Mice exhibited greater glymphatic solute clearance when asleep, suggesting the role of sleep in clearing metabolites from the brain. Source: http://www.flickr.com/photos/cclogg/
Many have wondered why the brain needs sleep to function optimally. Recently, researchers at the University of Rochester Medical Center have found that the brain rids itself of a potentially harmful protein during sleep via the glymphatic system (1).
Interstitial fluid, the fluid that fills the space in between brain cells, is filled with potentially harmful proteins like β-amyloid. This fluid, unlike other fluids in the body, is not drained by the lymphatic system.
Instead, in a system known as the glymphatic system, the brain’s interstitial fluid and the proteins within it leave through the veins while cerebrospinal fluid from the arteries comes in to replace it.
As β-amyloid concentrations are higher in the interstitial fluid during wakefulness than during sleep in both mice and humans, the researchers wanted to see if the rate of β-amyloid removal is related to the wake-sleep cycle.
The researchers put fluorescent tracers within the mice cerebrospinal fluid to measure how much and how quickly the fluid flowed into the brain when the mice were asleep and when they were awake. They observed a 95% reduction in interstitial fluid flow from sleeping mice to awake mice.
To test whether brain activity controlled the flow rate, the researchers monitored the mice before and after anesthesia was applied. There was not much inflow of cerebrospinal fluid while the mice were conscious, but once knocked out, the rate of inflow was similar to that of the sleeping mice.
Because arterial pressure increases when the body is active, the researchers initially expected the inflow of cerebrospinal fluid to be greater for conscious mice. To explain why inflow was instead greater in sleeping mice, the researchers hypothesized that the awake brain has a smaller interstitial space. Such a decrease in space would resist the incoming volume of fluid, reducing cerebrospinal inflow in the awake brain. Their findings supported their hypothesis, showing that conscious mice indeed have smaller interstitial space than sleeping mice.
The researchers also checked for a change in the interstitial volume for anesthetized mice. They found that the anesthetized mice had interstitial fluid volumes comparable to that of sleeping mice.
Additionally, they tested how well the glymphatic system removed β-amyloid by injecting radioactively labelled β-amyloid as well as an inert tracer into conscious, sleeping, and anesthetized mice. Sleeping and anesthetized mice removed β-amyloid about twice as quickly than their awake counterparts.
The researchers also sought to understand the cause of interstitial space reduction when mice are awake. Knowing that noradrenaline and related chemicals affect cell volume in cells outside of the brain, the researchers tested cerebrospinal inflow after treating the mice with chemicals that blocked the receptors for noradrenaline. With noradrenaline receptors blocked from injections of the chemical or direct applications, awake mice had similar levels of fluid inflow as asleep mice.
As accumulated protein β-amyloid is associated with Alzheimer’s disease (2), more research on sleep and its impact on the glymphatic system is needed.
References:
1. Nedergaard, Maiken et al., Science 342 (6156), 373-377. [DOI:10.1126/science.1241224]
2. Haiken, Melanie. “Sleep ‘Detoxes’ the Brain, New Research Suggests”. (2013) Available at http://www.forbes.com/sites/melaniehaiken/2013/10/18/sleep-detoxes-the-brain-new-research-suggests/ (26 October 2013)