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

Abstract

The continuous need for ion gradient restoration across the cell membrane, a prerequisite for synaptic transmission and conduction, is believed to be a major factor for brain's high oxidative demand. However, do energy requirements of signaling and nonsignaling components of cortical neurons and astrocytes vary with activity levels and across species? We derived oxidative ATP demand associated with signaling (P(s)) and nonsignaling (P(ns)) components in the cerebral cortex using species-specific physiologic and anatomic data. In rat, we calculated glucose oxidation rates from layer-specific neuronal activity measured across different states, spanning from isoelectricity to awake and sensory stimulation. We then compared these calculated glucose oxidation rates with measured glucose metabolic data for the same states as reported by 2-deoxy-glucose autoradiography. Fixed values for P(s) and P(ns) were able to predict the entire range of states in the rat. We then calculated glucose oxidation rates from human EEG data acquired under various conditions using fixed P(s) and P(ns) values derived for the rat. These calculated metabolic data in human cerebral cortex compared well with glucose metabolism measured by PET. Independent of species, linear relationship was established between neuronal activity and neuronal oxidative demand beyond isoelectricity. Cortical signaling requirements dominated energy demand in the awake state, whereas nonsignaling requirements were ∼20% of awake value. These predictions are supported by (13)C magnetic resonance spectroscopy results. We conclude that mitochondrial energy support for signaling and nonsignaling components in cerebral cortex are conserved across activity levels in mammalian species.

Fig. 1.

Relationship between glucose oxidation [CMR_glc(ox)] and neuronal activity as a function of OGI. (A) Comparison between calculated CMR_glc(ox) [calcCMR_glc(ox)] and measured CMR_glc(ox) [measCMR_glc(ox)] values. Values of measCMR_glc(ox) were derived from 2DG autoradiography in rat brain and PET in human brain, whereas values of calcCMR_glc(ox) were derived for an OGI of 5.6. The goodness of fit between measCMR_glc(ox) and calcCMR_glc(ox) for the rat data (red circles) is indicated by the gray line with an R² value of 0.96 (σ² = 0.0182 for 11 states). The human data (blue triangles) also showed a strong correlation (R² = 0.91 and σ² = 0.0023 for seven states). (B) Comparison between measured NA (measNA) and calculated glucose oxidation in neurons [calcCMR_glc(ox),N] in rat (red circles) and human (blue triangles) brains shows good correlation [R² = 0.98, where calcCMR_glc(ox),N = 0.90measNA + 0.12]. Because the data were normalized to the awake resting state values, the intercept on the vertical axis is about ∼20% of calcCMR_glc(ox),N in the awake state for both species. (C–E) Comparison of calculated total glucose oxidation [calcCMR_glc(ox)], calculated glucose oxidation in neurons [calcCMR_glc(ox),N], calculated glucose oxidation in astrocytes [calcCMR_glc(ox),A], calculated nonoxidative glucose consumption [calcCMR_glc(nonox)], and measured total glucose consumption (measCMR_glc), where calcCMR_glc(ox) = calcCMR_glc(ox),N + calcCMR_glc(ox),A and calcCMR_glc(nonox) = measCMR_glc − calcCMR_glc(ox). Ratios in rat brain (red), human brain (blue), and overall (purple) for (C) the value of the calcCMR_glc(ox),N in B for the nonanesthetized awake resting state [calcCMR_glc(ox),N,AR] minus the value of the intercept [i.e., (1-intercept)calcCMR_glc(ox),N,AR] and the values of (D) calcCMR_glc(ox),A/calcCMR_glc(ox) and (E) calcCMR_glc(nonox)/measCMR_glc measured across all activity levels. All error bars indicate SDs from the mean. All calculations were obtained with P_s = 4.81 × 10⁹ ATP/spike per neuron, P_ns,N = 9.20 × 10⁸ ATP/neuron per second, and P_ns,A = 6.85 × 10⁸ ATP/astrocytes per second). Details are in Tables 1, 2, and 3.

Fig. 2.

In vivo ¹³C MRS experiments reporting rates of neurotransmitter cycling [V_cyc(tot)] and glucose oxidation in neurons [CMR_glc(ox),N] and astrocytes [CMR_glc(ox),A]. (A) Values of V_cyc(tot) and CMR_glc(ox),N for rat (red circles) and human (blue triangles) cerebral cortex. The rat data represented many activity levels in the somatosensory cortex, whereas the human data were from the awake resting state in the visual cortex with varying degrees of gray vs. white matter partial volume (Table S3). Linear trends between changes in V_cyc(tot) and CMR_glc(ox),N suggest strong coupling between neurotransmitter activity and energy metabolism [R² = 0.92, where CMR_glc(ox),N = 0.87 V_cyc(tot) + 0.10], where the finite intercept ranging between 0.05 and 0.15 μmol/g per minute indicates energy consumption for nonsignaling conditions. (B) Ratios of V_cyc(tot)/CMR_glc(ox),N in the nonanesthetized awake resting state (filled bars) (Table S3) and CMR_glc(ox),A/CMR_glc(ox) for all conditions above isoelectricity (open bars) (Table S4) in rat (red), human (blue), and overall (purple). Similarity between the V_cyc(tot)/CMR_glc(ox),N ratios (filled bars) in rat and human suggests that the relationship between V_cyc(tot) and CMR_glc(ox),N in both species may be conserved. Likewise, correspondence between the CMR_glc(ox),A/CMR_glc(ox) ratios (open bars) suggests that the relationship between CMR_glc(ox),A and CMR_glc(ox) across species could be similar.