Search

Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research.

Lactate shuttled from the blood circulation, astrocytes, oligodendrocytes or even activated microglia (resident macrophages) to neurons has been hypothesized to represent a major source of pyruvate compared to what is normally produced endogenously by neuronal glucose metabolism. However, the role of lactate oxidation in fueling neuronal signaling associated with complex cortex function, such as perception, motor activity, and memory formation, is widely unclear. This issue has been experimentally addressed using electrophysiology in hippocampal slice preparations (ex vivo) that permit the induction of different neural network activation states by electrical stimulation, optogenetic tools or receptor ligand application. Collectively, these studies suggest that lactate in the absence of glucose (lactate only) impairs gamma (30–70 Hz) and theta-gamma oscillations, which feature high energy demand revealed by the cerebral metabolic rate of oxygen (CMRO2, set to 100%). The impairment comprises oscillation attenuation or moderate neural bursts (excitation–inhibition imbalance). The bursting is suppressed by elevating the glucose fraction in energy substrate supply. By contrast, lactate can retain certain electric stimulus-induced neural population responses and intermittent sharp wave-ripple activity that features lower energy expenditure (CMRO2 of about 65%). Lactate utilization increases the oxygen consumption by about 9% during sharp wave-ripples reflecting enhanced adenosine-5′- triphosphate (ATP) synthesis by oxidative phosphorylation in mitochondria. Moreover, lactate attenuates neurotransmission in glutamatergic pyramidal cells and fast-spiking, γ-aminobutyric acid (GABA)ergic interneurons by reducing neurotransmitter release from presynaptic terminals. By contrast, the generation and propagation of action potentials in the axon is regular. In conclusion, lactate is less effective than glucose and potentially detrimental during neural network rhythms featuring high energetic costs, likely through the lack of some obligatory ATP synthesis by aerobic glycolysis at excitatory and inhibitory synapses. High lactate/glucose ratios might contribute to central fatigue, cognitive impairment, and epileptic seizures partially seen, for instance, during exhaustive physical exercise, hypoglycemia and neuroinflammation. [ABSTRACT FROM AUTHOR]

Mitochondria are central for various cellular processes that include ATP production, intracellular [Ca.sup.2+] signaling, and generation of reactive oxygen species. Neurons critically depend on mitochondrial function to establish membrane excitability and to execute the complex processes of neurotransmission and plasticity. While much information about mitochondrial properties is available from studies on isolated mitochondria and dissociated cell cultures, less is known about mitochondrial function in intact neurons in brain tissue. However, a detailed description of the interactions between mitochondrial function, energy metabolism, and neuronal activity is crucial for the understanding of the complex physiological behavior of neurons, as well as the pathophysiology of various neurological diseases. The combination of new fluorescence imaging techniques, electrophysiology, and brain slice preparations provides a powerful tool to study mitochondrial function during neuronal activity, with high spatiotemporal resolution. This review summarizes recent findings on mitochondrial [Ca.sup.2+] transport, mitochondrial membrane potential ([DELTA][[PSI].sub.m]), and energy metabolism during neuronal activity. We will first discuss interactions of these parameters for experimental stimulation conditions that can be related to the physiological range. We will then describe how mitochondrial and metabolic dysfunction develops during pathological neuronal activity, focusing on temporal lobe epilepsy and its experimental models. The aim is to illustrate that 1) the structure of the mitochondrial compartment is highly dynamic in neurons, 2) there is a fine-tuned coupling between neuronal activity and mitochondrial function, and 3) mitochondria are of central importance for the complex behavior of neurons. brain slice preparation; electrophysiology; NADH; mitochondrial calcium transport; temporal lobe epilepsy