Glycogenolysis in Cerebral Cortex During Sensory Stimulation, Acute Hypoglycemia, and Exercise: Impact on Astrocytic Energetics, Aerobic Glycolysis, and Astrocyte-Neuron Interactions

Gerald A Dienel; Douglas L Rothman

doi:10.1007/978-3-030-27480-1_8

Glycogenolysis in Cerebral Cortex During Sensory Stimulation, Acute Hypoglycemia, and Exercise: Impact on Astrocytic Energetics, Aerobic Glycolysis, and Astrocyte-Neuron Interactions

Adv Neurobiol. 2019:23:209-267. doi: 10.1007/978-3-030-27480-1_8.

Authors

Gerald A Dienel^{1

2}, Douglas L Rothman³

Affiliations

¹ Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, USA. gadienel@uams.edu.
² Department of Cell Biology and Physiology, University of New Mexico, Albuquerque, NM, USA. gadienel@uams.edu.
³ Magnetic Resonance Research Center and Department of Diagnostic Radiology, Yale University, New Haven, CT, USA.

PMID: 31667811
DOI: 10.1007/978-3-030-27480-1_8

Abstract

Most glycogen in cerebral cortex is located in astrocytes, and the importance of glycogenolysis for critical functions, including neurotransmission and memory consolidation, is strongly supported by many studies. However, specific mechanisms through which glycogen sustains essential functions remain to be established by rigorous, quantitative studies. Cerebral cortical glycogen concentrations are in the range of 10-12 μmol/g in carefully-handled animals, and the calculated rate of glycogenolysis (CMR_glycogen) during sensory stimulation is approximately 60% that of glucose utilization (CMR_glc) by all cells, with lower rates during acute hypoglycemia and exercise to exhaustion. CMR_glycogen is at least fourfold higher when the volume fraction of astrocytes is taken into account. Inclusion of glycogen consumed during sensory stimulation in calculation of the oxygen-glucose index (OGI = CMR_O2/CMR_glc, which has a theoretical maximum of 6 when no other substrates are metabolized) reduces OGI from 5.0 to 2.8. Thus, at least 53% of the carbohydrate is not oxidized, suggesting that glycogen mobilization supports astrocytic glycolysis, not neuronal oxidation of glycogen-derived lactate that would cause OGI to exceed 6. Failure of glycogenolysis to dilute the specific activity of lactate formed from blood-borne [6-¹⁴C]glucose indicates compartmentation of glycolytic metabolism of glucose and glycogen and the rapid release from cerebral cortex of glycogen-derived lactate. Together, these findings invalidate the conclusion by others that glycogen-derived lactate is a major fuel for neurons during neurotransmission, memory consolidation, and exercise to exhaustion. Alternative mechanisms, including glucose sparing for neurons, are presented as testable explanations for data interpreted as lactate shuttling.

Keywords: Astrocyte; Brain activation; Cerebral cortex; Exercise; Glucose sparing; Glucose utilization; Glycogen; Glycogen shunt; Glycogen turnover; Hypoglycemia; Lactate; Lactate shuttling; Memory consolidation; Neuron; Neurotransmission; Oxygen consumption; Sensory stimulation.

MeSH terms

Animals
Astrocytes / metabolism*
Cerebral Cortex / cytology
Cerebral Cortex / metabolism*
Energy Metabolism*
Glycogenolysis*
Glycolysis*
Hypoglycemia / metabolism*
Neurons / metabolism*
Physical Conditioning, Animal / physiology*

Grants and funding

R01 MH109159/MH/NIMH NIH HHS/United States