhancement of drug seeking motivation after withdrawal, and employed retrograde tracing technology to further clarify the regulatory function of NAc projection to the key VP subregions. Then, we used chemogenetic technology to explore the effect of NAc-VP projection on drug seeking motivation after withdrawal. The implement of this study will help us understand the regulatory mechanism of abnormal drug-seeking motivation after withdrawal, and provide novel ideas to intervene relapse. Methods: In this study, we used the cocaine self-administration model in rats, and we conducted the following experiments: 1) we tested the level of drug seeking behavior at different time points after withdrawal; 2) we used the immunohistochemical method to detect the expression level of c-Fos positive cells in the key subregions of VP, and adopted the fiber photometry recordings of the expression level of Ca2+ to further clarify the subregional specificity and its neuron activation level; 3) we then used the fiber photometry recordings and retrograde tracing technology to clarify the functional change of NAc-VP neural projection; 4 ) at last, we used chemogenetic technology to verify that the weakened NAc-VP neural projection participates in the enhancement of drug-seeking motivation. Results: 1) On the 14th day after withdrawal, the drug seeking motivation in rats was significantly enhanced; 2) The expression level of c-Fos positive cells in ventromedial VP( VPvm) and ventral lateral VP(VPvl) subregions were significantly enhanced after withdrawal. Fiber photometry experiments showed that neurons in the VPvm subregion were significantly activated after withdrawal; 3) Fiber photometry and retrograde tracing experiments showed that NAc-VP neural projection was weakened after withdrawal; 4) The results of chemogenetic experiments showed that specifically inhibit NAc-VP neural projection increase the level of drug seeking motivation. Conclusions: This study clarified that VP neurons participate in the enhancement of drug-seeking motivation after withdrawal with subregional specificity, and the weakened NAc-VP neuronal projection mediates the strengthening of drug-seeking motivation after withdrawal, and this regulation function may work in a dis-inhibitory way.
Keyword觅药动机 戒断 腹侧苍白球 伏隔核 去抑制
Subtype硕士
Language中文
Degree Name理学硕士
Degree Discipline健康心理学
Degree Grantor中国科学院心理研究所
Place of Conferral中国科学院心理研究所
Document Type学位论文
Identifierhttp://ir.psych.ac.cn/handle/311026/39572
Collection健康与遗传心理学研究室
Recommended Citation
GB/T 7714
蒙怡铭. 伏隔核-腹侧苍白球功能去抑制介导戒断后觅药动机的机制[D]. 中国科学院心理研究所. 中国科学院心理研究所,2021.
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