Synaptic and Nuclear Signaling in Memory Formation

记忆形成中的突触和核信号传导

• 批准号: 7619962
• 负责人: Thomas J Carew
• 金额: $ 32.57万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-04 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619962
• 关键词: Adaptive Behaviors; Afferent Neurons; Animals; Anxiety; Aplysia; Area; Bathing; Behavioral; Brain; CCAAT-Enhancer-Binding Proteins; CPE-binding protein; CREB1 gene; Cell Nucleus; Cellular biology; Cyclic AMP-Dependent Protein Kinases; Disease; Employee Strikes; Environment; Event; Ganglia; Gene Expression; Genetic Transcription; Immediate-Early Genes; Invertebrates; Laboratories; Learning; Link; Mammals; Marines; Measures; Mediating; Memory; Memory Loss; Mental Retardation; Messenger RNA; Molecular; Molecular Analysis; Mood Disorders; Motor; Motor Neurons; Myxoid cyst; Neurons; Neuropeptides; Neurosciences; Nuclear; Pleural; Preparation; Process; Public Health; Recruitment Activity; Reflex action; Research; Research Personnel; Role; Sensory; Signal Transduction; Specific qualifier value; Synapses; Tail; Time; Translations; Variant; Withdrawal; age related; base; bone; forging; long term memory; neuromechanism; neuronal cell body; novel; programs; research study; synaptogenesis; therapeutic target

DESCRIPTION (provided by applicant): The ability to learn, remember and recall information about the world is critical to every aspect of adaptive behavior. Despite striking recent advances in understanding neural mechanisms of memory, surprisingly little is known about how synaptic and nuclear events in neurons are coordinated in space and time in the induction of memory. This question forms the core of the present research program, which has the unique feature of combining the strengths of two independent laboratories, both of which utilize the marine mollusk Aplysia as a powerful preparation for studying the molecular basis of memory. The Carew group at UCI will contribute expertise in relating synaptic and molecular plasticity directly to bone fide learning and memory, and the Martin group at UCLA will contribute expertise in the analysis of signaling mechanisms between the synapse and the nucleus. The combined efforts of these two groups provide a unique opportunity to explore a fundamental question in cell biology, the mechanisms by which different compartments of a neuron communicate during memory formation. The project will be carried out at three interactive levels of analysis, captured in three Specific Aims: AIM I is a BEHAVIORAL ANALYSIS which will utilize a novel behavioral preparation that permits examining a monosynaptic sensory-motor (SN-MN) component of a reflex during intermediate-term and long-term memory formation, while simultaneously manipulating the local molecular environment of somatic and synaptic components of the reflex. AIM II is a SYNAPTIC ANALYSIS examining the SN-MN component of the reflex in the intact CNS in a preparation that allows specifying the contribution of somatic and synaptic events to synaptic facilitation. Here we will examine the mechanisms of (i) local induction of intermediateterm facilitation (ITF), (ii) synaptic induction of long-term facilitation (LTF), and (iii) conjoint synaptic and nuclear induction of LTF. AIM III is a MOLECULAR ANALYSIS examining the requirement for memory formation of (i) local translation at the synapse, focusing on two specific molecules, sensorin, a SN-specific neuropeptide, and cytoplasmic polyadenylation element binding protein (CPEB), a localized mRNA, (ii) facilitated importin-mediated transport of signals from synaptic compartments to the nucleus, and (iii) MARK signaling to the nucleus, CREB and C/EBP-mediated transcription, and induction of the immediate early gene C/EBP. Relevance to public health: Understanding the mechanisms whereby synapticallv generated signals trigger changes in gene expression in the nucleus during memory formation provides a means of identifying therapeutic targets for a variety of disorders including mental retardation, age-related memory loss and neuropsvchiatric diseases such as anxiety and mood disorders.

描述（由申请人提供）：学习、记忆和回忆有关世界的信息的能力对于适应性行为的各个方面都至关重要。尽管最近在理解记忆的神经机制方面取得了惊人的进展，但令人惊讶的是，人们对神经元中的突触和核事件在记忆诱导过程中如何在空间和时间上协调知之甚少。这个问题构成了本研究项目的核心，该项目的独特之处在于结合了两个独立实验室的优势，这两个实验室都利用海洋软体动物海兔作为研究记忆分子基础的有力准备。加州大学尔湾分校的卡鲁小组将提供将突触和分子可塑性直接与真正的学习和记忆联系起来的专业知识，加州大学洛杉矶分校的马丁小组将提供分析突触和细胞核之间信号传导机制的专业知识。这两个小组的共同努力提供了一个独特的机会来探索细胞生物学中的一个基本问题，即记忆形成过程中神经元不同区室进行通信的机制。该项目将在三个交互层次上进行分析，捕获三个具体目标： AIM I 是一种行为分析，它将利用一种新颖的行为准备，允许在中期和长期记忆形成过程中检查反射的单突触感觉运动（SN-MN）成分，同时操纵反射的体细胞和突触成分的局部分子环境。 AIM II 是一种突触分析，检查完整中枢神经系统中反射的 SN-MN 成分，以便确定体细胞和突触事件对突触促进的贡献。在这里，我们将研究（i）中期促进（ITF）的局部诱导，（ii）长期促进（LTF）的突触诱导，以及（iii）LTF的联合突触和核诱导的机制。 AIM III 是一项分子分析，检查 (i) 突触局部翻译的记忆形成要求，重点关注两种特定分子：传感蛋白（一种 SN 特异性神经肽）和细胞质多腺苷酸化元件结合蛋白 (CPEB)（一种局部 mRNA），(ii) 促进输入介导的信号从突触区室到细胞核的转运，以及 (iii)向细胞核发出MARK信号、CREB和C/EBP介导的转录以及立即早期基因C/EBP的诱导。与公共健康的相关性：了解记忆形成过程中突触产生的信号触发细胞核内基因表达变化的机制，为识别各种疾病的治疗靶点提供了一种方法，包括精神发育迟滞、与年龄相关的记忆丧失以及焦虑和情绪障碍等神经精神疾病。