The science of sleep

Tuesday, 12 March, 2019

The science of sleep

Two separate studies published in recent weeks have revealed how sleep strengthens the immune system and cleans the brain — so long as you get enough of it.

Getting enough sleep is vital to supporting our immune system in fighting off pathogens, but scientists still don’t know exactly how sleep affects certain immune functions. Now, researchers from the Universities of Tübingen and Lübeck have discovered a new mechanism by which sleep supports the immune system, showing that the function of T cells — the white blood cells that are responsible for combating pathogens — was impaired after only three hours without sleep. Their study was published in the Journal of Experimental Medicine.

The scientists conducted a 24-hour experiment with volunteers: one group was allowed to sleep for eight hours at night, a second group stayed awake for the whole period. During the experiment, blood was regularly taken from the participants. In particular, the research team examined the binding strength of T cells to a molecule named ICAM-1 (intercellular adhesion molecule-1), which enables them to attach to other cells in a process known as adhesion. This is important for their function.

“T cells circulate constantly in the bloodstream looking for pathogens,” said first author Stoyan Dimitrov from the University of Tübingen. “Adhesion to other cells enables them to migrate to different areas in the body and, for example, dock onto infected cells in order to subsequently kill them.”

The study showed that the adhesion of T cells was significantly reduced in sleep-deprived subjects.

In order to further investigate how sleep affects T-cell function, plasma — the part of the blood that contains soluble substances such as hormones — was taken from sleeping and sleep-deprived subjects. This plasma was applied to isolated T cells for a few minutes. Plasma taken from sleep-deprived subjects reduced the adhesion significantly compared with the plasma from subjects who had slept.

In another experiment, the team was able to reverse this suppression of T-cell function by blocking Gαs-coupled receptors. Among other substances, the stress hormone adrenaline and prostaglandins, which play a role in inflammation, bind via these receptors.

“This shows that even following brief sleep deprivation soluble molecules activate these receptors and thereby impair the adhesion of the T cells,” said study head Luciana Besedovsky, also from the University of Tübingen.

In parallel experiments, the researchers were also able to show that some of the soluble molecules that bind to this receptor class — such as adrenaline, prostaglandins and the neuromodulator adenosine — strongly impair adhesion when administered directly to T cells. The same substances are also strongly elevated in a number of pathological conditions, such as chronic stress or cancer.

“This means that our findings also have clinical relevance outside sleep research,” said Dr Tanja Lange from the University of Lübeck. “They could explain why the immune system is suppressed in some diseases.”

Besedovsky concluded, “Just three hours without sleep are sufficient to reduce the function of important immune cells. Our results show a potential fundamental mechanism by which sleep helps us fight infection.”

Of course a good night’s sleep is important not just for fighting infection, but also for washing away waste and toxic proteins at the end of the day. But the depth of our sleep impacts the brain’s ability to efficiently carry out this function — which is a problem in older people, whose sleep tends to be lighter and more disrupted.

A study published in the journal Science Advances, led by Dr Maiken Nedergaard from the University of Rochester Medical Center, indicates that the slow and steady brain and cardiopulmonary activity associated with deep non-REM sleep are optimal for the function of the glymphatic system, the brain’s process of removing waste. The previously unknown glymphatic system was first described by Nedergaard and her colleagues in 2012, who revealed a system of plumbing that piggybacks on blood vessels and pumps cerebral spinal fluid (CSF) through brain tissue to wash away waste — a system that primarily works while we sleep.

Because the accumulation of toxic proteins such as beta amyloid and tau in the brain is associated with Alzheimer’s disease, researchers have speculated that impairment of the glymphatic system due to disrupted sleep could be a driver of the disease. This squares with clinical observations that show an association between sleep deprivation and heightened risk for Alzheimer’s.

In the current study, researchers conducted experiments with mice that were anaesthetised with six different anaesthetic regimens, tracking brain electrical activity, cardiovascular activity and the cleansing flow of CSF through the brain. They observed that a combination of the drugs ketamine and xylazine (K/X) most closely replicated the slow and steady electrical activity in the brain and slow heart rate associated with deep non-REM sleep. Furthermore, the electrical activity in the brains of mice administered K/X appeared to be optimal for function of the glymphatic system.

“The synchronised waves of neural activity during deep slow-wave sleep, specifically firing patterns that move from [the] front of the brain to the back, coincide with what we know about the flow of CSF in the glymphatic system,” said Dr Lauren Hablitz, a postdoctoral associate in Dr Nedergaard’s lab and first author of the study. “It appears that the chemicals involved in the firing of neurons, namely ions, drive a process of osmosis, which helps pull the fluid through brain tissue.”

The study thus reinforces the importance of deep sleep to the proper function of the glymphatic system — and as it becomes more difficult to consistently achieve deep non-REM sleep as we age, the study bolsters the link between sleep, ageing and Alzheimer’s disease. It also demonstrates that the glymphatic system can be manipulated by enhancing sleep — a finding that may point to potential clinical approaches, such as sleep therapy or other methods to boost the quality of sleep, for at-risk populations.

“Sleep is critical to the function of the brain’s waste removal system and this study shows that the deeper the sleep the better,” said Dr Nedergaard. “These findings also add to the increasingly clear evidence that quality of sleep or sleep deprivation can predict the onset of Alzheimer’s and dementia.”

Because several of the compounds used in the study were analogous to anaesthetics used in clinical settings, the results also shed light on the cognitive difficulties that older patients often experience after surgery. Mice in the study that were exposed to anaesthetics that did not induce slow brain activity saw diminished glymphatic activity, reflecting the significant percentage of elderly patients who experience a postoperative period of delirium and/or cognitive impairment. The researchers have suggested classes of drugs that could be used to avoid this phenomenon.

Top image credit: © Yuganov

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