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题名	多巴胺系统损伤对猕猴奖赏、运动控制以及空间工作记忆的影响
作者	晏婷
学位类别	博士
答辩日期	2014-05
授予单位	中国科学院研究生院
授予地点	北京
导师	马原野,胡新天
关键词	多巴胺系统 诱因凸显假说 帕金森病 工作记忆 单光子发射计算机断层成像术
其他题名	Effects of impaired dopamine systems on reward, motor control and spatial working memory in rhesus monkeys
学位专业	神经生物学
中文摘要	脑内多巴胺系统参与调节个体的奖赏、运动和认知功能。当个体在获得奖励时，他会产生相应的愉悦感，同时学习与奖励相关的环境和线索。当奖励或者相关线索再次出现时，个体会产生想要获取该奖励的渴望，并做出一系列行为来获取奖励。这些愉悦感、学习和渴望共同构成了奖赏效应。有研究表明多巴胺系统参与奖赏效应的调控，但是多巴胺系统在奖赏效应中起何种作用，是参与了整个奖赏效应还是只调节其中的某个组成部分？先后有许多研究者对这个问题进行了研究，并分别提出了“快感假说”、学习假说和“诱因凸显假说”。最早被提出也是接受度最高的是“快感假说”。该假说认为多巴胺调节个体的愉悦感，当多巴胺缺失时，个体对奖励的愉悦体验将下降。学习假说则认为多巴胺调节个体对奖励相关线索的学习能力。但是这两个假说受到其他研究者的质疑。他们提出的“诱因凸显假说”认为多巴胺并不影响快感和学习，只调节渴望。那么多巴胺系统的损伤是否只影响渴望，该系统在多大程度上参与调节奖赏效应，本文就这些问题展开研究。 通过对三组脑内多巴胺缺失程度不同的猕猴的吗啡条件位置性偏好研究，我们首次在猕猴上观察到，中度损伤猕猴多巴胺系统不影响奖赏效应的任何组成部分，但是重度损伤多巴胺系统会降低猕猴对吗啡的渴望，而快感和学习能力不受到影响。这些结果表明，猕猴多巴胺系统可能并不参与奖赏效应的快感和学习成分，它只影响渴望成分。此外，本研究还进一步提示奖赏效应的调节并不需要一个完整的多巴胺系统。只有在多巴胺系统重度损伤的情况下才会对奖赏效应产生显著影响，因为多巴胺系统中度损伤的个体能够对奖励产生与正常个体相同的奖赏效应。 除了奖赏效应，本文还研究了在多巴胺系统损伤的情况下，猕猴运动和认知功能的变化情况。有研究表明多巴胺系统损伤的猕猴会出现帕金森病运动症状，帕金森病经典药物左旋多巴主要缓解其中的运动迟缓症状。本研究首次发现能够提高脑内多巴胺水平的吗啡对帕金森病运动症状也具有一定的治疗作用，主要体现在缓解震颤上面。吗啡与左旋多巴的不同治疗效果进一步支持多巴胺系统损伤所引起的运动迟缓和震颤症状可能存在不同的发病机制。在多巴胺系统损伤与认知功能的研究中，此前的研究表明在运动症状出现前，猕猴的空间工作记忆能力就受到了多巴胺系统损伤的影响。本研究表明这种空间工作记忆能力与纹状体内多巴胺含量具有一定的相关性。 总之，本文的实验结果一致支持多巴胺系统在奖赏、运动和认知中起重要的作用，但是多巴胺系统在其中的具体作用和相关神经通路还需要进一步的实验验证。
英文摘要	Brain dopamine system has the ability to modulate an individual’s rewarding effects, motor and cognitive functions. The rewarding effects contain three components: the hedonic effects of reward an individual experienced (pleasure), the learning ability the individual used to associate pleasure with a specific environment (learning), and the incentive salience which makes the reward more attractive and motivates the individual to obtain the reward (motivation). Research using diverse methods have converged to the point that dopamine (DA) system is important to rewarding effects. And three hypotheses have been proposed to explain the role of dopamine system in rewarding effects: the hedonia hypothesis, the reward learning hypothesis and the incentive salience hypothesis. The most popular hypothesis is the hedonia hypothesis which suggests that dopamine system modulates the pleasure produced by reward. The learning hypothesis suggests that dopamine modulates the associations between the reward-related stimuli and the responses at the moment reward occurs. However, in the incentive salience hypothesis, dopamine only modulates motivation. The causal contribution of dopamine system in rewarding effects remains controversial. In this paper, we aim to find out which component of reward is modulated by dopamine and how many dopaminergic neurons are involved in the modulation. The conditioned place preference study demonstrated that the moderately impaired dopamine system would not affect any component of rewarding effects. However, severely impaired dopamine system would cause less motivation while hedonic impact and learning remained uninfluenced. Combined with previous studies, dopamine may not involved in reward hedonia or reward learning and memory, it only modulates motivation. This study also suggested that an intact dopamine system was not necessary to cause rewarding effects, an moderately impaired dopamine system was sufficient to rescue a normal reward in monkeys. In addition to the study of rewarding effects, the changes of motor and cognitive functions under an impaired dopamine system were also studied. Previous studies showed that dopamine-deficient monkeys displayed parkinsonian symptoms and L-Dopa, the most effective therapy, could alleviate some parkinsonian symptoms (such as bradykinesia). In this study, morphine, which had the ability to elevate brain dopamine levels, was found some beneficial effects on tremor. The different therapeutic effects between morphine and L-Dopa suggest the different pathogenesis between bradykinesia and tremor. The previous studies of the interactions between dopamine system and cognition showed that the impaired dopamine system induced spatial working memory dysfunction pre-dates motor dysfunction. In this study, the spatial working memory dysfunction was found to correlate with striatum dopamine levels. All the experiments consistently support that dopamine system is important to rewarding effects, motor and cognitive functions. However, more experiments are needed to investigate the precise role of dopamine system in these functions and the related neural bases.
语种	中文
公开日期	2014-06-18
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/7900]
专题	昆明动物研究所_认知障碍病理学 昆明动物研究所_神经系统编码
推荐引用方式 GB/T 7714	晏婷. 多巴胺系统损伤对猕猴奖赏、运动控制以及空间工作记忆的影响[D]. 北京. 中国科学院研究生院. 2014.

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