Linking metabolism, neural function, and aging

项目概要/摘要 衰老的一个普遍特征是认知功能的下降。衰老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 和分子治疗 模仿其各个方面的机制（DR 模拟物）正在接受深入研究，因为它们会延迟某些 衰老和神经退行性疾病的认知能力下降。这些扰动通常会延长寿命 几个物种。在秀丽隐杆线虫中，我们发现 DR 和一些 DR 模拟物也增强了简单的形式 学习的分子基础涉及哺乳动物的学习。我们发现 单一神经调节代谢物犬尿酸（KYNA）的变化解释了以下因素的有益作用： 线虫学习中的 DR 和多种 DR 模拟物。我们已经确定了 KYNA 的特定神经位点 产生以及表达 N-甲基 D-天冬氨酸受体 (NMDAR) 的神经元，其活动受到调节 由 KYNA 在学习背景下进行。这些发现与 KYNA 作为 NMDAR 的作用一致 对手。此外，我们发现年龄开始的学习能力下降很大一部分是由于 KYNA 的年龄依赖性积累。我们还发现了由疾病引起的学习缺陷的证据 tau 蛋白变体是一种与神经退行性变相关的蛋白质，其部分原因可能是由于 凯纳。值得注意的是，尽管 KYNA 水平与衰老密切相关，但变化并不会影响寿命。 因此，我们已经确定了各种代谢和压力扰动及其机制之间的直接联系 神经可塑性。 KYNA 具有作为潜在治疗策略的理想属性，例如降低 KYNA 水平， 即使在成人中启动，也能减缓线虫学习能力的下降。现有数据支持 KYNA 的观点 影响哺乳动物的认知，并且 KYNA 会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，尤其是在衰老过程中。一个 线虫和哺乳动物面临的特殊挑战是，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，但会通过影响远处的组织来影响 基材的可用性。为了实现我们的目标，我们将行为分析与分子遗传学、神经分析相结合 成像和直接生化代谢测量，以研究衰老、压力和衰老的交叉点 具有 KYNA 依赖性学习的代谢途径。我们将调查可能会玩的候选运输商 通过运输制造 KYNA 所需的底物发挥调节作用。我们将探索具有挑衅性的 假设蛋白质折叠应激非自主地影响通过犬尿氨酸途径细胞的通量 对学习产生不良影响。最后，我们将研究 KYNA 与保守的分子关系 记忆获取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.