A new model of circadian clock neurons

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Sleep Disorders | Sleep Review

It’s no secret that jet lag and night shift work can wreak havoc on how our body’s clock synchronizes our daily wake-sleep cycle, known as the circadian rhythm, but now researchers say they have come a step closer to understanding how our brain works are behavioral rhythms that are optimized for daily and not nightly life.

In a new study published Nov. 30 in the journal eLife, researchers reported recording and modeling the electrical activity of circadian clock neurons in a diurnal species – the four-lined grass mouse Rhabdomys pumilio.

To date, brain recording studies in nocturnal species have mainly been used to gain an understanding of the mammalian master circadian clock – located in the hypothalamic suprachiasmatic nucleus (SCN) of the brain, where nearly 20,000 neurons synchronize with the light-dark cycle via electrical signals Orchestrate rhythms in our physiology and behavior.

Researchers say the study is an advancement in further exploring the relationship between circadian rhythms and human health, including the relationship between daytime light exposure and circadian sleep disorders.

“Almost everything we know about the brain’s circadian clock comes from studies on nocturnal rodents such as rats and mice, which makes it difficult to transfer this knowledge to human circadian rhythms,” said Casey Diekman, co-author of the study and a mathematical biologist at New Jersey Institute of Technology, according to a press release. “This work is the first to describe the intricate electrical landscape of the SCN in a diurnal mammal, and it shows remarkable differences from nocturnal animals that can be important in adapting clock neuron function to the specific biological requirements of a diurnal species.”

“We found that the overall day / night pattern of SCN neuron activity in the diurnal rodent R. pumilio resembles the pattern previously observed in nocturnal species,” says Beatriz Bano-Otalora, co-first author of the study and a biologist , who works with the laboratories of Robert Lucas and Timothy Brown at the University of Manchester, in a statement. “We also found unique features in the behavior of R. pumilio’s SCN neurons that had never been seen before in nocturnal species.”

The team found that R. pumilio’s SCN neurons, like nocturnal rodents, fired spontaneously at a faster rate during the day than at night. This day / night rhythm of the rate of fire is the main signal that the SCN sends to the rest of the brain to tell the time of day.

“However, when we injected currents to inhibit these neurons, some cells showed a pronounced delay before firing again after the inhibition was lifted,” said Mino Belle, co-author of the study and a biologist at the University of Exeter. “This delay reaction is not present in the SCN of nocturnal rodents and can influence how R. pumilio clock neurons react to input received from other cells.”

To find out more, the team combined the voltage curves recorded by the rodent’s brain with a newly developed data assimilation algorithm. They created computer models that simulate the complex interaction of voltage-gated ion channels that create action potentials. The simulations showed that an increased conductivity of a certain ion channel, the transient A-potassium channel, was responsible for the delay reaction.

“The improved conductivity of this potassium channel indicated by our models could be beneficial for a diurnal species,” said Matthew Moye, co-first author of the study, a postdoctoral fellow at Merck & Co. who developed the team’s data assimilation algorithms as a PhD student at the Institute for Mathematical Sciences of the NJIT. “Vigilance leads to inhibitory behavioral feedback signals to the SCN, which in nocturnal animals helps to keep the SCN fire rates low at night. In diurnal animals this nocturnal inhibitory feedback is not present, so improved A-conductivity may be required to silence the SCN at night and to maintain the entire day / night ignition pattern. “

The team’s research follows separate results from Diekman and colleagues at Northwestern University, recently on the 15th signals at the cellular level. Diekman says the same data assimilation method developed to study R. pumilio neurons was used to build mathematical models from traces of tension in the fruit fly Drosophila melanogaster that ultimately show how Tango10 gene mutations contribute to circadian rhythms.

“Now that we have this powerful tool for extracting information from voltage waveforms, we hope to continue working with electrophysiology laboratories and applying data assimilation to records not only from neurons in the circadian clock but also from neurons associated with neurodegenerative diseases such as Alzheimer’s and Huntington’s, ”Diekman said.



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