Sundown Syndrome-like Symptoms in Fruit Flies May be Due to High Dopamine Levels

Perelman School of Medicine at the University of Pennsylvania researchers have discovered a mechanism involving the neurotransmitter dopamine that switches fruit fly behavior from being active during the day (diurnal) to nocturnal. This change parallels a human disorder in which increased agitation occurs in the evening hours near sunset and may also be due to higher than normal dopamine levels in the brain. Sundown syndrome occurs in older people with dementia or cognitive impairment.

Many geriatricians have noted an association between sundown syndrome and changes in the internal biological clock among people with dementia, observing disruptions in their sleep-wake cycles. The internal clock, which guides rhythms over a 24-hour day, is connected to how active humans are at different times of the day.

The lab of Amita Sehgal, PhD , professor of Neuroscience and a Howard Hughes Medical Institute investigator, found that in fruit flies dopamine acts to arouse flies through a protein called cryptochrome that normally functions as a photoreceptor. Flies, like humans, are typically diurnal. The findings were released online this week in Genes & Development.

Using a strain of fly that has a mutated Clock (Clk) gene and exhibits nocturnal behavior, the team found that increased night-time activity of the Clk mutant flies is associated with elevated dopamine signaling. Specifically, Clk mutant flies have increased levels of an enzyme used to make dopamine called tyrosine hydroxylase in fly brains. The night-time behavior also requires the circadian photoreceptor, cryptochrome (CRY), in specific cells of the fly brain. These cells also express CLK, as do others that may be responsible for the elevated dopamine.

"Our results suggest that typically the dopamine pathway and CRY promote acute arousal. They allow an animal to respond to acute stimulation by sensory stimuli with a transient increase in activity," says Sehgal. "However, chronic, increased signaling of the pathway leads to nocturnal activity, most likely because both CRY and dopamine activity are dampened by light." A switched behavioral cycle is the result.

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