INSIGHTS INTO THE BODY'S DAILY CLOCK MAY HELP OVERCOME JET-LAG, WORK FATIGUE
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INSIGHTS INTO THE BODY'S DAILY CLOCK MAY HELP OVERCOME JET-LAG, WORK FATIGUE.
ORLANDO, Sunday, Nov. 3 - New insights into the molecular workings of the body's circadian clock may one day lead to new medications that can help us reset specific biological rhythms and overcome jet lag, shift-work fatigue and other forms of sleep disturbances.
They may also help lead scientists to develop new treatments for clinical depression, which is often linked to sleep problems involved with the body's internal biological rhythms that keep pace with the 24-hour cycle of light and dark. The new studies were reported today during the 32nd annual meeting of the Society for Neuroscience.
Among the recent discoveries is the identity of a third, and previously unknown, type of photoreceptor in the eyes - one that daily helps set the body's circadian clock to the cues of sunlight, even in people who are functionally blind. Scientists have also found that when we eat our meals is a crucial factor in the timing of our circadian rhythms -perhaps more so than our exposure to sunlight. Other researchers are uncovering the mystery of how the master circadian clock, located in the suprachiasmatic nucleus (SCN) of the brain, lets the rest of the body know what time of day it is.
Scientists have long known that daylight sets the body's circadian clock through specialized nerve cells, called photoreceptors, in the eyes. Until very recently, only two types of photoreceptors were known to exist - the rods and cones. Scientists suspected, however, that another type of photoreceptor also resided somewhere in the eyes, primarily because of a paradoxical response to light in certain blind people and animals.
"When retinal photoreceptors degenerate - when rods and cones are lost - animals are functionally blind, but they still set their biological rhythms according to the day/night cycle," explains David Berson, PhD, associate professor of neuroscience at Brown University. "But if the eye is lost, this clock-setting response is lost, too. So we thought there had to be some other type of cells in the eye that was sensing light."
Berson and his colleagues have recently identified that third type of photoreceptor. They found it, surprisingly, among the retina's ganglion cells, which are output neurons that encode and transmit information from the eye to the brain.
"The ganglion cells play a key role in vision, but they were not considered to have any photoreceptors among them," Berson says.
Berson calls the newly-discovered photoreceptor "an intrinsically photosensitive retinal ganglion cell (ipRGC)." "They are radically different from rods and cones - in their structure, their location, their response to light, and how they function," says Berson. The ipRGC, for example, sends messages directly to certain visual centers of the brain, whereas rods and cones communicate only indirectly with the brain, by way of other retinal neurons.
The discovery of the ipRGC system came through experiments in which Berson and his colleagues injected a fluorescent dye into a rat's suprachiasmatic nucleus (SCN), the tiny part of the brain that that serves as the body's master circadian clock. The dye traveled back along the nerve fibers to the retina. The researchers then removed the rats' retinas and, under a microscope, recorded the electrical responses of the dye-filled cells. They found that the cells fired in response to light, whether or not they were connected to the retina or brain.
In collaboration with the laboratory of King-Wai Yau, PhD, of Johns Hopkins University in Baltimore, Berson has also found that the new photoreceptor cells contain a specific protein, called melanopsin, that may be their photopigment-the light-sensitive chemical that triggers the cells' response to light.
"Much remains to be learned about these new photoreceptor cells," says Berson. "We'd like to understand the biochemical process that allows these cells to respond to light and how their light responses differ from those in conventional retinal neurons. We'd also like to know whether rods and cones affect the new photoreceptors or whether the two kinds of information are kept strictly separate. Finally, we'd like to provide a complete accounting of the brain regions influenced by this specialized retinal output and what behavioral roles those brain regions play."
At the University of Texas Southwestern Medical Center, Steven McKnight, PhD, and his colleagues have been examining how circadian rhythms are intricately linked with cellular metabolism throughout the body. "Probably the most substantial thing that circadian rhythms do is to control the elementary intermediary metabolism of cells," says McKnight. "These clocks are not just in the brain, but everywhere - in the liver, in the gut, in the lungs, in the skeletal muscles - which means that our cells are metabolically different in the day than in the night."
Recently, McKnight's laboratory team has found that the timing of meals may play a more important role than previously thought in entraining, or adapting, the body's internal clocks to the external environment. Entrainment is what our bodies go through -including the readjustment of our sleep/wake patterns - when we experience jet lag or suddenly begin to work the night shift.
