title: Dynamic activation model for a glutamatergic neurovascular unit.
abstract: This article considers a dynamic spatially lumped model for brain energy metabolism and proposes to use the results of a Markov chain Monte Carlo (MCMC) based flux balance analysis to estimate the kinetic model parameters. By treating steady state reaction fluxes and transport rates as random variables we are able to propagate the uncertainty in the steady state configurations to the predictions of the dynamic model, whose responses are no longer individual but ensembles of time courses. The kinetic model consists of five compartments and is governed by kinetic mass balance equations with Michaelis-Menten type expressions for reaction rates and transports between the compartments. The neuronal activation is implemented in terms of the effect of neuronal activity on parameters controlling the blood flow and neurotransmitter transport, and a feedback mechanism coupling the glutamate concentration in the synaptic cleft and the ATP hydrolysis, thus accounting for the energetic cost of the membrane potential restoration in the postsynaptic neurons. The changes in capillary volume follow the balloon model developed for BOLD MRI. The model follows the time course of the saturation levels of the blood hemoglobin, which link metabolism and BOLD FMRI signal. Analysis of the model predictions suggest that stoichiometry alone is not enough to determine glucose partitioning between neuron and astrocyte. Lactate exchange between neuron and astrocyte is supported by the model predictions, but the uncertainty on the direction and rate is rather elevated. By and large, the model suggests that astrocyte produces and effluxes lactate, while neuron may switch from using to producing lactate. The level of ATP hydrolysis in astrocyte is substantially higher than strictly required for neurotransmitter cycling, in agreement with the literature.
authors.affiliation: Case Western Reserve University, Department of Mathematics and Cognitive Science, 10900 Euclid Ave., Cleveland, 44106 OH, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Calvetti
authors.forename: Erkki
authors.initials: E
authors.lastname: Somersalo
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001692:Biological Transport; D001921:Brain / Q000098:blood supply* / Q000378:metabolism*; D002560:Cerebrovascular Circulation; D003198:Computer Simulation; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006019:Glycolysis; D006454:Hemoglobins / Q000378:metabolism; D007700:Kinetics; D019344:Lactic Acid / Q000378:metabolism; D008959:Models, Neurological; D009474:Neurons / Q000201:enzymology; D010766:Phosphorylation; D012984:Software; D013997:Time Factors
chemical_list: D006454:Hemoglobins; D019344:Lactic Acid; D018698:Glutamic Acid; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D005947:Glucose