Temporal Processing by Growth Factors in Memory Formation

记忆形成中生长因子的时间处理

• 批准号: 10091527
• 负责人: Thomas J Carew
• 金额: $ 47.64万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10091527
• 关键词: Address; Adult; Afferent Neurons; Animals; Aplysia; Attention; Binding; Biological; Biological Models; Brain; Cell Nucleus; Cells; Clinical; Cognition Disorders; Cytosol; Data; Development; Disease; Event; Exhibits; Extracellular Protein; Extracellular Signal Regulated Kinases; Extracellular Space; Genetic Transcription; Goals; Growth Factor; Heart; Human; Laboratories; Learning; Ligands; MEKs; Mediating; Memory; Mental Health; Mitogen-Activated Protein Kinases; Molecular; Nature; Neurodegenerative Disorders; Neurosciences; Nuclear; Pathway interactions; Pattern; Phosphorylation; Phosphotransferases; Physiologic pulse; Process; Publishing; Regulation; Research; Role; Series; Serotonin; Shock; Signal Transduction; Site; Specificity; Stimulus; Synapses; Synaptic plasticity; System; Testing; Therapeutic Agents; Time; Training; Transforming Growth Factor beta; Up-Regulation; Work; analog; base; causal model; detector; experimental study; extracellular; inhibitor/antagonist; insight; long term memory; man; memory acquisition; nervous system disorder; novel; novel strategies; programs; response; therapeutically effective; time interval; training project; virtual

PROJECT SUMMARY/ABSTRACT A growing body of evidence suggests that growth factors (GFs), once considered to function mainly in development, also regulate synaptic plasticity and memory in the adult. This proposal reflects on an ongoing research program in our laboratory that has focused on the role of GFs in memory formation. The primary focus of this current project is to examine GF-mediated memory formation from a novel perspective, which takes into account the temporal aspect of their activity as part of the cellular computation involved in forming memories. Repeated-trial learning, a fundamental form of memory acquisition exhibited by virtually all animals, including man, requires a temporal interaction between an ongoing stimulus and the delayed effects of a previous stimulus. We will use a powerful paradigm to study repeated-trial training in the marine mollusk Aplysia, which develops long-term memory (LTM) for sensitization after only two training trials, but only if they are separated by a permissive and surprisingly specific time interval of ~45 min. This minimal system clearly separates the initiating stimulus (Trial 1) from the repeated stimulus (Trial 2), providing unparalleled access to the temporal interactions underlying repeated-trial LTM. We will investigate two GF-dependent mechanisms that our preliminary evidence suggests contribute significantly to temporal processing at the heart of repeated-trial learning. The first (explored in AIM 1) is a distributed mechanism for GF-dependent phosphorylation of extracellularly regulated kinase (ERK). The second mechanism (explored in AIM 2) is the multi-step signaling of a specific GF, TGFβ, which we propose similarly integrates the timing of training trials. Finally, in AIM 3 we will try to establish causal connections between the timing of single ERK phosphorylation, TGFβ availability, and the persistent effects of two-trial training The project holds promise for significant impact from both a basic scientific perspective and a clinical perspective. From a basic scientific perspective, Aplysia provides an exceptional experimental system that has the potential to demonstrate causal linkages between GF-mediated memory formation and its underlying synaptic and molecular mechanisms, while simultaneously exploring the temporal features of those mechanisms. And from a clinical perspective, the impact of this project addresses a major challenge in mental health: to understand and treat the devastating cognitive disorders that accompany neurodegenerative diseases. GF signaling has been directly implicated in many of these diseases and, since GFs are extracellular proteins, understanding when and where they act in the brain during memory formation could provide novel strategies for developing more specific and more effective therapeutic agents.

项目摘要/摘要 越来越多的证据表明，生长因子(GFS)曾被认为主要在 发育，也调节突触的可塑性和成年人的记忆。这项提案反映了一项正在进行的 我们实验室的一项研究计划，重点是GFS在记忆形成中的作用。初级阶段 本项目的重点是从一个新的角度来研究GF介导的记忆形成，这是 考虑到它们活动的时间方面，作为形成过程中所涉及的细胞计算的一部分 回忆。 重复试验学习是记忆获得的一种基本形式，几乎所有动物都表现出这种形式，包括 人类，需要持续刺激和先前刺激的延迟效应之间的时间相互作用 刺激。我们将使用一个强大的范例来研究海洋软体动物海兔的重复试验训练，这是 仅在两次训练试验后就形成了用于敏化的长期记忆(LTM)，但只有在它们分开的情况下 允许且令人惊讶的特定时间间隔为~45分钟。这个最小的系统清楚地将 从重复刺激(试验2)开始刺激(试验1)，提供无与伦比的进入时间的通道 重复试验LTM背后的相互作用。我们将研究我们的两个依赖于GF的机制 初步证据表明，在重复试验的核心环节，时间处理有重要作用 学习。第一个(在目标1中探索)是一种依赖于生长因子的磷酸化的分布机制。 细胞外调节激酶(ERK)。第二种机制(在AIM 2中探索)是多步骤信令 一种特定的GF，转化生长因子β，我们提出的类似地整合了训练试验的时间。最后，在AIM 3中，我们 将尝试建立单个ERK磷酸化的时间、转化生长因子β可获得性、 以及两次试验训练的持久效果 该项目有望从基础科学角度和临床应用两方面产生重大影响 透视。从基础科学的角度来看，海兔提供了一个特殊的实验系统，它具有 证明生长因子介导的记忆形成及其潜在原因之间的因果联系的可能性 突触和分子机制，同时探索这些细胞的时间特征 机制。从临床的角度来看，这个项目的影响解决了精神上的一个主要挑战 健康：了解和治疗伴随神经退行性疾病的破坏性认知障碍 疾病。生长因子信号与许多这些疾病有直接关系，而且由于GFS是细胞外的 蛋白质，了解它们在记忆形成过程中何时何地在大脑中发挥作用，可以提供新的 开发更具体和更有效的治疗剂的战略。