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New research in mice digs into how the bodys internal clocks manage release of important hormones.

For humans and animals, many aspects of normal behavior and physiology rely on the proper functioning of the bodys circadian clocks.

for a normal hormone rhythm to proceed, you need clocks in both the central pacemaker and this downstream region to work in tandem.

Heres how its supposed to work: Your brain sends signals to your body to release different hormones at certain times of the day. For example, you get a boost of the hormone cortisolnatures built-in alarm systemright before you usually wake up.

But hormone release actually relies on the interconnected activity of clocks in more than one part of the brain.

The new research shows how daily release of glucocorticoids depends on coordinated clock-gene and neuronal activity rhythms in neurons found in two parts of the hypothalamus, the suprachiasmatic nucleus (SCN) and paraventricular nucleus (PVN).

The new study, conducted with freely behaving mice, appears in Nature Communications.

Normal behavior and physiology depends on a near 24-hour circadian release of various hormones, says Jeff Jones, who led the study as a postdoctoral research scholar in biology atWashington University in St. Louis and recently started work as an assistant professor of biology at Texas A&M University.

When hormone release is disrupted, it can lead to numerous pathologies, including affective disorders like anxiety and depression and metabolic disorders like diabetes and obesity.

We wanted to understand how signals from the central biological clocka tiny brain area called the SCNare decoded by the rest of the brain to generate these diverse circadian rhythms in hormone release, says Jones, who worked with Erik Herzog, a professor at Washington University and senior author of the new study.

The daily timing of hormone release is controlled by the SCN. Located in the hypothalamus, just above where the optic nerves cross, neurons in the SCN send daily signals that are decoded in other parts of the brain that talk to the adrenal glands and the bodys endocrine system.

Cortisol in humans (corticosterone in mice) is more typically known as a stress hormone involved in the fight or flight response, Jones says. But the stress of waking up and preparing for the day is one of the biggest regular stressors to the body. Having a huge amount of this glucocorticoid released right as you wake up seems to help you gear up for the day.

Or for the night, if youre a mouse.

The same hormones that help humans prepare for dealing with the morning commute or a challenging work day also help mice meet their nightly step goals on the running wheel.

Using a novel neuronal recording approach, Jones and Herzog recorded brain activity in individual mice for up to two weeks at a time.

Recording activity from identified types of neurons for such a long period of time is difficult and data intensive, Herzog says. Jeff pioneered these methods for long-term, real-time observations in behaving animals.

Using information about each mouses daily rest-activity and corticosterone secretion, along with gene expression and electrical activity of targeted neurons in their brains, the scientists discovered a critical circuit between the SCN and neurons in the PVN that produce the hormone that triggers release of glucocorticoids.

Turns out, its not enough for the neurons in the SCN to send out daily signals; the local clock in the PVN neurons also has to be working properly in order to produce coordinated daily rhythms in hormone release.

Experiments that eliminated a clock gene in the circadian-signal-receiving area of the brain broke the regular daily cycle.

Theres certain groups of neurons in the SCN that communicate timing information to groups of neurons in the PVN that regulate daily hormone release, Jones says. And for a normal hormone rhythm to proceed, you need clocks in both the central pacemaker and this downstream region to work in tandem.

The findings in mice could have implications for humans down the road, Jones says. Future therapies for cortisol-related diseases and genetic conditions in humans will need to take into account the importance of a second internal clock.

Source: Washington University in St. Louis

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