“The forgetfulness brought on by insomnia may be countered with drugs,” says a report on BBC News today.
Research in mice looked at a chemical pathway in the part of the brain that deals with memory. It showed that sleep deprivation increases levels of an enzyme called PDE4 and reduces levels of a molecule called cAMP. The researchers were able to manipulate these pathways with a drug called Rolipram, which improved some of the memory problems of the sleep-deprived mice.
By identifying this molecular process in this laboratory, the researchers have opened up possibilities for drug development, but the practical uses of the treatment are yet to be demonstrated. As a sleep specialist told the BBC, “We really need to be thinking about ways to achieve adequate sleep in the first place – not how to deal with the consequences.”
Where did the story come from?
This research was carried out by Dr Christopher G Vecsey and colleagues from a range of neuroscience research groups in Pennsylvania, Glasgow and Toronto. The study was supported by at least six training grants, including grants from the US National Institutes of Health, the UK Medical Research Council and the European Union. The study was published in the peer-reviewed scientific journal Nature.
What kind of scientific study was this?
This was a laboratory animal study, in which the researchers identified molecular mechanisms that may cause brief sleep deprivation to alter brain function.
The researchers discuss the importance of the topic, saying that millions of people regularly have insufficient sleep. Past research on animal learning has shown that a major effect of sleep deprivation is memory deficiency in a part of the brain called the hippocampus. The hippocampus is a special area of densely packed nerves located deep within the brain. It forms part of the limbic system, which plays a major role in long-term memory and spatial navigation.
Over five hours, two groups of mice were either allowed to rest or were constantly disturbed by being handled. Each group then had their hippocampus’ response to electrical stimulation examined using a method called long-term potentiation. This technique has been used in previous neuroscience experiments to measure the cellular responses behind learning and memory.
Researchers then assessed the levels of a phosphodiesterase enzyme (PDE) called PDE4, one of five PDE enzymes involved in chemical reactions with a molecule called cAMP. The body uses cAMP as a cell messenger, triggering processes initiated by other chemicals that cannot pass through cell membranes.
There are several substances that inhibit the actions of PDE enzymes. The researchers injected the mice with one of these inhibitors, the drug Rolipram, which is already being investigated as a potential antidepressant and antipsychotic. They then retested the animals with long-term potentiation to see if the drug could reverse some of the effects of sleep deprivation seen in their previous tests.
Memory was then tested in the mice using a technique called contextual fear conditioning, in which the animals were taught to avoid a plate that delivered a small electric shock to their feet. How well they learned to avoid the plate was tested before and after sleep deprivation in both sets of mice, before and after the injection of the drug.
What were the results of the study?
The researchers say that sleep deprivation had several effects on cellular measures of memory in the mouse hippocampus. In particular, they noted reduced cAMP signalling (a reduction in the activity of this messenger) and an increase in the activity and concentration of the enzyme phosphodiesterase 4 (PDE4).
Treatment of mice with a phosphodiesterase inhibitor reversed the reduction in the activity of cAMP molecules that was brought on by sleep deprivation.
What interpretations did the researchers draw from these results?
The researchers say their findings demonstrate that brief sleep deprivation disrupts hippocampal function by interfering with cAMP signalling through increased PDE4 activity. They also conclude that drugs that improve cAMP signalling may provide a new way to improve brain function after sleep deprivation.
What does the NHS Knowledge Service make of this study?
This is an important piece of neuroscience research as it further defines how, at a molecular and behavioural level, sleep deprivation may impair memory. By further testing the observed effect in an experimental way with a drug, the researchers add strength to their evidence.
However, several more research steps would need to be performed to back up the claim that the researchers have found a treatment for the cognitive effects of sleep deprivation in humans. For example, further research could look at the effect of this drug on memory in humans, the safety of the drug or the thresholds at which sleep deprivation in humans begins to affect memory. It may also be interesting to compare how caffeine, another non-specific phosphodiesterase inhibitor, affects these pathways in mice. There may be other behavioural and molecular pathways involved in poor or irregular sleeping patterns, and these could also benefit from research.
There are several health benefits of sleep and, for the time being, non-rodents should aim to get sufficient sleep. Many people have difficulty sleeping, but it may be preferable to try non-drug methods first and only consider medication as a secondary option for treating sleep problems.
Analysis by Bazian
Edited by NHS Website
Links to the headlines
BBC News, 22 October 2009
Links to the science
Nature 2009; 461: 1122-1125