Identifying new mechanisms of long-term memory formation

识别长期记忆形成的新机制

• 批准号: 10763134
• 负责人: Morgan Elizabeth Stevenson
• 金额: $ 0.25万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10763134
• 关键词: Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Behavioral; Behavioral Assay; Biological Assay; Biological Models; CREB1 gene; Caenorhabditis elegans; Candidate Disease Gene; Chromatin; Code; Cognitive aging; Data; Dementia; Disease; Emotional; Ensure; Family; Fellowship; Financial cost; Gene Expression; Genes; Genetic; Genetic Transcription; Impaired cognition; Invertebrates; Knowledge; Learning; Life Style; Longevity; Maintenance; Memory; Memory Loss; Mentorship; Messenger RNA; Molecular; Mus; Nematoda; Nervous System; Neurodegenerative Disorders; Neuroglia; Neurons; Nuclear; Nuclear Receptors; Organism; Pathologic; Pathology; Pathway interactions; Patients; Prevalence; Protein Biosynthesis; Proteins; RNA Interference; Research; Research Personnel; Risk; Risk Factors; Risk Reduction; Role; Site; Small RNA; Societies; Supporting Cell; System; Techniques; Testing; Therapeutic; Tissues; Training; Transcript; Untranslated RNA; Vertebrates; career; cognitive ability; cognitive function; effective therapy; experimental study; healthspan; improved; infancy; long term memory; member; memory consolidation; posttranscriptional; programs; rapid testing; small molecule; social relationships; therapeutic target; tool; transcription factor; transcriptomics

Project Summary/Abstract One debilitating feature of aging is the loss of cognitive abilities, especially memory decline. Alzheimer’s disease reduces the healthspan of patients, resulting in a loss of independence and social relationships. The disease is also financially burdensome to patients and society. Despite the increase in the prevalence of Alzheimer’s disease, the mechanisms that underlie aberrant memory function are unclear, making the treatment of memory decline challenging. It is well established that the CREB transcription factor is required for long-term memory; however, not all factors involved in CREB-dependent long-term memory formation are known yet. Identifying factors upstream and downstream in the CREB cascade could reveal new mechanisms for the treatment and reversal of Alzheimer’s disease and other dementias. To identify new candidates that function within the CREB pathway and regulate long-term memory consolidation, this proposal will examine the role of specific nuclear factors (Aim 1), small non-coding RNAs (Aim 2), and glial factors (Aim 3) in CREB- dependent long-term memory. Nuclear factors regulate gene transcription, so identifying which factors modulate memory formation is critical. Small RNAs regulate gene expression transcriptionally and post- transcriptionally, but their function in adult neurons and, in turn memory, has not been tested. Glia have recently been implicated in memory, but how they support memory consolidation is largely unexplored. We are using the well-established aging model system C. elegans to determine where and how these factors function to regulate memory with age. Our lab has shown that the memory machinery, including the CREB requirement for long-term memory consolidation, is conserved in C. elegans and we developed behavioral assays to test learning and short-term and long-term associative memory. C. elegans serves as a powerful system to investigate the molecular mechanisms of memory. There are ample genetic tools available, and, with the worm’s simple nervous system, mechanisms by which candidate genes regulate memory can be easily probed. By using behavioral assays, tissue-specific isolation techniques, and transcriptomic approaches, these experiments will determine where and how specific nuclear factors, small RNAs, and glial factors function within the CREB pathway to regulate memory formation with age. This proposal examines multiple facets of CREB-dependent long-term memory and will identify new candidates and pathways required for memory formation. These findings could lead to better therapeutics for reversing or treating age-related cognitive decline in cases of neurodegenerative disease, including Alzheimer’s. The proposed research plan will provide the applicant with extensive training in behavioral, molecular, and tissue-specific transcriptomic approaches to study memory with age. The training in these techniques and the proposed individualized mentorship plan will ensure the applicant is prepared for a career as an independent investigator, studying mechanisms of memory and age-related cognitive decline.

项目概要/摘要 衰老的一个令人衰弱的特征是认知能力的丧失，尤其是阿尔茨海默氏症的记忆力下降。 疾病会缩短患者的健康寿命，导致患者丧失独立性和社会关系。 尽管这种疾病的患病率有所增加，但仍给患者和社会带来经济负担。 阿尔茨海默病是导致记忆功能异常的机制尚不清楚，因此 众所周知，记忆衰退的治疗需要 CREB ​​转录因子。 长期记忆；然而，并非所有参与 CREB ​​依赖性长期记忆形成的因素都是 识别 CREB ​​级联上游和下游的因素可以揭示新的机制。 用于治疗和逆转阿尔茨海默病和其他痴呆症。 CREB ​​通路内的功能并调节长期记忆巩固，该提案将检查 特定核因子（目标 1）、小非编码 RNA（目标 2）和神经胶质因子（目标 3）在 CREB-中的作用 依赖的长期记忆。核因子调节基因转录，因此确定哪些因子。 调节记忆形成至关重要。 转录，但它们在成年神经元以及神经胶质细胞中的功能尚未得到测试。 最近与内存有关，但它们如何支持内存整合在很大程度上尚未被探索。 使用完善的衰老模型系统线虫来确定这些因素在何处以及如何发挥作用 我们的实验室已经证明了记忆机制，包括 CREB ​​的要求。 用于长期记忆巩固的，在秀丽隐杆线虫中是保守的，我们开发了行为分析来测试 学习以及短期和长期联想记忆是一个强大的系统。 研究记忆的分子机制有很多可用的遗传工具。 蠕虫的简单神经系统，候选基因调节记忆的机制可以很容易地 通过使用行为测定、组织特异性分离技术和转录组学方法，这些。 实验将确定特定核因子、小RNA和神经胶质因子在何处以及如何发挥作用 该提案研究了 CREB ​​通路中随着年龄的增长调节记忆形成的多个方面。 CREB依赖的长期记忆并将识别记忆所需的新候选者和途径 这些发现可能会带来更好的疗法来逆转或治疗与年龄相关的认知能力。 拟议的研究计划将提供包括阿尔茨海默病在内的神经退行性疾病病例的减少。 申请人在行为、分子和组织特异性转录组学方法方面接受过广泛的培训 随着年龄的增长研究记忆力。 确保申请人为独立调查员的职业生涯做好准备，研究记忆机制 以及与年龄相关的认知能力下降。