Exercise-induced epigenetic mechanisms underlying neuronal plasticity and cognition

运动诱发的神经元可塑性和认知的表观遗传机制

基本信息

批准号：
9007752
负责人：
Carl Wayne Cotman
金额：
$ 60.67万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2021-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9007752
关键词：
Affect Aging Alzheimer&apos s Disease Animals Automobile Driving Behavior Behavioral Brain Brain-Derived Neurotrophic Factor ChIP-seq Cognition Cognitive Coupled DNA Polymerase II Data Dose Epigenetic Process Event Exercise Foundations Frequencies Gene Expression Goals HDAC3 gene Health Hippocampus (Brain)Histone Acetylation Human Impaired cognition Investigation Lead Location Memory Modification Molecular Mus Neurobiology Neuronal Plasticity Pattern Pharmacologic Substance Phosphorylation Site Physical Exercise Physical activity Process RNA Regulation Research Risk Factors Role Site Stimulus Synaptic plasticity Testing Time Translating aged base cognitive function cognitive performance experience flexibility genome-wide histone methylation histone modification improved inhibitor/antagonist long term memory modifiable risk neurobiological mechanism next generation sequencing novel public health relevance research study sedentary sedentary lifestyle transcriptome sequencing young adult

Affect Aging Alzheimer&apos s Disease Animals Automobile Driving Behavior Behavioral Brain Brain-Derived Neurotrophic Factor ChIP-seq Cognition Cognitive Coupled DNA Polymerase II Data Dose Epigenetic Process Event Exercise Foundations Frequencies Gene Expression Goals HDAC3 gene Health Hippocampus (Brain)Histone Acetylation Human Impaired cognition Investigation Lead Location Memory Modification Molecular Mus Neurobiology Neuronal Plasticity Pattern Pharmacologic Substance Phosphorylation Site Physical Exercise Physical activity Process RNA Regulation Research Risk Factors Role Site Stimulus Synaptic plasticity Testing Time Translating aged base cognitive function cognitive performance experience flexibility genome-wide histone methylation histone modification improved inhibitor/antagonist long term memory modifiable risk neurobiological mechanism next generation sequencing novel public health relevance research study sedentary sedentary lifestyle transcriptome sequencing young adult

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项目摘要

DESCRIPTION (provided by applicant): Exercise participation is an important determinant of cognitive health, particularly in aging. In fact, sedentary behavior has been singled out as the greatest modifiable risk factor causing cognitive decline and Alzheimer's Disease in the US, and ranks third worldwide. Despite the importance of physical activity and exercise, the exercise parameters that provide optimal cognitive health are not well defined, particularly with respect to the frequency and duration of exercise needed. Our data and others suggest that the exercise conditions that activate the underlying neurobiological mechanisms that enhance cognitive function can be flexible, and allow for intermittent and spaced exercise bouts. We propose the novel hypothesis that exercise establishes a type of "molecular memory" for the exercise stimulus, which regulates the frequency and duration of subsequent intermittent exercise that is needed to maintain cognitive benefits. The molecular memory remains during a defined temporal window, such that subsequent exercise (even low-level exercise normally sub-threshold to enhance long-term memory formation) can capitalize on the neurobiological events established by the initial experience of exercise, thus maintaining the benefits of exercise on cognitive function. We hypothesize that epigenetic mechanisms are fundamental for the molecular memory phenomenon, and serve to alter transcriptional processes through histone modifications to create stable changes in neuronal plasticity and giving rise to stable changes in behavior. Our goal in this proposal is to define the exercise parameters that establish a molecular memory, investigate the underlying mechanisms that enable exercise to more efficiently promote enhanced cognition, and explore if pharmaceutical manipulation can extend the molecular window established by exercise. Because benefits of exercise for improving cognition, particularly hippocampal function, rely in large part from induction of the key plasticiy molecule `brain-derived neurotrophic factor' (BDNF), we focus on BDNF induction and epigenetic modifications that control BDNF regulation. We propose three Aims. Aim 1 - Determine the effective exercise patterns and molecular memory temporal windows that result in long-term memory formation. Aim 2 - Determine the histone modification patterns resulting from exercise that establish a molecular memory for BDNF expression. Aim 3 - Determine if cognitive benefits of exercise can be prolonged by pharmacological manipulation of the epigenetic molecular memory established by exercise, using a novel selective histone deacetylase 3 (HDAC3) inhibitor. Overall, our research in this proposal will serve as a foundation for ultimately translating to humans the exercise parameters needed to maintain enhanced cognitive function.

描述（由适用提供）：锻炼参与是认知健康的重要决定因素，尤其是在衰老中。实际上，久坐的行为已被视为最大的可修改风险因素，导致认知能力下降和美国阿尔茨海默氏病，在全球范围内排名第三。尽管有体育锻炼和锻炼的重要性，但提供最佳认知健康的运动参数尚未得到很好的定义，尤其是在需要运动的频率和持续时间。我们的数据和其他数据表明，激活增强认知功能的基本神经生物学机制的运动条件可以灵活，并允许间歇性和间隔的运动曲线。我们提出了一种新的假设，即运动为运动刺激建立了一种“分子记忆”，该假设调节了维持认知益处所需的随后间歇性运动的频率和持续时间。分子记忆在定义的临时窗口中保留，因此随后的运动（即使是低级运动通常是亚阈值以增强长期记忆形成）可以利用由最初的运动经验确定的神经生物学事件，从而维持运动对认知功能的益处。我们假设表观遗传机制对于分子记忆现象至关重要，并通过组蛋白修饰来改变转录过程，从而在神经元可塑性方面产生稳定的变化，并导致行为稳定变化。我们在此提案中的目标是定义建立分子记忆的锻炼参数，研究使运动能够更有效地促进认知的潜在机制，并探索药物操纵是否可以扩展通过运动建立的分子窗口。由于运动对改善认知的好处，尤其是海马功能，因此很大程度上依赖于诱导关键的塑料分子“脑衍生的神经营养因子”（BDNF），因此我们专注于控制BDNF调节的BDNF诱导和表观遗传修饰。我们提出了三个目标。目标1-确定有效的运动模式和分子记忆临时窗口，从而导致长期记忆形成。 AIM 2-确定锻炼产生的组蛋白修饰模式，该模式为BDNF表达建立分子记忆。 AIM 3-使用一种新型的选择性组蛋白脱乙酰基酶3（HDAC3）抑制剂，确定运动的认知益处是否可以延长通过运动建立的表观遗传分子记忆。总体而言，我们在该提案中的研究将成为最终转化为人类维持增强认知功能所需的运动参数的基础。