Summary: Researchers have identified a key mechanism that senses when the brain needs an energy boost, involving astrocytes and the molecule adenosine. The discovery could lead to new therapies to maintain brain health and longevity, including combating cognitive decline and neurodegenerative diseases.
The study found that astrocytes monitor neuronal activity and activate energy supply pathways, ensuring efficient brain function. This advance opens the door to potential treatments for diseases such as Alzheimer’s.
Highlights:
- Astrocytes play a crucial role in supplying energy to neurons during high-demand activities.
- The adenosine molecule is essential for activating the glucose metabolism of astrocytes.
- Disruption of this energy stimulation mechanism impairs brain function, memory and sleep.
Source: UCL
A key mechanism that senses when the brain needs extra energy to sustain its activity has been identified in a study of mice and cells led by UCL scientists.
Scientists say their findings, published in Naturecould shed light on new therapies to maintain brain health and longevity, as other studies have shown that brain energy metabolism can be impaired late in life and contribute to cognitive decline and the development of neurodegenerative diseases.
Professor Alexander Gourine (UCL Neuroscience, Physiology & Pharmacology), lead author of the study, said: “Our brain is made up of billions of nerve cells, working together to coordinate many functions and perform complex tasks such as controlling movement, learning and forming memories. All of this computation is very energy intensive and requires a constant supply of nutrients and oxygen.”
“When our brain is more active, for example when we are performing a mentally demanding task, our brain needs an immediate energy boost, but the exact mechanisms that ensure the local on-demand supply of metabolic energy to active brain regions are not fully understood.”
Previous research has shown that many brain cells called astrocytes appear to play a role in providing brain neurons with the energy they need. Astrocytes, shaped like stars, are a type of glial cell, a non-neuronal cell found in the central nervous system.
When neighboring neurons require increased energy supply, astrocytes spring into action by rapidly activating their own glucose stores and metabolism, resulting in increased production and release of lactate. Lactate supplements the readily available energy supply for neurons in the brain.
Professor Gourine explains: “In our study, we discovered how astrocytes are able to monitor the energy consumption of neighboring nerve cells and trigger this process that provides additional chemical energy to active brain regions.”
In a series of experiments using mouse models and cell samples, the researchers identified a set of specific receptors in astrocytes that can sense and monitor neuronal activity and trigger a signaling pathway involving a key molecule called adenosine.
The researchers discovered that the metabolic signaling pathway activated by adenosine in astrocytes is exactly the same as the pathway that recruits energy stores in muscles and the liver, for example when we exercise.
Adenosine activates astrocyte glucose metabolism and energy supply to neurons to ensure that synaptic function (neurotransmitters transmitting communication signals between cells) continues at a sustained rate under conditions of high energy demand or reduced energy supply.
The researchers found that when they disabled key astrocyte receptors in mice, the animals’ brain activity was less efficient, including significant alterations in overall brain metabolism, memory and sleep disruptions, demonstrating that the signaling pathway they identified is vital for processes such as learning, memory and sleep.
Dr Shefeeq Theparambil, first and co-corresponding author, who began the study at UCL before joining Lancaster University, said: “Identifying this mechanism could have wider implications as it could be a way to treat brain diseases in which brain energetics are downregulated, such as neurodegeneration and dementia.”
Professor Gourine adds: “We know that the brain’s energy homeostasis is progressively altered with aging and that this process is accelerated during the development of neurodegenerative diseases such as Alzheimer’s disease.
“Our study identifies an attractive and easily druggable target and therapeutic opportunity for brain energy rescue to protect brain function, maintain cognitive health, and promote brain longevity.”
Funding: The researchers were supported by Wellcome and the study involved scientists from UCL, Lancaster University, Imperial College London, King’s College London, Queen Mary University of London, the University of Bristol, the University of Warwick and the University of Colorado.
About this neuroscience research news
Author: Chris Lane
Source: UCL
Contact: Chris Lane – UCL
Picture: Image credited to Neuroscience News
Original research: Free access.
“Adenosine signaling to astrocytes coordinates brain metabolism and function” by Alexander Gourine et al. Nature
Abstract
Adenosine signaling to astrocytes coordinates metabolism and brain function
The brain’s computations performed by billions of nerve cells depend on an adequate and uninterrupted supply of nutrients and oxygen.
Astrocytes, ubiquitous glial neighbors of neurons, regulate glucose uptake and metabolism in the brain, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood.
Here, we show, using in vitro and in vivo experimental animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by the neuromodulatory adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate
A signaling pathway leading to rapid activation of astrocyte glucose metabolism and release of lactate, which replenishes the extracellular pool of readily available energy substrates.
Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes have shown that adenosine-mediated metabolic signaling is essential for maintaining synaptic function, particularly under conditions of high energy demand or reduced energy supply.
Decreased A2B receptor expression in astrocytes led to major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory, and disrupted sleep.
These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signaling in astrocytes adjusts brain energy metabolism to support fundamental functions such as sleep and memory.