Penn researchers identify neurons that link circadian rhythms with behavioral outcomes.

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

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