Linking metabolism, neural function, and aging

项目摘要/摘要 衰老的一个普遍特征是认知功能的减退。老龄化也是最大的风险之一。 神经退行性疾病发展的因素。饮食限制、DR和分子 模仿它的某些方面的机制，即DR模拟学，正在进行密集的研究，因为它们推迟了一些 衰老和神经退行性疾病的认知衰退。这些扰动通常会延长 几个物种。在线虫中，我们发现DR和一些DR模拟也增强了一种简单的形式 它的分子基础与哺乳动物的学习有关。我们发现， 一种单一的神经调节代谢物犬尿酸(KYNA)的变化解释了 DR和多DR模拟对线虫学习的影响。我们已经确定了KYNA的特定神经部位 N-甲基-D-天冬氨酸受体(NMDAR)表达神经元的产生及其活动受调控 由KYNA在学习的背景下编写。这些发现与KYNA作为NMDAR的作用一致 对抗者。此外，我们还发现，学习能力开始下降的很大一部分原因是 KYNA的年龄累积量。我们还发现了由一种疾病引起的学习缺陷的证据 Tau的变体，一种与神经退行性变有关的蛋白质，可能部分是由于 凯娜。值得注意的是，尽管与衰老交织在一起，但KYNA水平的变化不会影响寿命。 因此，我们已经明确了各种代谢和应激干扰及其机制之间的直接联系。 神经可塑性。Kyna作为一种潜在的治疗策略具有可取的属性，如降低KYNA水平， 即使在成虫中开始学习，蠕虫的学习能力也会下降。现有数据支持KYNA 影响哺乳动物的认知，KYNA随着年龄的增长而积累。 我们的目标是了解调节KYNA积累的因素，特别是在衰老过程中。一个 线虫和哺乳动物面临的特别挑战是，尽管色氨酸无处不在， 神经KYNA可以在高度局部化的空间中产生，但会受到远处组织的影响 底物利用率。为了实现我们的目标，我们将把行为分析与分子遗传、神经 成像和直接生物化学代谢物测量，以研究衰老、压力和 代谢途径与依赖KYNA的学习。我们将调查一名可能扮演 通过其运输所需的底物发挥调节作用，使KYNA。我们将探索挑衅性 蛋白质折叠应激通过犬尿氨酸途径非自主地影响细胞通量的假说 对学习的不利影响。最后，我们将研究KYNA与保守区的分子关系 记忆获得的机制以及新发现的积极促进遗忘的机制。

PROJECT SUMMARY/ABSTRACT A general characteristic of aging is diminution of cognitive functions. Aging is also one of the greatest risk factors for the development of neurodegenerative disorders. Dietary restriction, DR, and molecular mechanisms that mimic aspects of it, DR mimetics, are under intense investigation as they delay some of the cognitive declines of aging and neurodegenerative disorders. These perturbations generally extend lifespan in several species. In C. elegans, we have discovered that DR and some DR mimetics also enhance a simple form of learning, whose molecular underpinnings are involved in learning in mammals. We have discovered that changes in a single, neuromodulatory metabolite, kynurenic acid (KYNA), account for the beneficial effects of DR and multiple DR mimetics on learning in C. elegans. We have identified the specific neural sites of KYNA production as well as N-methyl D-aspartate receptor (NMDAR)-expressing neurons whose activity is regulated by KYNA in the context of learning. These findings are consistent with KYNA serving as an NMDAR antagonist. Additionally, we have discovered that a significant portion of age-onset decline in learning is due to age-dependent accumulation of KYNA. We have also found evidence that learning defects caused by a disease variant of tau, a protein associated with neurodegeneration, may be, in part, due to unanticipated increases in KYNA. Significantly, despite being intertwined with aging, changing KYNA levels does not affect lifespan. Thus, we have pinpointed a direct link between a variety of metabolic and stress perturbations and mechanism of neural plasticity. KYNA has desirable attributes as a potential therapeutic strategy as reducing KYNA levels, even when initiated in adults, blunts learning declines in worms. Existing data support the notion that KYNA affects mammalian cognition and that KYNA accumulates with age. Our goal here is to understand the factors that regulate KYNA accumulation, especially during aging. A particular challenge in both C. elegans and mammals is that despite ubiquitous availability of tryptophan, neural KYNA can be produced in highly localized spaces yet be influenced by distant tissues through effects on substrate availability. To achieve our goals, we will combine behavioral assays with molecular genetic, neural imaging, and direct biochemical metabolite measurements to investigate the intersection of aging, stress, and metabolic pathways with KYNA-dependent learning. We will investigate a candidate transporter that may play a regulatory role through its transport of the substrate needed to make KYNA. We will explore the provocative hypothesis that protein folding stress affects flux through the kynurenine pathway cell non-autonomously with detrimental effects on learning. Finally, we will investigate the molecular relationship of KYNA to conserved mechanisms of memory acquisition as well as newly discovered mechanisms that actively promote forgetting.