Memory lapses: opportunities for adaptive behaviour

联想条件反射是动物在复杂的感觉环境中学习利用特定感觉的预测价值的最基本手段之一。它提供了一种基本的机制，使我们能够对与机会或威胁相关的感觉信号做出自适应的反应。例如，某些嗅觉可能预示着食物的存在。通过学习这种关联，动物可以更有效地定位和利用食物资源。有些感觉可能与威胁有关，在这种情况下，习得的适应性反应可能是退缩。在联想记忆初步形成之后，有一个巩固期，在此期间，条件行为逐渐变得更加持久。然而，最近我们发现，在巩固记忆的过程中，会出现短暂的遗忘期，在此期间，感觉环境的意外变化会阻碍记忆向长期储存的进展。随着巩固的进行，记忆丧失和易感性的时间点对应于对不同潜在分子和细胞机制的依赖性的转变。我们发现记忆的形成易受干扰，这表明联想条件反射是一个远比迄今为止所认识的更为灵活的过程。本提案的总体目标是促进我们对关键巩固期行为灵活性的基本机制的理解。我们将充分利用软体动物龙类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20,000个神经元，但它与包括人类在内的更复杂的动物一样，具有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的水平上研究行为适应和灵活性的普遍形式，这在更复杂的动物中是不可能的。因为我们知道记忆形成的过程及其潜在的细胞和分子机制在进化上是高度保守的，这项研究很可能揭示同样适用于简单和复杂动物的行为灵活性的原则和机制。从长远来看，这项研究可能会导致发现新的药物或程序，可以改变记忆形成的灵活性，这可能对治疗记忆障碍有潜在的好处。

Associative conditioning is one of the most basic means by which animals learn to exploit the predictive value of particular sensations in a complex sensory environment. It provides a fundamental mechanism underlying the ability to respond adaptively to sensory signals that are associated with for example opportunity or threat. For instance, certain olfactory sensations may presage the presence of food. By learning such an association, an animal can more effectively locate and exploit food resources. Some sensations may become associated with threat, in which case the learned adaptive response might be withdrawal. Following the initial formation of an associative memory there is a period of consolidation, during which the conditioned behaviour becomes progressively more permanent. Recently however, we found that during consolidation there are brief periods of amnesia during which the progression to long-term storage can be blocked by unanticipated changes in the sensory environment. The time-points of memory lapses and susceptibility correspond to transitions in the dependency on different underlying molecular and cellular mechanisms as consolidation proceeds. Our discovery of the susceptibility of memory formation to interference suggests that associative conditioning is a far more flexible process than hitherto appreciated. The overarching aim of this proposal is to advance our understanding of the fundamental mechanisms underlying behavioural flexibility during the critical consolidation period. 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 cellular 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 with the potential benefit that this may have for the treatment of memory disorders.