Identifying new mechanisms of long-term memory formation

项目摘要/摘要 衰老的一个令人衰弱的特征是认知能力的丧失，特别是记忆力的下降。阿尔茨海默氏症 疾病缩短了患者的健康寿命，导致丧失独立性和社会关系。这个 疾病也给患者和社会带来了经济负担。尽管流行性出血热患病率上升 阿尔茨海默病，记忆功能异常的机制尚不清楚，使 治疗记忆力衰退具有挑战性。众所周知，CREB转录因子是 长时记忆；然而，并非所有参与CREB依赖的长时记忆形成的因素都是 目前还不知道。识别CREB级联中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。要确定新的候选人， 在CREB通路中的作用和调节长期记忆巩固，这项建议将研究 特异性核因子(目标1)、小分子非编码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 调节记忆形成是至关重要的。小RNA在转录和转录后调控基因表达 但它们在成年神经元中的功能，以及反过来的记忆，还没有得到测试。神经胶质细胞有 最近与记忆有关，但它们如何支持记忆巩固在很大程度上还没有被探索。我们是 使用成熟的衰老模型系统线虫来确定这些因素在哪里发挥作用以及如何发挥作用 随着年龄的增长来调节记忆。我们的实验室已经证明了记忆机制，包括CREB要求 对于长期的记忆巩固，在线虫中是保守的，我们开发了行为分析来测试 学习与短期和长期联想记忆。线虫是一种强大的系统 研究记忆的分子机制。有足够的遗传工具可用，而且有了 蠕虫简单的神经系统，候选基因调节记忆的机制很容易 探查过了。通过使用行为分析、组织特异性分离技术和转录本方法，这些 实验将确定特定的核因子、小RNA和神经胶质因子在哪里以及如何发挥作用。 在CREB通路中调节随年龄增长的记忆形成。这份提案从多个方面考察了 CREB依赖的长期记忆，并将识别新的候选和记忆所需的途径 队形。这些发现可能导致逆转或治疗年龄相关认知的更好疗法 神经退行性疾病的病例减少，包括阿尔茨海默氏症。拟议的研究计划将提供 在行为、分子和组织特异性转录方法方面接受过广泛培训的申请者 研究随年龄增长的记忆。这些技巧的培训和拟议的个性化指导计划将 确保申请人为独立研究人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。

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.