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We know calcium is good for our bones, but it might
also be the key to a good night sleep. Researchers
at the RIKEN Quantitative Biology Center (QBiC) and
the University of Tokyo in Japan have unveiled a new
theory for how sleep works. Published in the journal
Neuron, the work shows how slow-wave sleep depends
on the activity of calcium inside neurons.
“Although sleep is a fundamental physiologic
function, its mechanism is still a mystery,”
according to group director and corresponding author
Hiroki Ueda.
A multi-disciplinary research team led by Ueda used
a variety of scientific techniques, including
computational modeling and studying knockout mice,
to search for the fundamental mechanism underlying
sleep. Professor Ueda is a medical doctor by
training, but as a researcher investigating sleep
disorders, he favors a broad and deep approach that
relies equally on in silico, in vitro, and in vivo
modeling. He explains, “Because our study presents a
new theory of sleep, we needed to support it with
different methodologies.”
In silico, the team created a computational neural
model to predict which currents within a neuron are
critical for maintaining the type of neural activity
associated with slow-wave sleep.
Fumiya Tatsuki, co-first author and undergraduate
student at the University of Tokyo explains, “Our
model made four predictions, which provided us with
four starting points to search for critical genes
involved in sleep. Each prediction was tested and
proven correct in experiments with knockout mice or
by pharmacological inhibition, and we were
ultimately able to identify seven genes that work in
the same calcium-related pathway to control sleep
duration”.
Twenty-one knockout mice were created using recently
developed CRISPR technology, which Ueda’s team has
been refining into a highly accurate, highly
efficient, in vitro system called triple CRISPR.
Results published earlier this year indicated near
100% success rate. Additionally, co-first author
Genshiro Sunagawa developed an automated sleep
monitoring system for this study that proved
invaluable for continuously collecting the necessary
behavioral data.
Based on the computer models, triple CRISPR
technology, and the new sleep-monitoring system, KO
mice lacking target genes were observed in vivo for
changes in sleep duration. By identifying mice with
abnormal sleep patterns, the team was able to
pinpoint seven genes that were critical for
increasing or decreasing sleep duration.
All seven genes allow calcium-dependent changes in
neurons that make them resist becoming active — a
process called hyperpolarization.
As predicted by the model, down-regulating six of
these genes reduced sleep duration in KO mice and
down-regulating the final gene led to longer bouts
of sleep.
As Shoi Shi, co-first author and graduate student at
the University of Tokyo, explains, “Our paper
revealed that sleep is regulated by calcium-related
pathways. One surprise was that contrary to current
theories, inhibiting NMDA receptors directly evoked
neuronal excitation, which contributed to reduced
sleep.”
Notes Ueda, “these findings should contribute to the
understanding and treatment of sleep disorders and
neurologic diseases that have been associated with
them. In addition to becoming new molecular targets
for sleep drugs, the genes we have identified could
also become targets for drugs that treat certain
psychiatric disorders that occur with sleep
dysfunction.”
Sunagawa cautions that much work is still needed.
“Although our study reveals a mechanism for sleep
regulation, the molecular details of the mechanism
are still unknown, as is the real relationship
between sleep dysfunction and psychiatric
disorders.”
For more information
Tatsuki F, Sunagawa GA, Shi S, Susaki EA, Yukinaga
H, Perrin D, Sumiyama K, Ukai-Tadenuma M, Fujishima
H, Ohno R, Tone D, Ode KL, Matsumoto K, Ueda HR
(2016).
Involvement of Ca2+-dependent hyperpolarization in
sleep duration in mammals.
Neuron. doi: 10.1016/j.neuron.2016.02.032
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