An odd mutant fruit fly, fifteen years ago, caught the attention and curiosity of Dr. Ravi Allada, a circadian rhythms expert at Northwestern University. It led the neuroscientist to discover recently how an animal’s biological clock wakes it up in the morning and puts it to sleep at night.
It turns out the clock’s mechanism is much like a light switch.
In a study of brain circadian neurons that govern the daily sleep-wake cycle’s timing, Allada and his research team found that high sodium channel activity in these neurons during the day turn the cells on and ultimately awaken an animal, and high potassium channel activity at night turn them off, allowing the animal to sleep.
Investigating further, the researchers were surprised to discover the same sleep-wake switch in both flies and mice. Said Allada, senior author of the study, and professor and chair of neurobiology in the Weinberg College of Arts and Sciences:
“This suggests the underlying mechanism controlling our sleep-wake cycle is ancient. This oscillation mechanism appears to be conserved across several hundred million years of evolution. And if it’s in the mouse, it is likely in humans, too.”
Internal Clock Reset
Understanding this mechanism better could lead to new drug targets to address sleep-wake trouble related to jet lag, shift work and other clock-induced problems. Eventually, it might be possible to reset a person’s internal clock to suit his or her situation.
The researchers call this a “bicycle” mechanism. Two pedals that go up and down across a 24-hour day, conveying important time information to the neurons.
That the researchers found the two pedals, a sodium current and potassium currents, active in both the simple fruit fly and the more complex mouse was unexpected. Said Matthieu Flourakis, the lead author of the study:
“Mice are nocturnal, and flies are diurnal, or active during the day, but their sleep-wake cycles are controlled in the same way.”
The researchers discovered that when sodium current is high, the neurons fire more, awakening the animal, and when potassium current is high, the neurons quiet down, causing the animal to slumber. The balance between sodium and potassium currents controls the animal’s circadian rhythms.
“Our starting point for this research was mutant flies missing a sodium channel who walked in a halting manner and had poor circadian rhythms. It took a long time, but we were able to pull everything — genomics, genetics, behavior studies and electrical measurements of neuron activity — together in this paper, in a study of two species.
Now, of course, we have more questions about what’s regulating this sleep-wake pathway, so there is more work to be done.”
Matthieu Flourakis, Elzbieta Kula-Eversole, Alan L. Hutchison, Tae Hee Han, Kimberly Aranda, Devon L. Moose, Kevin P. White, Aaron R. Dinner, Bridget C. Lear, Dejian Ren, Casey O. Diekman, Indira M. Raman, Ravi Allada.
A Conserved Bicycle Model for Circadian Clock Control of Membrane Excitability.
Cell, 2015; 162 (4): 836 DOI: 10.1016/j.cell.2015.07.036
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