UM scientist sheds light on workings of internal clock

August 21, 2006|By CHRIS EMERY | CHRIS EMERY,SUN REPORTER

Andrea Meredith's mice have a terrible sense of timing. "It's as if they can't tell the difference between day and night," said Meredith, a neuroscientist at the University of Maryland School of Medicine.

Usually, rodents roam at night and sleep all day, even if kept in total darkness. But keep Meredith's mice in the dark, and they will hop onto their exercise wheels regardless of the hour.

The odd behavior is the result of a change that Meredith engineered in a microscopic structure of their brains. The neuroscientist has been exploring possible links between the structure of cells known as "clock neurons" and specific behavioral patterns in the mice, experts say.

What she has found sheds new light on the part of the brain that acts as an internal clock, generating circadian rhythms in animals and humans. It may be a key step in understanding and treating sleep disorders, jet lag, depression and other human health problems linked to errant daily rhythms, experts say.

"People want to know, how does that internal clock tell the rest of the organism how to operate?" said Jennifer Loros, a professor at Dartmouth Medical School, who studies circadian rhythms in fungus. "This begins to connect the link between rhythmic [nerve activity] and rhythmic behavioral output."

The first documented evidence of circadian rhythms dates to 1729, when French scientist Jean-Jacques d'Ortous de Mairan found that mimosa plants kept in a dark closet still opened their leaves during the day and closed them at night.

Later, similar self-generated rhythms were found in humans and most animals. Blood pressure, body temperature, digestion, libido and other basic functions in humans and mice vary according to a near 24-hour daily cycle. (Such patterns have not been found, however, in cave fish and other creatures that never see the light of day.)

There are practical reasons to have what amounts to a self-winding internal clock.

"If you have a little field mouse living in its burrow, it doesn't have any light, but it still needs to know when to go up and seek food," said Meredith. "If it goes up at the wrong time, there are predators there and it gets eaten."

In recent decades, researchers found that circadian rhythms in mammals are generated by the suprachiasmatic nucleus (SCN), a small region of the brain composed of clock neurons.

One key study by University of Oregon scientists involved golden hamsters, whose internal clocks usually follow a strict 24.1-hour cycle. When they replaced the SCN of a normal golden hamster with one from a mutant hamster that followed a shorter 22-hour schedule, the previously normal rodent adopted the mutant schedule.

Sunlight usually helps a creature's biological clock keep time. Light-sensitive nerves in the eyes connect to the clock neurons and match internal time to the outside light cycle. This tie to the environment becomes evident when a person switches time zones quickly and jet lag sets in.

"The light-dark cycle shifts, but the clock hasn't shifted yet," Meredith said.

Experts believe the brain's ability to generate its own rhythm, even in the absence of light, stems from a "core clock," a cycle in the clock neurons' genetic machinery that repeats about every 24 hours.

While scientists know where in the brain the clock is located and think they understand the genetic mechanism of the core clock, little is known of how the clock controls behavior, experts said.

Meredith decided to study this problem after moving to Stanford University in 2001 to take a position as a postdoctoral researcher. Meredith, now 32, received a bachelor's degree in biology at the University of Maryland, Baltimore County, at age 20, and a doctorate at the University of Texas Southwestern Medical School, in Dallas.

At Stanford, Meredith studied tiny gates, known as ion channels, embedded in the outside wall of the clock neurons. Ion channels allow electrically charged ions such as sodium and potassium to flow in and out of the neurons. This flow forms the basis of brain function by allowing electrical signals to travel quickly from one cell to another.

Meredith specifically studied gates known as BK channels that control large flows of potassium out of the cell. Prior research suggested that BK channels were controlled by the core clock, so it made sense to Meredith that the channels might play some role in the generation of circadian behaviors.

To make the connection, Meredith, a self-described scientific jack-of-all-trades, brought a mixed bag of new scientific tools and techniques to an old problem.

The first step required her to combine genetic engineering with behavioral science. She engineered mice that had no functioning BK channels in their clock neurons, then watched how they acted. When exposed to light, the engineered mice behaved just like those with BK channels: They ran on their wheels at night and slept during the day. But when the engineered mice were kept in the dark they went haywire.

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