RESEARCH ARTICLE Multi-timescale Modeling of Activity- Dependent Metabolic Coupling in the Neuron-Glia-Vasculature Ensemble

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulat-ing evidence, however, indicates that lactate produced in astrocytes (a type of glial cell) can also fuel neuronal activity. The quantitative aspects of this so-called astrocyte-neuron lactate shuttle (ANLS) are still debated. To address this question, we developed a detailed biophysical model of the brain’s metabolic interactions. Our model integrates three model-ing approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formu-lation of neuronal membrane excitability and a biophysical model of metabolic pathways. This approach provides a template for large-scale simulations of the neuron-glia-vasculature (NGV) ensemble, and for the first time integrates the respective timescales at which energy metabolism and neuronal excitability occur. The model is constrained by rela-tive neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabo-lites at rest and by the temporal dynamics of NADH upon activation. These constraints produced four observations. First, a transfer of lactate from astrocytes to neurons emerged in response to activity. Second, constrained by activity-dependent NADH transients, neuro