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November / December 2003


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Clockwork

Illustration by Michael Mardosa


Clockwork
Circadian rhythm research by a UMaine psychologist could one day lead to better treatment for depression and alcoholism

About the Illustration: In the next six to 10 years, Alan Rosenwasser expects to characterize the effects of acute alcohol ingestion, as well as chronic alcoholism, on circadian rhythms. In particular, he hopes to better understand how alcohol affects the functioning of brain areas and brain chemicals involved in circadian rhythms, and how manipulating or changing the rhythm can alter alcohol sensitivity.
 

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When Alan Rosenwasser hopped a flight from the United States to Japan this fall, his world turned upside down. Rosenwasser had symptoms of jet lag as his body's circadian clock struggled to get in sync with the new light/dark environment that was 11 hours different than that on the East Coast.

To his body, day was night and vice versa.

Despite his fatigue, sleep disruption and cognitive slowing, Rosenwasser, one of the scientific leaders in circadian rhythm research, couldn't have been more satisfied.

"I have to admit, before I left, my curiosity (about how I would feel) was piqued," says the biopsychologist, who has been involved in circadian rhythm research — chronobiology — for nearly 30 years. "With the more basic animal research I do, the experience is relevant."

A professor of psychology at the University of Maine, Rosenwasser analyzes circadian behavioral rhythms in rodents as models for humans. Circadian rhythms are 24-hour biological cycles in living things that regulate physiological and behavioral processes, including heart rate, hormone levels and metabolism. Environmental cues, especially daily cycles of light and dark, set the internal circadian clock that keeps the body running smoothly. Disruption of circadian rhythms can cause jet lag, health and safety problems in night-shift work, sleep problems and mood disorders, such as depression.

Science is seeking to understand and overcome these limitations. It's not a matter of fooling Mother Nature, but rather an attempt to understand daily psychobiological function to improve public health and develop better treatments for various medical conditions.

"In many ways, we live in an environment in which we did not evolve," says Rosenwasser, whose research focuses on the relationship of circadian rhythms and depression, drugs and alcohol. "Even 100 years ago, people at this latitude in Maine probably went to bed at 8 p.m. or earlier in the winter. Today, we stay up with the lights and television on. We use alarm clocks to get up and we fly around the globe, crossing time zones. More than half of the American workforce is employed on some kind of nontraditional schedule. In all these ways, we're living a lifestyle that is not compatible with our evolved brain mechanisms."

Most people associate circadian rhythms with higher-order animals. But the reality is that most living things — plants, insects, microorganisms and animals, both vertebrate and invertebrate — have circadian clocks, and all of them have similarities, especially when it comes to taking cues from light-dark cycles.

"The earliest single-celled organisms lived in a light-dark cycle that resulted in the evolution of built-in clocks allowing them to respond to the two different environments," says Rosenwasser. "We retained that throughout evolution."

Some of the most recent circadian rhythm research has shed light not only on the logical way the clocks work, but the common genes and proteins that run the clock, or pacemaker, in the brain. For example, genes first identified in the fruit fly have proven important to understanding the mammalian clock.

"When I got into this field, it was strongly believed that in animals, light and dark were considered the primary factors regulating the clock; in people, social and cognitive factors were suggested to be more important than light," says Rosenwasser. "Since then, more research has shown that human circadian clocks are very sensitive to light, just as they are in animals. In addition, better animal studies have shown that animals' circadian clocks also are influenced by social and behavioral functions, not just light."

Rosenwasser and psychologist Norman Adler from the University of Pennsylvania were among the first scientists to suggest that there were multiple internal clocks in the body — a complex network of interdependent oscillators and coupling pathways. Their landmark analysis was published in 1986 in the journal Neuroscience and Biobehavioral Reviews. In recent years, molecular biologists have identified genes and proteins associated with circadian rhythms not only in the brain, but in other organs of the human body.

In his behavioral neuroscience research, Rosenwasser has studied the interface between circadian rhythms and depression, and alcohol and drug consumption and withdrawal. The overarching questions: Does a "broken clock" cause depression or susceptibility to substance abuse? Or do depression and substance abuse affect brain chemicals and biorhythms? His goal is to understand the issues related to abnormal circadian conditions during depression and alcohol-induced states in animal models.

Rosenwasser uses rats in his research because of their ability to mimic human depression, and the effects of anti-depressant and pro-depressant drugs. In the past year and a half, his work has moved into the effects of alcohol on the circadian clock.

"There's a fair amount of data that show the disruption of biological rhythms in alcoholics going through withdrawal, but little or nothing in the literature as to whether rhythm abnormalities in alcoholics are due to disruption of the basic clock mechanism. To me, it's scientifically important to distinguish between overt rhythms and the clock-like mechanisms that control them," says Rosenwasser, who collaborates with cellular and molecular neurobiologists at UMaine and in the larger scientific community. "It's the difference between the hands of a clock and its gears; often we must infer the behavior of the underlying clock ‘gears' in the nervous system from the behavior of the clock's ‘hands' — in this case, the biological rhythms that are expressed under varying environments. There may be a broken rhythm even though the underlying clock is normal. The use of animal models makes this process much easier (to explore) than it would be in human studies."

In upcoming research, Rosenwasser hopes to shed light on the biological factors potentially involved in alcohol abuse susceptibility. He will use two strains of rats bred for their high and low alcohol preference to study differences in their biological rhythms and the effects alcohol has on them.

"I expect that we may see a link because of serotonin (an important brain messenger) that is implicated in depression and anxiety disorders, and that is affected by alcohol. The neurotransmitter (serotonin) also is known to be involved in regulating the circadian clock," he says. "Potentially, alterations in serotonin levels may manifest in differences in preferences for alcohol and other drugs, mood states, and circadian rhythm alterations."

In the next six to 10 years, Rosenwasser expects to characterize the effects of acute alcohol ingestion, as well as chronic alcoholism, on circadian rhythms. In particular, he hopes to better understand how alcohol affects the functioning of brain areas and brain chemicals involved in circadian rhythms, and how manipulating or changing the rhythm can alter alcohol sensitivity.

The results of such work could lead to new treatments for recovering alcoholics to prevent relapse, and even help predict who is most likely to be an alcoholic.

"Twenty years from now, there will be effective treatments that really promote the ability of people to adjust to time zone changes and night shifts," Rosenwasser says. "We're at a stage of awareness now rather than at the state of knowing effective treatments. Potentially, we will look at the effective use of chronobiologically based treatments for depression, anxiety, drug abuse and other disorders."

by Margaret Nagle
November-December, 2003

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