Circadian clockwork takes unexpected turns

One group of neurons follow a different pattern than others that guide the brain’s master clock

On the television show “24” a silent countdown usually means a character has died. But for some cells in the brain’s time-keeping center, silent running is part of life.

Cells in the suprachiasmatic nuclei, a tiny group of neurons in the hypothalamus, serve as a master clock to regulate the body’s circadian rhythms — daily fluctuations in hormone release, body temperature, blood pressure and other processes — and help set meal and bed times. The cells follow a predictable daily pattern, firing electrical signals faster during the day and quieting at night. Or so scientists thought.

A new study shows that some cells in the SCN work themselves into a frenzy and then fall silent in the middle of the afternoon, a pattern most scientists did not expect and one that would kill most brain cells. The study appears in the Oct. 9 Science and shows that the SCN contains at least two different populations of neurons, each having its own rhythm and one showing this extreme behavior.

The finding is “actually very shocking,” says Martha Gillette, a neuroscientist at the University of Illinois at Urbana-Champaign who was not involved with the study.

In recent years biologists have characterized several proteins that serve as gears in the molecular circadian clock. Levels of those proteins rise and fall in rhythmic patterns over the day and night, setting the circadian rhythm. Almost every cell in the body contains such molecular clocks, but it wasn’t clear exactly how the oscillation of these protein levels directs cellular activities, such as releasing hormones, or, in the case of neurons, firing jolts of electricity to communicate with each other, Gillette says.

Previously, researchers had shown that the SCN contains a particularly robust circadian molecular clock. Green fluorescent protein helps scientists track quantities of one component of that molecular clock, a protein called period 1. Levels of period 1 peak during the day and are low at night. That oscillation seemed to coincide with the known firing pattern of the SCN neurons, so scientists thought the molecular clock must be responsible for setting the firing pattern.

But cells that make period 1 don’t fire in the traditional pattern, found Hugh Piggins and Mino Belle of the University of Manchester in England. The researchers carefully measured electrical activity in SCN cells from a mouse brain, comparing cells that make period 1 with cells that don’t. They found that cells without period 1 follow the expected firing pattern. But cells producing the protein fired at a moderate rate in the morning, then became so overexcited in the afternoon that they could no longer fire an electrical signal, recovering activity again about dusk. Piggins likens the activity to hand clapping. “It’s almost as if the hands are moving so quickly but not actually contacting each other to produce a clap.”

Collaborators of the Manchester team, Daniel Forger and Casey Diekman at the University of Michigan, saw the result coming. The researchers made a mathematical model that predicted that some cells could experience this type of over-excited meltdown. Scientists who measure electrical activity in cells scoffed at the idea, Forger says. “Everyone else thought our model was wrong,” he says. “When we talked to experimentalists, they said, ‘this is outrageous.’”

Healthy brain cells don’t behave this way, says Charles Allen, an electrophysiologist at the Oregon Health & Science University in Portland. “Traditionally a cell that shows this kind of activity is ready to die.” This excited state creates a toxic buildup of calcium in most cells, and researchers are unsure how SCN neurons cope with this load for several hours a day.

Exactly how the turning of period 1 and other molecular-clock gears creates this firing pattern is still unknown. People’s natural circadian clock operates on a cycle slightly longer than 24 hours, and the period-1–producing neurons may help the SCN use light cues to reset circadian rhythms to a 24-hour cycle, speculates Christopher Colwell, a neuroscientist at the University of California, Los Angeles.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.

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