Neurotransmitter release is well known to occur at specialized synaptic regions that include presynaptic active zones and postsynaptic densities. At cholinergic synapses in the chick ciliary ganglion, however, membrane formations and physiological measurements suggest that release distant from postsynaptic densities can activate the predominantly extrasynaptic α7 nicotinic receptor subtype. We explored such ectopic neurotransmission with a novel model synapse that combines Monte Carlo simulations with high-resolution serial electron microscopic tomography. Simulated synaptic activity is consistent with experimental recordings of miniature excitatory postsynaptic currents only when ectopic transmission is included in the model, broadening the possibilities for mechanisms of neuronal communication.

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. The brain has remarkable information processing capacity, yet is also very energy efficient. How this metabolic efficiency is achieved given the spatial and metabolic constraints inherent to the designs and energy requirements of brain cells is a fundamental question in neurobiology. The major cell classes in mammalian nervous systems include neurons, glia and the microvasculature that supplies the molecular substrates of energy and metabolism. Together, this neuron-glia-vasculature (NGV) ensemble constitutes the functional unit that underlies the cost infrastructure of computation. In spite of its importance, a comprehensive understanding of this dynamic system remains elusive. While it is well established that glucose feeds the brain, few of the details regarding the destiny of glucose intermediates in metabolic pathways are known. Controversy remains regarding the degree of cooperativity between glia and neurons in sharing lactate, the product of aerobic glycolysis (Warburg effect) and one of the substrates for further energy extraction by oxidative processes. Specifically, while experimental data support the occurrence of a flow of lactate from glia to neurons, the astrocyte-neuron lactate shuttle (ANLS), some theoretical considerations have been proposed to support the occurrence of lactate transport in the other direction (NALS). Our computational model is the first to integrate multiple timescales of the NGV unit. It provides a quantitative mathematical description of metabolic activation in neurons and astrocytes, and of the macroscopic measurements obtained during brain imaging that uses metabolism as a proxy for neuronal activity.

A computational model is presented for the simulation of three-dimensional electrodiffusion of ions. Finite volume techniques were used to solve the Poisson-Nernst-Planck equation, and a dual Delaunay-Voronoi mesh was constructed to evaluate fluxes of ions, as well as resulting electric potentials. The algorithm has been validated and applied to a generalized node of Ranvier, where numerical results for computed action potentials agree well with cable model predictions for large clusters of voltage-gated ion channels. At smaller channel clusters, however, the three-dimensional electrodiffusion predictions diverge from the cable model predictions and show a broadening of the action potential, indicating a significant effect due to each channel's own local electric field. The node of Ranvier complex is an elaborate organization of membrane-bound aqueous compartments, and the model presented here represents what we believe is a significant first step in simulating electrophysiological events with combined realistic structural and physiological data.

The mechanism of rapid energy supply to the brain, especially to accommodate the heightened metabolic activity of excited states, is not well-understood. We explored the role of glycogen as a fuel source for neuromodulation using the noradrenergic stimulation of glia in a computational model of the neural-glial-vasculature ensemble (NGV). The detection of norepinephrine (NE) by the astrocyte and the coupled cAMP signal are rapid and largely insensitive to the distance of the locus coeruleus projection release sites from the glia, implying a diminished impact for volume transmission in high affinity receptor transduction systems. Glucosyl-conjugated units liberated from glial glycogen by NE-elicited cAMP second messenger transduction winds sequentially through the glycolytic cascade, generating robust increases in NADH and ATP before pyruvate is finally transformed into lactate. This astrocytic lactate is rapidly exported by monocarboxylate transporters to the associated neuron, demonstrating that the astrocyte-to-neuron lactate shuttle activated by glycogenolysis is a likely fuel source for neuromodulation and enhanced neural activity. Altogether, the energy supply for both astrocytes and neurons can be supplied rapidly by glycogenolysis upon neuromodulatory stimulus. Although efficient compared to computers, the human brain utilizes energy at 10-fold the rate of other organs by mass. How the brain is supplied with sufficient on-demand energy to support its activity in the absence of neuronal storage capacity remains unknown. Neurons are not capable of meeting their own energy requirements, instead energy supply in the brain is managed by an oligocellular cartel composed of neurons, glia and the local vasculature (NGV), wherein glia can provide the ergogenic metabolite lactate to the neuron in a process called the astrocyte-to-neuron shuttle (ANLS). The only means of energy storage in the brain is glycogen, a polymerized form of glucose that is localized largely to astrocytes, but its exact role and conditions of use are not clear. In this computational model we show that neuromodulatory stimulation by norepinephrine induces astrocytes to recover glucosyl subunits from glycogen for use in a glycolytic process that favors the production of lactate. The ATP and NADH produced support metabolism in the astrocyte while the lactate is exported to feed the neuron. Thus, rapid energy demands by both neurons and glia in a stimulated brain can be met by glycogen mobilization.