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Dopamine mechanisms underlying bidirectional effects of cue salience on Pavlovian learning

线索显着性对巴甫洛夫学习双向影响的多巴胺机制

基本信息

批准号：
BB/M024148/1
负责人：
Elizabeth Tunbridge
金额：
$ 55.77万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM024148%2F1
关键词：
Dopamine mechanisms underlying bidirectional effects

项目摘要

Animals learn to use cues in the environment to predict the occurrence of rewarding events (e.g. the presence of food). However, natural environments are highly complex and some cues are more attention-grabbing (or salient) than others, and it is not clear how animals select which cues they should learn about. The actions of the chemical messenger dopamine, in a brain region called the nucleus accumbens (NAc), is essential for learning about the relationship between individual cues and the presence of reward. The role of NAc dopamine in this type of learning has been well-studied and we have several good theoretical models that link NAc dopamine and learning to explain how these associations are formed. Although these models take into account how salient cues are, we have recently found that the relationship between cue salience and learning of this type is more complex than is currently appreciated. Specifically, we have found that a particular type of genetically-altered mouse is much more sensitive to the salience of a cue than normal mice: they learn faster than normal mice when a cue is highly salient, but slower when it is less salient. Additionally, the genetic alteration that these mice carry implicates dopamine in another brain region - the cortex - in mediating this enhanced sensitivity. This is surprising, as the cortex is not normally thought to be involved in this type of learning. Therefore, this research will investigate what it is about specific cues that make them more or less salient, whether the relationship between NAc dopamine and learning is different in the genetically-altered mice, and whether the cortex is responsible for causing these differences. To do this, we will take advantage of two newly-developed and powerful techniques. Firstly, we are able to use fast-scan cyclic voltammetry to record NAc dopamine at a very fine timescale whilst animals learn which cues predict reward. This means that an animal's behaviour at a given moment in time can be directly related to its NAc dopamine, something which is essential for developing good theoretical models about the link between these factors. Secondly, we will use virally-mediated gene transfer to selectively remedy the genetic alteration found in the mice in either the cortex or NAc, to see whether doing so returns the mice's behaviour to normal. This will allow us to test which brain regions cause the behavioural difference that we see in the genetically-altered mice. Understanding how animals select which cues to learn about is fundamental to lots of types of behaviours. Understanding how differences between cues shape this process is essential to developing good theoretical models of learning. This research will provide new information about this relatively-neglected process, and will investigate the role that dopamine in the NAc and cortex plays. These studies will contribute to our understanding of how different brain regions work together as a whole, something which is critical to fully understand what might go wrong in brain disorders.

动物学会使用环境中的线索来预测奖励事件的发生（例如食物的存在）。然而，自然环境是高度复杂的，有些线索比其他线索更引人注目（或突出），目前还不清楚动物如何选择它们应该学习的线索。化学信使多巴胺在大脑中一个叫做神经核（NAc）的区域中的作用，对于了解个体线索和奖励之间的关系至关重要。NAc多巴胺在这种类型的学习中的作用已经得到了很好的研究，我们有几个很好的理论模型将NAc多巴胺和学习联系起来，以解释这些联系是如何形成的。尽管这些模型考虑到了线索的显著性，但我们最近发现，线索显著性与这种类型的学习之间的关系比目前所认识的要复杂得多。具体来说，我们发现，一种特定类型的基因改变小鼠比正常小鼠对提示的显著性更敏感：当提示高度显著时，它们比正常小鼠学习得更快，但当提示不那么显著时，它们学习得更慢。此外，这些小鼠携带的基因改变暗示了另一个大脑区域--皮质--中的多巴胺介导了这种增强的敏感性。这是令人惊讶的，因为通常认为皮层不参与这种类型的学习。因此，这项研究将调查是什么特定的线索，使他们或多或少突出，NAc多巴胺和学习之间的关系是否在基因改变的小鼠中是不同的，以及皮层是否负责造成这些差异。为此，我们将利用两种新开发的强大技术。首先，我们能够使用快速扫描循环伏安法以非常精细的时间尺度记录NAc多巴胺，同时动物学习哪些线索预测奖励。这意味着动物在特定时刻的行为可能与其NAc多巴胺直接相关，这对于开发关于这些因素之间联系的良好理论模型至关重要。其次，我们将使用病毒介导的基因转移来选择性地补救在小鼠皮层或NAc中发现的遗传改变，看看这样做是否会使小鼠的行为恢复正常。这将使我们能够测试哪些大脑区域导致我们在基因改变小鼠中看到的行为差异。了解动物如何选择要学习的线索是许多类型行为的基础。理解线索之间的差异如何塑造这一过程对于开发良好的学习理论模型至关重要。这项研究将为这个相对被忽视的过程提供新的信息，并将调查多巴胺在NAc和皮层中的作用。这些研究将有助于我们理解不同的大脑区域如何作为一个整体协同工作，这对于充分理解大脑疾病中可能出现的问题至关重要。