Retroactive effect of dopamine on hippocampal spike timing-dependent plasticity

大脑如何将我们的经历储存在记忆中？在我们每天经历的所有事件中，为什么有些会被记住，有些则不会？许多因素可能影响我们的记忆力。我们是否记得一件特定的事件不仅受到事件发生时的影响，也受到事件发生后的影响。例如，奖励的呈现可以帮助我们记住奖励之前的事件。在这个提议中，我们将研究奖励如何影响记忆的基本机制。人们普遍认为，记忆是通过大脑神经细胞之间连接的变化来存储的。这被称为突触可塑性。在这个项目中，我们将研究这些变化是如何被诱导的基本规则，特别是大脑中的奖励信号多巴胺是如何影响这种可塑性的。为了解决这些问题，我们将使用一种被称为光遗传学的新技术。这项技术使我们能够使用激光激活特定类型的细胞。这种特异性是通过仅在一种特定细胞类型中表达光敏蛋白来实现的。通过这种方式，我们可以在大脑中分离出一个特定的连接，我们可以在这些连接上释放多巴胺。我们将测试多巴胺能够改变突触可塑性规则的假设。具体来说，我们将测试多巴胺是否能够追溯调节可塑性，从而帮助解释奖励如何影响导致奖励的事件的记忆。我们还将研究多巴胺作用于突触可塑性产生这些变化的分子级联。这一结果将给我们提供关于记忆的新见解，并可能为改善老年人的记忆和治疗记忆障碍开辟新的途径。

How can the brain store our experiences in memory? And of all the events that we experience each day, why is it that some are remembered and others not? Many factors may influence how well we remember. Whether we remember a particular event or not is influenced not only by what happens during the event, but also by what happens after the event. For example, the presentation of a reward may help us remember the event that preceded the reward. In this proposal, we will study the basic mechanisms for how reward may influence memory. It is generally believed that memories are stored as changes in the connections between the nerve cells of the brain. This is known as synaptic plasticity. In this project, we will investigate the basic rules for how these changes are induced, and specifically, how a reward signal in the brain, dopamine, can influence this plasticity. To address these questions, we will use a new technique, known as optogenetics. This technique enables us to activate specific cell types using a laser. The specificity is achieved by expressing a light-sensitive protein in only one specific cell type. In this way, we can isolate a specific connection in the brain, and we can release dopamine specifically onto those connections. We will test the hypothesis that dopamine is capable of altering the rules of synaptic plasticity. Specifically, we will test whether dopamine is capable of modulating plasticity retroactively, and thus help explain how rewards may influence memory for events that led up to the reward. We will also investigate the molecular cascades that dopamine acts on to produce these changes in synaptic plasticity. The results should give us new insights into memory and could potentially open up new avenues for improving memory in ageing individuals and for treating memory disorder.