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In haunted houses across the country this month, threatening figures will jump out of the shadows, prompting visitors — wide-eyed and heart racing —to instinctively freeze and flee.

Evolutionarily speaking, this “innate threat response” is key to survival, helping a wide variety of animal species escape predators. But when stuck in overdrive it can cause problems for humans.

A ������Ƶ18 research team has identified a novel brain circuit responsible for orchestrating this threat response. Known as the interpeduncular nucleus (IPN), this dense cluster of specialized neurons not only jump starts that freeze-and-flee reaction but dials it down when animals learn there’s no real danger.

Assistant Professor Susanna Molas

In people with anxiety or post-traumatic stress disorder (PTSD), this circuit may be broken, the authors said.

The findings could help explain why some people have a greater appetite for risk than others and lead to new therapies for psychiatric disorders.

“The brain’s threat system is like an alarm. It needs to sound when danger is real, but it needs to shut off when it’s not,” said first author Elora Williams, a graduate student in the Department of Psychology and Neuroscience. “Our study shows how the brain learns to fine-tune those responses through experience, helping us adapt to the world.”

The findings were published .

False alarm

For the study, Williams and senior author Susanna Molas, assistant professor in the Department of Psychology and Neuroscience, developed something akin to a mouse haunted house.

For three consecutive days, they periodically projected a predator-like shadow, or “visual looming stimulus,” on a screen above a large arena where mice were busy navigating a maze.

Cameras rolled. Through the use of an imaging technique called fiber photometry, which uses fluorescent proteins to signal neural activity, the researchers measured what was happening in real-time inside the mouse brains.

On day one, when the ominous figure appeared overhead, the mice, as expected, froze.

This makes sense, explained Molas. Freezing is a fundamental stress-response, enabling animals including humans to focus their heightened senses on detecting where a danger might be coming from, and how fast it’s approaching.

The mice then fled to a shelter in the corner and hunkered down, before eventually venturing out again.

By day two, the mice began to respond differently to the looming shadow. They stopped freezing, spent less time in the nest and did more exploring. By day three, the spooky figure barely fazed them.

Their brain activity also changed.

On day one, when the shadow appeared, their IPN crackled to life, with cells called GABAergic neurons putting the body on high alert by signaling fear-related brain regions. By day three, once the animals realized the threat wasn’t real, much of the IPN had gone dark.

Brain cells in the interpenduclear nucleus glow green in a mouse's brain after a shadow appears on the ceiling.

Other types of neurons in the IPN activated when the animals entered the shelter area, signaling safety and helping to “silence the brain’s alarm,” Williams said.

In other experiments, the team used a technique called optogenetics, which uses light to manipulate brain cells, to control the activity of neurons within the IPN circuit. The impact on the mouse behavior was profound.

When GABAergic neurons were silenced before the shadow appeared, the animals froze less and spent less time hiding in the shelter. When those neurons were switched on throughout the three-day experiment, the animals never got used to the looming shadow.��

Elora Williams, PhD candidate

“Collectively, these findings implicate the IPN as a critical circuit for helping us process potential threats and adapt accordingly when we learn they aren’t putting us in danger,” said Molas.

Short-circuited

For decades, research using older methods, like Pavlovian conditioning, has pointed to the amygdala and hippocampus as key players in fear and threat response.

The new study is the first to identify the lesser-known IPN, a tiny part of the ancient midbrain, as a key tool in enabling us to adapt to false threats and get past unwarranted fears.

More research is needed, but it’s possible that risk-takers might have a less active IPN, while those who struggle to bounce back after a frightening experience might have more activity in that circuit.

Disruptions in the IPN could also play a role in fueling anxiety, post-traumatic stress disorder and other psychiatric disorders, the authors said.

They’ve already launched their next studies.

Ultimately, they hope their discovery could lead to new ways to precisely target the IPN.

“Identifying the neuronal circuits underlying threat processing and adaptive learning is vital to understanding the neuropathology of anxiety and other stress-related conditions,” said Williams.

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