Shedding
Light on the “Black Box of Sleep Regulation”
Homeostatic processes in the body that have patterns throughout a period of around 24 hours, circadian rhythms were established as endogenously regulated in 1729 with the experiments of Jean Jacques on plant behavior. The neural correlate associated with control of circadian rhythms in mammals is the Suprachiasmatic Nucleus (SCN), a small part of the hypothalamus. Within the SCN are circadian pacemaker neurons tasked with movement between natural states. Although our body has many physiological loops that fall under a circadian rhythm, one that most easily comes to mind is sleep. The brain has 3 main states it transitions between: wakefulness, non-REM sleep, and REM sleep.
During
the morning, the pacemaker neurons are depolarized rendering them active. In
the evening, these neurons are hyperpolarized and thus inactive. Pacemaker
neurons are related to the conductances of two cations, potassium ion and
sodium ion. While much research has developed ideas behind the mechanisms of
these neurons, there lacks an understanding of how pacemaker neurons modulate
the shift from active to inactive states and vice-versa. Research with Drosophila, has suggested a bicycle
model for how pacemaker cells alternate states in a period (Fluorakis, 2015).
During the day, sodium concentrations are high while at night potassium
concentrations prevail. An inverse alternation between the two ions maintains
firing of pacemaker neurons. A mammalian ion channel called NALCN has been
associated with the increase in sodium. In fruit flies, this channel is known
as the Narrow Abdomen (NA). NA mutants display a phenotype where pacemaker
neurons no longer show the typical firing rates ‘anticipating’ morning or
evening.
In a recent study from the University of
Tsukuba in Japan, mice were studied to identify gene products responsible for
circadian control. By inducing random mutations in the mice and recording
changes in their behavior, researchers narrowed down two genes. In agreement
with the drosophila studies, mutations in the NALCN gene coding for the ion
channel was found to be a major contributor to disorderly rhythms. They deemed
this phenotype “Dreamless” because the mouse showed unstable and shortened REM
sleep. The researchers proposed that REM-terminating neurons had excessive
activity due to increases in ion conductances through the malfunctioning
channel. The other phenotype researchers observed was larger sleep times. They cleverly
called this mutation “Sleepy”. The mutation was found on the SIK3 gene which
produces the SIK3 enzyme. Specifically, amino acids of the enzyme was modified
to show altered phosphorylation. This molecular change results in a larger need
for sleep satiated by arrhythmic sleep times.
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Researcher Yanagisawa marked these studies as the
start of a “long journey into the blackbox of sleep regulation.” Understanding the endogenous
guiding figures of our circadian rhythms is crucial to questioning the nature
of sleep disorders. Some people face prolonged fatigue although they appear to
be allowing themselves enough time at night to rest. Such research begins to
suggest that maybe we need to not look phase by phase of our body states, but
instead understand what makes our physiology rhythmic in the first place.
References:
Flourakis, M.,
Kula-Eversole, E., Hutchison, A. L., Han, T. H., Aranda, K., Moose, D. L., …
Allada, R. (2015). A Conserved Bicycle Model for Circadian Clock Control of
Membrane Excitability. Cell, 162(4), 836–848. http://doi.org/10.1016/j.cell.2015.07.036
University of Tsukuba.
(2016, November 2). Genetic analysis identifies proteins controlling sleep in
mice. ScienceDaily. Retrieved December 10, 2016 from www.sciencedaily.com/releases/2016/11/161102142147.htm
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