Synaptic and Nuclear Signaling in Memory Formation

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适应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如何在空间和时间上协调记忆的诱导知之甚少。这个问题构成了本研究计划的核心，该计划具有结合两个独立实验室的优势的独特功能，这两个实验室都利用海洋软体动物Aaplasia作为研究记忆分子基础的有力准备。加州大学洛杉矶分校的卡鲁小组将贡献突触和分子可塑性直接与真正的学习和记忆相关的专业知识，加州大学洛杉矶分校的马丁小组将贡献突触和细胞核之间信号机制分析的专业知识。这两个小组的共同努力为探索细胞生物学中的一个基本问题提供了一个独特的机会，即神经元的不同区域在记忆形成过程中进行交流的机制。该项目将在三个交互式分析水平上进行，具体目标如下：AIM I是一种行为分析，它将利用一种新型的行为准备，允许在中期和长期记忆形成期间检查反射的单突触感觉-运动（SN-MN）组件，同时操纵反射的躯体和突触组件的局部分子环境。AIM II是一种突触分析，检查了制备物中完整CNS中反射的SN-MN组分，该制备物允许指定体细胞和突触事件对突触易化的贡献。在这里，我们将研究（i）局部诱导的中期易化（ITF），（ii）突触诱导的长期易化（LTF），（iii）联合突触和核诱导的LTF的机制。AIM III是一种分子分析，检查以下记忆形成的要求：（i）突触处的局部翻译，重点是两种特定分子，传感蛋白（SN特异性神经肽）和细胞质聚腺苷酸化元件结合蛋白（CPEB）（一种定位mRNA），（ii）促进输入蛋白介导的信号从突触区室转运至细胞核，以及（iii）MARK信号传导至细胞核，CREB和C/EBP介导的转录，以及诱导立即早期基因C/EBP。与公共卫生的相关性：了解记忆形成过程中突触产生的信号触发细胞核中基因表达变化的机制，提供了一种确定各种疾病治疗靶点的方法，这些疾病包括精神发育迟滞、年龄相关性记忆丧失和神经精神病学疾病，如焦虑和情绪障碍。

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.