When we see danger, we react. Whether we choose to run and hide or confront our threat head-on, our “instant” decision is the result of a complex brain mechanism that integrates visual data and triggers an appropriate response. How does this occur? A new study explains.
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We may soon be able to ‘turn on’ a courage switch in the brain, helping people to overcome symptoms of post-traumatic stress disorder.

In the animal kingdom, vision is vital for survival. This important sense informs the brain about predators and other threats, and in turn, the brain generates an appropriate reaction: courage or fear, fight or flight.

But how does this process take place? How do animals — humans included — integrate visual information with the appropriate brain circuits that control firstly our emotional states, and afterward, our behavior and actions?

New research brings us closer to an answer. Scientists led by Andrew Huberman, an associate professor of neurobiology and ophthalmology at Stanford University School of Medicine in California, have found the brain circuits “responsible” for the decision to either fight or flee in the face of danger.

Although the study was conducted in mice, the findings are relevant for humans. In fact, the results have important implications for understanding and managing post-traumatic stress disorder (PTSD), addiction, and phobias.

Lindsey Salay is the first author of the paper, which has now been published in the journal Nature.

The brain circuit of fear

To examine the rodents’ response to a threat, Salay and team simulated the approach of a bird of prey and used the c-Fos neuronal marker to track the activity of the mice’s neurons.

The researchers found increased activity in neurons that were grouped in a structure called the ventral midline thalamus (vMT).

Using brain mapping, the scientists were able to see what sensory information comes in and what information goes out of the vMT.

They revealed that the vMT receives information from a wide range of brain areas that process internal states, such as that of fear, but that it sends information out very selectively, to only two main areas: the basolateral amygdala and the medial prefrontal cortex.

The amygdala processes fear, aggression, and other emotions, while the medial prefrontal cortex uses its executive function to modulate emotional responses. The area is also deeply involved in anxiety.

Additional analysis shed yet more light on the trajectory of the brain circuit involved in the rodents’ response to the ominous predator.

Apparently, a nerve tract starts from the “xiphoid nucleus” — a cluster of neurons in the vMT — and continues to the basolateral amygdala.

Another tract follows an analogous path, this time from the so-called nucleus reuniens — another cluster of neurons built around the xiphoid nucleus — and leading up to the medial prefrontal cortex.

‘Turning on’ the courage switch

Having observed this trajectory in the brain, the researchers wondered whether or not selectively inhibiting certain neurons along these pathways produce specific fight-or-flight reactions.

To find out, Salay and team stimulated only the activity of the xiphoid nucleus while confronting the rodents with the image of the bird of prey. This made the mice freeze in front of the predator.

After that, they stimulated the activity of the tract that goes from the nucleus reuniens to the medial prefrontal cortex. This caused a surprising reaction: the mice became aggressive, getting ready to defend themselves.

Senior investigator Huberman describes the rodents’ behavior as one of undeniable courage. “You could hear their tails thumping against the side of the chamber,” he explains. “It’s the mouse equivalent of slapping and beating your chest and saying, ‘OK, let’s fight!'”

A second experiment confirmed the results: stimulating exclusively the nucleus reuniens for half a minute before showing the predator produced the same behavioral response: rather than hiding, the mice rattled their tails and exposed themselves in unprotected areas, ready to fight.

Huberman says that the findings are highly relevant to humans, given that human brains have a similar structure to the vMT.

He suggests that people living with phobias, anxiety, or PTSD might soon benefit from the findings, as reducing the activity in their vMT or in the adjacent neuronal clusters may help these people to overcome their fears.

This opens the door to future work on how to shift us from paralysis and fear to being able to confront challenges in ways that make our lives better.”

Andrew Huberman