Mechanisms of Long-Term Memory Maintenance in Aplysia.

描述(申请人提供)：在美国，有相当大比例的人患有长期记忆障碍；其中包括阿尔茨海默病(AD)、创伤后应激障碍(PTSD)、糖尿病和抑郁症。除了形成新记忆的问题外，患有这些疾病的患者可能难以获取旧记忆，特别是在疾病的晚期，或者--就创伤后应激障碍而言--患者可能难以调节创伤性长期记忆。一个重要且目前尚未解决的问题是，一些患者经历的记忆困难在多大程度上源于提取问题或物理记忆痕迹本身的退化。为了回答这个问题，神经学家必须更多地了解大脑如何维持长期记忆。与长期持有的观念相反，即使是健康的人，老年人的记忆也不稳定，但在某些情况下，可能会变得惊人地不稳定。此外，一旦处于这种不稳定的状态，记忆可能会永久中断。长期记忆的两种现象，即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：在被给予先前学习过的经历的提醒提示后，先前巩固的那次经历的记忆可能会被干扰原始记忆巩固的治疗方法打乱，比如接触蛋白质合成抑制剂。所以- 在蛋白激酶C(PKC)的一种特定亚型被抑制后，观察到了一种称为记忆擦除的现象。PKM？含有非典型PKC的催化结构域，但缺乏调节域，因此具有结构性活性。有人提出，这一性质赋予了PKM中介内存维护的能力。记忆重新巩固和记忆擦除的现象仍然知之甚少，也存在争议。在某种程度上，这些问题源于哺乳动物大脑的巨大复杂性，以及在重新巩固和记忆擦除研究中所研究的记忆形式的复杂性。这个项目将开发一个简单的模型实验系统，用于对记忆重新巩固和记忆擦除进行简化论分析。该项目的重点将是在海洋蜗牛海兔身上进行一种非联想形式的学习，即长期敏化(LTS)。这种生物为研究长期记忆维持提供了几个主要优势，包括研究一种形式的长期(24小时)突触可塑性， 这就是所谓的长期促进，它明确地调节了学习。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背后的神经生物学机制。来自拟议研究的数据将有助于开发治疗长期记忆障碍的方法，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.