Study Reports First-Ever Modeling of Electrical Activity of Circadian Clock Neurons in Diurnal Species


It’s no secret that jet lag and night work can wreak havoc on how our body’s internal clock synchronizes our daily sleep-wake cycle, known as the circadian rhythm, but researchers now say they are one step closer to understanding how the brain creates behavioral rhythms optimized for daytime rather than nightlife.

In a new study published on November 30 in the journal eLife, researchers reported the very first recording and modeling of the electrical activity of circadian clock neurons in a diurnal species -; the four-striped grass mouse, Rhabdomys pumilio.

Until now, brain recording studies of nocturnal species have mainly been used to understand the master circadian clock of mammals -; located in the suprachiasmatic hypothalamic nucleus (SCN) of the brain, where nearly 20,000 neurons synchronize with the light-dark cycle via electrical signals to orchestrate circadian rhythms in our physiology and behavior.

The researchers say the study is a step forward towards a more precise exploration of the link between circadian rhythms and human health, including the relationship between daylight exposure and circadian clock-related sleep disturbances.

Almost everything we know about the brain’s circadian clock comes from studies of night-active rodents such as rats and mice, making it difficult to translate this knowledge into human circadian rhythms. This work is the first to describe the complex electrical landscape of the SCN in a diurnal mammal, and it has highlighted notable differences from nocturnal animals that may be important in tailoring the function of clock neurons to specific biological demands. of an active species during the day. “

Casey Diekman, study co-author and mathematical biologist at the New Jersey Institute of Technology

“We found that the overall day / night pattern of SNA neuron activity in diurnal rodents R. pumilio is similar to the pattern previously seen in species that are active at night, ”said Beatriz Bano-Otalora, co-first author of the article and biologist working with the laboratories of Robert Lucas and Timothy Brown at the University of Manchester. have also found unique characteristics in the way R. pumilio SCN neurons behave like never before in nocturnal species. “

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

“However, when we injected currents to inhibit these neurons, some cells exhibited a pronounced delay before resuming fire after the release of the inhibition,” explained Mino Belle, co-author of the article and biologist at the University of Exeter. “This retardation response to fire is not present in the SCN of nocturnal rodents and may affect how R. pumilio clock neurons respond to input they receive from other cells. “

To find out more, the team combined the voltage traces recorded from the rodent’s brain with a newly developed data assimilation algorithm. They built computer models simulating the complex interaction of voltage-gated ion channels that produce action potentials. The simulations showed that the increase in conductivity of a particular ion channel, the transient A-potassium channel, was responsible for the delay response to fire.

“The improved conductance of this potassium channel that our models have pointed out could be beneficial for a diurnal species,” said co-first author of the article, Matthew Moye, postdoctoral researcher at Merck & Co. who began to develop them. The team’s data assimilation algorithms as a PhD student in the Department of Mathematical Sciences at NJIT. “Arousal induces inhibitory behavioral feedback signals to the SCN, which in nocturnal animals helps keep SCN trigger rates low at night. In diurnal animals, this nocturnal inhibitory feedback is not present, so improved type A conductance may be necessary to silence the SCN at night and preserve the overall day / night firing pattern. “

The team’s research follows separate findings by Diekman and colleagues at Northwestern University, recently published on November 15 in Proceedings of the National Academy of Sciences, which revealed the role of the Tango10 gene as a critical link between the circadian clock and the production of daily wake 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 fruit fly voltage traces Drosophila melanogaster, finally showing how mutations in the Tango10 gene contribute to disruption of daily rhythms.

“Now that we have this powerful tool to extract information from voltage traces, we hope to continue to collaborate with electrophysiology labs and apply data assimilation to recordings of not just circadian clock neurons,” but also neurons associated with neurodegenerative diseases such as Alzheimer’s and Huntington’s disease, ”said Diekman.

Source:

Journal reference:

Bano-Otalora, B., et al. (2021) Daily electrical activity in the circadian master clock of a diurnal mammal. eLife. doi.org/10.7554/eLife.68179.


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