How Do You Rapidly Feed A Hungry Brain?

The remarkable computing capacity of the brain has roots in the structural and functional design features of neurons, glia and the circuits they form. Electrical properties, geometrical details, and biochemical constituents endemic to diverse cell types all contribute to effective biological computations. Energy management equally underlies efficiency; the human brain operates with less wattage than a light bulb, considerably less than any supercomputer.

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Superficially, it would be easy to say that the primary brain food is glucose, a common sugar. Glucose is, in fact, a basic food for all cells in your body and the metabolic mechanisms for extracting energy from this energy-rich molecule are widely conserved across life on earth. But dig deeper into the metabolism of glucose and one finds a complex, highly-regulated molecular labyrinth.

Deriving useful energy from glucose involves coaxing electrons (also referred to as reducing equivalents) from bonds around the 6-carbon sugar backbone and passing them down through a sequence of reactions where they eventually come to rest in the grasp of oxygen. Along the way, multiple energy couriers are formed such as ATP and NADH, as well as lactate, a unique energy transporting molecule that can be shared between astrocytes (a type of glial cell) and neurons in a process known as the astrocyte-to-neuron lactate shuttle (ANLS).

Among the challenges of feeding a hungry brain, an organ whose weight-adjusted energy appetite is 10-fold that of other organs, is responding to on-demand energy for regions suddenly experiencing high activity. One way of supplying enhanced need is an increased flow of blood-borne glucose and oxygen to support aerobic metabolism, a process that can be measured clinically with positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) techniques.

Another solution involves a more rapidly accessible local energy supply in the form of a polymerized glucose molecule called glycogen. Glucose stored in glycogen granules is unavailable for participation in energy production and the brain is not able to store as much glycogen as do muscle and liver tissues. Most brain glycogen is found in astrocytes, with very little storage capacity in neurons, and its functional significance is unclear.

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Neuromodulators such as norepinephrine (NE) that are diffusely released in many brain regions during excitation by various stimuli can trigger intracellular signaling cascades in astrocytes. These so-called second messenger systems are chains of enzyme-catalyzed reactions that can lead to the liberation of glucose molecules from glycogen for fodder in the energy-yielding glycolytic pathway.

A research team led by Prof. Pierre J. Magistretti from the King Abdullah University of Science and Technology (KAUST), in Saudi Arabia, and the Blue Brain Project of the École Polytechnique Fédérale de Lausanne (EPFL) led by Prof. Henry Markram, in Switzerland, explored the possible role of glycogen in providing on-demand energy for elevated brain activity. Their unique approach combined 3D electron microscopic (EM) reconstructions of brain tissue labeled for glycogen molecules together with computer simulations of the neuro-glial-vasculature (NGV) oligocellular ensemble (for more details see Coggan et al., Front Neurosci., 2018; doi: 10.3389/fnins.2018.00664). The NGV is considered to be the energy management cartel in the brain since neurons cannot feed themselves independently.

The results of this collaboration demonstrated that glycogen is preferentially localized in fine astrocytic processes in the vicinity of neuronal synapses, a convenient location to support heightened synaptic transmission. Their computer simulations began with the release of the neuromodulator NE from locus coeruleus inputs near an NGV unit. Activation of NE receptors on the astrocyte set in motion a cAMP-mediated signaling cascade that liberated glucose from glycogen. The subsequent glycolytic cascade finally produced ATP, NADH, and lactate.

While the ATP was used by the glia themselves for local energy needs, the simulations also showed that the rapidly produced lactate was exported through the extracellular space to the neighboring neuron where it could be converted to pyruvate for oxidative metabolism. These results lend strong support for an active role of glycogen in rapid brain energy metabolism and predict that ANLS is a major mechanism whereby energy can be provided to suddenly active neurons in response to various stimuli.

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These findings are described in the article entitled Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate, recently published in the journal PLoS Computational Biology. This work was conducted by Jay S. Coggan, Daniel Keller, Henry Markram, and Felix Schürmann from the École Polytechnique Fédérale de Lausanne (EPFL),  Corrado Calì and Heikki Lehväslaiho from the King Abdullah University of Science and Technology, and Pierre J. Magistretti from the École Polytechnique Fédérale de Lausanne (EPFL) and King Abdullah University of Science and Technology.

References:

  1. Coggan JS, Calì C, Keller D, Agus M, Boges D, Abdellah M, Kare K, Lehväslaiho H, Eilemann S, Jolivet RB, Hadwiger M, Markram H, Schürmann F, Magistretti PJ. A Process for Digitizing and Simulating Biologically Realistic Oligocellular Networks Demonstrated for the Neuro-Glio-Vascular Ensemble. Front Neurosci. 2018 Sep 25;12:664. doi: 10.3389/fnins.2018.00664.
  1. Coggan JS, Keller D, Calì C, Lehväslaiho H, Markram H, Schürmann F, Magistretti PJ. Norepinephrine stimulates glycogenolysis in astrocytes to fuel neurons with lactate. PLoS Comput Biol. 2018 Aug 30;14(8):e1006392. doi: 10.1371/journal.pcbi.1006392.

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