Axons: The cost of communication in the brain
Imaging ATP in axons reveals that they rely on glucose from the blood and lactate produced by glial cells as sources of energy.
- University of British Columbia, Canada
Although metabolism is considered to be a dull subject by some, it is vital to life. The metabolic processes that convert food into energy are particularly important for the brain: although it accounts for just 2% of total body weight, the brain is responsible for 20% of the body’s total energy expenditure. Most of this energy comes from adenosine triphosphate (or ATP for short), which the body produces by metabolizing glucose and oxygen.
The neurons in the brain are made up of four distinct parts: the dendrites, which receive information from other neurons at special structures called synapses; the cell body, where the nucleus and genetic material are located; the axon, which carries information away from the cell; and the synapses at the end of the axon, where information is passed on to the dendrites of other neurons. The cell bodies, dendrites and synapses are located in the gray matter of the brain, while axons make up the white matter.
To use an analogy that may soon be redundant in the era of cell phones, axons are to neurons what telephone cables are to land-line phones. Like telephone cables, axons transmit information over long distances as electrical signals called action potentials (which are based on differences in the concentrations of certain ions inside and outside the neuron). There is usually a small voltage across the membrane of a neuron called a resting membrane potential. However, when a neuron is stimulated, various ions suddenly travel into or out of the neuron, changing this voltage and creating an action potential that travels along the axon. The efficiency with which information is communicated over long distances by complex networks is an impressive feature of our brains.
In humans, the white matter accounts for 50% of the brain volume (Laughlin and Sejnowski, 2003). The first signs of neurodegenerative diseases in the brain can often be seen in axons; a specific loss of axons in the white matter affects brain functions such as memory or vision, even though the cell bodies of neurons may still be intact. To better understand neurological diseases associated with degenerating axons and white matter lesions (Iadecola, 2013; Hirrlinger and Nave, 2014), it is important to quantify the amount of energy needed to fuel action potentials and axonal activity. Previous estimates based on glucose uptake measurements indicate that white matter consumes only one third of what gray matter requires.
Mathematical models suggest that the gray matter requires a lot of energy for synaptic transmission, which involves molecules called neurotransmitters traveling from a pre-synaptic neuron to a post-synaptic neuron (Attwell and Laughlin, 2001). Most of the energy in the white matter, however, is used for generating an action potential and subsequently reestablishing the resting membrane potential (Harris and Attwell, 2012). Yet, the energy use of the white matter is still poorly understood, as it has been difficult to measure the exact amount of ATP consumption during the generation of action potentials in the axons.
Now, in eLife, Johannes Hirrlinger, Klaus-Armin Nave and colleagues – including Andrea Trevisiol of the Max Planck Institute for Experimental Medicine as first author – report that they have used optical sensors to directly measure the ATP consumption required to power action potentials (Trevisiol et al., 2017) This new approach allowed them to do two things for the first time: to visualize the energy use of action potentials in real time, and to determine the metabolic source of the ATP. The experiments were performed on an adapted version of the mouse optic nerve, a well-established nerve model for white matter electrophysiology (Stys et al., 1991; Brown et al., 2003).
Trevisiol et al. first uncovered a remarkable correlation between ATP levels and the generation of action potentials. When action potentials were evoked more frequently, the ATP levels decreased, indicating that action potentials rapidly consume energy. On the other hand, when the ATP production was interrupted, action potentials in the axons declined and progressively failed, because they did not spread as effectively. However, the technique cannot determine the exact levels of energy consumption because their optical sensor cannot measure the absolute concentration of ATP.
Trevisiol et al. subsequently showed that axons rely on several sources of energy for ATP production. Although glucose from the blood is the principal source, the researchers were able to show that the axons also use lactate as an energy source. It is thought that glial cells called astrocytes, which are found in both white and gray matter, metabolize a form of glucose called glycogen to produce lactate (Brown et al., 2003; Suzuki et al., 2011). Other glial cells called oligodendrocytes can also supply lactate (which they produce by metabolizing glucose) (Fünfschilling et al., 2012; Lee et al., 2012). This suggests that a complex energy supply network in which multiple cell types and metabolic energy sources are used to maintain the ATP levels is crucial for axons to work properly.
This development of an imaging approach that can monitor changes in ATP levels is an important step in quantifying the metabolic costs of communication via white matter axons. It also gives us a clever insight into defining the important supporting roles of glia cells in maintaining the health of the white matter itself via the production of lactate.
References
-
An energy budget for signaling in the grey matter of the brainJournal of Cerebral Blood Flow & Metabolism 21:1133–1145.https://doi.org/10.1097/00004647-200110000-00001
-
Glycogen regulation and functional role in mouse white matterThe Journal of Physiology 549:501–512.https://doi.org/10.1113/jphysiol.2003.042416
-
The energetics of CNS white matterJournal of Neuroscience 32:356–371.https://doi.org/10.1523/JNEUROSCI.3430-11.2012
Article and author information
Author details
Leigh Wicki-Stordeur
Louis-Philippe Bernier
Publication history
Copyright
© 2017, MacVicar et al.
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,241
- views
-
- 353
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Axons: The cost of communication in the brain
eLife 6:e27894.
https://doi.org/10.7554/eLife.27894
Further reading
-
- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
-
- Neuroscience
Gamma oscillations in brain activity (30–150 Hz) have been studied for over 80 years. Although in the past three decades significant progress has been made to try to understand their functional role, a definitive answer regarding their causal implication in perception, cognition, and behavior still lies ahead of us. Here, we first review the basic neural mechanisms that give rise to gamma oscillations and then focus on two main pillars of exploration. The first pillar examines the major theories regarding their functional role in information processing in the brain, also highlighting critical viewpoints. The second pillar reviews a novel research direction that proposes a therapeutic role for gamma oscillations, namely the gamma entrainment using sensory stimulation (GENUS). We extensively discuss both the positive findings and the issues regarding reproducibility of GENUS. Going beyond the functional and therapeutic role of gamma, we propose a third pillar of exploration, where gamma, generated endogenously by cortical circuits, is essential for maintenance of healthy circuit function. We propose that four classes of interneurons, namely those expressing parvalbumin (PV), vasointestinal peptide (VIP), somatostatin (SST), and nitric oxide synthase (NOS) take advantage of endogenous gamma to perform active vasomotor control that maintains homeostasis in the neuronal tissue. According to this hypothesis, which we call GAMER (GAmma MEdiated ciRcuit maintenance), gamma oscillations act as a ‘servicing’ rhythm that enables efficient translation of neural activity into vascular responses that are essential for optimal neurometabolic processes. GAMER is an extension of GENUS, where endogenous rather than entrained gamma plays a fundamental role. Finally, we propose several critical experiments to test the GAMER hypothesis.
