Identifying new mechanisms of long-term memory formation

识别长期记忆形成的新机制

• 批准号: 10534033
• 负责人: Morgan Elizabeth Stevenson
• 金额: $ 6.72万
• 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/10534033
• 关键词: Address; 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; Lead; Learning; Life Style; Longevity; Maintenance; Memory; Memory Loss; Mentorship; Messenger RNA; Molecular; Mus; Nematoda; Nervous system structure; 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; 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; memory consolidation; 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.

项目摘要/摘要 衰老的一个使人衰弱的特征是认知能力的丧失，尤其是记忆力下降。阿尔茨海默氏症 疾病减少了患者的健康状况，导致独立性和社会关系丧失。这 疾病对患者和社会也是经济上的破旧。尽管患病率有所增加 阿尔茨海默氏病，基于异常记忆功能的机制尚不清楚，使得 记忆下降挑战的治疗。众所周知，需要CREB转录因子 长期记忆；但是，并非所有涉及CREB依赖性长期记忆形成的因素都是 已知。识别Creb级联的上游和下游的因素可以揭示新的机制 为了治疗和反向阿尔茨海默氏病和其他痴呆症。确定新候选人 在CREB途径中的功能并调节长期记忆巩固，该建议将检查 特定核因子（AIM 1），小型非编码RNA（AIM 2）和神经胶质因子（AIM 3）的作用（AIM 3） 依赖的长期记忆。核因子调节基因转录，因此确定哪些因素 调节内存形成至关重要。小RNA在转录和后调节基因表达 在转录上，但它们在成年神经元中的功能又没有测试。神经胶质有 最近在内存中暗示了它们，但是它们如何支持记忆合并是意外的。我们是 使用良好的老化模型系统C.秀丽隐杆线虫来确定这些因素在何处以及如何作用 随着年龄的增长来调节记忆。我们的实验室表明，内存机械，包括CREB要求 对于长期记忆巩固，在秀丽隐杆线虫中保守，我们开发了行为测定以测试 学习以及短期和长期的关联记忆。秀丽隐杆线虫是一个强大的系统 研究记忆的分子机制。有足够的遗传工具，以及 蠕虫的简单神经系统，候选基因调节记忆的机制很容易 探测。通过使用行为测定，组织特异性隔离技术和转录组方法，这些 实验将确定特定的核因子，小RNA和神经胶质因子的何处以及如何起作用 在CREB途径内，以随着年龄的增长来调节记忆形成。该提案考试的多个方面 依赖CREB的长期内存，并将确定内存所需的新候选者和途径 形成。这些发现可能会导致更好的治疗剂逆转或治疗与年龄相关的认知 包括阿尔茨海默氏症在内的神经退行性疾病病例的下降。拟议的研究计划将提供 对行为，分子和组织特异性转录组方法进行广泛培训的申请人 随着年龄的增长学习记忆。这些技术的培训和拟议的个性化训练计划将 确保申请人为独立研究者的职业做好准备，研究记忆机制 和与年龄有关的认知下降。