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Developmental Biology - Circadian Rhythm

Circadian Rhythm Controls Sleep & Body Temperature

A stress hormone helps control the circadian rhythm of brain cells...


As day turns into night, and night turns into day, the vast majority of living organisms follow a fixed circadian rhythm that controls everything from sleep to body temperature.

This internal clock is found in everything from bacteria to humans and is controlled by some very distinct hereditary genes, known as clock genes.

In our brain, clock genes are particularly active in the suprachiasmatic nucleus. It sits just above the point where our optic nerves cross, and sends signals to our brain about the surrounding light level. From here, the suprachiasmatic nucleus regulates the rhythm of a number of other areas of our body, including our cerebellum and cerebral cortex.

However, these three areas of the brain are not directly linked by neurons, and this made researchers at the University of Copenhagen curious. Using test rats, they have now demonstrated that the circadian rhythm is controlled by means of signalling agents in the blood, such as the stress hormone corticosterone.
"In humans, the hormone is known as cortisol, and although the sleep rhythm in rats is the opposite of ours, we basically have the same hormonal system."

Martin Fredensborg Rath PhD, Associate Professor, Department of Molecular Neuroscience, University of Copenhagen, Denmark.

Rath explains that recent years have seen increasing scientific research on clock genes, as previous research on these genes found a correlation between depression and irregularities in the body's circadian rhythms. Research results are published in the journal Neuroendocrinology.

New Method with Medical Micropumps

In the study with the stress hormone corticosterone, researchers removed the suprachiasmatic nucleus in a number of rats. As expected, this removed the circadian rhythm of the animals.

Among other things, the body temperature and activity level of the rats went from circadian oscillations to a more even or constant state without fluctuations. The same was observed in the rats' otherwise rhythmic hormone production.
However, the circadian rhythm of the cerebellum was restored when the rats were subsequently implanted with a special programmable micropump, normally used to dose medication in specific quantities.

In this case, however, researchers used the pump to emit carefully metered doses of corticosterone at different times of the day and night, similar to the animals' natural rhythm.

"Nobody has used these pumps for anything like this before. So technically, we were onto something completely new," says Martin Fredensborg Rath.

For that reason, researchers spent the best part of a year carrying out a large number of control tests to ensure the new method was valid.

Interaction Between Neurons and Hormones

The new method paid off. With the artificial corticosterone supplement, researchers were again able to read a rhythmic activity of clock genes in the cerebellum of the rats, even though their suprachiasmatic nucleus had been removed.
"This is hugely interesting from a scientific point of view, as it means we have two systems - the nervous system and the hormonal system - that communicate perfectly and influence one another. All in the course of a reasonably tight 24-hour program.

With these test results and the new method in our toolbox, researchers' next step is to study other rhythmic hormones in a similar manner, including hormones from the thyroid gland.


Martin Fredensborg Rath

Abstract
Neurons of the cerebellar cortex contain a circadian oscillator with circadian expression of clock genes being controlled by the master clock of the suprachiasmatic nucleus (SCN). However, the signaling pathway connecting the SCN to the cerebellum is unknown. Glucocorticoids exhibit a prominent SCN-dependent circadian rhythm and high levels of the glucocorticoid receptor have been reported in the cerebellar cortex; we therefore hypothesized that glucocorticoids may control rhythmic expression of clock genes in the cerebellar cortex. We here applied a novel methodology by combining electrolytic lesion of the SCN with implantation of a micropump programmed to release corticosterone in a circadian manner mimicking the endogenous hormone profile. By use of this approach, we were able to restore the corticosterone rhythm in SCN lesioned male rats. Clock gene expression in the cerebellum was abolished in rats with a lesioned SCN, but exogenous corticosterone restored the daily rhythm in clock gene expression in the cerebellar cortex, as revealed by quantitative real-time PCR and radiochemical in situ hybridization for detection of the core clock genes Per1, Per2 and Arntl. On the other hand, exogenous hormone did not restore circadian rhythms in body temperature and running activity. RNAscope in situ hybridization further revealed that the glucocorticoid receptor colocalizes with clock gene products in cells of the cerebellar cortex, suggesting that corticosterone exerts its actions by binding directly to receptors in neurons of the cerebellum. However, rhythmic clock gene expression in the cerebellum was also detectable in adrenalectomized rats, indicating that additional control mechanisms exist. These data show that the cerebellar circadian oscillator is influenced by SCN-dependent rhythmic release of corticosterone.

Authors
Tenna Berin, Henrik Hertz and Martin Fredensborg Rath


Acknowledgments
The authors declare no competing interests.

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Nov 14 2019   Fetal Timeline   Maternal Timeline   News  


Nutritional Memory Counters Affects of Diet Restriction in Older Mice

Clock genes active in the suprachiasmatic nucleus of the rat brain (TOP A) regulate body temperature and activity levels. Hormonal balance shifts in response to light (BOTTOM B).
CREDIT Department of Neuroscience, University of Copenhagen


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