Updating of memories during memory consolidation

包括人类在内的动物都是通过探索环境和通过试错来评估特定经验的预测价值来学习的。这种基本的学习形式被称为联想条件反射，它使动物能够对与奖励或惩罚有关的感官信号做出适应性反应。通过学习这种联系，动物可以更有效地定位和利用食物资源或避免威胁。在联想记忆最初形成之后，会有一段巩固期，在此期间，记忆会逐渐变得更加持久。我们发现，在巩固过程中，有短暂的健忘症，在此期间，向长期记忆储存的进展可能被感官环境的意外变化所阻碍或改变。最近，我们为这种整合的灵活性提供了进一步的证据，表明在这些失效期间更重要或最近的经历可以从根本上改变原始协会的命运。事实上，它可能导致用第二种联想取代第一种联想。虽然失误可能看起来像记忆存储中的非适应性缺陷，但我们认为它们在提供改变记忆痕迹的机会方面很重要。在失效点更新记忆的优点是，在提供新的或更重要的经验被纳入甚至取代原始记忆的机会的同时，防止了昂贵的巩固过时记忆的过程。这个提议的目的是促进我们对这种导致一个内存被另一个内存交换的基本类型的内存更新的理解。为了实现这一目标，我们将利用软体动物lynaea相对简单的大脑和行为所提供的优势。尽管这种动物的中枢神经系统只有大约2万个神经元，但它却拥有包括人类在内的更复杂的动物所表现出的联想记忆形成的所有基本特征。这使我们能够在细胞和分子细节水平上研究一种普遍形式的行为适应和灵活性，这在更复杂的动物中是不可能的。因为我们知道记忆形成过程及其潜在的神经和分子机制在进化上是高度保守的，这项研究很可能揭示行为灵活性的原则和机制，这些原则和机制同样适用于简单和复杂的动物。从长远来看，这项研究可能会导致新的药物或程序的发现，这些药物或程序可以改变记忆形成的灵活性，包括这可能对治疗创伤后应激障碍（PTSD）等记忆障碍有潜在的好处。在PTSD中，创伤性事件的记忆变得非常强烈，几乎不容易受到干扰。所有抑制这种记忆的尝试都是针对在压力经历后很长一段时间内，当记忆已经被长期储存时，可能会被唤起的再巩固过程。我们在巩固过程中的记忆阻塞和替代方面的工作，可能为这一临床领域的基础研究提供另一种机会。

SummaryAnimals, including humans, learn by exploring the environment and assessing the predictive value of a particular experience by trial and error. This basic form of learning, called associative conditioning, enables animals to adaptively respond to sensory signals that are associated with reward or punishment. By learning such an association, an animal can more effectively locate and exploit food resources or avoid threats. Following the initial formation of an associative memory there is a period of consolidation, during which the memory becomes progressively more permanent. We showed that during consolidation there are brief periods of amnesia during which the progression to long-term memory storage can be blocked or altered by unanticipated changes in the sensory environment. Recently we provided further evidence for this flexibility of consolidation by showing that a more important or recent experience during these lapse periods can fundamentally change the fate of the original association. Indeed it can result in the replacement of the first association with a second one. Although lapses may look like non-adaptive deficits in memory storage, we claim that they are important in providing opportunities for alteration of the memory trace. The updating of the memory at lapse points has the advantage of preventing the costly process of consolidation of an obsolete memory while providing opportunity for new or more important experience to be incorporated into or even replace the original memory. The aim of this proposal is to advance our understanding of this fundamental type of memory updating that results in the swapping of one memory by another. To achieve this, we will exploit the advantages offered by the relatively simple brain and behaviour of the mollusc Lymnaea. While having a CNS of only ~20,000 neurons, this animal nevertheless shares all of the basic features of associative memory formation displayed by far more complex animals, including humans. This allows us to study a universal form of behavioural adaptation and flexibility at a level of cellular and molecular detail that would not be possible in more complex animals. Because we know that the process of memory formation and its underlying neural and molecular mechanisms are evolutionarily highly conserved, this research is likely to reveal principles and mechanisms of behavioural flexibility that apply equally to both simple and complex animals.In the longer term this research may lead to the discovery of new drugs or procedures that can modify the flexibility of memory formation including the potential benefit that this may have for the treatment of memory disorders including post-traumatic stress disoder (PTSD). In PTSD the memory of a traumatic event becomes very strong and almost unsusceptible to interference. All the attempts to supress this memory have targeted the reconsolidation process that can be evoked long time after the stressful experience when the memory has already been stored for the long-term. Our work on memory blocking and replacement during the process of consolidation, may offer alternative opportunities for fundamental research in this clinical area.