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

体力活动带来认知益处的新肌脑轴

• 批准号: 8878155
• 负责人: THOMAS A. RANDO
• 金额: $ 67.29万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878155
• 关键词: Address; Adult; Affect; Age; Age-associated memory impairment; Aging; Alzheimer' s Disease; Animal Model; Animals; Biological; Biology; Blood Circulation; Brain; Cells; Cognitive; Collaborations; Developed Countries; Elderly; Endocrine; Endocrine Glands; Energy Metabolism; Epigenetic Process; Exercise; Exercise stress test; Experimental Models; Gene Deletion; Health; Hippocampus (Brain); Homeostasis; Human; Impaired cognition; In Situ; In Vitro; Individual; Injection of therapeutic agent; Intercellular Fluid; Intervention; Lead; Link; Maintenance; Mediating; Mediator of activation protein; Memory; Microdialysis; Microglia; Modeling; Molecular; Molecular Profiling; Mus; Muscle; Muscle Fibers; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Organ; Organism; Osteogenesis; Parabiosis; Parkinson Disease; Pathway interactions; Physical activity; Physiological; Plant Roots; Plasma; Population; Proteome; Proteomics; Quality of life; Regulation; Research; Resolution; Rodent; Scientific Advances and Accomplishments; Skeletal Muscle; Societies; Synaptic plasticity; Technical Expertise; Testing; Time; Tissues; Transcript; Validation; age effect; age related; age related cognitive change; aged; aging brain; angiogenesis; base; body system; cognitive function; cognitive reappraisal; efficacy testing; epigenetic memory; epigenome; epigenomics; genome-wide; in vivo; innovation; middle age; myogenesis; neurogenesis; prevent; research study; screening; tool; transcriptomics

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.

描述（由申请人提供）：人类的衰老与认知功能的逐渐下降有关，其后果对受影响的个体来说是巨大的。鉴于人口变化导致老年人比例和受认知能力下降影响的人比例呈指数级增长，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各个层面产生深远的影响。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因素的研究步伐。可以增强认知功能的最有力的干预措施之一是身体活动。这已经在从啮齿动物到人类的各种生物体中得到证实。尽管这种干预措施具有重要性和效力，但运动增强认知活动的机制仍然难以捉摸。在这里，我们建议测试一个令人兴奋的假设，即肌肉分泌一些因子促进神经发生和突触可塑性以维持认知功能，并且这些因子在运动过程中通过肌肉活动而增加（“运动因子”）。这一假设牢牢扎根于不断扩大的肌肉研究领域 作为分泌器官，参与各种内分泌网络，调节能量代谢、血管生成和骨形成等生理现象。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，肌肉源性因子促进神经元稳态的维持。 我们将使用体外和体内方法在神经发生、神经元功能和认知活动的小鼠模型中探索这一假设。利用我们在血浆蛋白质组学方面的专业知识，我们将表征来自控制肌肉和运动或衰老改变的肌肉的肌肉蛋白质组。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，既是为了探索运动改变肌肉和神经元功能的机制，也是为了测试任何“分子记忆”来解释运动对大脑的持久影响。分泌组的直接测试将使用联体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表征肌肉-大脑轴，检查该轴通过运动的分子基础和调节，并了解运动对神经元活动持久影响的基础，其中每一个都将提供一个全新的框架，在其中了解身体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衰退提供潜在的革命性方法。