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.

项目总结/摘要 越来越多的证据表明，生长因子（GFs），曾经被认为主要在 发育，也调节突触可塑性和成年记忆。这一提议反映了一个正在进行的 我们实验室的一个研究项目，专注于GFs在记忆形成中的作用。主 本项目的重点是从一个新的角度研究GF介导的记忆形成， 考虑到它们活动的时间方面，作为形成中涉及的细胞计算的一部分， 回忆 重复试验学习，几乎所有动物都表现出的记忆获得的基本形式，包括 人，需要一个正在进行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例来研究海洋软体动物Aaprussia的重复试验训练， 仅在两次训练试验后，就能发展出用于敏化的长期记忆（LTM），但前提是它们必须分开 通过一个允许的和令人惊讶的特定时间间隔约45分钟。这个最小的系统清楚地分离 启动刺激（试验1）从重复刺激（试验2），提供无与伦比的访问时间 重复试验LTM的基础相互作用。我们将研究两种GF依赖性机制， 初步证据表明，在重复试验的核心， 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）是多步信号传导 一个特定的GF，TGFβ，我们提出类似的整合训练试验的时间。最后，在AIM 3中， 将试图建立单个ERK磷酸化的时间，TGFβ可用性， 以及两次试验训练的持续效果 该项目有望从基础科学角度和临床角度产生重大影响。 perspective.从基础科学的角度来看，Arachsia提供了一个特殊的实验系统， 证明GF介导的记忆形成与其潜在的 突触和分子机制，同时探索这些时间特征 机制等从临床的角度来看，这个项目的影响解决了心理上的一个主要挑战， 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GF信号传导直接涉及许多这些疾病，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起作用，可以提供新的 开发更具体和更有效的治疗药物的策略。