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

描述(申请人提供)：人类的衰老与认知功能的进行性下降有关，其后果对受影响的个人来说是巨大的。任何可以延缓或防止与年龄相关的认知衰退的科学进步都将在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，老年人的比例呈指数级增长，受认知衰退影响的人的比例也在增加。动物模型的使用大大加快了影响认知功能和年龄相关变化的因素的研究步伐。能够增强认知功能的最有力的干预措施之一是体力活动。这一点已经在从啮齿动物到人类的各种生物中得到了证明。尽管这种干预的重要性和有效性，但运动增强认知活动的机制仍然难以捉摸。在这里，我们建议检验一个具有挑衅性的假设，即肌肉中有促进神经发生和突触可塑性的因子来维持认知功能，并且这些因子在运动过程中因肌肉活动而增加(运动因子)。这一假设牢牢植根于不断扩大的肌肉研究领域 作为分泌器官，参与调节能量代谢、血管生成和骨形成等生理现象的各种内分泌网络。在认知功能调节的背景下，我们提出“肌肉-大脑”轴是一种 进化上保守的内分泌途径，连接两个原始器官系统，与肌肉衍生的因子促进神经元内稳态的维持。我们将使用体外和体内方法在小鼠的神经发生、神经功能和认知活动的模型中探索这一假说。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因运动或衰老而改变的肌肉中鉴定肌肉蛋白质组。肌肉和大脑(海马体)都将接受运动引起的转录和表观遗传变化的测试，这既是为了探索运动改变肌肉和神经功能的机制，也是为了测试是否存在任何解释运动对大脑的持久影响的“分子记忆”。分泌体的直接测试将使用共生配对和血浆注射进行，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描述肌肉-脑轴的特征，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，每一种方法都将提供一个全新的框架，在其中了解体育活动对大脑功能的有益影响，并共同为治疗与年龄相关的认知下降提供一种潜在的革命性方法。

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.