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

项目摘要/摘要 随着正常衰老，学习、巩固和检索信息的能力开始下降，这是一个主要风险 阿尔茨海默病(AD)和痴呆症的致病因素。除衰老外，久坐行为在 作为导致认知功能下降和加剧AD的风险因素，美国和世界排名第三。更大的和 阿尔茨海默病女性认知障碍的加速比率强调了确定 运动预防男女正常衰老和阿尔茨海默病认知衰退的机制。正如所观察到的 我们的实验室和其他人通过锻炼来促进海马体依赖的学习，这种情况通常是 亚阈值编码和记忆巩固，需要脑源性神经营养的诱导 因子(BDNF)。我们的数据表明，特定的运动模式可以激活对此的分子记忆 在久坐不动的行为期间持续的经历，并使短时间的锻炼能够再次， 诱导海马区脑源性神经营养因子，促进记忆。我们已经提出表观遗传机制在 这种运动的“分子记忆”，因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(因为几乎每一次表观遗传修饰 是一种代谢物)，并建立细胞功能的稳定变化，从而导致行为的长期变化。 这项建议中的初步数据使我们提出了新的假设，即特定的运动模式 建立一个分子反馈回路，整合乙酰-辅酶A代谢的限速方面和 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。我们在这项提案中的目标是在年老的野生型和5xFAD女性中定义 和雄性小鼠，建立分子记忆的运动参数，以考察其影响 运动的乙酰辅酶A代谢途径和组蛋白修饰，并确定 对这个分子反馈环的操作克服了突触可塑性和记忆的缺陷 在衰老和5xFAD雌雄小鼠中形成。我们提出了三个目标。目标1-确定具体程度 运动方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、组蛋白修饰和基因的影响 在衰老野生型小鼠和5xFAD小鼠中的表达。目的3-确定改善海马区的效果 乙酰辅酶A缺乏对衰老和5xFAD小鼠基因表达、突触可塑性和记忆的影响 队形。总体而言，成功完成这项建议中的研究将提高我们对 表观基因组如何整合来自新陈代谢(乙酰辅酶A动力学)和经验的信息 (锻炼)，这种相互作用如何随着年龄的增长和AD的背景而受损，以及如何从药理学角度 调节乙酰辅酶A动力学可能改善年龄和AD相关的认知功能障碍。

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.