Scientists identify a mysterious brain signal tied to stress and hormone pulses

A new study published in PNAS offers evidence that certain brain cells involved in regulating stress do not simply respond to threats, but operate on a repeating internal rhythm—roughly once every hour—even in calm conditions. Researchers at the University of Otago found that these neurons, located in the hypothalamus, exhibit spontaneous cycles of activity that align with patterns of alertness and behavior. The study suggests these patterns may play a broader role in shaping sleep, arousal, and possibly mood.

Scientists have long known about the body’s circadian rhythm, the roughly 24-hour cycle that governs sleep and wakefulness. But there are other biological cycles that occur over shorter periods. These so-called ultradian rhythms regulate many aspects of physiology, including hormone levels and fluctuations in behavior.

One particularly important example is the stress hormone cortisol, which pulses throughout the day every 60 to 90 minutes. While the medical importance of these pulses is well recognized—they influence energy levels, metabolism, and immune responses—the mechanisms that generate them have remained uncertain.

The Otago researchers were especially interested in understanding whether the brain’s stress-control system might contain its own internal rhythm generator. A specific set of neurons known as corticotropin-releasing hormone (CRH) neurons, located in the paraventricular nucleus (PVN) of the hypothalamus, plays a central role in triggering the hormonal stress response.

These neurons activate the hypothalamic-pituitary-adrenal (HPA) axis, leading to the release of cortisol and other hormones. Previous studies had focused mostly on how these neurons respond to external stressors, but the new research aimed to find out what they were doing in the absence of any obvious stress.

“While most people appreciate that our stress response system turns on when we encounter danger, not many people realize that this system is also active over the normal day night cycle. For this reason, I became interested in understanding more about the normal daily rhythms in the stress axis and how they are controlled,” said study author Karl Iremonger, an associate professor and director of the Centre for Neuroendocrinology at the University of Otago.

The researchers used a technique called fiber photometry, which allows them to monitor the real-time activity of specific neurons deep within the brain of living, freely moving animals. By genetically modifying mice and rats to express a fluorescent protein that lights up when neurons are active, the team could measure changes in neural signals with a high degree of precision. They also used an advanced video-tracking system, powered by deep learning software, to monitor subtle changes in the animals’ movement patterns.

The researchers connected the animals to the photometry recording system and let them move freely in their home cages for over 24 hours. To reduce stress effects related to handling, the first four hours of recordings were excluded from analysis. Across the day and night, CRH neurons displayed repeated bursts of activity that lasted around 15 minutes and occurred roughly every hour. These events were dubbed “upstates.” Notably, the frequency of these upstates was higher during the animals’ active (dark) phase compared to their resting (light) phase.

These brain rhythms were closely tied to changes in the animals’ behavior. Every time a mouse initiated movement—such as waking up and beginning to explore its cage—there was a corresponding rise in CRH neuron activity. The researchers ran statistical tests to determine the direction of this relationship and found that changes in brain activity typically preceded movement. In other words, the neurons seemed to be setting the stage for behavioral arousal, rather than simply reacting to it.

“We were surprised at how closely associated the rhythms in stress brain circuit activity were with physical activity (arousal) rhythms,” Iremonger told PsyPost. “This had not been previously shown before.”

To test whether CRH neurons could actively drive behavioral arousal, the team used a technique known as chemogenetics. This approach allowed them to artificially stimulate these neurons using a designer drug, which activated genetically modified receptors only present in the CRH neurons. When these neurons were activated in mice that were otherwise at rest, the animals showed a significant and prolonged increase in movement. This provided direct evidence that CRH neuron activity can prompt behavioral changes even in the absence of external threats.

The researchers then turned to rats, which are often used in studies of hormonal rhythms because they allow for easier blood sampling. Using CRISPR gene-editing technology, the team developed a rat line that enabled them to record CRH neuron activity and measure hormone levels in tandem. Similar to the mice, the rats exhibited hourly bursts of CRH activity, and these were again correlated with movement patterns. They also took blood samples every few minutes from the rats to measure corticosterone, the rodent equivalent of cortisol.

The findings indicated that in many cases, CRH activity preceded a pulse of corticosterone by about 15 minutes. But the relationship was not perfectly synchronized. Sometimes a burst of CRH activity did not lead to a hormone pulse, and sometimes hormone pulses occurred without a clear spike in CRH activity. On average, however, the data showed a consistent pattern: the neural bursts tended to come first.

The results support the idea that CRH neurons operate on an internal rhythm that influences behavior and hormone secretion. These patterns seem to act like a built-in “wake-up” signal, preparing the body for increased alertness. The research provides evidence that ultradian rhythms in behavior and stress hormones are, at least in part, generated by predictable fluctuations in brain activity.

It also suggests that these rhythms are not random. They are shaped by time of day and appear to be tied to the animal’s natural sleep-wake cycle. This has potential implications for understanding how stress affects health. Disruptions in the normal rhythmic activity of these neurons could interfere with sleep and potentially contribute to mood disorders.

“This study shows that there are a population of brain cells that turn on and off with an hourly rhythm,” Iremonger explained. “This rhythm not only drives a rhythm in stress hormone release, but also mediates a rhythm in arousal.”

But the study, like all research, has some limitations. “It is currently impossible to study brain stress circuits in humans as this level of detail,” Iremonger noted. “For this reason, we study them in rats and mice. While stress circuits in the brain are conserved between rodents and humans, there is always a chance there are slight differences in how the function.”

Another open question is how these rhythms are generated in the first place. Unlike circadian rhythms, which are governed by a central master clock in the brain, ultradian rhythms appear to arise from local circuits. The study hints at the possibility that neighboring regions, such as the subparaventricular zone, could be involved. More research will be needed to explore how these circuits interact.

“The next step in our research is to understand the other parts of the brain that send signals to the stress brain cells to control their excitability patterns over the day night cycle,” Iremonger said.

The study, “Ultradian rhythms of CRHPVN neuron activity, behaviour and stress hormone secretion,” was authored by Shaojie Zheng, Caroline M. B. Focke, Calvin K. Young, Isaac Tripp, Dharshini Ganeshan, Emmet M. Power, Daryl O. Schwenke, Allan E. Herbison, Joon S. Kim, and Karl J. Iremonger.