Cerebral energetics and the glycogen shunt: neurochemical basis of functional imaging

Abstract

Positron-emission tomography and functional MRS imaging signals can be analyzed to derive neurophysiological values of cerebral blood flow or volume and cerebral metabolic consumption rates of glucose (CMR(Glc)) or oxygen (CMR(O(2))). Under basal physiological conditions in the adult mammalian brain, glucose oxidation is nearly complete so that the oxygen-to-glucose index (OGI), given by the ratio of CMR(O(2))/CMR(Glc), is close to the stoichiometric value of 6. However, a survey of functional imaging data suggests that the OGI is activity dependent, moving further below the oxidative value of 6 as activity is increased. Brain lactate concentrations also increase with stimulation. These results had led to the concept that brain activation is supported by anaerobic glucose metabolism, which was inconsistent with basal glucose oxidation. These differences are resolved here by a proposed model of glucose energetics, in which a fraction of glucose is cycled through the cerebral glycogen pool, a fraction that increases with degree of brain activation. The "glycogen shunt," although energetically less efficient than glycolysis, is followed because of its ability to supply glial energy in milliseconds for rapid neurotransmitter clearance, as a consequence of which OGI is lowered and lactate is increased. The value of OGI observed is consistent with passive lactate efflux, driven by the observed lactate concentration, for the few experiments with complete data. Although the OGI changes during activation, the energies required per neurotransmitter release (neuronal) and clearance (glial) are constant over a wide range of brain activity.

Figure 1

Proposed pathways of energy metabolism and glutamate–glutamine neurotransmitter cycling between neurons and glia. Action potentials reaching the presynaptic neuron cause release of vesicular glutamate into the synaptic cleft, where it is recognized by glutamate receptors postsynaptically and cleared by Na⁺-coupled transport into glia, where it is enzymatically converted to glutamine, which passively diffuses back to the neuron and, after reconversion to glutamate, is repackaged into vesicles. A direct consequence of the metabolic model (12, 13) is that neuronal firing is quantitatively linked to clearance of extracellular glutamate by the astrocyte, which requires 2 moles of ATP per mole of glutamate cycled between neurons and astrocytes (see text for details). (A) Ideally, 1 mole of glucose produces 2 moles of ATP in the astrocyte via glycolysis. The two equivalents of lactate generated in the astrocyte are completely oxidized in the neuron to generate ≈34 ATP molecules. This creates a scenario where the stoichiometry between oxygen and glucose (i.e., OGI) is 6. Under normal rates of neuronal firing, the rate of energy production via glycolysis is sufficient to restore Na⁺ gradient and glutamine synthesis in the astrocyte, and matches the glutamate release by the neuron. (B) Alternatively, to generate 2 moles of ATP in the astrocyte via the glycogen shunt, 2 moles of glucose have to be used and 4 moles of lactate to be produced. Some of the extra lactate is effluxed into the blood, whereas the rest is oxidized in the neuron to generate ≈34 ATP molecules. However, in this case, the stoichiometry between oxygen and glucose consumption (i.e., OGI) is 3. Under high neuronal firing rates, because the rate of glial energy production via glycolysis is not rapid enough, the glycogen shunt is activated to restore Na⁺ gradient and glutamine synthesis in the astrocyte such that the glutamate release by the neuron is matched. The main difference between A and B is that the latter produces 1 ATP/glucose less, which is energetically less efficient for glutamate clearance. Thus, more lactate is produced in the latter case where some is effluxed into the blood circulation. BBB, blood brain barrier; GLC, glucose; GLN, glutamine; GLU, glutamate; LAC, lactate.

Figure 2

¹³C MRS measurements of glutamate neurotransmitter cycling, V_cycle, and the rate of glucose oxidation, CMR_Glc(ox), with graded anesthesia in rat brain (12). The best linear fit (solid line) to the data (filled symbols) produces CMR_Glc(ox) = 1.04 V_cycle + 0.10, which indicates that each mole of neurotransmitter glutamate cycling requires oxidation of one mole of glucose. Because the resting awake state value for CMR_Glc(ox) in rat cortex is ≈0.8 μmol⋅g⁻¹⋅min⁻¹, ≈85% of the cortical energy consumption is dedicated to V_cycle. Thus, in the resting, awake state, a very small component of energy production via glucose oxidation (see small intercept) is dedicated to nonsignaling functions of glutamatergic neurons, and the rest is dedicated to neurotransmitter function. (Adapted from figure 4 of ref. .)

Figure 3

Glycogen provides a rapid ancillary source for astrocytic energy production, with slower replenishment of the glycogen in between spikes. This process allows astrocytic clearance of glutamate to accommodate the increased neuronal release during heightened rates of neuronal firing. The glycogen consumed is subsequently replenished by glycogen synthesis to maintain a steady state concentration, as shown in cases of low (A) and fast (B) firing rates. Under rapid firing bursts, the glycogen synthesis may not completely replenish glycogen breakdown, and hence a new steady state concentration of glycogen would be reached (not shown). The increased flux through the glycogen shunt, i.e., a cycle of glycogen degradation and synthesis, results in an energetically less efficient conversion of glucose to lactate (Fig. 1B). In brief, the proposed model suggests that, during increased firing rates, timely degradation and synthesis of glycogen provide astrocytic energy for neurotransmitter clearance, and as a consequence of which, OGI is decreased and lactate is elevated—a process that is energetically less efficient.

Figure 4

The proposed pathways of energy metabolism in brain, which includes both glycolysis and the glycogen shunt. If a small fraction of glucose (x) is diverted through the shunt, then the total amount of ATP produced per mole of glucose is (2 − x), which is the net of the following reactions:

Figure 5

The OGI vs. lactate dependence (lines) in the mammalian brain can be determined from experimental data (cross symbol): resting human/rat brain with OGI = 5.52 (1); active human brain with OGI = 5.16 (6); and seizure activity in rat brain with OCI = 4.14 (1). The total amount of lactate produced in rat brain during biccuculine-induced seizure is 8 mM whereas the resting lactate level in human brain is 0.6 m M. Using the Michaelis-Menten transport kinetics for lactate (Eq. 6) and the OGI relationship (Eq. 2), a relationship can be derived that is independent of T_max. Therefore, changes in lactate (from the seizure point) can be reflected into changes in OGI for a range of K_m values for lactate transport across the blood-brain barrier. The best fit of the model to the scarce data is with K_m of 2.5 mM, which corresponds to T_max of about 0.75 μmol⋅g⁻¹⋅min⁻¹.