Energy metabolism is essential to brain function and Bioinformatics, but its study is experimentally challenging. Similarly, biologically accurate computational models are too complex for simple investigations. Here, we analyse an experimentally-calibrated multiscale model of human brain energy metabolism using Computational Singular Perturbation. This approach leads to the novel identification of functional periods during and after synaptic activation, and highlights the central reactions and metabolites controlling the system's behaviour within those periods. We identify a key role for both oxidative and glycolytic astrocytic metabolism in driving the brain's metabolic circuitry. We also identify phosphocreatine as the main endogenous energy supply to brain cells, and propose revising our view of brain energy metabolism accordingly. Our approach highlights the importance of glial cells in brain metabolism, and introduces a systematic and unbiased methodology to study the dynamics of complex biochemical networks that can be scaled, in principle, to metabolic networks of any size and complexity.

We have previously shown that the physiological size of postsynaptic currents maximises energy efficiency rather than information transfer across the retinothalamic relay synapse. Here, we investigate information transmission and postsynaptic energy use at the next synapse along the visual pathway: from relay neurons in the thalamus to spiny stellate cells in layer 4 of the primary visual cortex (L4SS). Using both multicompartment Hodgkin-Huxley-type simulations and electrophysiological recordings in rodent brain slices, we find that increasing or decreasing the postsynaptic conductance of the set of thalamocortical inputs to one L4SS cell decreases the energy efficiency of information transmission from a single thalamocortical input. This result is obtained in the presence of random background input to the L4SS cell from excitatory and inhibitory corticocortical connections, which were simulated (both excitatory and inhibitory) or injected experimentally using dynamic-clamp (excitatory only). Thus, energy efficiency is not a unique property of strong relay synapses: even at the relatively weak thalamocortical synapse, each of which contributes minimally to the output firing of the L4SS cell, evolutionarily-selected postsynaptic properties appear to maximise the information transmitted per energy used.

Glucose is the main energy substrate in the adult brain under normal conditions. Accumulating 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 modeling approaches, the Buxton-Wang model of vascular dynamics, the Hodgkin-Huxley formulation 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 relative neuronal and astrocytic oxygen and glucose utilization, by the concentration of metabolites 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, neuronal oxidative metabolism increased first upon activation with a subsequent delayed astrocytic glycolysis increase. Third, the model correctly predicted the dynamics of extracellular lactate and oxygen as observed in vivo in rats. Fourth, the model correctly predicted the temporal dynamics of tissue lactate, of tissue glucose and oxygen consumption, and of the BOLD signal as reported in human studies. These findings not only support the ANLS hypothesis but also provide a quantitative mathematical description of the metabolic activation in neurons and glial cells, as well as of the macroscopic measurements obtained during brain imaging.

Sodium entry during an action potential determines the energy efficiency of a neuron. The classic Hodgkin-Huxley model of action potential generation is notoriously inefficient in that regard with about 4 times more charges flowing through the membrane than the theoretical minimum required to achieve the observed depolarization. Yet, recent experimental results show that mammalian neurons are close to the optimal metabolic efficiency and that the dynamics of their voltage-gated channels is significantly different than the one exhibited by the classic Hodgkin-Huxley model during the action potential. Nevertheless, the original Hodgkin-Huxley model is still widely used and rarely to model the squid giant axon from which it was extracted. Here, we introduce a novel family of Hodgkin-Huxley models that correctly account for sodium entry, action potential width and whose voltage-gated channels display a dynamics very similar to the most recent experimental observations in mammalian neurons. We speak here about a family of models because the model is parameterized by a unique parameter the variations of which allow to reproduce the entire range of experimental observations from cortical pyramidal neurons to Purkinje cells, yielding a very economical framework to model a wide range of different central neurons. The present paper demonstrates the performances and discuss the properties of this new family of models.

Integrate-and-Fire-type models are usually criticized because of their simplicity. On the other hand, the Integrate-and-Fire model is the basis of most of the theoretical studies on spiking neuron models. Here, we develop a sequential procedure to quantitatively evaluate an equivalent Integrate-and-Fire-type model based on intracellular recordings of cortical pyramidal neurons. We find that the resulting effective model is sufficient to predict the spike train of the real pyramidal neuron with high accuracy. In in vivo-like regimes, predicted and recorded traces are almost indistinguishable and a significant part of the spikes can be predicted at the correct timing. Slow processes like spike-frequency adaptation are shown to be a key feature in this context since they are necessary for the model to connect between different driving regimes.