It’s pretty easy to upset our body clocks; shift work or flying half way across the world will do it. But disrupting our daily rhythms does more than just frustratingly muck up your sleeping pattern; behavioral, metabolic and even cognitive abnormalities are all associated with disturbances to our body, or circadian, clocks.
But what if it were possible to wind the clock back, forcing it to reset itself so that these problems do not ensue? Scientists are endeavoring to achieve this, and it seems that we could be tantalizingly close, as researchers have just unraveled the key brain processes that facilitate both clock resetting and precise timekeeping. Not only could this potentially lead to new ways to treat various disorders associated with things like jet lag and shift work, but it may also open up new treatment avenues for certain neuropsychiatric conditions like depression.
Scientists actually demonstrated it is possible to reset the clock a few months ago by using light to artificially stimulate neurons within our body’s “master clock,” which is a bundle of brain cells within a region known as the suprachiasmic nucleus (SCN). However, this involved genetic modification of mice and the insertion of an optical fiber in their brains, an approach that is hardly ready for humans just yet. Furthermore, while certainly interesting, it did not inform us of how precisely light is altering the levels of the recently identified clock components that together control its rhythmicity. Since our circadian clock responds to light and darkness from the environment, this was a fairly significant gap in our knowledge.
To learn more, scientists from McGill and Concordia universities began investigating the role of a protein called eIF4E. That’s because this molecule plays a pivotal role in gene expression, the process that results in the synthesis of a particular protein from a DNA sequence. Researchers assumed that light must somehow control the expression of the clock components, but they didn’t know how.
As described in Nature Neuroscience, their investigations revealed that the clock actually resets when eIF4E combines with a phosphate molecule, a process known as phosphorylation. Light actually drives the phosphorylation of eIF4E, which was found to specifically promote the expression of key clock genes, known as the Period genes, which contribute to cellular rhythmicity. When these proteins are produced in abundance, the clock resets and precise timekeeping is facilitated.
To further probe this process, the researchers engineered mice to produce a mutated eIF4E that could not be phosphorylated. They found that, compared with control mice, the mutants responded much less efficiently to the resetting effect of light. By exposing the mice to different light/dark cycles than they were used to, they found that, unlike the controls, the mutants were unable to synchronize their body clocks to the changes.
Although it’s difficult to say when these findings can be put to clinical use, the study is important because it identifies new potential targets, which could ultimately lead to the development of ways to manipulate the clock.
“Disruption of the circadian rhythm is sometimes unavoidable but it can lead to serious consequences,” explains co-author Shimon Amir. “We’ve taken an important step towards being able to reset our internal clocks—and improve the health of thousands as a result.”