Brain-derived ketone bodies can replace glucose to power neural function

The vertebrate brain is exquisitely sensitive to disruptions in glucose metabolism, and failure of adequate glucose delivery causes neurological dysfunction. Here, we discovered an animal with the capacity to defy this rule: We show that neural activity in frogs, animals with seemingly typical glucose demands, can stop metabolizing glucose by, in part, shifting to ketone bodies made exclusively within the brain after emergence from hibernation. This involves ketone body synthesis and transport from astrocytes to neurons to power synaptic transmission, along with the upregulation of gene expression that controls fatty acid catabolism and ketone body transport. Brain-derived ketone bodies also prevent decrements in activity that occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise strongly impair neural performance in most animals. More broadly, they reveal the vertebrate brain has the capacity to serve as its own fuel reserve during the cessation of glucose metabolism, switching seamlessly to locally sourced ketone bodies while maintaining neural activity. This reframes glucose metabolism in the vertebrate brain not as a hard-wired necessity, but as a plastic trait that can in some cases be entirely abandoned. Significance The brain relies on a continuous supply of glucose from the blood to support the large energy demands of neural activity. When glucose delivery is disrupted, neural activity collapses within minutes. Here, we demonstrate that hibernation induces a large capacity for frogs, animals with seemingly normal glucose needs, to operate neural circuits without glucose metabolism, replacing it ketone bodies produced exclusively within the brain. These results reveal that a brain-derived, non-glucose fuel reserve can power neural function in the absence of glucose delivery. These findings reframe neural activity’s reliance on continuous glucose metabolism as a plastic trait, rather than a hard-wired constraint.