Scientists discover a stress clock in the brain that ticks every hour

Stress is not simply a response to acute stressful episodes. It occurs in the brain where a natural rhythmic pattern regulates the stress system of our body, even on a calm day. This rhythmic pattern might also explain why you suddenly feel alert at certain times, even if you cannot tell why.

Researchers at Ōtākou Whakaihu Waka have demonstrated that brain cells that control stress rhythms can switch on and off in a rhythmic, clock-like fashion, approximately every hour. Their results also document how and when these bursts signal a stress wave of hormones and how they coincide with when we may feel alert or awake.

“We are showing that the brain has hidden timing systems. These bursts of neuronal activity in the brain appear to act like a natural ‘wake-up’ signal and can often lead to a surge in stress hormones, or cortisol,” explains Associate Professor Karl Iremonger, senior author from Otago’s Department of Physiology and Centre for Neuroendocrinology. "The present world-first research will unlock a new avenue to explore how these rhythmic patterns may underpin health, mood, and sleep."

The results published in the Proceedings of the National Academy of Sciences (PNAS) used a scientific method called photometry, which allowed scientists to shine light into the brains of mice and rats and measure the rhythmic activity of certain neurons over time.

Researchers observed animals during spontaneous free movement both day and night. This provided insight into the relationship of brain activity to sleep-wake cycles and the release of hormones. They directed their attention to a population of neurons that express corticotropin-releasing hormone (CRH), located in the paraventricular nucleus of the hypothalamus (CRHPVN), that manage the neuroendocrine stress axis and stress-related behaviors.

In both mice and a newly created line of rats, CRHPVN neurons exhibited a remarkable ultradian rhythm, entering a state of increased activation approximately once per hour. The timing of these increased neuronal activities equated with the greater frequency of arousal and movement.

CRH neurons were not firing haphazardly. In some cases, the peak firing of the neurons preceded a release of corticosteroid pulses (e.g., cortisol). But the connections were not perfect: Some corticosteroid pulses happened without changes in firing rates of the neurons, while other bouts of increased firing of the neurons occurred without a release of corticosteroids.

But the hourly rhythm was apparent. This means that the brain's central coordination point of stress management is almost continuously engaged with the body to integrate alertness. "We found that these changes were in coordination with the patterns of sleep and waking, suggesting that the release is associated with waking or alertness to some auditory cue," Iremonger remarked.

The team also evaluated what happened if they activated the CRH neurons artificially. The researchers utilized chemogenetics, an approach that selectively activates different classes of neurons, to trigger bouts of activation in otherwise resting animals.

What happened? Rats and mice that had been resting suddenly developed hyperactivity. This experiment demonstrated that, in addition to the controls of stress hormones, CRH neurons can drive behavioral responses. Based on what Iremonger found, these cells drive both the release of stress hormones and how active or fidgety you may feel.

The discovery raises significant questions regarding links between mental health and stress management. If this hourly rhythm is disturbed (e.g., chronic stress, poor sleep, or some mental health disorder), it raises the possibility that this could lead to changes in mood or insomnia.

According to Iremonger, understanding these typical patterns would provide a framework to develop new treatments. “Our research is giving us a better way to understand how the brain is coordinating the normal rhythms of release of stress hormones. And knowing where those brain signals are coming from will hopefully allow us to start to understand how stress hormone levels relate to alertness and mental health.”

Drugs that dampen the activity of CRH neurons might help in treating conditions based on overactive stress responses. Damping down the system may bring the temporal frequency of the stress hormone release back into some form of rhythm, which would help in sleep and mood.

Future studies may delineate how these rhythms change with age, environment, or illness. Scientists also want to examine whether humans exhibit a similar pattern, and how this might be observed reliably without invasive technology.

For the moment, this work gives voice to looking at stress not just as a response to pressure, but as a constant ticking clock in your brain that helps keep you ready, alert, and sometimes unexpectedly restless.

Research findings are available online in the journal Proceedings of the National Academy of Sciences.

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