Stress hormones keep an hourly rhythm, shaping mood and energy

Stress hormones do not surge in one long wave, they arrive in steady pulses that tick through the day and steer metabolism. A new study in mice and rats shows that the brain cells driving those pulses fire on an almost clock-like hourly schedule, even when no threat is in sight.

Professor Karl Iremonger and colleagues at the University of Otago discovered the pattern by watching stress neurons glow in real time inside freely moving animals.

Their findings link these hourly bursts to brief spikes in the stress hormone cortisol and to short bouts of wakefulness.

Brain’s precise stress rhythm

An ultradian rhythm repeats more than once in 24 hours, and cortisol follows that rule by spiking about 12 to 18 times each day in healthy adults.

The team shows that corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus march in lockstep with that rhythm. They switch from quiet to active roughly every 60 minutes.

Hourly pulses have been reported in blood samples for decades, yet skeptics argued they were a quirk of laboratory measurements. Direct brain recordings reveal a constant cell rhythm matching hormone patterns during both day and night.

Such precision hints at an internal timer that is independent of the master circadian clock in the suprachiasmatic nucleus.

Exactly how this shorter timer works remains an open question. Computer models suggest feedback loops between CRH cells and downstream adrenal signals could create a self-sustaining oscillator.

Tracking animal stress pulses

To peek inside a living brain without restraint, the researchers used fiber photometry. This technique delivers and collects light through a hair-thin optic cable.

The team engineered CRH neurons to produce a calcium-sensitive fluorescent protein so that each burst of activity produced brief flashes detectable through the fiber.

Light pulses were recorded continuously for up to three days while animals ate, slept, and explored. The signal rose sharply for a few minutes every hour, then faded – a pattern that mirrored hourly blips in the animals’ core temperature and movement.

Because mice are nocturnal, bursts clustered during the night when the animals roamed, yet the hourly spacing never broke.

That consistency allowed the team to predict upcoming activity peaks with simple statistics. This is a step toward forecasting stress reactivity in real time.

Chemogenetic tools offered a second line of evidence. When the group artificially forced CRH neurons into an “on” state, resting animals snapped to attention and began frantic grooming within seconds.

Stress bursts prompt sudden waking

“These bursts of brain cell activity seem to act like a natural ‘wake-up’ signal and often lead to a rise in stress hormones, or cortisol,” said Iremonger.

Each neural flare preceded a brief switch from quiet rest to alert scanning, suggesting the stress system doubles as a rapid response alarm that keeps animals ready for change.

The optical recordings also showed that some hormone pulses followed the neural peaks while others did not. That mismatch implies additional checkpoints, perhaps in the pituitary or adrenal glands, that decide whether a neural warning should translate into a systemic hormone surge.

Earlier work in the nucleus accumbens found that activating local CRH neurons can flip mice from sleep to wakefulness in milliseconds. Taken together, the evidence positions CRH cells as key players that manage both body chemistry and behavioral state.

“Our new research is helping us to understand how the brain controls these normal rhythms of stress hormone release,” said Iremonger. Mapping that network could explain why some people feel alert at night or tired during the day.

Hormones tied to mood disorders

Chronic stress is a hallmark of depression, and many patients show overactive CRH signaling and flattened hormone rhythms.

Drug developers have chased CRH receptor 1 blockers for years, and a recent structure-guided screen produced compounds that eased depressive behaviors in mice.

Hourly brain pulses may be the physiological target those drugs must tame. If the rhythm turns erratic, patients could face unpredictable swings in energy, sleep, and emotion – a scenario often reported in mood disorders.

Disrupted ultradian patterns also appear in adrenal insufficiency. Standard three-times-a-day steroid pills create long plateaus instead of sharp pulses.

The PULSES clinical trial showed that delivering hydrocortisone in brief microdoses improved fatigue and emotional processing in such patients.

Taken with the Otago findings, the trial suggests that mimicking the natural hourly beat matters as much as the total daily dose. Endocrinologists are now testing wearable pumps that release cortisol in programmable bursts to restore both circadian and ultradian balance.

New frontiers in stress rhythms

Future work will probe the molecular gears behind the hourly switch, from ion channels on CRH neurons to feedback from circulating cortisol and brainstem arousal centers.

Genetic screens could reveal why stress rhythms shift with age, sex, and early-life adversity – factors already known to reshape hormone patterns.

The Otago team also plans to study humans using noninvasive neuroimaging paired with fast saliva sampling. Showing that the same brain hormone choreography exists in people would pave the way for rhythm-based diagnostics in psychiatry and sleep medicine.

In the future, simple wearables could detect erratic stress patterns early – before symptoms develop – much like smartwatches that alert users to irregular heartbeats.

Behavioral interventions, timed light exposure, or low-dose CRH blockers could then nudge the rhythm back on track with fewer side effects than blunt hormone suppression.

Ultimately, the research suggests that good health depends not just on maintaining cortisol levels within a safe range, but on allowing those levels to fluctuate at the right times.

The study is published in Proceedings of the National Academy of Sciences.

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