Neuronal Fatigue in Aging Hippocampus during Sustained Metabolic Demand

描述（由申请人提供）：衰老可能与对代谢挑战的反应能力降低相关，导致例如认知任务疲劳或对底物缺乏的易感性增加，如相对低血糖或缺氧。我们假设，内在CNS生物能量学调节中的细胞和分子变化（即，神经元-神经胶质相互作用、有氧和无氧代谢途径、底物可用性等）在老化过程中可能会损害对持续能量需求的适应性反应。我们建议研究长期的代谢需求和疲劳的情况下，从老年动物的孤立脑组织，在缺乏系统性因素，如不良的血管或全身底物供应，以确定内在的变化，神经元代谢和神经胶质细胞的相互作用。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，以及导致局部组织规模上的代谢调节的内在回路和其他因素。初步实验表明，与年轻动物的组织相比，老化海马中的神经元功能和线粒体氧化还原状态更容易受到代谢应激的影响，例如葡萄糖水平降低和突触刺激延长，这表明老年人可能在较长时间内支持氧化代谢速率增加的能力降低。我们将通过研究氧利用率、线粒体氧化还原状态和神经元活性之间的能量关系，使用直接组织乳酸、葡萄糖和Po 2测量、NAD（P）H荧光和海马神经元反应，评估长期代谢应激期间神经元疲劳和神经元-胶质细胞相互作用。这些技术将在延长的突触刺激（增加的代谢需求）和有限的底物递送条件下使用。这些结果将有助于理解局部组织反应和生物能量学如何影响衰老中的代谢。了解神经元疲劳的潜在机制可能表明新的治疗靶点，这可能会提高持续认知任务的性能。

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.