Being asleep or awake may hinge on brain salts

Simply changing salt levels in the fluid bathing brain cells can send mice to sleep and wake them up, new research shows, challenging previous theories that wakefulness is dictated by the chemicals cells use to communicate.

Fengfei Ding from the University of Rochester in the US and colleagues examined how different salt ions – atoms with a positive or negative charge – stimulate or lull neurons, and found they could send a mouse’s brain into slow-wave sleep by changing the cocktail of salts, such as potassium, in its brain fluid.

The findings, published in Science, may explain how the whole brain is able to activate billions of cells quickly upon awakening.

“First and foremost, we learn more about how sleep is controlled,” says Maiken Nedergaard, University of Rochester neuroscientist and senior author of the study.

“The fact that a simple alteration of extracellular ion composition can wake a sleeping animal up and put a wake animal to sleep is direct evidence for that this mechanism plays a key role in regulating consciousness.”

Prior to this study, it was generally thought that a complex mix of neurotransmitters – chemical messengers released by firing neurons to communicate to other neurons as well as muscle and gland cells – woke up the brain.

These chemicals are made in structures deep within the brain, but the neurotransmitter hypothesis doesn’t explain how the whole brain can wake almost immediately, or how it winds down this activity to go to sleep.

One side-effect of the neurotransmitter hypothesis, it was thought, is that the brain upon waking floods with ions – in particular, those with a positive charge. They do, indeed, control a brain cell’s activity. By flowing in and out of a neuron, they shift the cell’s charge across its membrane from negative to positive and back again.

This propagates an “action potential” down the length of the neuron – an electrical signal which, via neurotransmitters, can “jump” to a connecting cell.

That positively charged ions outside neurons exert control over the sleep cycle, rather than be a side-effect of the neurotransmitter hypothesis, isn’t new. In the 1930s, ions in breast milk were thought to help lull babies to sleep.

So Ding and her colleagues mixed various cocktails of ions to mimic cerebral spinal fluid – the fluid in which the brain and spinal cord sit – and infused them onto brain slices and into live mice.

They saw concoctions high in calcium and magnesium seemed to perk them up, while those high in potassium dropped the brain cells’ activity to a sleep-like state. While in the sleepy state, neurons and their support cells shrunk slightly, which the researchers suggest provides more room for cerebral spinal fluid to wash away waste.

Hans-Peter Landolt and Sebastian Holst from the University of Zurich write in a Perspective piece that the work doesn’t explain local sleep, where one part of the brain goes into snooze mode but not another.

But, they add, targeting the pumps that “that control ion flow across cell membranes may be promising new targets for treating sleep-wake disorders”.

Future work may examine how ions affect rapid eye movement (REM) sleep, which is a different beast. Unlike slow-wave sleep, the brain patterns produced during REM sleep are a cross between slow-wave sleep and being awake.

And the study doesn’t mean eating more potassium salt will make you sleepier. Your body’s pretty good at keeping salt levels stable in its cerebral spinal fluid, and boosting intake is unlikely to help.