Mechanisms of Long-Term Memory Maintenance in Aplysia.

描述（由申请人提供）：在美国，相当大比例的人患有长期记忆障碍;其中包括患有阿尔茨海默病（AD）、创伤后应激障碍（PTSD）、糖尿病和抑郁症的人。除了形成新记忆的问题之外，患有这些疾病的患者可能难以访问旧记忆，特别是在疾病的晚期，或者在PTSD的情况下，患者可能难以调节创伤性长期记忆。一个重要的，目前尚未解决的问题是，在多大程度上，一些患者经历的记忆困难源于检索问题或物理记忆痕迹本身的退化。为了回答这个问题，神经科学家必须更多地了解大脑如何保持长期记忆。 与长期以来的观点相反，即使在健康的个体中，老年人的记忆也不稳定，但在某些情况下，可能会变得非常不稳定。此外，一旦处于这种不稳定状态，记忆可能会永久中断。长期记忆的两种现象，称为记忆再巩固和记忆擦除，在这方面引起了特别的关注。记忆再巩固指的是这样一种发现，即在对先前学习过的经验给予提醒提示后，先前巩固的记忆可能会被干扰原始记忆巩固的治疗所破坏，例如暴露于蛋白质合成抑制剂。所以... 在抑制蛋白激酶C（PKC）的一种特殊亚型（称为PKM）后，观察到了所谓的记忆擦除。PKM含有非典型PKC的催化结构域，但缺乏调节结构域，因此具有组成性活性。这个属性，它已被提出，赋予PKM的容量介导的内存维护。记忆再巩固和记忆擦除的现象仍然知之甚少和有争议。在某种程度上，这些问题源于哺乳动物大脑的巨大复杂性，以及记忆形式的复杂性，这些记忆形式已经在重新巩固和记忆擦除的研究中得到了检验。本计画将发展一个简单的模型实验系统，以还原论分析记忆再巩固与记忆抹除。该项目的重点将是一种非联想形式的学习，长期敏化（LTS），在海洋蜗牛，Aaprissia。这种生物体为长期记忆维持的研究提供了几个主要优势，包括研究长期（>24小时）突触可塑性的能力， 被称为长期促进，这明确地介导了学习。PI将使用行为，细胞和分子技术来确定记忆重新巩固和记忆擦除的神经生物学机制。来自拟议研究的数据将有助于开发长期记忆障碍的治疗方法，包括AD和PTSD。

DESCRIPTION (provided by applicant): A significant percentage of people in the US have disorders of long-term memory; among these are people suffering from Alzheimer's disease (AD), posttraumatic stress disorder (PTSD), diabetes and depression. In addition to problems forming new memories, patients suffering from these diseases can have difficulty accessing older memories, especially in the advanced stages of the diseases, or-in the case of PTSD-patients may have difficulty regulating traumatic long-term memories. An important, and at present unresolved, question is the extent to which the memory difficulties experienced by some patients stem from retrieval problems or to degradation of the physical memory traces themselves. In order to answer this question, neuroscientists must learn more about how the brain maintains long-term memories. Contrary to long-held beliefs, older memories are not stable, even in healthy individuals, but, under some circumstances, can be rendered strikingly labile. Furthermore, once in this labile state the memories can become permanently disrupted. Two phenomena of long-term memory, termed memory reconsolidation and memory erasure, have attracted particular attention in this regard. Memory reconsolidation refers to the finding that, after having been given a reminder cue for a previously learned experience, a previously consolidated memory of that experience can become disrupted by treatments, such as exposure to inhibitors of protein synthesis, that interfere with original memory consolidation. So- called memory erasure has been observed following inhibition of a specific isoform of protein kinase C (PKC), known as PKM¿. PKM¿ contains the catalytic domain of an atypical PKC, but lacks the regulatory domain and is therefore constitutively active. This property, it has been proposed, endows PKM¿ with the capacity mediate memory maintenance. The phenomena of memory reconsolidation and memory erasure remain poorly understood and controversial. In part, these problems stem from the enormous complexity of the mammalian brain, as well as the complexity of the forms of memory that have been examined in studies of reconsolidation and memory erasure. This project will develop a simple model experimental system for a reductionist analysis of memory reconsolidation and memory erasure. The focus of the project will be on a nonassociative form of learning, long-term sensitization (LTS), in the marine snail, Aplysia. This organism offers several major advantages for the study of long-term memory maintenance, including the ability to investigate a form of long-term (>24 hr) synaptic plasticity, known as long-term facilitation, that unambiguously mediates the learning. The PI will use behavioral, cellular and molecular techniques to determine the neurobiological mechanisms that underlie memory reconsolidation and memory erasure. Data from the proposed studies will facilitate the development of treatments for disorders of long-term memory, including AD and PTSD.