Metabolic Dynamics in Central Nervous System

The central nervous system is one of the most energy‐demanding tissues in the body, relying almost exclusively on glucose to meet its needs for ATP, biosynthesis and redox balance. Neurons and glial cells engage in a highly coordinated metabolic partnership, with astrocytes often taking up and partially oxidising glucose to supply neurons with intermediates such as lactate or alanine. Glycolysis, the tricarboxylic acid cycle and ancillary routes such as the pentose phosphate pathway are spatially and temporally compartmentalised across cell types to support synaptic transmission, ion homeostasis and neurotransmitter turnover. Key cycles, notably the glutamate–glutamine shuttle, couple excitatory and inhibitory signalling to metabolic processes, ensuring neurotransmitter pools are maintained and ammonia is safely detoxified. Beyond serving as fuels, several metabolites have been identified as signalling molecules that modulate neuronal excitability, gene expression and neurovascular coupling. Dysregulation of these pathways is implicated in cognitive dysfunction, stroke, epilepsy and neurodegenerative disorders, and emerging strategies aim to target specific enzymes or transporters to restore metabolic balance and promote resilience.

Research from Nature Portfolio

Recent studies have revealed an alternative glia–neuron shuttle mediated by alanine during memory formation. In an in vivo model of olfactory learning, glycolysis in astrocytes generates alanine, which is exported and converted back to pyruvate in cholinergic neurons to sustain the heightened mitochondrial demands of memory circuits. This work demonstrates an elegant compartmentalisation of energy metabolism and identifies alanine aminotransferase as a critical mediator of glial–neuronal coupling.

Foundational imaging work has re-examined the astrocyte–neuron lactate shuttle hypothesis by tracking a fluorescent glucose analogue in awake mammals. Two-photon microscopy showed that neuronal glucose uptake predominates during sensory stimulation and is supported by high levels of neuronal hexokinase. These findings position neurons, rather than astrocytes, as the principal locus of activity-dependent glucose consumption, reshaping our understanding of cerebral energy flow.

Metabolic Dynamics in Central Nervous System publication trend

The graph below shows the total number of articles in metabolic dynamics in central nervous system across all publications each year (not limited to Nature Index journals).

Technical terms

Astrocyte: A type of glial cell that regulates neurotransmitter levels, supports the blood–brain barrier and mediates metabolic support for neurons.

Neuron: The primary signalling cell of the nervous system, specialised for rapid electrical communication and reliant on mitochondria for ATP production.

Glycolysis: The cytosolic pathway that breaks down glucose into pyruvate, generating small amounts of ATP and NADH.

Astrocyte–neuron lactate shuttle: A model in which lactate produced by astrocytes from glucose is transported to neurons and oxidised in mitochondria.

Glutamate–glutamine cycle: The process by which glutamate released at synapses is taken up by astrocytes, converted to glutamine and returned to neurons for neurotransmitter resynthesis.

Mitochondria: Intracellular organelles that carry out oxidative phosphorylation to synthesise ATP and regulate redox balance.

References

1. Glycolysis-derived alanine from glia fuels neuronal mitochondria for memory in Drosophila. Nature Metabolism (2023).
2. Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism. Nature Communications (2015).
3. Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology (2021).
4. Is L-Lactate a Novel Signaling Molecule in the Brain?. Cerebrovascular and Brain Metabolism Reviews (2015).
5. Synaptic Energy Use and Supply. Neuron (2012).