Satisfying hungry cells with energy

Novel tools allow cell-specific investigations of brain energy metabolism. Compartmentalization of brain energy metabolism postulated by the astrocyte-neuron lactate shuttle hypothesis (left panel). Expression of genetically encoded substrate sensors (middle panels) allow the measurement of e.g. real-time lactate concentrations in neurons (upper panel on the right (red) or glucose concentrations in astrocytes (lower panel (blue)). Black arrows mark administration times of respective substrates.Scanning electron micrograph of a vascular corrosion cast from the primary visual cortex. Arteries are shaded in red and veins in blue. Scale bar = 1mm.

The brain relies on a continuous energy supply. Under normal circumstances, glucose represents the main energy substrate for the brain. Although the brain constitutes only 2% of the body weight, the energy-consuming processes of the brain account for about 25% of total body glucose utilization. In total, the human brain of an adult burns approximately 120 gram of glucose during a whole day.

For decades the notion that glucose is taken up and metabolized by individual brain cells according to their relative need was carved in stone. However, twenty years ago, a novel concept was introduced. The so-called astrocyte-neuron lactate shuttle hypothesis postulates main glucose uptake by astrocytes – brain cells located between neurons and blood vessels. Only after glycolytic degradation, lactate is transported to neurons where it serves as an energy substrate.

Past in vivo studies did not have the capability to resolve aspects of brain energy metabolism on a sufficient temporal and spatial level. As a consequence, the validity of the model has not been unambiguously demonstrated yet.

Recently, we established the combined use of genetically encoded substrate sensors and two-photon laser scanning microscopy in the intact brain. This toolset allows real-time measurements of substrate concentrations (e.g. glucose, lactate, pyruvate) in individual cellular compartments.

At present, we focus mainly on the following questions:

  1. How do individual cells cooperate metabolically in the intact brain?
  2. What is the role of astrocytic lactate transporters for proper neuronal energy supply?
  3. Is the integrity of astrocytic networks an essential prerequisite for adequate lactate delivery to neurons?

A more complete understanding of the mechanisms and compartments involved in brain energetics is fundamental for a full understanding not only of the physiology but also the pathophysiology of brain function. Indeed, many neurological pathologies such as neurodegenerative diseases, stroke, epilepsy, migraine and brain tumors display abnormalities in brain energy metabolism.