Neuronal Fatigue in Aging Hippocampus during Sustained Metabolic Demand

持续代谢需求期间老化海马的神经元疲劳

• 批准号: 8097946
• 负责人: DENNIS Alan TURNER
• 金额: $ 28.18万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8097946
• 关键词: Aerobic; Affect; Age; Aging; Animals; Bioenergetics; Brain; Cell Respiration; Characteristics; Cognitive; Coupling; Electrodes; Elements; Fatigue; Fluorescence; Glucose; Glutamates; Glycogen; Goals; Hippocampus (Brain); Hydrogen Peroxide; Hypoglycemia; Hypoxia; Image; In Vitro; Inbred F344 Rats; Individual; Lead; Measurement; Measures; Mediator of activation protein; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolic stress; Metabolism; Mitochondria; Molecular; Neuroglia; Neurons; Oxidation-Reduction; Oxygen; Pathway interactions; Performance; Predisposition; Preparation; Reactive Oxygen Species; Regulation; Relative (related person); Role; Slice; Source; Synapses; Techniques; Time; Tissues; Training; Uncoupling Agents; Vascular System; age related; aged; aging hippocampus; brain tissue; deprivation; extracellular; improved; in vivo; juvenile animal; mitochondrial membrane; novel; public health relevance; research study; response; spreading depression; trafficking

DESCRIPTION (provided by applicant): Aging can be associated with a decreased ability to respond to metabolic challenges resulting, for example, in fatigue on cognitive tasks or increased susceptibility to substrate deprivation, such as relative hypoglycemia or hypoxia. We hypothesize that cellular and molecular changes in the regulation of intrinsic CNS bioenergetics (i.e., neuronal-glial interactions, aerobic and anaerobic metabolic pathways, substrate availability, etc.) during aging can impair adaptive responses to sustained energy demand. We propose to study prolonged metabolic demand and fatigue in isolated brain tissue from aged animals, in the absence of systemic factors such as poor vasculature or systemic substrate supply, to identify intrinsic changes in neuronal metabolism and neuronal-glial interactions. In vitro brain slices obtained from aged animals retain the in vivo metabolic characteristics of that age, as well as the intrinsic circuits and other factors leading to regulation of metabolism on a local tissue scale. Preliminary experiments indicate that neuronal function and mitochondrial redox state in aging hippocampus are more vulnerable to metabolic stress, such as lowered glucose levels and prolonged synaptic stimulation, compared to tissue from younger animals, suggesting that aged individuals may have reduced ability to support an increased rate of oxidative metabolism for an extended period of time. We will evaluate neuronal fatigue and neuronal-glial interactions during prolonged metabolic stress by studying the energetic relationships between oxygen utilization, mitochondrial redox state, and neuronal activity, using direct tissue lactate, glucose and Po2 measurements, NAD(P)H fluorescence, and neuronal responses in hippocampus. These techniques will be used during prolonged synaptic stimulation (increased metabolic demand) and conditions of limited substrate delivery. These results will facilitate understanding how local tissue responses and bioenergetics affect metabolism in aging. The understanding of the mechanisms underlying neuronal fatigue may indicate novel targets for treatment which may enhance performance on sustained cognitive tasks. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand how metabolism in the brain changes with aging, assessing both mechanisms underlying fatigue to persistent responses and possible treatment directions. The goal is to assess components of oxidative and glycolytic metabolism, particularly during sustained metabolic demand, over minutes, which are intrinsic to neurons and glia. The in vitro slice preparation proposed here allows assessment of local metabolic interactions directly in brain tissue, without direct involvement of the vascular system and systemic provision of substrates.

描述（由申请人提供）：衰老可能与应对代谢挑战的能力降低有关，例如，在认知任务上疲劳或增加对底物剥夺的易感性，例如相对低血糖症或低氧病。我们假设在衰老过程中，细胞和分子的调节调节（即神经元相互作用，有氧和厌氧代谢途径，底物的可用性等）的细胞和分子变化会在衰老过程中会损害持续能量需求的适应性反应。我们建议在没有系统性因素（例如脉管系统差或全身性底物供应）的情况下研究孤立的脑组织中长期的代谢需求和疲劳，以鉴定神经元代谢和神经元 - 神经元相互作用的内在变化。从老年动物获得的体外脑切片保留了该年龄的体内代谢特征，以及内在电路和其​​他因素，导致在局部组织量表上调节代谢。初步实验表明，与年轻动物的组织相比，在海马衰老中的神经元功能和线粒体氧化还原状态更容易受到代谢压力的影响，例如降低的葡萄糖水平和长时间的突触刺激，这表明年龄个体可能降低了衰老的能力长时间的氧化代谢。我们将使用直接组织乳酸，葡萄糖和PO2测量值，NAD（p）H荧光，和神经元的H荧光，我们将通过研究氧利用，线粒体氧化还原态和神经元活性之间的能量关系，评估长期代谢应激期间神经元疲劳和神经元 - 膜相互作用的NAD（P）H荧光，以及神经元的荧光，海马的反应。这些技术将在长时间的突触刺激（代谢需求增加）和底物递送有限的条件下使用。这些结果将有助于理解局部组织反应和生物能力如何影响衰老中的代谢。对神经元疲劳基础机制的理解可能表明治疗的新靶标可能会增强持续认知任务的表现。 公共卫生相关性：该提案旨在了解大脑中的代谢如何随老化而变化，评估了持续反应和可能的治疗方向的两种机制。目的是评估氧化和糖酵解代谢的组成部分，尤其是在持续的代谢需求期间，超过几分钟，这些代谢是神经元和神经胶质的固有的。这里提出的体外切片制剂允许直接评估脑组织中局部代谢相互作用，而无需直接涉及血管系统和底物的全身提供。