Food for thought: a virus-like signal for the energetic demands of higher cognitive functions

深思：一种类似病毒的信号，满足更高认知功能的能量需求

• 批准号: 10702143
• 负责人: Tania Reis
• 金额: $ 98.53万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10702143
• 关键词: Address; Adipose tissue; Association Learning; Back; Behavioral; Body part; Brain; Calories; Capsid; Capsid Proteins; Cells; Chronic; Circulation; Communication; Consumption; Coupled; Custom; Cytoskeleton; Diet; Disparate; Energy Supply; Fatty acid glycerol esters; Goals; Impaired cognition; Learning; Mediating; Memory; Messenger RNA; Metabolic Control; Metabolic syndrome; Metabolism; Modeling; Modification; Molecular; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurons; Obesity; Organ; Pathway interactions; Play; Process; Property; Proteins; Research; Rest; Retroviridae; Role; Signal Transduction; Synapses; System; Testing; Tissues; Travel; Virus; Virus-like particle; cognitive function; design; dietary excess; energy balance; experimental study; neurodevelopment; protein expression; protein oligomer; transmission process

To maintain organismal energy balance, energy molecules extracted from the diet or liberated from stored forms must be distributed appropriately throughout the body. By integrating and distributing signals to and from disparate tissues and organs, the brain plays a major role as a command center in organismal energy balance. The brain is also a hungry organ, consuming a disproportionate amount of energy relative to its size. Higher-level cognitive functions like learning and forming memories burn even more energy. Energy imbalance, such as a chronic high-calorie diet, perturbs cognitive functions like learning and memory, but the underlying mechanism is not clear. Metabolic syndromes like obesity are also associated with neurodevelopmental and neurodegenerative disorders. Most studies of organismal energy balance focus on how the brain uses a few known pathways to mediate inter-organ communication, but it is not known how cognitive functions specifically signal the brain’s demand for fuel and mobilize energy from stores in other parts of the body. The proposed studies test an entirely new model in which virus-like particles synthesized during learning/memory activity in brain neurons travel to fat storage tissues and induce mobilization of stored energy. Arc (activity-regulated cytoskeleton-associated protein) was known for decades to be induced by learning/memory activity in neurons, where Arc oligomers promote synaptic activity and plasticity. Arc proteins evolved from a retrovirus and retained the ability to assemble into virus-like capsids that spread from cell to cell. A ground-breaking hypothesis to be tested here proposes that Arc capsids travel from the brain to fat storage cells, where they signal brain activity and trigger release of energy into circulation. Levels of circulating energy feed back onto Arc expression via metabolic control of N6-methyladenosine (m6A) modification of Arc mRNA. Together, these coupled processes are proposed to comprise a homeostatic circuit that integrates the brain’s need for fuel and maintains organismal energy balance. The experimental system addresses the basic features of this circuit from the behavioral to the molecular level, including a conserved requirement for Arc in associative learning and cognitive dysfunction when excess dietary calories overwhelm the system. The planned research will determine properties of Arc required for communication with fat storage cells and how it alters organismal metabolism to supply energy to the brain. Other experiments will identify the key components of diet that alter m6A modification and virus-like Arc assembly and test custom diets designed to ameliorate cognitive dysfunction. This project will establish the mechanistic details of a previously unknown brain–adipose signaling axis and a homeostatic circuit where uncoupling leads to neurodevelopmental and neurodegenerative disease.

为了维持机体的能量平衡，从饮食中提取的能量分子或从 储存的形式必须适当地分布在整个身体中。通过整合和分发 大脑是不同组织和器官之间相互传递信号的主要指挥中心 生物能量平衡。大脑也是一个饥饿的器官，消耗不成比例的 相对于其大小的能量。更高层次的认知功能，如学习和形成 记忆燃烧更多的能量。能量不平衡，如长期高热量饮食， 认知功能，如学习和记忆，但潜在的机制尚不清楚。代谢 像肥胖症这样的综合征也与神经发育和神经变性有关， 紊乱大多数关于生物体能量平衡的研究都集中在大脑如何利用一些已知的能量平衡。 途径来调解器官间的沟通，但不知道如何认知功能 特别是大脑对燃料的需求，并从大脑其他部分的储存中调动能量。 身体拟议的研究测试了一个全新的模型，其中病毒样颗粒在 大脑神经元的学习/记忆活动转移到脂肪储存组织，并诱导 储存能量Arc（活性调节的细胞凋亡相关蛋白）几十年来一直被认为是 由神经元中的学习/记忆活动诱导，其中Arc寡聚体促进突触活动， 可塑性Arc蛋白从逆转录病毒进化而来，并保留了组装成病毒样蛋白的能力。 在细胞间传播的衣壳。这里要检验的一个突破性假设提出， 弧形衣壳从大脑旅行到脂肪储存细胞，在那里它们发出大脑活动的信号并触发 释放能量进入循环。循环能量水平通过以下方式反馈到Arc表达上： Arc mRNA的N6-甲基腺苷（m6 A）修饰的代谢控制。这些结合在一起的 这些过程被提出来包括一个稳态回路，该回路整合了大脑对燃料的需求， 维持机体能量平衡。该实验系统解决了这一基本特征， 电路从行为到分子水平，包括一个保守的要求弧， 当过量的饮食热量压倒系统时，会导致联想学习和认知功能障碍。 计划中的研究将确定与脂肪存储通信所需的Arc属性 细胞以及它如何改变生物体的新陈代谢来为大脑提供能量。其他实验将 确定改变m6 A修饰和病毒样Arc组装的饮食的关键组分，并测试 旨在改善认知功能障碍的定制饮食。该项目将建立机械 一个以前未知的脑脂肪信号轴和一个稳态回路的细节， 解偶联导致神经发育和神经变性疾病。