Scientists unlocking the secrets of stress

Humans evolved a stress response to cope with imminent threats. But in the modern world, that same system can lead to chronic anxiety and depression. Now, a team of scientists at the University of Otago is using cutting-edge technology to understand why the stress system can sometimes become overactive – and how we can switch it off.

We all know how terrifying it can be to speak in front of a crowd for the first time: our hearts pound and we break out in a sweat. Sometimes, we simply seize up.

Seasoned public speakers, however, seldom experience this sense of panic – and it’s for complex reasons that are enabling University of Otago researchers to better understand the science of stress.

Over millions of years, humans have evolved processes to deal with threats in a host of ways.

There’s the famous and primal fight-or-flight system, in which our brains trigger a cascade of hormones like adrenaline and cortisol, preparing the body to act in the face of danger.

Unlike many animals, our prefrontal cortex also enables us to imagine threats before they arrive, like a looming job interview, or to dwell upon them after they’ve passed, like feeling we flubbed it.

All this stems from specific populations of neurons deep within our brains that act as a control centre, regulating the release of stress hormones, influencing our mood, and helping us to survive.

When this intricate system becomes overactive, it can contribute to a host of problems, from chronic anxiety and depression to disrupted sleep cycles.

For many decades, explains Associate Professor Karl Iremonger, scientists had only a rudimentary understanding of these complex processes – largely because they had to measure hormones in the blood to infer what was occurring in the brain.

They were eventually able to identify two main stress hormone systems: the steroid system, which includes cortisol, and the catecholamine system, which governs adrenaline and noradrenaline.

“But hormone levels have always been a really blunt tool to infer brain activity, just because they can work so slowly,” says Karl, a neuroendocrinologist within Otago’s Centre for Neuroendocrinology and Faculty of Biomedical Sciences.

“Over time, we started discovering that the level of stress hormones in the blood – or what we might call stress behaviours – don’t always correlate with what’s going on in the brain. There’s often not a one-to-one relationship.”

He says the breakthrough that allowed scientists to finally define the links between these circuits and our physiological responses came in 2015, with a new wave of technological advances in the fields of optogenetics and fibre photometry.

By being able to measure and record brain cell activity on a second-by-second basis, scientists could directly record the activity of specific stress neurons in real time.

This revealed that the stress system was far more complex and nuanced than a simple on-off switch.

Karl and his Otago colleagues, including fellow neuroendocrinologist Dr Joon Kim from the Department of Physiology, sought to take a closer look.

Adapting to stress

Rather than wait for expensive commercial fibre photometry systems to become available, Joon and collaborators built their own, at a fraction of the cost.

Joon and Karl freely released their fibre photometry system, which is now being used across the world.

This kick-started Joon’s move into developing other open-source neuroscience tools, while also allowing them to observe the brain's inner workings – leading to some unexpected insights.

In one such discovery, Joon used this technology to uncover how the brain activity of animals changes during an important process called stress habituation.

This, he explains, goes back to the experienced public speaker whose brain has been able to deactivate the stress response.

“Your stress hormones are likely very high the first time you do it: but as you do it again and again, and you learn that it’s not a threat, your stress system adapts and calms down.”

Joon says this ability to adapt is a cornerstone of a healthy stress response. But for people suffering from chronic anxiety or post-traumatic stress disorder (PTSD), the process can be broken.

“For those that really dislike public speaking, their stress levels actually go up even higher.”

The team’s research is now focused on understanding what mechanisms allow some people to create that “dampened stress response with each exposure” and how they might be able to facilitate it in others.

That involves not just blunting the stress response with a tranquiliser, as some treatments do, but finding a way to promote the body's natural, healthy adaptation.

Elsewhere, their work has already shown the stress system isn’t just designed for dealing with external threats but is part of a daily rhythm that’s closely tied to our health.

Karl points to our cortisol levels, which naturally peak in the morning to prepare us for the day ahead, before gradually declining to their lowest point at night.

This rhythm acts as a coordinator for our entire circadian cycle. When the rhythm is disrupted by chronic stress, it can lead to sleep-wake cycle issues and other health conditions.

In a recent study, the researchers showed how tightly this daily rhythm is linked to our arousal states, finding that, when an animal is more vigilant and awake, its stress neurons are more active.

This has now led them to investigate how wake-promoting neurotransmitters, like orexin and histamine, might be talking directly to the stress circuits.

The collaborative advantage

The team has also made a fascinating discovery about the role of social connection as a buffer against stress.

In one research project, they used a ‘designer’ drug to mildly activate stress neurons in animals over a two-week period, which was enough to induce depressive-like behaviours.

But they found that if they group-housed the animals, they could prevent or ameliorate some of these negative effects.

“So, it appears that stress in isolation is definitely much worse than stress in a group,” Joon says.

Karl credits much of the team's success to multi-disciplinary collaboration within Otago, where he now leads the Centre for Neuroendocrinology (CNE).

“In the CNE, we study similar circuits in the same region of the brain, the hypothalamus. Often, someone might come up with a really good idea about one brain circuit, that idea gets talked about, and people think, ‘actually, that idea may explain how this other circuit works’.”

This cross-pollination has fostered a unique environment that has lifted everyone’s performance and output, he says.

Meanwhile, many big research questions lie ahead of them, waiting to be solved.

One such enigma is the reason for sex differences in stress responses, Karl says.

A simple answer might be that stress neurons themselves differ between males and females – yet the group’s research suggests female sex hormones are able to change the entire stress system, from the brain to pituitary and adrenal glands.

“It’s far more complicated than we imagined.”

For helping advance new treatments, such work has a double utility.

“It helps us to better understand how the stress system works in healthy individuals, and at the same time, it reveals new drug targets for when it isn't working correctly.”