Scaling of Brain Metabolism with a Fixed Energy Budget per Neuron: Implications for Neuronal Activity, Plasticity and Evolution

Abstract

It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.

Cortical energy demands of signaling and nonsignaling components in brain are conserved across mammalian species and activity levels

“…Firing rate measurements in the awake primate cortex are slightly higher than values found in human brain (24). Given that CMR glc in awake primate cortex is about 0.5 μmol/g per minute (25), which is between awake CMR glc in rat and human (i.e., 0.8 vs. 0.3 μmol/g per minute, respectively), we expect that similar budget calculations can be made for primate cortex with the same P s and P ns values based on cellular density variations across the species (17). Although neuronal recordings in primate brain do not usually report quantitative firing rates (26), basic features of action potentials in the human cerebral cortex are quite similar to those features typically found in other animals, including rats and primates (27)(28)(29).…”

“…To test whether P ns,N , P ns,A , and P s derived from the rat (Table 1) were representative of those values in human cerebral cortex, we calculated E ns in the human by simply multiplying the P ns,N and P ns,A terms with η N and η A , respectively [i.e., cellular density is about 2.6 times lower in human vs. rat (17)]. Neuronal activity for each state in the human was represented by EEG-measured bispectral index (BIS) values ranging from 0 to 100 (Table S2) as used intraoperatively (18).…”

“…2 for the awake condition in the rat (Table 2), and (Σδ j ) human is the cortical thickness in the human (Table 3). This conversion, from f BIS scale in humans to <f> scale in rats, accounts for differences in average neuronal density and cortical thickness between rat somatosensory and human visual cortices (15)(16)(17)19). …”

“…16 shows neuron vs. astrocyte densities are similar, and figure 2a in ref. 17 shows rat and human neuronal densities differ by ∼2.6. † Estimated from Fig.…”

“…These findings imply that relative energy costs of fundamental features of cortical communication (e.g., action potentials, pre-and postsynaptic potentials, glial neurotransmitter and K + clearance, etc.) as well as physiological mechanisms for supplying mitochondrial energy for neuropil operations (e.g., hemoglobin, voltage-gated ion channels, glutamate and GABA receptors, and glucose and oxygen transport) are well-preserved through evolution (17,28,29,(44)(45)(46)(47)(48)(49). A constant interspecies ATP demand of cortical activity emphasizes the relevance of animal testing in experimental neuroscience studies.…”