July 11, 2005 Philadelphia, PA - Researchers at the University of Pennsylvania School of Medicine have determined how serotonin decreases the body's sensitivity to light and that exposure to constant darkness leads to a decrease in serotonin levels in the brain of fruit flies. These findings suggest that serotonin may play a role in maintaining circadian rhythm, as well as modulating light-related disorders such as seasonal affective disorder (SAD). Senior author Amita Sehgal, PhD, Professor of Neuroscience at Penn and a Howard Hughes Medical Institute (HHMI) Investigator, and colleagues report their findings in the July 7 issue of Neuron.
The body's 24-hour (circadian) clock controls cycles of wakefulness and sleep, as well as the rhythm of other physiological functions, such as body temperature and blood pressure. Although the body functions on roughly a 24-hour schedule, this cycle is capable of being reset by environmental disturbances. In Sehgal's lab, fruit flies provide the model system for examining entrainment, the synchronization of the internal clock to the environment.
"In humans, a light pulse in the early evening delays rhythm-if it stays light later, you stay up later," says Sehgal. "Disturbances in the late evening advance the body clock-an early dawn leads to an early rise."
Entrainment was tested in flies by exposing them to a pulse of light during the dark period. Closely resembling the body clock adjustment seen in humans, Sehgal's flies reset their body clock following the "night-time" disturbances. However, this adjustment was lessened when the flies were treated with serotonin prior to the test.
Sehgal speculates that serotonin is acting to protect the body clock from being over-responsive to light disturbances. "You do not want your clock to be so supersensitive to light that small fluctuations are going to throw it out of whack," she explains. "Serotonin appears to modulate the response of the body clock to light."
In flies, a protein called cryptochrome drives the response of the body clock to light. Under normal circumstances, light excites cryptochrome located within the brain, which in turn, interacts directly with the clock protein to reset the clock. Sehgal and colleagues discovered that serotonin works by attaching to the serotonin 1B receptor, altering the activity of another protein, GSK3bß, which further changes the cascade of events leading to the resetting of the clock.
Sehgal points to the clinical implications for understanding the interaction between GSK3ß and serotonin. Lithium, a drug commonly prescribed to treat bipolar disorder, targets GSK3ß. "Lithium resets the clock in all organisms that have been examined," explains Sehgal. "Assuming that the mechanism works the same way for mammals, the implication would be that antidepressants other than Lithium can also affect the clock."
Sehgal and colleagues also studied the role of serotonin in dark adaptation, the experience of increased sensitivity to light following long periods of darkness. After seven days in constant darkness, flies demonstrated significantly reduced levels of serotonin compared to flies exposed to the normal light-dark cycle. Interpreting the relationship of serotonin as it influences circadian rhythm, Sehgal suggests, "In situations of dark adaptation, you may become more sensitive to light because serotonin goes down."
The reduction of serotonin levels in flies kept in constant darkness may provide scientists with insight into the etiology and treatment of SAD, a mood disorder related to reduced sunlight during winter. "People with seasonal affective disorder will respond to medications such as Prozac to increase serotonin," says Sehgal. "Patients also respond to light therapy. We now believe that light is also increasing serotonin-perhaps this is why both of these treatments are effective."
By identifying the mechanism of interaction between serotonin and the body clock, as well as the environmental factors influencing the levels of serotonin in the brain, Sehgal and colleagues hope to be able to shed light on the possible role of circadian activity on affective disorders. The interplay of serotonin, light, and the circadian system suggests a close relationship between circadian regulation and mental health.
Sehgal's co-authors are Quan Yuan, Fangju Lin, and Xiang Zhong Zheng, all from Penn and HHMI. The research was funded by the Howard Hughes Medical Institute.
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