Kynurenic Acid, Sleep and Cognition

睡眠质量差或睡眠中断，由于睡眠障碍、精神疾病等原因 障碍，或衰老，与认知功能障碍有关。中国的赤字 睡眠中断可能导致的学习和记忆会产生反复而深远的影响 在日常功能上。可以理解的是，解开两者之间的共同分子机制 睡眠障碍和神经认知障碍--这可能导致新的治疗方法 缓解这些结果的方法--是非常重要的。我们的项目旨在测试 总体假设是犬尿酸(KYNA)，一种星形胶质细胞衍生的代谢物 犬尿氨酸途径(KP)是色氨酸代谢的关键分子环节 睡眠障碍和认知功能障碍。我们将研究，在老鼠身上，a)机制 睡眠剥夺(SD)与KYNA形成增加之间的联系；b)KYNA在连接中的作用 睡眠障碍和认知障碍；以及c)KYNA合成的治疗价值 抑制以克服SD后的认知功能障碍。一种新开发的特异性抑制剂 犬尿氨酸转氨酶II(KAT II)，KYNA形成的主要酶，将 被用作机械检验假说的实验工具。有三个具体的 旨在检验我们的假设。目的#1：研究脑部KP代谢的动力学， 肝脏，SD后取血。工作假说：犬尿氨酸途径的外周变化 代谢驱动增加SD大鼠海马区KYNA的形成。目标2：达到 研究KYNA形成的上调和下调对睡眠结构的影响。 工作假说：KYNA的升高对睡眠和对Kat的靶向抑制有不利影响 II可以提高睡眠质量。目的#3：评价KYNA合成抑制对大鼠肾小管上皮细胞的影响 减轻SD后海马区介导的认知功能障碍，改善睡眠质量。 工作假说：抑制Kat II是克服睡眠的有效策略 失落导致的认知功能障碍。这些实验的成功完成将定义 KP代谢、睡眠障碍和海马区调节之间的因果关系 认知功能。拟议的研究将促进我们对共同的 睡眠障碍和神经认知障碍之间的分子机制，为 寻找新的治疗方法来缓解这些结果。

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.