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.

项目总结/摘要 衰老的一个令人衰弱的特征是认知能力的丧失，特别是记忆力下降。阿尔茨海默 疾病缩短了患者的健康寿命，导致丧失独立性和社会关系。的 疾病也给患者和社会带来经济负担。尽管艾滋病的流行率有所上升， 阿尔茨海默氏病，导致记忆功能异常的机制尚不清楚， 记忆力衰退的治疗具有挑战性。已经确定CREB转录因子是 然而，并非所有参与CREB依赖性长期记忆形成的因素都是 已知的。确定CREB级联反应的上游和下游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。确定新的候选人， 在CREB通路中发挥作用并调节长期记忆巩固，这项提案将研究 特异性核因子（Aim 1）、小的非编码RNA（Aim 2）和胶质细胞因子（Aim 3）在CREB-1中的作用 依赖性长期记忆核因子调节基因转录，因此确定哪些因子 调节记忆的形成至关重要。小RNA在转录和转录后调节基因表达。 但是它们在成年神经元和记忆中的功能还没有被测试过。胶质细胞有 最近被认为与记忆有关，但它们如何支持记忆巩固在很大程度上是未知的。我们 使用成熟的老化模型系统C.来确定这些因子在哪里以及如何发挥作用 来调节记忆力我们的实验室已经表明，记忆机制，包括CREB的要求， 对于长期记忆巩固，在C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的联想记忆。C. elegans作为一个强大的系统， 研究记忆的分子机制。有足够的遗传工具可用，而且，随着 蠕虫简单的神经系统，候选基因调节记忆的机制可以很容易地 试探通过使用行为分析、组织特异性分离技术和转录组学方法， 实验将确定特定的核因子、小RNA和神经胶质因子在何处以及如何发挥作用 在CREB通路中调节随着年龄增长的记忆形成。本提案审查了 CREB依赖的长期记忆，并将确定新的候选人和记忆所需的途径 阵这些发现可能会导致更好的治疗方法来逆转或治疗与年龄相关的认知功能障碍。 包括阿尔茨海默氏症在内的神经退行性疾病病例的减少。研究计划将提供 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， 研究随着年龄增长的记忆力。这些技术的培训和拟议的个性化指导计划将 确保申请人为独立调查员的职业生涯做好准备，研究记忆的机制 以及与年龄相关的认知能力下降