Exercise-induced epigenetic mechanisms underlying neuronal plasticity and cognition

 描述（由申请人提供）：运动参与是认知健康的重要决定因素，特别是在老龄化中。事实上，久坐行为已被选为导致美国认知能力下降和阿尔茨海默病的最大可改变风险因素，在全球排名第三。尽管身体活动和锻炼很重要，但提供最佳认知健康的锻炼参数并没有很好地定义，特别是关于 所需的锻炼频率和持续时间。我们的数据和其他数据表明，激活增强认知功能的潜在神经生物学机制的运动条件可以是灵活的，并允许间歇性和间隔性的运动。我们提出了一个新的假设，即运动建立了一种类型的“分子记忆”的运动刺激，调节频率和持续时间的后续间歇性运动，需要保持认知的好处。分子记忆在限定的时间窗口期间保持，使得随后的运动（即使是通常低于阈值的低水平运动，以增强长期记忆形成）可以利用由最初的运动经历建立的神经生物学事件，从而保持运动对认知功能的益处。我们假设，表观遗传机制是分子记忆现象的基础，并通过组蛋白修饰改变转录过程，以产生稳定的神经元可塑性变化，并引起稳定的行为变化。我们在这项提案中的目标是定义建立分子记忆的运动参数，研究使运动能够更有效地促进增强认知的潜在机制，并探索药物操作是否可以延长运动建立的分子窗口。由于运动对改善认知，特别是海马功能的益处，在很大程度上依赖于关键可塑性分子“脑源性神经营养因子”（BDNF）的诱导，我们专注于BDNF诱导和控制BDNF调节的表观遗传修饰。我们提出三个目标。目的1 -确定导致长期记忆形成的有效运动模式和分子记忆时间窗。目的2 -确定运动引起的组蛋白修饰模式，建立BDNF表达的分子记忆。目的3 -确定运动的认知益处是否可以通过药理学操纵运动建立的表观遗传分子记忆来延长，使用新型选择性组蛋白脱乙酰酶3（HDAC 3）抑制剂。总的来说，我们在这项提案中的研究将成为最终将维持增强的认知功能所需的运动参数转化为人类的基础。

 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.