Kynurenic Acid, Sleep and Cognition

犬尿酸、睡眠和认知

• 批准号: 9912211
• 负责人: Ana Pocivavsek
• 金额: $ 29.2万
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912211
• 关键词: Acetylcholine; Address; Adult; Aging; American; Astrocytes; Attenuated; Blood; Brain; Brain region; Cognition; Cognitive; Cognitive deficits; Data; Down-Regulation; Electrophysiology (science); Enzymes; Functional disorder; Hippocampus (Brain); Homeostasis; Impaired cognition; Impairment; Kynurenic Acid; Kynurenine; Kynurenine-oxoglutarate aminotransferase; Lead; Learning; Link; Liver; Measures; Mediating; Memory; Metabolism; Microdialysis; Molecular; N-Methylaspartate; Neurocognitive Deficit; Outcome; Pathway interactions; Performance; Peripheral; Rattus; Recovery; Reporting; Research; Rodent; Role; Sleep; Sleep Architecture; Sleep Deprivation; Sleep Disorders; Sleep disturbances; Testing; Therapeutic; Tryptophan Metabolism Pathway; Up-Regulation; cognitive function; daily functioning; design; enzyme activity; experimental study; extracellular; improved; in vivo; inhibitor/antagonist; novel; novel therapeutic intervention; novel therapeutics; prevent; receptor; sleep quality; tool

Poor sleep quality or disrupted sleep, due to reasons such as sleep disorders, psychiatric disturbances, or aging, are associated with impairments in cognitive function. Deficits in learning and memory that can result from disrupted sleep have recurring and profound impacts on daily function. Understandably, unraveling the common molecular mechanisms between sleep disturbances and neurocognitive impairments – which may lead to new therapeutic approaches to alleviate these outcomes – is of great importance. Our project is designed to test the overall hypothesis that kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway (KP) of tryptophan metabolism, represents a key molecular link between sleep disturbances and cognitive dysfunction. We will examine, in rats, a) the mechanisms linking sleep deprivation (SD) and increased KYNA formation; b) the role of KYNA in connecting sleep dysfunction and cognitive deficits; and c) the therapeutic value of KYNA synthesis inhibition to overcome cognitive deficits after SD. A newly developed specific inhibitor of kynurenine aminotransferase II (KAT II), the main enzyme responsible for KYNA formation, will be used as an experimental tool to mechanistically test the hypothesis. There are three specific aims to test our hypothesis. Aim #1: To examine the dynamics of KP metabolism in the brain, liver, and blood after SD. Working hypothesis: Peripheral changes in kynurenine pathway metabolism drive increased KYNA formation in the hippocampus after SD. Aim #2: To investigate the impact of up- and down- regulation of KYNA formation on sleep architecture. Working hypothesis: Elevations in KYNA adversely impact sleep and targeted inhibition of KAT II can improve sleep quality. Aim #3: To evaluate the impact of KYNA synthesis inhibition in attenuating hippocampal-mediated cognitive dysfunction and improving sleep quality after SD. Working hypothesis: Inhibition of KAT II serves as an efficacious strategy to overcome sleep loss-induced cognitive dysfunction. Successful completion of these experiments will define causal relationships between KP metabolism, sleep disturbances, and hippocampal-mediated cognitive functions. The proposed research will advance our understanding of common molecular mechanisms between sleep disturbances and neurocognitive impairments, paving the way for novel therapies to alleviate these outcomes.

睡眠质量差或睡眠中断，由于睡眠障碍，精神病等原因 干扰或衰老与认知功能的损伤有关。赤字 睡眠中断可能导致的学习和记忆会产生反复和深远的影响， 日常功能。可以理解的是，解开了 睡眠障碍和神经认知障碍-这可能导致新的治疗方法 减轻这些后果的方法是非常重要的。我们的项目旨在测试 犬尿烯酸（KYNA），一种星形胶质细胞衍生的代谢物， 色氨酸代谢的犬尿氨酸途径（KP），代表了色氨酸代谢与 睡眠障碍和认知功能障碍。我们将研究，在大鼠中，a）机制 联系睡眠剥夺（SD）和增加的KYNA形成; B）KYNA在联系睡眠剥夺（SD）和增加的KYNA形成中的作用 睡眠功能障碍和认知缺陷;和c）KYNA合成的治疗价值 抑制以克服SD后的认知缺陷。一种新开发的特异性抑制剂 犬尿氨酸氨基转移酶II（KAT II），负责KYNA形成的主要酶，将 可以作为一种实验工具来机械地检验假设。有三个具体的 旨在验证我们的假设。目的#1：为了检查脑中KP代谢的动力学， SD后的肝脏和血液。工作假设：犬尿氨酸通路的外周变化 代谢驱动增加SD后海马中KYNA的形成。目标2： 研究KYNA形成的上调和下调对睡眠结构的影响。 工作假设：KYNA升高对睡眠和KAT靶向抑制产生不利影响 可以改善睡眠质量。目的#3：评价KYNA合成抑制对小鼠脑缺血的影响。 减轻脑缺血介导的认知功能障碍，改善SD后的睡眠质量。 工作假设：抑制KAT II是克服睡眠的有效策略 丧失性认知功能障碍成功完成这些实验将定义 KP代谢、睡眠障碍和代谢紊乱之间的因果关系 认知功能拟议的研究将促进我们对共同的理解 睡眠障碍和神经认知障碍之间的分子机制， 寻找新的治疗方法来缓解这些结果。