Our bodies evolved to alternate rhythmically through sleep
and wake periods with the 24-hr cycle of the day. These “circadian rhythms” are
controlled by specific neurons in the brain that act as molecular clocks. The experience
of jet lag when we change time zones is the out-of-sync period before
the brain’s internal clock re-aligns with the external environment.
How does this molecular clock work in the brain? Decades of
research have uncovered that environmental signals, such as light, are
integrated into a circadian clock by specific neurons in the brain. However,
little is understood about how these circadian clock cells drive biological
effects such as sleep, locomotion, and metabolism. A study by Penn researchers
published earlier this year in Cell has discovered critical neural circuits linking the circadian clock neurons to
behavioral outputs.
The researchers used the fruit fly Drosophila as a model organism because like humans, they also have
circadian rhythms, yet they are very easy to manipulate genetically and many
powerful tools exist to study the 150 circadian clock neurons in their brains.
The study found that a crucial part of the circadian output network exists in
the pars intercerebralis (PI), the functional equivalent of the human
hypothalamus.
“Flies are normally active during the day and quiescent at
night, but when I activate or ablate subsets of PI neurons, they distribute
their activity randomly across the day,” describes the study’s first author, Daniel
Cavanaugh, PhD, a post-doc working in the lab of Amita Sehgal, PhD.
Importantly, the research showed that modulating the PI neurons lead to
behavioral changes without affecting the molecular oscillations in central
circadian clock neurons, indicating that the PI neurons link signals from the
circadian clock neurons to behavioral outputs.
The study also showed that the PI neurons are anatomically
connected to core clock neurons using a technique involving the fluorescent
protein GFP. Cavanaugh explains, “The GFP molecule is split into two
components, which are expressed in two different neuronal [cell] populations.
If those populations come into close synaptic contact with one another, the
split GFP components are able to reach across the synaptic space to
reconstitute a fluorescent GFP molecule, which can be visualized with
fluorescence microscopy.”
Additionally, their experiments showed that a peptide called
DH44, a homolog to the mammalian corticotropin-releasing hormone, is expressed
in PI neurons and important for maintaining circadian-driven behavioral
rhythms.
While these new data are interesting for understanding
general mechanisms of biology, they also have implications for human health and
disease.
“People exposed to chronic circadian misalignment, such as
occurs during shift work, show increased rates of heart disease, diabetes,
obesity, cancer, and gastrointestinal disorders,” says Cavanaugh. “In order to
understand the connection between circadian disruption and these diseases, we
have to understand how the circadian system works to control the physiological
outputs that underlie these disease processes.”
-Mike Allegrezza
-Mike Allegrezza