Neural mechanisms of memory updating

虽然对记忆的神经生物学机制已经进行了几十年的实验研究，但重要的领域仍然知之甚少。其中之一是了解大脑中的细胞机制如何使记忆得以修改。一种新的高调的方法来更新记忆的行为可能是有用的，在未来的治疗记忆障碍，如创伤后压力和强迫性奖励寻求。然而，对这个过程的神经生物学机制知之甚少，本项目将集中于一种特定形式的记忆的行为更新。这些是情境恐惧记忆，它们很强大，很容易研究。此外，他们的基本机制的初始收购/巩固和持久性/再巩固的描述。我们最近已经证明，建立的情境恐惧记忆可以被修改和减少，只要简单地检索记忆，然后在很短的时间内将其置于灭绝程序中。这导致了一个长期的重新评估，以前的恐惧条件下，现在是安全的。我们有数据表明，这个过程依赖于记忆在提取时被"重新激活"，并表明它招募了一个延长的神经生物学活动阶段，以修改记忆。目前的项目将测试基于这些初步发现的具体假设：1。再激活诱导的细胞过程的时程被随后的消退训练延长.这种延长的细胞活动在最初由记忆再激活诱导的相同神经元中。细胞活动的延长意味着记忆在更长的时间内容易受到破坏。4.行为记忆更新依赖于记忆的重新激活，这意味着它应该是可能的，甚至在行为条件下，通常不支持这一进程，以测试这些假设，我们将使用多学科的方法，行为测试，离体分子神经生物学，在体内的分子和行为药理学分析。研究者在所有这些方法上都有经验，尽管他们以前没有在重新巩固或行为矫正的环境中结合起来。假设的性质和测试它们所需的方法需要使用实验动物。老鼠是最没有知觉的物种，它们与人类保持着一定程度的生物相似性，因此我们的结论可以合理地应用于对人类学习和记忆的理解。虽然该项目的直接目标是对学习和记忆过程进行更深入的基本理解，但这项研究在理解持续性记忆障碍方面具有潜在的临床意义，例如创伤后应激障碍，特定的恐惧症和毒瘾事实上，最近关于行为记忆更新的论文的高调性质是由于其对学习和记忆的基本理解及其潜在的翻译影响的影响。

While there have been several decades of experimental research into the neurobiological mechanisms of memory, significant areas remain poorly understood. One of these is the understanding of how the cellular mechanisms in the brain enable memories to be modified. An emerging high-profile approach to the behavioural updating of memories may be useful in the future treatment of memory disorders such as posttraumatic stress and compulsive reward-seeking. However, very little is known about the underlying neurobiological mechanisms of this process.This project will focus on the behavioural updating of a specific form of memories. These are contextual fear memories, which are robust and easily studied. Moreover, their underlying mechanisms of initial acquisition/consolidation and persistence/reconsolidation are well-described. We have recently demonstrated that established contextual fear memories can be modified and diminished, simply by briefly retrieving the memory and then a short time later subjecting it to an extinction procedure. This leads to a long-lasting revaluation of the previously fear-conditioned context as now being safe. We have data showing that this process relies upon the memory being "reactivated" at retrieval, and suggesting that it recruits a prolonged phase of neurobiological activity in order to modify the memory. The current project will test specific hypotheses based upon these initial findings:1. The timecourse of reactivation-induced cellular processes is prolonged by subsequent extinction training.2. This prolonged cellular activity is in the same neurons that at initially induced by memory reactivation.3. The prolonged cellular activity means that the memory is vulnerable to disruption for a longer period.4. The reliance of the behavioural memory updating upon memory reactivation means that it should be possible to pharmacologically stimulate memory reactivation even under behavioural conditions that do not normally support this process.In order to test these hypotheses, we will use a multidisciplinary approach of behavioural testing, ex vivo molecular neurobiology, and in vivo molecular and behavioural pharmacological analyses. The investigators are experienced in all these approaches, though they have not previously been combined in a reconsolidation or behavioural modification setting.The nature of the hypotheses and the approaches needed to test them require the use of experimental animals. Rats are the least sentient species that retain a level of biological similarity to humans such that our conclusions can reasonably be applied to the understanding of human learning and memory.While the immediate aims of the project are geared towards a greater basic understanding of learning and memory processes, this research has potential clinical implications in the understanding of persistent memory-based disorders such as post-traumatic stress, specific phobias and drug addiction. Indeed, the high-profile nature of the recent papers on behavioural memory updating is due to its implications both for the basic understanding of learning and memory and its potential translational impact.