by the University of Michigan
ANN ARBOR, Mich. — University of Michigan mathematicians and their British colleagues say they’ve identified the signal that the brain sends to the rest of the body to control biological rhythms, a finding that overturns a long-held theory about our internal clock.
Understanding how the human biological clock works is an essential step toward correcting sleep problems like insomnia and jet lag. New insights about the body’s central pacemaker might also, someday, advance efforts to treat diseases influenced by the internal clock, including cancer, Alzheimer’s disease and bipolar disorder, said University of Michigan mathematician Daniel Forger.
“Now that we know what the signal is, we should in the future be able to change it in order to help people,” said Forger, an associate professor of mathematics and a member of the U-M’s Center for Computational Medicine and Bioinformatics.
The body’s main time-keeper resides in a region of the central brain called the suprachiasmatic nuclei, or SCN. For decades, researchers have believed that it is the rate at which SCN cells fire electrical pulses – faster during the day and slower at night – that controls time-keeping throughout the body.
Imagine a metronome in the brain that ticks quickly throughout the day, then slows its pace at night. The rest of the body hears the ticking and adjusts its daily rhythms, also known as circadian rhythms, acSurcordingly.
That’s the idea that has prevailed for more than two decades.
But new evidence compiled by Forger and his colleagues shows that the old model is “completely wrong,” he said. The true signaling mechanism is very different: The timing signal sent from the SCN is encoded in a complex firing pattern that had previously been overlooked, he said.
“We have cracked the code for the circadian day, and that information could have a tremendous impact on all sorts of diseases that are affected by the clock,” Forger said.
Forger and U-M graduate student Casey Diekman, along with colleagues at the University of Manchester in England, report their findings
in the Oct. 9 edition of Science.
The British team collected data on firing patterns from more than 400 mouse SCN cells. Forger and Diekman plugged the experimental data into a mathematical model that helped test and verify the new theory.
Though the experimental work was done with mice, Forger said it’s likely that the same mechanism is at work in humans.
In mammals, the SCN contains both clock cells (which express a gene call per1) and non-clock cells.
For years, circadian-biology researchers have been recording electrical signals from a mix of both types of cells. That led to a misleading picture of the clock’s inner workings.
But Forger’s British colleagues were able to separate clock cells from non-clock cells by zeroing in on the ones that expressed the per1 gene. Then they recorded electrical signals produced exclusively by the clock cells. The pattern that emerged matched the predictions made by Forger’s model, bolstering the audacious new theory.
“This is a really clear example of a model making a prediction that’s completely at odds with what the biologists are saying, yet turns out to be dead-on,” Forger said. “We have a very solid case here, and it would be very hard for anyone to argue against it.”
The researchers found that during the day, SCN cells containing per1 sustain an electrically excited state but do not fire. They fire for a brief period around dusk, then remain quiet throughout the night before releasing another burst of activity around dawn. This fi ring pattern is the signal, or code, the brain sends to the rest of the body so it can keep time.
“The old theory was that the cells in the SCN which contain the clock are fi ring fast during the day but slow at night. But now we’ve shown that the cells that actually contain the clock mechanism are silent during the day, when everybody thought they were firing fast,” Diekman said.
