Longevity Briefs: How Sleep Loss Disrupts The Brain’s Wiring In Rats

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

Sleep loss is an all-too-common problem that only gets worse as we age. Older adults often sleep less or have more fragmented sleep, and there is a strong association between poor sleep, cognitive decline and dementia. It’s still not entirely clear how sleep loss harms the brain at a cellular level. Sleep seems to be important for the brain’s ‘housekeeping’, presenting an opportunity to dispose of waste like mis-folded proteins, such as amyloid beta, that are associated with neurodegenerative disease.

Research has also shown that poor sleep is associated with changes in white matter structure. White matter can be viewed as the ‘wiring’ of the brain, responsible for transferring information between different brain regions, as opposed to the grey matter where most of the brain’s ‘computation’ occurs. White matter is white because its nerve fibres are insulated by a fatty material called myelin, which results in faster electrical impulses. But how exactly could sleep loss be disrupting white matter integrity, and what role does this play in cognitive decline? In this study, researchers offer some answers.

The discovery:

Researchers were able to show that prolonged sleep restriction thins myelin, slowing down signal transmission between brain hemispheres, and that these changes are tied to problems with how oligodendrocytes (cells that maintain myelin) handle cholesterol.

Researchers took 20 rats and put half of them in a sleep-restriction environment for 10 days. They then gave these mice behavioural tests and performed a detailed analysis of their brains using magnetic resonance imaging (MRI), electron microscopy and by making electrical recordings. They found that white matter structure changed in the ways that might be expected, with myelin becoming thinner in the sleep deprived rats. They also found that this thinning of myelin was associated with around 33% slower electrical conduction across the corpus callosum – the structure that connects the right and left hemispheres of the brain together.

The researchers also measured brain activity during non-REM sleep (NREM), which refers to the deeper stages of sleep that are thought to be important for integrating new information. NREM sleep is characterised by synchronised electrical activity across the whole brain, but researchers found that in rats that had been sleep deprived, the signals in the right and left hemispheres were desynchronised – something that is observed in many neurological conditions.

Molecular analyses revealed that the oligodendrocytes of sleep deprived rats had down-regulated genes involved in cholesterol and lipid (fat) transport, which appeared to result in reduced cholesterol content in myelin membranes. Researchers then tested whether these changes could be prevented by treating sleep deprived rats with 2‑hydroxypropyl‑β‑cyclodextrin (a compound that redistributes cholesterol to myelin membranes), given in 3 doses before, during and after sleep deprivation. While this did not fully protect the structure of the white matter, it completely prevented the slowing of electrical signals. Remarkably, they also found that while sleep-deprived rats had significantly worse cognitive and motor function when compared to control rats, these deficits were completely prevented by cyclodextrin treatment, suggesting a causal link between oligodendrocyte cholesterol handling, conduction speed and cognitive function.

The implications:

This research provides a potential mechanism for how chronic sleep deprivation leads to loss of cognitive function. Sleep loss disrupts cholesterol processing by oligodendrocytes, which leads to thinning of the myelin that insulates white matter neurons, slowing down conduction and synchronisation between brain hemispheres. In this study, researchers did repeat some experiments in chronically stressed mice and found that the white matter changes did not occur, suggesting that it was sleep deprivation specifically (and not the stress resulting from sleep deprivation) that caused these changes.

It remains to be seen whether these findings apply to sleep deprived humans – remember that most humans do not become chronically sleep deprived because something is actively keeping them awake, as was the case in this experiment. Poor sleep patterns develop over time in response to all kinds of different factors, which most likely include changes that have already taken place in the brain during ageing. While poor sleep quality is associated with loss of white matter integrity in humans, we still don’t know how important this is for cognitive decline.