Yamashita Masatoshi, Yamamoto Takanobu
Department of Neuroscience, Psychology and Behaviour, University of Leicester, Lancaster Road, Leicester LE1 9HN, United Kingdom.
Department of Psychology, Tezukayama University, 3-1-3, Gakuenminami, Nara-shi, Nara 631-8585, Japan.
Brain Res. 2017 Nov 15;1675:116-126. doi: 10.1016/j.brainres.2017.09.002. Epub 2017 Sep 8.
Brain tryptophan and its neuroactive metabolites play key roles in central fatigue. However, previous brain function analysis targets may have included both glia and neurons together. Here, we clarified the fatigue-cognitive circuit of the central-peripheral linkage, including the role of glial-neuronal interaction in cognition. Using a rat model of central fatigue induced by chronic sleep disorder (CFSD), we isolated presynaptic terminals and oligodendrocytes. Results showed that compared to control group, presynaptic levels of tryptophan, kynurenine, and kynurenic acid, but not serotonin, in the CFSD group were higher in the hypothalamus and hippocampus. Moreover, CFSD group had higher oligodendrocytic levels of tryptophan, and impaired spatial cognitive memory accuracy and increased hyperactivity and impulsivity. These findings suggest that dynamic change in glial-neuronal interactions within the hypothalamus-hippocampal circuit causes central fatigue, and increased tryptophan-kynurenic acid pathway activity in this circuit causes reduced cognitive function. Additionally, CFSD group had 1.5 times higher plasma levels of tryptophan and kynurenine. Furthermore, in rats undergoing intraperitoneal administration of kynurenine (100mg/kg) versus vehicle, kynurenine-treated rats showed enhanced production of kynurenic acid in the hippocampus, with suppressed recall of retained spatial cognitive memory. The study revealed that uptake of periphery-derived kynurenine and tryptophan into the brain enhances kynurenic acid production in the brain, and the three factors produce amplification effect involved in the role of central-peripheral linkage in central fatigue, triggering cognitive dysfunction.
脑内色氨酸及其神经活性代谢产物在中枢性疲劳中起关键作用。然而，以往的脑功能分析靶点可能同时包括了神经胶质细胞和神经元。在此，我们阐明了中枢 - 外周联系的疲劳 - 认知回路，包括神经胶质细胞 - 神经元相互作用在认知中的作用。利用慢性睡眠障碍诱导的中枢性疲劳大鼠模型（CFSD），我们分离出了突触前终末和少突胶质细胞。结果显示，与对照组相比，CFSD组下丘脑和海马中色氨酸、犬尿氨酸和犬尿喹啉酸的突触前水平升高，但血清素水平未升高。此外，CFSD组少突胶质细胞中的色氨酸水平较高，空间认知记忆准确性受损，多动和冲动增加。这些发现表明，下丘脑 - 海马回路内神经胶质细胞 - 神经元相互作用的动态变化导致中枢性疲劳，并且该回路中色氨酸 - 犬尿喹啉酸途径活性增加导致认知功能下降。此外，CFSD组血浆中色氨酸和犬尿氨酸水平高出1.5倍。此外，在腹腔注射犬尿氨酸（100mg/kg）与注射溶剂的大鼠中，犬尿氨酸处理的大鼠海马中犬尿喹啉酸生成增加，保留的空间认知记忆的回忆受到抑制。该研究表明，外周来源的犬尿氨酸和色氨酸进入脑内会增强脑内犬尿喹啉酸的生成，这三个因素产生放大效应，参与中枢 - 外周联系在中枢性疲劳中的作用，引发认知功能障碍。
