Scribble signalosome and active forgetting

项目摘要/摘要 记忆形成和巩固的机制已经被深入研究了几十年。令人惊讶的是， 遗忘的过程想必同样重要，但实际上却被忽视了。幸运的是，这个关注点是 最近，人们对了解记忆是如何被遗忘的兴趣发生了变化，这是基于神经科学的兴趣。它 人们认为，遗忘通过减少过时信息的影响来增强记忆的灵活性。在……里面 此外，遗忘可能会删除以前经验的具体细节，从而促进概括。 因此，遗忘可以在不断变化和嘈杂的环境中做出明智的决策。研究与实践 遗忘很重要，不仅因为它会增加我们对记忆是如何处理的理解 还因为许多精神疾病可能与健忘缺陷有关。这是一个 在学习和记忆的研究领域处于起步阶段，这将在未来几年发挥重要作用。 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理 这揭示了嗅觉记忆形成、巩固和提取的逻辑。第一个是 蘑菇体(MB)、肯扬细胞(KC)突触活动的调节是联想学习的基础。一秒钟 其宗旨是通过cAMP信号对KC可塑性进行调控。第三个是蘑菇体输出 神经元(MBON)接受来自KC的输入，它们的激活影响接近或回避行为。一个 第四个原则是，多巴胺神经元(DAN)被厌恶或奖赏的刺激激活，以提供US 在经典条件作用过程中的输入。最近，研究已经开始对敌手有了一些了解 记忆获得和巩固的过程，即记忆遗忘。分子遗传学研究近况 已经确定了小G蛋白rac1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，这种多巴胺能活动受 动物的行为状态。目前的项目试图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的相对新作用。长期目标是定义 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和 多结构域蛋白以及揭示其亚细胞定位。目标2将剖析分子 遗忘信号体的体系结构。我们将确定Scribble的蛋白质-蛋白质相互作用 我们可能会发现更多的分子参与了对遗忘的调节。目标3将探索 通过跟踪观察到的神经元可塑性的进展，记忆遗忘的神经相关性 Mbon以及Scribble和其他被遗忘的监管机构(如RAC)如何影响这种可塑性。 目前这一提议的意义在于我们目前对记忆是如何形成的认识很差 被遗忘了。

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.