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: 10397503
• 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/10397503
• 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; 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.

项目概要/摘要 越来越多的证据表明，生长因子（GF）曾经被认为主要在 发育，还调节成人的突触可塑性和记忆。该提案反映了正在进行的 我们实验室的研究项目重点关注 GF 在记忆形成中的作用。初级 当前项目的重点是从新的角度研究 GF 介导的记忆形成， 考虑到它们活动的时间方面，作为形成过程中涉及的细胞计算的一部分 回忆。 重复尝试学习，几乎所有动物都表现出的记忆获取的基本形式，包括 人，需要持续的刺激和先前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式来研究海洋软体动物海兔的重复试验训练， 仅在两次训练试验后就可以形成敏感化的长期记忆（LTM），但前提是它们是分开的 大约 45 分钟的允许且令人惊讶的特定时间间隔。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），提供无与伦比的时间访问 重复试验 LTM 的相互作用。我们将研究两种 GF 依赖性机制 初步证据表明，对重复试验核心的时间处理有显着贡献 学习。第一个（在 AIM 1 中探索）是 GF 依赖性磷酸化的分布式机制 细胞外调节激酶（ERK）。第二种机制（在 AIM 2 中探索）是多步信号 特定的 GF，TGFβ，我们建议类似地整合训练试验的时间。最后，在 AIM 3 中我们 将尝试在单个 ERK 磷酸化时间、TGFβ 可用性、 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角度产生重大影响 看法。从基础科学的角度来看，Aplysia 提供了一个特殊的实验系统， 证明 GF 介导的记忆形成及其潜在因素之间因果关系的潜力 突触和分子机制，同时探索这些的时间特征 机制。从临床角度来看，该项目的影响解决了心理方面的重大挑战 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。 GF 信号传导与许多此类疾病直接相关，并且由于 GF 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发现 开发更具体和更有效的治疗药物的策略。