Transformation to ischaemia tolerance of frog brain function corresponds to dynamic changes in mRNA co-expression...

Neural activity is costly and requires continuous ATP from aerobic metabolism. Brainstem motor function of American bullfrogs normally collapses after minutes of ischaemia, but following hibernation, it becomes ischaemia-tolerant, generating output for up to 2 h without oxygen or glucose delivery. Transforming the brainstem to function during ischaemia involves a switch to anaerobic glycolysis and brain glycogen. We hypothesized that improving neural performance during ischaemia involves a transcriptional program for glycogen and glucose metabolism. Here we measured mRNA copy number of genes along the path from glycogen metabolism to lactate production using real-time quantitative PCR. The expression of individual genes did not reflect enhanced glucose metabolism. However, the number of co-expressed gene pairs increased early into hibernation, and by the end, most genes involved in glycogen metabolism, glucose transport and glycolysis exhibited striking linear co-expression. By contrast, co-expression of genes in the Krebs cycle and electron transport chain decreased throughout hibernation. Our results uncover reorganization of the metabolic transcriptional network associated with a shift to ischaemia tolerance in brain function. We conclude that modifying gene co-expression may be a critical step in synchronizing storage and use of glucose to achieve ischaemia tolerance in active neural circuits.