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一个重要决定因素，尤其是在衰老过程中。事实上，久坐行为在美国被列为导致认知能力下降和阿尔茨海默病的最大可改变的风险因素，在全球排名第三。尽管体力活动和锻炼很重要，但提供最佳认知健康的锻炼参数并没有得到很好的定义，特别是在 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，并允许间歇性和间歇性的运动。我们提出了一个新的假设，即运动为运动刺激建立了一种“分子记忆”，它调节了维持认知益处所需的后续间歇性运动的频率和持续时间。分子记忆在特定的时间窗口中保持，因此随后的运动(即使是通常低于阈值的低水平运动以增强长期记忆形成)可以利用最初运动经验建立的神经生物学事件，从而保持运动对认知功能的好处。我们假设表观遗传机制是分子记忆现象的基础，并通过组蛋白修饰来改变转录过程，从而产生神经元可塑性的稳定变化和行为的稳定变化。我们在这个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认知增强的潜在机制，并探索药物操纵是否可以延长由运动建立的分子窗口。由于运动对改善认知的益处，特别是海马体功能，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，因此我们专注于BDNF的诱导和控制BDNF调节的表观遗传修饰。我们提出了三个目标。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-确定运动产生的组蛋白修饰模式，以建立对BDNF表达的分子记忆。目的3-使用一种新的选择性组蛋白脱乙酰基酶3(HDAC3)抑制剂，确定是否可以通过药物操作运动建立的表观遗传分子记忆来延长运动的认知益处。总体而言，我们在这项提案中的研究将作为最终将维持增强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.