Isoflurane anesthesia disrupts the cortical metabolome

Abstract

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 prefrontal cortex (PFC) as a brain region known to modulate states of consciousness. Anesthesia was used as a tool to eliminate wakefulness. Untargeted metabolomic analyses were performed on microdialysis samples obtained from mouse PFC during wakefulness and during isoflurane anesthesia. Analyses detected 2153 molecules, 91 of which could be identified. Analytes were grouped as detected during both wakefulness and anesthesia (n=61), and as unique to wakefulness (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) four-fold 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 isoflurane anesthesia. Nucleosides and analogs were significantly increased during anesthesia. Molecules associated with carbohydrate metabolism, maintenance of lipid membranes, and normal cell functions were significantly decreased during anesthesia. Significant state-specific changes also were discovered among molecules comprising lipids and fatty acids, monosaccharides, and organic acids. Considered together, these molecules regulate point to point transmission, volume conduction, and cellular metabolism. The results identify a novel ensemble of candidate molecules in PFC as putative modulators of wakefulness and the loss of wakefulness.

Prefrontal Cortex Metabolome Is Modified by Opioids, Anesthesia, and Sleep

“…During anesthesia relative to wakefulness there was a significant, 4-fold change in 21 of the metabolites. During anesthesia 11 of these 21 molecules decreased and 10 molecules increased (23).…”

“…The finding of sleep-selective decreases in prefrontal cortex metabolites encouraged study of the prefrontal cortex metabolome during the isofluraneinduced loss of wakefulness (23). Microdialysis samples were obtained from mouse prefrontal cortex during wakefulness and during isoflurane anesthesia (FIGURE 1B, RIGHT) (23).…”

“…Additional evidence indicates that the prefrontal cortex also contributes to the process of opioid abuse (19)(20)(21). A second context for this focus on the prefrontal cortex derives from recent discoveries that concentrations of molecules comprising the prefrontal cortical metabolome are significantly altered during the loss or obtundation of wakefulness (11,(22)(23)(24).…”

“…One aim of this review is to advocate for combining the analytic and conceptual approaches of systems and reductionistic biology. The combined approach discussed here is focused on neurochemistry of the prefrontal cortex (11,22,23), a brain region interacting with multiple networks exhibiting state-selective activation and deactivation (2)(3)(4).…”

“…Each of these three sections outlines analytic chemical and computational approaches that enabled measuring and modeling a chemical connectome underlying state-selective physiology. Time-dependent analyses are a unifying feature of the studies reviewed below (11,(22)(23)(24). Evaluation of time as a putative causal variable is essential for efforts to understand complex systems (38).…”