Uncovering brain-wide molecular determinants of individual memory performance across lifespan

揭示个体一生记忆表现的全脑分子决定因素

• 批准号: 10472237
• 负责人: Rachel Nicole Arey
• 金额: $ 142.77万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10472237
• 关键词: Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Behavior; Behavioral; Brain; Brain region; Caenorhabditis elegans; Complex; Disease; Exhibits; Genomics; Human; Individual; Invertebrates; Lead; Learning; Longevity; Memory; Memory Loss; Modeling; Molecular; Nervous System Physiology; Nervous system structure; Neurodevelopmental Disorder; Neurons; Neurosciences; Organism; Pathway interactions; Performance; Physiological; Process; Synapses; System; Techniques; Technology; Training; Validation; Work; age related; epigenomics; genetic manipulation; improved; individual variation; insight; long term memory; nervous system disorder; novel therapeutics; preservation; prevent; response; therapy development; transcriptome; transcriptomics

Project Summary One of the most crucial functions of an organism's nervous system is the ability to form long-term memories. However, the molecular mechanisms underlying long-term memory formation have yet to be fully elucidated, due to the fact that memory is a complex process requiring a coordinated response across multiple neuron types and brain regions. Moreover, it is unknown how these essential memory components contribute to variability in individual memory performance, which is particularly prominent in the context of age-related memory loss. Identifying the molecules involved in these processes is important not only to gain insight into normal brain function but can also lead to an understanding of disease states such as age-related cognitive decline, neurodevelopmental disorders, and Alzheimer's disease. A major barrier to identifying the molecular regulators of long-term memory is the sheer complexity of the mammalian nervous system; therefore, we propose to use the invertebrate model C. elegans, in which all neurons and synaptic connections in the organism are already known, to molecularly “define memory.” Here we propose to combine a number of cutting-edge techniques with behavior in this simple system to generate the most precise snapshot to date of the nervous system-wide molecular changes that are necessary for memory formation. In Project 1, we will combine behavioral training, spatial transcriptomics, new techniques that we have developed to simultaneously profile transcriptomes of somatic and synaptic subcompartments, and temporally and spatially precise gene manipulation to reveal the most complete molecular snapshot of mechanisms necessary for memory formation to date. In Project 2, we will use unbiased behavioral profiling to uncover strategies of variability in memory performance, which we will used to predict individuals likely to exhibit improved memory performance with age. We will then use epigenomics and genomics techniques to determine which essential memory components may regulate individual memory performance, followed by functional validation in the context of age-related memory loss. Combined, the proposed work will not only advance our understanding of one of the fundamental questions in the field of neuroscience but will also reveal new pathways that may be disrupted in neurological disorders, along with new targets for the development of therapies that prevent disrupted memory due to neurological disease.

项目摘要 生物体神经系统最关键的功能之一是形成长期记忆的能力。 但是，长期记忆形成的基础机制尚未完全阐明， 由于记忆是一个复杂的过程，需要在多个神经元上进行协调的响应 类型和大脑区域。此外，这些基本记忆成分如何贡献 单个内存性能的可变性，这在与年龄有关的背景下特别突出 记忆丧失。确定这些过程中涉及的分子不仅要深入了解 正常的大脑功能，但也可能导致对疾病状态（例如与年龄有关的认知）的理解 衰落，神经发育障碍和阿尔茨海默氏病。识别分子的主要障碍 长期记忆的调节因子是哺乳动物神经系统的纯粹复杂性。因此，我们 提出使用无脊椎动物模型C.秀丽隐杆线虫的提议，其中所有神经元和突触连接中的所有神经元和突触连接 有机体已经知道，以“定义记忆”。在这里，我们建议将许多 在这个简单系统中，具有行为的尖端技术，以生成迄今为止最精确的快照 神经系统范围内的分子变化是记忆形成所必需的。在项目1中，我们将 结合行为训练，空间转录组学，我们已经开发的新技术 体细胞和突触子组门的轮廓转录组，以及临时和空间精确的基因 操纵以揭示记忆形成所需机制的最完整的分子快照 迄今为止。在项目2中，我们将使用公正的行为分析来揭示内存可变性的策略 性能，我们将用来预测可能随着年龄的增长而表现出改善的记忆表现。 然后，我们将使用表观基因组学和基因组学技术来确定哪些必需记忆成分 可以调节个体记忆力，然后在与年龄相关的背景下进行功能验证 记忆丧失。结合在一起，拟议的工作不仅会提高我们对其中一项基本的理解 神经科学领域的问题，但也将揭示可能在神经学中破坏的新途径 疾病，以及开发疗法的新目标，以防止由于 神经疾病。