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，人们对神经元中突触和核事件如何在空间和时间上协调诱导记忆知之甚少。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作为研究记忆分子基础的有力准备。UCI的Carew小组将在突触和分子可塑性与骨性学习和记忆之间的直接联系方面提供专业知识，UCLA的Martin小组将在突触和细胞核之间的信号机制分析方面提供专业知识。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，即神经元的不同隔室在记忆形成过程中相互交流的机制。该项目将在三个互动层面进行分析，具体目标如下：AIM I是一种行为分析，它将利用一种新的行为准备，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是一项突触分析，检查完整中枢神经系统中反射的SN-MN成分，该准备允许指定躯体和突触事件对突触促进的贡献。在这里，我们将研究(i)局部诱导中期促进（ITF）， （ii）突触诱导长期促进（LTF）和（iii）突触和核联合诱导LTF的机制。AIM III是一项分子分析，研究了(i)突触局部翻译的记忆形成需求，重点关注两个特定分子，传感器素（一种sn特异性神经肽）和胞质聚腺苷化元件结合蛋白（CPEB），一种本地化的mRNA， （ii）促进了进口蛋白介导的信号从突触室到细胞核的运输，以及（III） MARK信号传导到细胞核，CREB和C/ ebp介导的转录。以及直接早期基因C/EBP的诱导。与公共卫生相关：了解突触产生的信号在记忆形成过程中触发细胞核基因表达变化的机制，为确定各种疾病的治疗靶点提供了一种手段，包括智力迟钝、年龄相关的记忆丧失和神经精神疾病，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.