‘Chemical metronome’ helps the brain to keep time

Imperial researchers uncover a ‘chemical metronome’ in the brain, which helps to synchronise the master clock telling us when it’s time to sleeep.

In a study of brain cells from mice and humans, researchers have found that star-shaped cells called astrocytes rhythmically produce a chemical pulse that helps the brain’s master clock to keep time, influencing our circadian rhythm and sleep-wake cycle.

According to the researchers, the work (published in The EMBO Journal) helps us to understand how astrocytes synchronise the brain circuits maintaining circadian rhythm and could have implications for treating jetlag, sleep disorders and even slowing or preventing neurodegenerative diseases.

Dr Marco Brancaccio, from the Department of Brain Sciences at Imperial College London, said: “While this work is at an early stage and there is much still to explore, we hope our discovery will help us to better understand how the brain keeps time and how astrocytes work together with neurons to influence mammalian behaviour.

"It could potentially lead to new ways to treat disrupted circadian rhythms in insomnia, and even help to slow the onset of dementia.”

Keeping time

Circadian rhythms help to maintain human health, including our sleep-wake cycle. Different cell types across the body may have their own internal clocks, but in mammals, they are all controlled by a ‘master clock’ in the suprachiasmatic nucleus (SCN) – a tiny structure located deep in the brain.

Previous work by the Imperial researchers showed that astrocytes, which carry out a range of maintenance functions in the brain, may play a role in regulating circadian rhythm. But exactly how they did this was unclear.

It could potentially lead to new ways to treat disrupted circadian rhythms in insomnia, and even help to slow the onset of dementia. Dr Marco Brancaccio Department of Brain Sciences

In the latest study, the team studied the brains of mice and human brain cells to better understand the role these cells play.

They found that astrocytes regularly release a neurotransmitter called GABA, which peaked every 24-hours.

This regular pulse was found to act as a kind of chemical metronome, helping to synchronise the neurons of the SCN and so indirectly impacting circadian rhythm and the sleep-wake cycle.

Natalie Ness, a PhD researcher and first author of the study, said: “Our research highlights a surprising role for astrocytes in the brain’s internal clock system.

"These cells produce a daily rhythm of GABA – a signalling molecule normally associated with neurons. This rhythmic GABA release from astrocytes helps fine-tune the brain’s timekeeping across the day.

“When we block or disrupt this astrocyte-derived signal, it has a knock-on effect on neurons of the SCN, disrupting activity and gene expression patterns known to be crucial in maintaining circadian rhythms in physiology and behaviour.”

Protecting brain function

The researchers say that their discovery could help us to better understand how time-related information is encoded in the brain and drives complex behaviour in mammals.

They explain that as astrocytes are early markers in several brain diseases, such as Parkinson’s and Alzheimer’s, protecting their rhythms could potentially protect brain function and delay the onset of disease or slow its progression.

Dr Brancaccio added: “Our latest findings may offer a new perspective for better understanding neurodegenerative disease, but it remains a very complex picture.

"Disrupted levels of GABA are known to be prominent in Alzheimer’s disease, and altered GABA production by astrocytes has been associated with disease in large gene expression studies in patients.

“However, while we generally think about astrocytic GABA as something related to disease, our current work highlights it as a fundamental mechanism of internal resilience.

“In the early stages of disease, these sorts of mechanisms may be derailed, gradually weakening the core circuitry of the brain – like our internal master clock – with huge implications for our physiology and behaviour.

“As we look for “tipping points” by which disrupted sleep-wake cycles could lead us to the path of disease, bolstering astrocytic GABA rhythms appears an exciting candidate for preventative interventions.”

The work was supported by funding from the UK Dementia Research Institute and Imperial College President’s Scholarship.

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‘Rhythmic astrocytic GABA production synchronizes neuronal circadian timekeeping in the suprachiasmatic nucleus’ by Natalie Ness, Sandra Díaz-Clavero, Marieke M B Hoekstra, and Marco Brancaccio is published in The EMBO Journal. DOI: https://doi.org/10.1038/s44318-024-00324-w

Main image: Shutterstock / Chaponta