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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