McKnight and his colleagues looked at how the three environmental cues critical to entrainment - light, food and activity - affect the transcription feedback cycle known as Clock:Per in mice. Scientists have known for several years that circadian rhythms in all organisms are controlled by this simple cycle. In diurnal animals, such as humans, the system is on in the day and off at night. In nocturnal animals, such as mice, the opposite pattern is observed: The Clock transcription factor switches its target genes on at night, yet is inactive during the day due to the function of the negative arm (Per) of the feedback cycle.
Scientists have also known that if you take a nocturnal animal, such as a mouse, and restrict its access to food so that it can only eat during the day, it will become diurnal, even though light cues tell the animal that it should be sleeping during the day.
McKnight and his team decided to explore the biochemical basis for this behavior. The researchers found that the Clock transcription factor acts as a redox sensor, determining when cells are going to use up or store energy from food. Specifically, the researchers discovered that the Clock transcription factor is active in the mice when cells contain an excess of reduced nicotinamide adenine dinucleotide (NAD) - in other words, when the cells are using up energy. Conversely, the Clock transcription factor is more inactive when the cellular redox state is more oxidized - or when the cells were resting.
"This may mean that food is much more important for entrainment of circadian rhythms than light," says McKnight.
Many of the advances in unraveling the molecular basis of circadian rhythms has come through studying the fruit fly Drosophila melanogaster. Paul Taghert, PhD, and his colleagues at the Washington University School of Medicine have studied signals released by the master circadian clock cells in Drosophila. They have found that these 20 or so neurons are among the few in the fruit fly's brain that produce a small signaling protein called pigment dispersing factor (PDF). Flies lacking PDF are incapable of maintaining circadian rest/activity rhythms in the absence of environmental cues, such as sunlight. Thus, PDF appears to be the principle circadian transmitter in the fruit fly, and is the first one recognized in any animal.
Taghert's group, along with researchers at Washington University and at the Affymetrix Company, has also reported on circadian gene expression using microarray devices, miniaturized devices that individually measure the expression levels of more than 10,000 genes simultaneously. "The scope of genomic sequencing together with the power of new technologies has made it possible to define with a lot of precision which genes are cycling on a daily basis and which are not," says Taghert.
Surprisingly, Taghert and his colleagues have found that in the fly head only 22 genes reliably cycle in circadian fashion. Scientists had thought that the number would be much higher. "This suggests that many of the important mechanisms relating to the clock do not involve gene transcription," says Taghert.
Most of the 22 genes weren't previously associated with circadian phenomena. Scientists hope that by studying these genes, they will discover new information about how the master circadian clock works and how it sends signals to the rest of the organism. The identities of these genes may prove useful as entrees to identify drug targets to help alleviate problems associated with aberrant circadian rhythms, such as jet lag and sleep difficulties related to shift work.
"We've been able to identify the critical signals coming from the clock," says Taghert. "As we pursue their pathways we will be better able to define the neural circuits that control daily rhythmic activity patterns."
In other experiments involving the fruit fly Drosophila melanogaster, Amita Sehgal, PhD, and her colleagues at the University of Pennsylvania Medical School have recently identified a molecular/neural pathway through which the central circadian clock transmits its signals to the rest of an organism. This finding presents the first picture of a circuit that drives circadian-related behavior and physiology.
The Sehgal group's experiments involved fruit flies that carry a gene similar to that for the human nerve disorder neurofibromatosis type 1 (NF1).The researchers discovered that flies with this mutant gene lose their 24-hour sleep/wake cycle. By then tracing the information flow within the neural networks of flies with the NF1 gene, the researchers found that the gene regulates a well-known signaling pathway called the Ras/MAPK pathway.
The effects of the Ras/MAPK pathway on sleep/wake cycles are not exerted in neurons that actually contain the master circadian clock. The master clock cells secrete a hormone, which then regulates this pathway in other cells. Thus, this pathway functions within the circuit that transmits information from the clock neurons to the sleep/wake centers in the brain. "We believe this marks a significant step in helping us understand how the circadian clocks communicates time-of-day signals with the rest of the body," says Sehgal.
Because Droophila melanogaster displays rest and activity cycles that are very similar to the sleep/wake cycles of humans, it's very likely that the pathway is the same in humans. "It may be possible one day to identify molecules that could be targeted by drugs to help relieve jet lag and other clock-related problems," says Sehgal.
Sehgal experiments may also lead to a better understanding of NF1. An inherited neurological disorder that occurs in about 1 in 3,000 babies, NF1 is characterized by "cafe-au-lait" (brown-and-cream colored) spots, neurofibromas (benign tumors in the coverings of nerves), and Lisch nodules (tan or brown benign tumors on the iris of the eye). Anecdotal evidence, says Sehgal, suggests that people with the disorder often have sleep problems.
"Our findings make the NF1-mutant fly a more useful model for the study of neurofibromatosis in humans," Sehgal says.
