Sleep is incredibly important in humans for a variety of
reasons such as alertness, feeding, and cognition. A key player in regulating
our sleep cycles is the function of our intrinsic circadian rhythms. Circadian
rhythms are present in a vast number of different species and play a pivotal
role in regulating cell and tissue metabolism. Disruption of our circadian rhythms
is attributed to a vast array of disorders such as neurodegeneration,
cardiovascular disease, and metabolic syndrome. Recent research has allowed us
to look deeper into the molecular mechanisms behind how individual cells may
maintain and rely on their own circadian rhythms, as well as those
aforementioned disorders may be modulated by specific human behaviors.
Speaking of cellular mechanisms relating to these rhythms,
Dr. Cavanaugh and fellow researchers explored these rhythms using fruit flies
as their model organism in a publication titled “The cell-intrinsic circadian
clock is dispensable for lateral posterior clock neuron regulation of
Drosophila rest-activity rhythms” (Cavanaugh et al., 2025) Interestingly
enough, fruit flies are actually an invaluable tool to use when studying circadian
research due to their quick generational spawn times, robust genetic toolkits,
and useful status as an analog for other complex human behaviors (including courtship,
aggression, memory, etc.). They exhibit clear rest-activity rhythms as well.
These researchers wanted to see how intrinsic clock cells in Drosophila,
called Lateral posterior neurons (LPNs) played a role in controlling the rest
activity (or sleep patterns) of Drosophila. So, their primary questions
were if LPNs needed their own internal clock in order to regulate this behavior
and if the activity of these LPNs were necessary for rest activity rhythms. The
experimental setups had flies set up in a temperature and light-controlled
environment, with the flies literally inside of small tubes. The passing of the
flies within the tubes represented their “activity”, monitored by an infrared
laser which depicted when flies were most active and when they were resting. Their
experimental model flies had the lights turned off so that their circadian
rhythms were independently active. They used the CRISPR gene editing technique
to manipulate genes PER and TIM, believed to be responsible for the flies’
circadian rhythm. By silencing these genes, they were able to shut off the
LPN’s clock, however the flies were still able to regulate their circadian
rhythms to a similar extent prior to gene manipulation. On the contrary, by
silencing the LPN neurons completely, the researchers did manage to disrupt the
rest patterns of the flies, implying these LPN neurons were necessary for
proper sleep functioning.
In a similar investigation regarding circadian rhythms, scientists
in “Circadian Rhythm Disorder-Related Dysfunctions are Exacerbated by Aging and
Ameliorated by Time-Restricted Feeding” explored the effects of disrupting these
cellular clocks (Huo, F., Liu, Q., Zhang, S. et al.). What they were
principally trying to learn was how aging could increase the circadian rhythm disruption
(CRD)’s vulnerability, whether the gut microbiome acted as a mediator for any
CRD-related dysfunction, and if time-restricted feeding (TRF) could alleviate these
effects in aged mice. Their research used mice rather than Drosophila,
but mammalian circadian rhythms are also analogous. The method of disrupting
the circadian rhythm was by inverting the day/night cycle every 3 days,
inducing stress. Then, they would take it further by alternating between 48-hour
periods of light and then dark. Finally, they would then expose the mice to
continuous light exposure. Their testing methods evaluated behavioral changes
in cognition, mood, anxiety, and motor activity through associated tasks and
tests. For the gut microbiome analysis, they gathered fecal samples and conducted
16s rRNA sequencing for microbiota composition. On a level even deeper for analysis,
they looked at various molecular tools such as Western blotting and qPCR for
tissue analysis. After inducing these stressful conditions, they then conducted
the TRF (which was only between 8 PM and 8 AM). Their results showed that aging,
both cognitively and cellularly rapidly increased the vulnerability of
circadian disruption. The gut microbiota was no exception to being disrupted as
well (pro-inflammatory markers, etc.). But what was most interesting was how
TRF significantly improved the behavioral and gut outcomes following the CRD. It
revealed that there may be potential for promoting a 12 hour fasted state that
helps “realign” some of these negative effects of a disrupted circadian rhythm.
Both of these studies reveal incredible insight into some
deeper understanding of how critical circadian rhythms are to many organisms,
including humans. By monitoring cellular effects and mechanisms, this opens the
door for future research into clinical trials for treatment regarding many
common sleep disorders affecting humans, where that circadian rhythm may be
disrupted.
References
Cavanaugh, et al. The cell-intrinsic circadian clock is dispensable
for lateral posterior clock neuron regulation of Drosophila rest-activity
rhythms. Neurobiology of Sleep and Circadian Rhythms (2025). https://doi.org/10.1016/j.nbscr.2025.100124
Huo, F., Liu, Q., Zhang, S. et al. Circadian
Rhythm Disorder-Related Dysfunctions are Exacerbated by Aging and Ameliorated
by Time-Restricted Feeding. Neurosci. Bull. (2025). https://doi.org/10.1007/s12264-025-01552-8
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