Molecular control of protein synthesis, glucose metabolism, and apoptosis in the brain of hibernating thirteen-lined ground squirrels

Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) are excellent models for studying acute brain ischemia because they show high resistance to reductions in blood flow and oxygen delivery without evidence of neurological damage. In this study, we analyzed the insulin signaling pathway and regulation of mitochondrial substrate oxidation in three regions of ground squirrel brain (forebrain, cerebellum, and brainstem), comparing summer, late torpor, and interbout arousal conditions. We found select decreases in phospho-Akt in the cerebellum during torpor compared with summer animals, as well as select increases in the forebrain during interbout arousal, suggesting that Akt may influence either metabolism or cytoprotective pathways. The phosphoprotein abundance of glycogen synthase kinase 3 beta (GSK3 beta) showed the most consistent trend across all three brain regions, with peak increases observed during deep torpor, suggesting a crucial role for this protein during hibernation. Furthermore, all three regions of the brain showed increased phospho-protein abundance of pyruvate dehydrogenase at serine 232 during both deep torpor and interbout arousal, and serine 300 during interbout arousal only, whereas other phosphorylation sites showed a region-specific expression pattern. Information collected from these studies sheds light on the molecular controls governing insulin signaling and fuel utilization in the brain of hibernating ground squirrels.