Neural mechanisms underlying memory destabilization and modification

我们对哺乳动物大脑中记忆储存的理解已经取得了很大的进展。然而，还有很多东西有待发现。最近的研究对长期记忆是一种稳定不变的现象的观念提出了挑战。相反，记忆及其在大脑中的生物基质可以在一生中改变，这种可修改性可能有助于确保存储的信息是当前的和与正在进行的行为相关所需的适应过程。与此一致的是，我们最近的研究表明，在不稳定的状态下，老鼠对以前遇到的物体的记忆可以被重新激活和修改。我们也暗示了神经递质乙酰胆碱在这些影响中，表明在长期目标记忆变得可修改之前，它是稳定的必要条件。拟议的研究计划将深入研究这一现象的机制基础和行为含义。乙酰胆碱作用于许多不同的受体，在大脑中发挥作用。我们之前的工作已经暗示了一种特定的受体亚型（M1）在对象记忆不稳定。提出的研究将调查在乙酰胆碱诱导的M1受体激活后的神经元事件，最终导致记忆不稳定。我们将使用药物抑制与M1受体激活相关的已建立的神经元信号机制，试图阻止大鼠的目标记忆不稳定，从而证明这些信号对于假定的记忆更新过程的必要性。我们还将进行类似的实验，使用恐惧条件反射任务来评估老鼠的长期情绪记忆。这将使我们能够研究上述机制的普遍性。最后，我们将使用一种新的大鼠行为测试来直接分析这些机制在可测量的记忆修改中的作用。在已知客体记忆不稳定的条件下，大鼠将被呈现新的刺激，试图修改不稳定的信息。初步的研究已经证明了这个新任务的原理，并且已经显示出可测量的记忆修改，我们建议调查上述记忆不稳定机制在这个潜在的适应性过程中所起的作用。从哺乳动物大脑的基本信息存储功能的角度来看，确定广义记忆修改机制将是一个有价值的发现。此外，对这些机制的阐明将最终帮助我们更好地理解为什么以及如何一些记忆改变而另一些不改变，这些信息可能在一些应用环境中是有益的，在这些环境中，适应不良和持续的情绪记忆严重扰乱了日常生活（例如，恐惧症，创伤后应激障碍，与年龄相关的认知不灵活性）。

Great progress has been made in our understanding of memory storage in the mammalian brain. However, much remains to be discovered. Recent research has challenged the notion that long-term memory is a stable and unchanging phenomenon. Rather, memories and their biological substrates in the brain can be altered throughout life, and this modifiability probably contributes to adaptive processes required to ensure that stored information is current and relevant to ongoing behaviour. Consistent with this, our recent research has shown that rats' memories for previously encountered objects can be reactivated and modified while in a destabilized state. We have also implicated the neurotransmitter acetylcholine in these effects, showing that it is necessary for the destabilization of long-term object memories before they can become modifiable. The proposed research program will delve deeper into the mechanistic basis and behavioural implications of this phenomenon. Acetylcholine acts on a number of different receptors to exert effects in the brain. Our previous work has implicated one specific receptor sub-type (M1) in object memory destabilization. The proposed research will investigate the neuronal events following acetylcholine-induced M1 receptor activation that culminate in memory destabilization. We will use drugs to inhibit established neuronal signaling mechanisms related to M1 receptor activation in an attempt to prevent object memory destabilization in rats, thereby demonstrating the necessity of these signals for the putative memory updating process. We will also conduct similar experiments using a fear conditioning task that assesses long-term emotional memory in rats. This will enable us to study the generalizability of the mechanisms identified above. Finally, we will use a novel behavioural test for rats to perform direct analysis of the involvement of these mechanisms in measurable memory modification. Following conditions known to destabilize object memories, rats will be presented with new stimuli in an attempt to modify the destabilized information. Preliminary studies have demonstrated proof of principle with this new task, and having shown measurable memory modification, we propose to investigate the role that the above memory destabilization mechanisms play in this potentially adaptive process. Identification of a generalized memory modification mechanism would be a valuable finding from the perspective of the basic information storage functions of the mammalian brain. Furthermore, elucidation of such mechanisms will ultimately help us to better understand why and how some memories change and others do not, information that could be beneficial in a number of applied settings where maladaptive and persistent emotional memories significantly disrupt daily life (e.g., phobias, post-traumatic stress disorder, age-related cognitive inflexibility).