Scribble signalosome and active forgetting

项目总结/摘要 几十年来，人们一直在深入研究记忆形成和巩固的机制。令人惊讶的是， 遗忘的过程，想必也同样重要，却几乎被忽视了。幸运的是，这一重点是 最近，人们对理解记忆是如何被遗忘的兴趣不断变化，并以神经科学为基础。它 遗忘被认为通过减少过时信息的影响来增强记忆的灵活性。在 此外，遗忘可能会删除以前经验的具体细节，从而促进泛化。 因此，遗忘允许在不断变化和嘈杂的环境中做出明智的决策。研究 遗忘很重要，不仅因为它会增加我们对记忆如何处理的理解 这不仅是因为大脑，还因为许多精神疾病可能与遗忘缺陷有关。这是一 这是学习和记忆研究中的一个新兴领域，在未来几年将非常重要。 利用果蝇进行的分子、细胞和系统神经科学研究揭示了几个主要原则 揭示了嗅觉记忆形成、巩固和恢复的逻辑。首先是 蘑菇体（MB）凯尼恩细胞（KC）突触活动的调节是联想学习的基础。第二 原则是KC可塑性的调节采用cAMP信号传导。第三是蘑菇体产量 神经元（MBOn）接收来自KC的输入，并且它们的激活影响接近或回避行为。一 第四个原则是，多巴胺神经元（DAn）被厌恶或奖励刺激激活，以提供我们 在经典条件作用下的输入。最近的研究开始揭示这种拮抗剂的作用 记忆获取和巩固的过程，即，记忆遗忘最近的分子遗传学研究 已经确定了小G蛋白Rac 1在遗忘嗅觉记忆中的作用。此外，多巴胺 受体Damb介导遗忘过程，这种多巴胺能活性受 动物的行为状态。目前的项目旨在建立在我们目前对记忆丧失的理解基础上 通过探索多结构域支架蛋白Scribble的相对新的作用。长期目标是确定 这种支架蛋白及其相互作用蛋白的分子和功能性质。目标1将增加 我们对Scribble如何通过解开其基因的复杂性来调节遗忘的基本理解， 多结构域蛋白以及揭示其亚细胞定位。目标二号将解剖分子 遗忘信号体的结构。我们将确定Scribble的蛋白质-蛋白质相互作用， 我们很可能会发现更多的分子参与遗忘的调节。目标3将探讨 神经相关的记忆遗忘，通过以下的神经可塑性的进展观察， MBOn以及这种可塑性如何受到Scribble和其他遗忘调节器（如Rac）的影响。 当前提议的重要性在于我们目前对记忆是如何运作的理解不足 忘了

PROJECT SUMMARY/ABSTRACT Mechanisms for memory formation and consolidation have been intensely studied for decades. Surprisingly, the process of forgetting, presumably of equal importance, has been virtually ignored. Fortunately, this focus is shifting and recent neuroscience-based interest in understanding how memories are forgotten has emerged. It is thought that forgetting enhances memory flexibility, by reducing the influence of obsolete information. In addition, forgetting may remove specific details of previous experiences, thereby promoting generalization. Thus, forgetting allows intelligent decision-making in an ever-changing and noisy environment. Research on forgetting is important not only because it will increase our understanding of how memories are processed by the brain but also because many psychiatric disorders may be associated with deficits in forgetting. This is a fledgling field in the study of learning and memory that will take great importance in the future years. Molecular, cellular and systems neuroscience studies using Drosophila have uncovered several major tenets that reveal the logic by which olfactory memories are formed, consolidated and retrieved. The first is that modulation of mushroom body (MB) Kenyon cell (KC) synaptic activity underlies associative learning. A second tenet is that the modulation of KC plasticity employs cAMP signaling. A third is that the mushroom body output neurons (MBOn) receive input from the KC and their activation influences approach or avoidance behavior. A fourth tenet is that dopamine neurons (DAn) are activated by aversive or rewarding stimuli to provide the US input during classical conditioning. Most recently, studies have started to shed some light on the antagonist process to memory acquisition and consolidation, i.e., memory forgetting. Recent molecular genetic studies have identified a role for the small G protein Rac1 in forgetting of olfactory memories. In addition, the dopamine receptor Damb, mediates the process of forgetting and this dopaminergic activity is modulated with the behavioral state of the animal. The current project seeks to build on our current understanding of memory loss by exploring a relatively new role for multidomain scaffolding protein, Scribble. The long-term goal is to define the molecular and functional nature of this scaffolding protein and its interacting proteins. Aim 1 will increase our basic understanding of how Scribble regulates forgetting by untangling the complexity of its gene and the multidomain protein as well as by revealing its subcellular localization. Aim 2 will dissect the molecular architecture of the forgetting signalosome. We will identify Scribble’s protein-protein interactions with the likelihood that we will find additional molecules involved in the regulation of forgetting. Aim 3 will explore the neural correlates of memory forgetting, by following the progression of the neuronal plasticity observed in MBOn and how is this plasticity affected by Scribble and other forgetting regulators like Rac. The significance of the current proposal resides in our poor current understanding of how memories are forgotten.