A coherent neurobiological framework for functional neuroimaging provided by a model integrating compartmentalized energy metabolism

Abstract

Functional neuroimaging has undergone spectacular developments in recent years. Paradoxically, its neurobiological bases have remained elusive, resulting in an intense debate around the cellular mechanisms taking place upon activation that could contribute to the signals measured. Taking advantage of a modeling approach, we propose here a coherent neurobiological framework that not only explains several in vitro and in vivo observations but also provides a physiological basis to interpret imaging signals. First, based on a model of compartmentalized energy metabolism, we show that complex kinetics of NADH changes observed in vitro can be accounted for by distinct metabolic responses in two cell populations reminiscent of neurons and astrocytes. Second, extended application of the model to an in vivo situation allowed us to reproduce the evolution of intraparenchymal oxygen levels upon activation as measured experimentally without substantially altering the initial parameter values. Finally, applying the same model to functional neuroimaging in humans, we were able to determine that the early negative component of the blood oxygenation level-dependent response recorded with functional MRI, known as the initial dip, critically depends on the oxidative response of neurons, whereas the late aspects of the signal correspond to a combination of responses from cell types with two distinct metabolic profiles that could be neurons and astrocytes. In summary, our results, obtained with such a modeling approach, support the concept that both neuronal and glial metabolic responses form essential components of neuroimaging signals.astrocyte-neuron interactions ͉ blood oxygenation level-dependent signal ͉ lactate ͉ mathematical model ͉ NADH F unctional imaging methods that include functional MRI (fMRI), magnetic resonance spectroscopy (MRS), positron emission tomography, and optical imaging are widely used to explore brain activity (1). Signals recorded with these techniques originate from hemodynamic and metabolic changes occurring upon activation. Understanding the precise nature of these changes has led to renewed interest in cellular and molecular investigations in the regulation of brain energy metabolism and blood flow. Presently, a major challenge is to propose a coherent framework to link (i) cellular data obtained in vitro, e.g., in slices or cell cultures; (ii) data obtained in animal in vivo using, for instance, electrophysiological methods, biosensors, or fluorescence microscopy; and (iii) functional neuroimaging data obtained in humans.In this context, several experimental data have challenged the classical view of brain energy metabolism, that complete oxidation of glucose in neurons is the sole process relevant to brain function. Fox and Raichle (2) reported, on the basis of their positron emission tomography data, that during a stimulation, the increased fraction of glucose consumption can be greater than the concomitant increase fraction of oxygen consumption. This observation is supported by MRS recordings t...

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