A New Muscle-Brain Axis Underlying the Cognitive Benefits of Physical Activity

描述（由申请人提供）：人类衰老与认知功能的进行性下降有关，其后果对受影响的个体来说是巨大的。任何能够延缓或预防与年龄相关的认知能力下降的科学进步都将对社会的各个层面产生深远的影响，因为人口结构正在发生变化，老年人的比例和受认知能力下降影响的人的比例呈指数级增长。动物模型的使用大大加快了对影响认知功能和年龄相关变化的因素的研究步伐。可以增强认知功能的最强大的干预措施之一是体育活动。这在从啮齿动物到人类的生物体中已经得到证实。尽管这种干预的重要性和效力，运动增强认知活动的机制仍然难以捉摸。在这里，我们建议测试挑衅性的假设，有肌肉分泌的因素，促进神经发生和突触可塑性，以维持认知功能，这些因素增加了肌肉活动在运动过程中（“运动因素”）。这一假设是牢牢地植根于不断扩大的研究领域的肌肉 作为分泌器官，参与各种内分泌网络，其功能是调节生理现象，如能量代谢、血管生成和骨形成。在认知功能调节的背景下，我们提出，“肌肉-大脑”轴是一个 进化上保守的内分泌途径，连接两个原始器官系统，肌肉衍生因子促进神经元稳态的维持。 我们将使用体外和体内的方法来探讨这一假设在神经发生，神经元功能和认知活动的小鼠模型。利用我们在血浆蛋白质组学方面的专业知识，我们将从对照肌肉和运动或衰老改变的肌肉中表征肌肉蛋白质组。肌肉和大脑（海马体）都将被测试由运动引起的转录和表观遗传变化，以探索运动改变肌肉和神经元功能的机制，并测试任何“分子记忆”以解释运动对大脑的任何持续影响。将使用联体配对和血浆注射进行分泌体的直接测试，候选测试将包括体外神经发生和体内肌肉特异性基因缺失的研究。这些多方面的方法将使我们能够表征肌肉-大脑轴，检查运动对该轴的分子基础和调节，并了解运动对神经元活动的持久影响的基础，每一个都将提供一个全新的框架，在此框架内了解身体活动对大脑功能的有益影响，并共同提供一种潜在的革命性治疗方法。与年龄相关的认知能力下降

DESCRIPTION (provided by applicant): Aging in humans is associated with a progressive decline in cognitive function, the consequences of which are enormous for affected individuals. Any scientific advance that could delay or prevent age-related cognitive decline would have a profound impact at every level of society given the demographic changes that are occurring with an exponentially increasing percentage of elderly individuals and the percentage of those individuals who are affected by cognitive decline. The use of animal models has greatly accelerated the pace of research on factors that influence cognitive function and age-related changes. One of the most robust interventions that can enhance cognitive function is physical activity. This has been shown in organisms ranging from rodents to humans. Despite the importance and potency of this intervention, the mechanisms by which exercise enhances cognitive activity remain elusive. Here we propose to test the provocative hypothesis that there are factors secreted by muscle that promote neurogenesis and synaptic plasticity to maintain cognitive function and that these factors are increased by muscle activity during exercise ("exercise factors"). This hypothesis is firmly rooted in the expanding field of research on muscle as a secretory organ, participating in various endocrine networks that function to regulate physiological phenomena such as energy metabolism, angiogenesis, and bone formation. Within the context of regulation of cognitive function, we propose that a "muscle-brain" axis is an evolutionarily conserved endocrine pathway that links two primordial organ systems, with muscle-derived factors promoting maintenance of neuronal homeostasis. We will use both in vitro and in vivo approaches to explore this hypothesis in murine models of neurogenesis, neuronal function, and cognitive activity. Capitalizing on our expertise in plasma proteomics, we will characterize the muscle proteome from control muscle and muscle altered by exercise or aging. Both muscle and brain (hippocampus) will be tested for transcriptional and epigenetic changes induced by exercise, both to explore the mechanisms by which exercise modifies muscular and neuronal function and also to test for any "molecular memory" to explain any persistent effects of exercise on the brain. Direct tests of secretomes will be performed using parabiotic pairings and plasma injections, and candidate testing will include studies of neurogenesis in vitro and muscle-specific gene deletions in vivo. These multifaceted approaches will allow us to characterize the muscle-brain axis, to examine the molecular basis and regulation of that axis with exercise, and to understand the basis for the lasting effects of exercise on neuronal activity, each of which would provide an entirely new framework within which to understand the beneficial effects of physical activity on brain function and together offering a potentially revolutionary approach to the treatment of age-related cognitive decline.