Metabolomic analysis of mouse prefrontal cortex reveals upregulated analytes during wakefulness compared to sleep
Metabolomic analysis of mouse prefrontal cortex reveals upregulated analytes during wakefulness compared to sleep
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DOI：
10.1038/s41598-018-29511-6
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发表时间：
2018-07-25
影响因子：
4.6
通讯作者：
Cirelli, Chiara
中科院分区：
文献类型：
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作者：
Bourdon, Allen K.;Spano, Giovanna Maria;Cirelli, Chiara
通过鉴定脑细胞外液中的内源性分子，代谢组学可以提供对睡眠调节机制和功能的深入了解。在这里，我们研究了皮质代谢组在睡眠、睡眠剥夺和自发觉醒期间的变化。小鼠被植入电极用于慢性睡眠/觉醒记录，并植入针对前额叶和初级运动皮层的微透析探针。采用超高效液相色谱-高分辨质谱法测定代谢产物。使用偏最小二乘判别分析、线性混合效应模型方差分析和机器学习算法评估代谢物的睡眠/觉醒变化。在大多数样品中可靠地检测到30多种已知代谢物。当通过逻辑回归分类器使用时，这些代谢物在睡眠、自发觉醒和强制觉醒中的分布足以在80-100%的情况下将小鼠分配到其正确的实验组（成对）。这些代谢物中有11种在清醒状态下的水平明显高于睡眠状态。一些变化扩展了之前的发现（谷氨酸、高香草酸、乳酸、丙酮酸、色氨酸、尿苷），而其他变化则是新颖的（D-葡萄糖酸、N-乙酰基-β-丙氨酸、N-乙酰基谷氨酰胺、乳清酸、琥珀酸/甲基丙二酸）。从头嘧啶途径，葡萄糖酸盐分流和有氧糖酵解的上调可能反映了唤醒依赖性的需要，以促进许多重要成分的合成，从核酸到突触膜。
By identifying endogenous molecules in brain extracellular fluid metabolomics can provide insight into the regulatory mechanisms and functions of sleep. Here we studied how the cortical metabolome changes during sleep, sleep deprivation and spontaneous wakefulness. Mice were implanted with electrodes for chronic sleep/wake recording and with microdialysis probes targeting prefrontal and primary motor cortex. Metabolites were measured using ultra performance liquid chromatography-high resolution mass spectrometry. Sleep/wake changes in metabolites were evaluated using partial least squares discriminant analysis, linear mixed effects model analysis of variance, and machine-learning algorithms. More than 30 known metabolites were reliably detected in most samples. When used by a logistic regression classifier, the profile of these metabolites across sleep, spontaneous wake, and enforced wake was sufficient to assign mice to their correct experimental group (pair-wise) in 80-100% of cases. Eleven of these metabolites showed significantly higher levels in awake than in sleeping mice. Some changes extend previous findings (glutamate, homovanillic acid, lactate, pyruvate, tryptophan, uridine), while others are novel (D-gluconate, N-acetyl-beta-alanine, N-acetylglutamine, orotate, succinate/methylmalonate). The upregulation of the de novo pyrimidine pathway, gluconate shunt and aerobic glycolysis may reflect a wake-dependent need to promote the synthesis of many essential components, from nucleic acids to synaptic membranes.