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 生物体神经系统最重要的功能之一是形成长期记忆的能力。 然而，长期记忆形成的分子机制尚未完全阐明， 由于记忆是一个复杂的过程，需要跨多个神经元的协调反应 类型和大脑区域。此外，还不清楚这些基本的记忆成分是如何贡献的 个人记忆表现的变异性，这在与年龄有关的背景下尤为突出 失忆。确定参与这些过程的分子不仅对于洞察 大脑功能正常，但也可能导致对疾病状态的理解，如与年龄相关的认知 衰弱、神经发育障碍和阿尔茨海默病。识别分子的一个主要障碍 长期记忆的调节是哺乳动物神经系统的绝对复杂性；因此，我们 建议使用无脊椎动物模型线虫，在该模型中，所有神经元和突触连接在 生物体已经为人所知，从分子上“定义记忆”。在这里，我们建议将多个 在这个简单的系统中使用尖端技术和行为来生成迄今为止最精确的快照 整个神经系统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，空间转录学，我们同时开发的新技术 体细胞和突触亚室的转录谱，以及时间和空间上的精确基因 揭示记忆形成所需机制的最完整的分子快照 到目前为止。在项目2中，我们将使用无偏见的行为分析来揭示记忆中的可变性策略 表现，我们将用它来预测个人可能会随着年龄的增长表现出更好的记忆表现。 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重要的记忆成分 可以调节个体的记忆表现，然后在与年龄相关的背景下进行功能验证 失忆。综上所述，建议的工作不仅将推进我们对其中一个基本问题的认识 神经科学领域的问题，但也将揭示神经学中可能被破坏的新途径 障碍，以及开发新的靶点，以防止由于 神经系统疾病。