| 题名 | 与奖赏学习记忆相关的神经机制研究 |
| 作者 | 刘畅 |
| 学位类别 | 博士 |
| 答辩日期 | 2012-04 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 马原野 |
| 关键词 | 奖赏性学习记忆 神经环路 多巴胺 体感皮层 条件化位置偏好 |
| 其他题名 | Related Neural Mechanism in Reward Learning and Memory |
| 学位专业 | 神经生物学 |
| 中文摘要 | 学习和记忆是两个相互关联的神经过程。学习是生物依赖于经验来改变自身行为以适应环境的神经活动过程，记忆则是学习到的信息储存和提取的神经活动过程。奖赏性和厌恶性学习记忆能够使动物趋利避害，更好的适应环境。尽管学习记忆的脑机制一直为人们所研究，但仍需要进一步的研究，为我们揭示大脑工作之谜提供一定的实验依据。 在本论文中，第一部分，我将阐述对果蝇奖赏性嗅觉联合学习记忆的神经环路的研究。首先我将介绍果蝇作为研究神经机制的重要模式生物的原因，有关果蝇嗅觉联合学习记忆的研究方法（经典嗅觉条件化）、技术（遗传操控特定神经元的表达），关于嗅觉联合学习记忆神经环路的研究现状，以及我的研究工作：通过基因操作研究多巴胺神经元在果蝇嗅觉奖赏性学习记忆环路中的作用。已有的研究表明，多巴胺在昆虫中介导厌恶性信号，且在细胞水平鉴定了PPL1神经元群和PAM神经元群中的MB-M3神经元完成厌恶强化作用，将惩罚信号分别传递到蘑菇体的垂直叶和水平叶的端部；却一直认为章鱼胺参与奖赏性的学习记忆过程，但是没有细胞水平的鉴定以及奖赏环路的描述。在我们的研究中，通过在自由活动的果蝇上短暂的激活或抑制特定的PAM神经元群（protocerebral anterior medial cluster），我们发现PAM神经元介导奖赏信号的传递。在体钙成像研究结果揭示了这群神经元能够被糖水激活，且激活的程度因饥饿而增加。该研究中，我们第一次阐明：在昆虫中，多巴胺作为一种奖赏性神经递质参与并调控奖赏性学习记忆；鉴定了在奖赏信号通路中发挥作用的特定的多巴胺神经元群，通过dDA1受体将奖赏性信号传递到蘑菇体的水平叶而完成奖赏性的学习记忆；且完善了蘑菇体内的局部神经环路的空间分布特征以及初步揭示了章鱼胺和多巴胺信号通路的关系。 第二部分，药物成瘾是一种特殊而极端的奖赏记忆，也是一直引起关注的社会问题。在本部分中，我将介绍药物成瘾相关记忆研究的行为学范式（条件化位置偏好模型），并结合药理学、脑区局部损伤等方法研究了药物相关记忆的特征，探讨哺乳动物中相关脑区在奖赏性条件化中的作用。该研究发现：吗啡相关记忆的产生过程需要体感皮层的参与，而记忆提取导致渴求的过程需要内感觉皮层的参与。 虽然我们的研究结果揭示了果蝇奖赏学习记忆的部分环路以及哺乳动物中参与吗啡相关记忆的一重要脑区，但完全研究清楚奖赏性学习记忆的脑机制，并找到攻克药物成瘾的治疗方案仍需大量的后续研究。 |
| 英文摘要 | Learning and memory are two corresponding neural processes. Learning is a neural actitivity depending on experience and changing organ’s behaviour to adapt the enviorement.Memory is a neural processing which storages and retrieves learned information. Reward and punishment learning and memory protect animals to approach the benefits and avoid risks for better life. Although researches are exploring the mechanism of the brain work, a large amount of studies are required to reveal the truth in the future. In the first chapter of this thesis, I will explain the research on neural circuits underlying appetitive olfacotory associated learning and memory in Drosophila melanogaster.I will introduce the methods and technics to study the olfactory learning and memory in flies such as classical olfactory conditioning and gene manipulation (i.e., GAL4/UAS system), introduce the current status of studies on neural circuits in olfactory associative learning and memory, and my project: a subset of dopamine neurons signal reward for odour memory. Previous studies revealed that dopamine signals aversive reinforcement in insects, and identified that PPL1 cluster and MB-M3 neurons in PAM convey aversive reinforcement to vertical lobes and tip of horizontal lobes of the mushroom body, respectively. Octopamine was thought to be involved in appetitive learning and memory, but no cellular identification and circuit description. In our study, by transient activation and inactivation of target neurons in intact behaving flies, we show that a group of dopamine neurons in the protocerebral anterior medial (PAM) cluster signals the sugar reward. In vivo calcium imaging revealed that these dopamine neurons are activated by sugar stimulus and the activation is increased in starved flies. Our results highlight the cellular specificity underlying the various roles of dopamine and the importance of spatially segregated local circuits within the mushroom bodies.We identified the specific dopamine cluster neurons tht signal reward to the horizontal lobes of the mushroom body for the first time, and suggested a prelimary relationship between octopamine and dopamine signaling. Drug addiction is a particular and extreme rewarded memory, and a concerned social issue. In the second chapter, I will introduce conditioned place preference model of drug related memory and local leision in the rats’brain as the tools to investigate the characters of drug related memory and the role of corresponding brain area in reward conditioning.We revealed that somatosensory cortices are required for the acquisition of morphine related memory whereas the urge to seek drugs requires the insular cortex. Although our studies have demonstrated neural circuits of reward learning and memory in flies, and one of important brain cortices in morphine related memory formation in rats. However, we can not completely understand the mechanism of reward learning and memory, and solve the drug abuse problems. Thus, lots of works need to be done in future. |
| 语种 | 中文 |
| 公开日期 | 2013-04-22 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7366]  |
| 专题 | 昆明动物研究所_认知障碍病理学 |
| 推荐引用方式 GB/T 7714 | 刘畅. 与奖赏学习记忆相关的神经机制研究[D]. 北京. 中国科学院研究生院. 2012. |
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