Investigating the interface of epigenetics and metabolism underlying memory formation in the adult, aging, and AD brain

研究成人、衰老和 AD 大脑中记忆形成的表观遗传学和代谢界面

• 批准号: 10420533
• 负责人: Carl Wayne Cotman
• 金额: $ 66.6万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420533
• 关键词: ATAC-seq; Acetyl Coenzyme A; Acetyl-CoA Carboxylase; Acetylation; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease risk; Behavior; Brain; Brain-Derived Neurotrophic Factor; Cell Culture Techniques; Cell Nucleus; Cell physiology; Censuses; Chromatin; Cognition; Cognitive; Data; Enzymes; Epigenetic Process; Equilibrium; Exercise; Feedback; Female; Foundations; Frequencies; Future; Gene Expression; Gene Expression Regulation; Goals; Health; Hippocampus (Brain); Histone Acetylation; Histone H3; Impaired cognition; Impairment; Individual; Intervention; Lead; Learning; Long-Term Potentiation; Longevity; Lysine; Measures; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Modification; Molecular; Mus; Neurons; Pathway interactions; Pattern; Pharmacology; Population; Regulation; Reporting; Research; Risk Factors; Signal Transduction; Synaptic Transmission; Synaptic plasticity; Therapeutic; Time; United States; Update; Wild Type Mouse; Woman; Work; age related; aged; aging brain; aging hippocampus; brain health; design; epigenetic regulation; epigenome; experience; gene repression; histone modification; improved; insight; long term memory; male; memory consolidation; memory process; modifiable risk; mouse model; normal aging; novel; novel strategies; prevent; sedentary lifestyle; sex; spatial memory; therapeutic development; transcriptome sequencing

Project Summary/Abstract The ability to learn, consolidate and retrieve information begins to decline with normal aging, a major risk factor for Alzheimer’s Disease (AD) and dementia. In addition to aging, sedentary behavior ranks first in the US and third in the world as a risk factor for causing cognitive decline and exacerbating AD. Greater and accelerated rates of cognitive impairment in women with AD underscore the need for identifying the mechanisms by which exercise prevents cognitive decline in normal aging and AD in both sexes. As observed by our labs and others, hippocampus-dependent learning is facilitated by exercise in situations that are usually subthreshold for encoding and memory consolidation and requires the induction of brain-derived neurotrophic factor (BDNF). Our data suggest that specific exercise patterns can engage a ‘molecular memory’ for that experience that persists through periods of sedentary behavior and enables a short exercise session, to again, induce hippocampal BDNF and facilitate memory. We have proposed that epigenetic mechanisms mediate this “molecular memory” of exercise, as the epigenome represents a signal transduction platform that is capable of encoding past experience, current metabolic states (because nearly every epigenetic modification is a metabolite) and establishing stable changes in cell function that lead to long-term changes in behavior. Preliminary data in this proposal lead us to propose the novel hypothesis that specific patterns of exercise establish a molecular feedback loop that integrates rate-limiting aspects of acetyl-CoA metabolism and histone acetylation/methylation mechanisms to modulate gene expression required for long-term memory formation and synaptic plasticity. Our goal in this proposal is to define, in aging wild type and 5xFAD female and male mice, the exercise parameters that establish a molecular memory, to investigate the effect of exercise on acetyl-CoA metabolic pathways and histone modifications and to determine whether manipulations to this molecular feedback loop overcome deficiencies in synaptic plasticity and memory formation in aging and 5xFAD female and male mice. We propose three Aims. Aim 1 - Determine how specific exercise patterns affect synaptic plasticity and memory formation in aging wild type mice and 5xFAD mice. Aim 2 - determine the effect of exercise on acetyl-CoA metabolic pathways, histone modification, and gene expression in aging wild type mice and 5xFAD mice. Aim 3 - determine the effect of ameliorating hippocampal acetyl-CoA deficiencies in aging and 5xFAD mice on gene expression, synaptic plasticity and memory formation. Overall, successful completion of the research in this proposal will improve our understanding of how the epigenome integrates information from metabolism (acetyl-CoA dynamics) and experience (exercise), how this interplay becomes impaired with aging and in the context of AD, and how pharmacological modulation of acetyl-CoA dynamics may improve age- and AD-related cognitive dysfunction.

项目摘要/摘要 随着正常衰老，学习，合并和检索信息的能力开始下降，这是一个主要风险 阿尔茨海默氏病（AD）和痴呆症的因素。除了衰老，久坐行为在 美国和世界上的第三个是导致认知能力下降和加剧广告的危险因素。更大和 AD妇女的认知障碍率加速了，强调了确定的需求 运动的机制可以阻止两性正常衰老和AD的认知能力下降。如观察到的 通过我们的实验室和其他人，海马依赖性学习是通过通常在通常的情况下进行的 用于编码和记忆巩固的子阈值，需要诱导脑衍生的神经营养 因子（BDNF）。我们的数据表明，特定的运动模式可以参与“分子记忆” 在久坐行为的时期内一直存在的经验，并使短暂的锻炼会再次 诱导海马BDNF和最喜欢的记忆。我们提出表观遗传机制介导 锻炼的这种“分子记忆”，因为表观基因组代表一个信号传输平台 能够编码过去的代谢状态（因为几乎所有表观遗传修饰）能够编码过去的经验 是一种代谢物），并在细胞功能上建立了稳定的变化，从而导致行为长期变化。 该提案中的初步数据使我们提出了一种新的假设，即锻炼的特定模式 建立一个分子反馈回路，该回路整合了乙酰-COA代谢和 组蛋白乙酰化/甲基化机制调节长期记忆所需的基因表达 形成和突触可塑性。我们在此提案中的目标是定义野生型和5xfad女性的定义 和雄性小鼠，即建立分子记忆的运动参数，以研究 在乙酰辅酶A代谢途径和Hisstone修饰上进行运动，并确定是否是否 操纵此分子反馈回路克服突触可塑性和记忆力的缺陷 衰老和5xfad雌性和雄性小鼠的形成。我们提出了三个目标。目标1-确定如何具体 运动模式会影响衰老的野生型小鼠和5xFAD小鼠的合成可塑性和记忆形成。 AIM 2-确定运动对乙酰-COA代谢途径，组蛋白修饰和基因的影响 在衰老的野生型小鼠和5xFAD小鼠中的表达。 AIM 3-确定改善海马的效果 衰老和5xFAD小鼠的乙酰-COA缺陷在基因表达，突触可塑性和记忆力 形成。总体而言，该提案中成功完成研究将提高我们对 表观基因组如何整合新陈代谢（乙酰-COA动力学）和经验的信息 （练习），这种相互作用如何因衰老和AD的背景而受到损害，以及药理学如何 乙酰-COA动力学的调节可能会改善年龄和广告相关的认知功能障碍。