Dopamine mechanisms underlying bidirectional effects of cue salience on Pavlovian learning

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，自然环境非常复杂，一些线索比其他线索更吸引人注意(或更突出)，目前还不清楚动物如何选择它们应该了解的线索。化学信使多巴胺在大脑伏隔核(NAC)区域的活动，对于了解个体线索和奖赏存在之间的关系是必不可少的。NAC多巴胺在这类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，解释这些联系是如何形成的。尽管这些模型考虑了线索的显著程度，但我们最近发现，线索显著与这类学习之间的关系比目前所理解的要复杂得多。具体地说，我们发现，有一种特定类型的转基因小鼠比正常小鼠对线索的突出度更敏感：当线索高度突出时，它们比正常小鼠学习得更快，但当线索不那么突出时，它们学习得更慢。此外，这些小鼠携带的基因改变牵涉到大脑另一个区域--大脑皮层--的多巴胺参与调节这种增强的敏感性。这令人惊讶，因为大脑皮层通常被认为不参与这种类型的学习。因此，这项研究将调查使它们或多或少突出的特定线索是什么，NAC多巴胺和学习之间的关系在基因改变的小鼠中是否不同，以及皮质是否导致这些差异。要做到这一点，我们将利用两项新开发的强大技术。首先，我们能够使用快速扫描循环伏安法在非常精细的时间尺度上记录NAC多巴胺，同时动物了解哪些线索可以预测奖赏。这意味着动物在特定时刻的行为可以与它的NAC多巴胺直接相关，这对于建立关于这些因素之间联系的良好理论模型是必不可少的。其次，我们将使用病毒介导的基因转移来选择性地修复在大脑皮质或NAC中发现的小鼠的基因变化，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了我们在基因改变的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。了解线索之间的差异是如何塑造这一过程的，对于开发良好的学习理论模型至关重要。这项研究将提供关于这一相对被忽视的过程的新信息，并将调查多巴胺在NAC和皮质中所起的作用。这些研究将有助于我们理解不同的大脑区域是如何作为一个整体一起工作的，这对于充分理解大脑紊乱中可能出现的问题至关重要。

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.