Causal coupling between neural activity, metabolism, and behavior across the Drosophila brain

Coordinated activity across networks of neurons is a hallmark of both resting and active behavioral states in many species, including worms, flies, fish, mice and humans. These global patterns alter energy metabolism in the brain over seconds to hours, making oxygen consumption and glucose uptake widely used proxies of neural activity. However, whether changes in neural activity are causally related to changes in metabolic flux in intact circuits on the sub-second timescales associated with behavior, is unknown. Moreover, it is unclear whether transitions between rest and action are associated with spatiotemporally structured changes in neuronal energy metabolism. Here, we combine two-photon microscopy of the entire fruit fly brain with sensors that allow simultaneous measurements of neural activity and metabolic flux, across both resting and active behavioral states. We demonstrate that neural activity drives changes in metabolic flux, creating a tight coupling between these signals that can be measured across large-scale brain networks. Further, these studies reveal that the initiation of even minimal behavioral movements causes large-scale changes in the pattern of neural activity and energy metabolism, revealing unexpected structure in the functional architecture of the brain. The relationship between neural activity and energy metabolism is likely evolutionarily ancient. Thus, these studies provide a critical foundation for using metabolic proxies to capture changes in neural activity and reveal that even minimal behavioral movements are associated with changes in large-scale brain network activity.