summary: Researchers have identified a key mechanism involving astrocytes and the molecule adenosine that detects when the brain needs an energy boost – a discovery that could lead to new therapies to maintain brain health and longevity, particularly in combating cognitive decline and neurodegenerative diseases.
The study found that astrocytes monitor neuronal activity and activate energy supply pathways to ensure efficient brain function, a groundbreaking discovery that could provide potential treatments for diseases such as Alzheimer’s.
Key Facts:
- Astrocytes play a key role in providing energy to neurons during high-stress activities.
- The adenosine molecule is essential for activating glucose metabolism in astrocytes.
- When this energy-boosting mechanism is disrupted, brain function, memory, and sleep are impaired.
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A key mechanism that detects when the brain needs an extra energy boost to support activity has been identified in a study of mice and cells led by UCL scientists.
The scientists NatureOther studies have found that brain energy metabolism is impaired in older age, which can lead to cognitive decline and the development of neurodegenerative diseases, so the findings may lead to new therapies to maintain brain health and longevity.
Lead author Alexander Gourin, Professor of Neuroscience, Physiology and Pharmacology, University of London, said: “Our brains are made up of billions of nerve cells that work together to coordinate numerous functions and carry out complex tasks such as controlling movement, learning and forming memories. All this computational processing is extremely energy intensive and requires a constant supply of nutrients and oxygen.”
“During times of greater brain activity, such as during mentally demanding tasks, the brain needs immediate energy replenishment, but the exact mechanisms that provide on-demand, localized metabolic energy to active brain regions are not fully understood.”
Previous research has revealed that large numbers of brain cells called astrocytes, which are star-shaped and belong to a type of glial cell, a non-neuronal cell found in the central nervous system, may be responsible for providing the brain’s neurons with the energy they need.
When nearby neurons require an increased energy supply, astrocytes rapidly activate their own glucose stores and metabolism, leading to increased production and release of lactate, which replenishes the energy pools available to neurons in the brain.
Professor Goulin explained: “Our study uncovers how astrocytes can monitor the energy use of neighbouring neurons and initiate this process of providing additional chemical energy to active brain regions.”
In a series of experiments using mouse models and cell samples, the researchers identified a specific set of receptors in astrocytes that can detect and monitor neural activity and activate a signaling pathway involving an essential molecule called adenosine.
The researchers discovered that the metabolic signalling pathways activated by adenosine in astrocytes are exactly the same as those that mobilise energy stores in muscles and the liver during exercise, for example.
Adenosine activates glucose metabolism in astrocytes and the energy supply to neurons, ensuring that synaptic function (neurotransmitters that carry communication signals between cells) continues even when energy demand is high or energy supply is reduced.
The researchers found that inactivating a key astrocyte receptor in mice reduced the efficiency of the animals’ brain activity and led to significant impairments in brain-wide metabolism, memory and sleep disruptions, demonstrating that the signaling pathway they identified is essential for processes such as learning, memory and sleep.
“Identifying this mechanism could have wider implications as it could be a way to treat brain diseases where the brain experiences reduced energy, such as neurodegeneration and dementia,” said lead and co-corresponding author Dr Shefiq Teparamvir, who began his research at University College London before moving to Lancaster University.
Professor Goulin added: “We know that brain energy homeostasis is gradually impaired with age and that this process is accelerated during the development of neurodegenerative diseases such as Alzheimer’s.”
“Our study has identified an attractive, readily druggable target and therapeutic opportunity for brain energy rescue aimed at protecting brain function, maintaining cognitive health and promoting brain longevity.”
Funding: The researchers were supported by Wellcome and the study included scientists from University College London, Lancaster University, Imperial College London, King’s College London, Queen Mary, University of London, University of Bristol, University of Warwick and University of Colorado.
About this Neuroscience Research News
author: Chris Lane
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contact: Chris Lane – UCL
image: Image courtesy of Neuroscience News
Original Research: Open access.
“Adenosine signaling regulates brain metabolism and function” Alexander Gurin et al. Nature
Abstract
Adenosine signaling regulates brain metabolism and function
The brain’s computations, carried out by billions of nerve cells, depend on an adequate and uninterrupted supply of nutrients and oxygen.
Astrocytes, the ubiquitous glial cells of neurons, control glucose uptake and metabolism in the brain, but the precise mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs have not been fully elucidated.
Here, using experimental in vitro and in vivo animal models, we show that neuronal activity-dependent metabolic activation of astrocytes is mediated by the neuromodulator adenosine, which acts on astrocytic A2B receptors, whose stimulation recruits the canonical cyclic adenosine 3′,5′-monophosphate-protein kinase.
The signaling pathway rapidly activates glucose metabolism in astrocytes, releasing lactate that replenishes the extracellular pool of readily available energy substrates.
Experimental mouse models with conditional deletion of the gene encoding the A2B receptor in astrocytes have demonstrated that adenosine-mediated metabolic signaling is essential for the maintenance of synaptic function, especially when energy demands are high or energy supplies are reduced.
Knockdown of A2B receptor expression in astrocytes led to a profound reprogramming of brain energy metabolism, inhibited synaptic plasticity in the hippocampus, severely impaired recognition memory, and disrupted sleep.
These data identify adenosine A2B receptors as astrocytic sensors of neural activity and demonstrate that cAMP signaling in astrocytes regulates brain energy metabolism to support fundamental functions such as sleep and memory.