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: 10636957
• 负责人: Marcelo Andres Wood
• 金额: $ 73.67万
• 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/10636957
• 关键词: ATAC-seq; Acceleration; 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; Dementia; Enzymes; Epigenetic Process; Equilibrium; Exercise; Feedback; Female; Frequencies; Future; Gene Expression; Gene Expression Regulation; Goals; Health; Hippocampus; Histone Acetylation; Histone H3; Impaired cognition; Impairment; Individual; Intervention; Learning; Long-Term Potentiation; Longevity; Lysine; Measures; Mediating; Memory; Metabolic; Metabolic Pathway; Metabolism; Methylation; Modeling; Modification; Molecular; Mus; Neurons; Pathway interactions; Pattern; 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; pharmacologic; 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.

项目总结/摘要 学习、巩固和检索信息的能力开始随着正常的衰老而下降，这是一个主要的风险 阿尔茨海默病（AD）和痴呆症的因素。除了衰老，久坐行为在 在美国和世界上排名第三，是导致认知能力下降和加重AD的危险因素。更大和 AD女性认知功能障碍的加速率强调了识别 运动预防正常衰老和AD中男女认知能力下降的机制。观察到 通过我们的实验室和其他机构，在通常情况下， 编码和记忆巩固的亚阈值，需要诱导脑源性神经营养素 脑源性神经营养因子（BDNF）。我们的数据表明，特定的锻炼模式可以为此建立一种“分子记忆”。 在久坐行为期间持续存在的体验，并允许进行短暂的锻炼，再次， 诱导海马BDNF和促进记忆。我们已经提出，表观遗传机制介导 这种“分子记忆”的运动，作为表观基因组代表了一个信号转导平台， 能够编码过去的经验，当前的代谢状态（因为几乎每一个表观遗传修饰 是一种代谢物），并建立稳定的细胞功能变化，导致长期的行为变化。 在这个提议中的初步数据使我们提出了一个新的假设，即特定的运动模式 建立整合乙酰辅酶A代谢限速方面的分子反馈回路， 组蛋白乙酰化/甲基化机制调节长期记忆所需基因表达 形成和突触可塑性。我们在本提案中的目标是定义衰老野生型和5xFAD女性 和雄性小鼠，运动参数，建立分子记忆，以调查的影响， 运动对乙酰辅酶A代谢途径和组蛋白修饰的影响，并确定是否 对这种分子反馈回路的操纵克服了突触可塑性和记忆的缺陷 在衰老和5xFAD雌性和雄性小鼠中形成。我们提出三个目标。目标1 -确定具体程度 运动模式影响衰老野生型小鼠和5xFAD小鼠的突触可塑性和记忆形成。 目的2 -确定运动对乙酰辅酶A代谢途径、组蛋白修饰和基因表达的影响。 在衰老野生型小鼠和5xFAD小鼠中表达。目的3 -确定改善海马的效果 衰老和5xFAD小鼠中乙酰辅酶A缺乏对基因表达、突触可塑性和记忆的影响 阵总的来说，成功完成本提案中的研究将提高我们对 表观基因组如何整合来自代谢（乙酰辅酶A动力学）和经验的信息 （运动），这种相互作用如何随着年龄的增长和AD的背景下受损，以及药理学如何 乙酰辅酶A动力学的调节可以改善年龄和AD相关的认知功能障碍。