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Temporal Processing by Growth Factors in Memory Formation

记忆形成中生长因子的时间处理

基本信息

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
项目类别：
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

项目摘要

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/文摘