Pocivavsek Ana, Baratta Annalisa M, Mong Jessica A, Viechweg Shaun S
Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD.
Department of Pharmacology, University of Maryland School of Medicine, Baltimore, MD.
Sleep. 2017 Nov 1;40(11). doi: 10.1093/sleep/zsx141.
Tryptophan metabolism via the kynurenine pathway may represent a key molecular link between sleep loss and cognitive dysfunction. Modest increases in the kynurenine pathway metabolite kynurenic acid (KYNA), which acts as an antagonist at N-methyl-d-aspartate and α7 nicotinic acetylcholine receptors in the brain, result in cognitive impairments. As glutamatergic and cholinergic neurotransmissions are critically involved in modulation of sleep, our current experiments tested the hypothesis that elevated KYNA adversely impacts sleep quality.
Adult male Wistar rats were treated with vehicle (saline) and kynurenine (25, 50, 100, and 250 mg/kg), the direct bioprecursor of KYNA, intraperitoneally at zeitgeber time (ZT) 0 to rapidly increase brain KYNA. Levels of KYNA in the brainstem, cortex, and hippocampus were determined at ZT 0, ZT 2, and ZT 4, respectively. Analyses of vigilance state-related parameters categorized as wake, rapid eye movement (REM), and non-REM (NREM) as well as spectra power analysis during NREM and REM were assessed during the light phase. Separate animals were tested in the passive avoidance paradigm, testing contextual memory.
When KYNA levels were elevated in the brain, total REM duration was reduced and total wake duration was increased. REM and wake architecture, assessed as number of vigilance state bouts and average duration of each bout, and theta power during REM were significantly impacted. Kynurenine challenge impaired performance in the hippocampal-dependent contextual memory task.
Our results introduce kynurenine pathway metabolism and formation of KYNA as a novel molecular target contributing to sleep disruptions and cognitive impairments.
通过犬尿氨酸途径的色氨酸代谢可能是睡眠缺失与认知功能障碍之间的关键分子联系。犬尿氨酸途径代谢物犬尿喹啉酸（KYNA）在大脑中作为N-甲基-D-天冬氨酸和α7烟碱型乙酰胆碱受体的拮抗剂，其适度增加会导致认知障碍。由于谷氨酸能和胆碱能神经传递在睡眠调节中起关键作用，我们目前的实验检验了以下假设：升高的KYNA会对睡眠质量产生不利影响。
成年雄性Wistar大鼠在时间geber时间（ZT）0腹腔注射溶剂（生理盐水）和犬尿氨酸（25、50、100和250mg/kg），犬尿氨酸是KYNA的直接生物前体，以快速提高大脑中的KYNA水平。分别在ZT 0、ZT 2和ZT 4测定脑干、皮层和海马中的KYNA水平。在光照阶段评估与警觉状态相关的参数，分为清醒、快速眼动（REM）和非快速眼动（NREM），以及NREM和REM期间的频谱功率分析。另外的动物在被动回避范式中进行测试，以测试情境记忆。
当大脑中KYNA水平升高时，总REM持续时间减少，总清醒持续时间增加。REM和清醒结构，以警觉状态发作次数和每次发作的平均持续时间评估，以及REM期间的θ功率受到显著影响。犬尿氨酸激发损害了海马依赖性情境记忆任务中的表现。
我们的结果表明犬尿氨酸途径代谢和KYNA的形成是导致睡眠中断和认知障碍的新分子靶点。
