Humans are diurnal animals, meaning that we usually
sleep at night and are awake during the day, due at
least in part to light or the lack thereof.
Overexpression of the neuropeptide prokineticin 2 (Prok2) results in an increase in expression of the sleep-promoting neuropeptide galanin (shown in white) when zebrafish are kept in the light, but not when they are kept in the dark, compared to wild type control animals. These images show galanin expression in the anterior hypothalamus, a brain region known to promote sleep in mammals.
Credit: Courtesy of the Prober laboratory
Light is known to affect sleep indirectly by
entraining — modifying the length of — our circadian
rhythms and also rapidly and directly due to a
phenomenon known as masking.
But while a great deal is known about how light
affects circadian rhythms, little is known about the
direct effects of light on sleep: Why do we tend to
wake up if the lights are flipped on in the middle
of the night?
Why does darkness make us sleepy?
Caltech researchers in the laboratory of Professor
of Biology David Prober say they have discovered at
least part of the answer: a specific protein in the
brain that responds to light and darkness to set the
correct balance between sleep and wakefulness.
"Researchers had previously identified the
photoreceptors in the eye that are required for the
direct effect of light on wakefulness and sleep,"
says Prober. "But we wanted to know how the brain
uses this visual information to affect sleep."
The Prober laboratory uses zebrafish as a model
organism for studying sleep.
The animals are optically transparent, allowing for
noninvasive imaging of their neurons; they also have
a diurnal sleep/wake pattern like that of humans.
To investigate how their sleep responds to light,
Wendy Chen, a former graduate student in Prober's
lab, led studies examining a particular protein in
the zebrafish brain called prokineticin 2 (Prok2).
Chen genetically engineered zebrafish to overexpress
Prok2, resulting in an abundance of the protein.
She found that in contrast to normal zebrafish,
these animals were more likely to fall asleep during
the day and to wake up at night.
Surprisingly, the effects did not depend on the
engineered fish's normal circadian sleep/wake cycle
but rather depended only on whether the lights were
on or off in their environment.
These observations suggest that an excess of Prok2
suppresses both the usual awakening effect of light
and the sedating effect of darkness.
Chen then generated zebrafish with mutated forms of
Prok2 and its receptor, and observed light-dependent
sleep defects in these animals.
For example, Chen found that zebrafish with a
mutated Prok2 receptor were more active when the
lights were on and less active when the lights were
off, the opposite of what she had observed in
animals that overexpressed Prok2 and had functional
"Though diurnal animals such as zebrafish spend most
of their time asleep at night and awake during the
day, they also take naps during the day and
occasionally wake up at night, similar to many
humans," Prober says.
"Our study's results suggest that levels of Prok2
play a critical role in setting the correct balance
between sleep and wakefulness during both the day
and the night."
Next, the researchers wanted to know how Prok2 was
modulating light's effects on sleep.
To answer this question, they decided to examine
whether other proteins in the brain that are known
to affect sleep were required for the effects of
Prok2 on sleep behavior.
They found that the sedating effect of Prok2
overexpression in the presence of light requires
galanin, a known sleep-promoting protein.
They also found that Prok2 overexpression increased
the level of galanin expression in the anterior
hypothalamus, a key sleep-promoting center in the
But in animals that were engineered to lack galanin,
overexpression of Prok2 did not increase sleep.
These findings provide the first insights into how
light may interact with the brain to affect sleep
and provide a basis for scientists to begin
exploring the genes and neurons that underlie the
However, further work is needed to fully explain how
light and dark directly affect sleeping and waking,
and to determine whether Prok2 has a similar
function in humans.
If it does, this work might eventually lead to new
sleep - and wake - promoting drugs.
Other Caltech co-authors are postdoctoral scholars
Chanpreet Singh and Grigorios Oikonomou. Sabine
Reichert and Jason Rihel of University College
London also contributed to the study.
The work was funded by the National Institutes of
Health; the Edward Mallinckrodt, Jr. Foundation; the
Rita Allen Foundation; and the Brain & Behavior
For more information
Light-dependent regulation of sleep/wake states by
prokineticin 2 in zebrafish.
Aberdeen Centre for
Energy Regulation and Obesity