Isoflurane anesthesia disrupts the cortical metabolome

Identifying similarities and differences in the brain metabolome during different states of consciousness has broad relevance for neuroscience and state-dependent autonomic function. This study focused on the pre-frontal cortex (PFC) as a brain region known to modulate states of consciousness. Anesthesia was used as a tool to eliminate wakeful-ness. Untargeted metabolomic analyses were performed on micro-dialysis samples obtained from mouse PFC during wakefulness and during isoflurane anesthesia. Analyses detected 2,153 molecules, 91 of which could be identified. Analytes were grouped as detected dur-ing both wakefulness and anesthesia (n = 61) and as unique to wake-fulness (n = 23) or anesthesia (n = 7). Data were analyzed using univariate and multivariate approaches. Relative to wakefulness, during anesthesia there was a significant (q < 0.0001) fourfold change in 21 metabolites. During anesthesia 11 of these 21 molecules decreased and 10 increased. The Kyoto Encyclopedia of Genes and Genomes database was used to relate behavioral state-specific changes in the metabolome to metabolic pathways. Relative to wakefulness, most of the amino acids and analogs measured were significantly decreased during isoflur-ane anesthesia. Nucleosides and analogs were significantly increased during anesthesia. Molecules associated with carbohydrate metabo-lism, maintenance of lipid membranes, and normal cell functions were significantly decreased during anesthesia. Significant state-spe-cific changes were also discovered among molecules comprising lip-ids and fatty acids, monosaccharides, and organic acids. Considered together, these molecules regulate point-to-point transmission, vol-ume conduction, and cellular metabolism. The results identify a novel ensemble of candidate molecules in PFC as putative modu-lators of wakefulness and the loss of wakefulness. NEW & NOTEWORTHY The loss of wakefulness caused by a single concentration of isoflurane significantly altered levels of interrelated metabolites in the prefrontal cortex. The results support the interpretation that states of consciousness reflect dynamic inter-actions among cortical neuronal networks involving a humbling number of molecules that comprise the brain metabolome.