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Survival trumps both the need for food and reproduction in prey animals. Just as they are seeking food or a mate, they suddenly turn back – just to be on the safe side. This behavior is well known. Until now, however, no one has been able to explain how this automatic prioritization of safety takes place in the brain. But now, a team of researchers from the University of Copenhagen has made an important discovery.

The researchers have found a group of neurons – nerve cells – in the mouse brain that are part of a network of brain connections that ensure the mouse prioritizes its survival, even when tempted with a treat or a potential mate.

This new knowledge could one day benefit people with movement disorders such as Parkinson's disease or spinal cord injuries. The research is supported by the Lundbeck Foundation and has just been published in the prestigious journal Nature Neuroscience.

The discovery was made by a team of researchers from the Department of Neuroscience in Professor Ole Kiehn's laboratory, and the NNF Center for Basic Metabolic Research in Associate Professor Christoffer Clemmensen's laboratory, with Assistant Professor Nathalie Krauth as the principal investigator.

Professor Ole Kiehn explains that the new discovery was unexpected:

“We were surprised, because this was not what we were looking for, and although we’ve long known about this behavior in prey animals – that they seemingly turn around without clear motivation – we didn’t know where in the brain that mechanism was anchored.”

What did you originally expect to find out?

We wanted to find the connection between movement and food-seeking by examining the connections between two brain areas involved in regulating hunger and walking, respectively:
One, the lateral hypothalamus (abbreviated LHA), helps regulate hunger. The other is an area in the brainstem, the pedunculopontine nucleus (abbreviated PPN). When a mouse – or a human – starts to walk, it's due to signals sent from that area via the spinal cord to the muscles in the legs and feet to initiate movement.

From earlier experiments with rats and cats, we had an idea that if you stimulate the part of the LHA that regulates hunger, the animals would seek out food. But surprisingly, the opposite almost occurred.

What did you find?

When we stimulated this nerve cell network in the brain—even in hungry mice that were in an area where they could find food—they ran away. We saw the same mechanism when the mice had the opportunity to seek contact with the opposite sex. We also discovered that if we gave the mice a chance to seek shelter, they would run to it. And importantly, we identified a specific type of neuron in this network that is crucial for that behavior.

How do you interpret your discovery?

We believe we have identified the group of neurons that are essential for prey animals—such as mice and birds—to have an automatic safety behavior against predators. When this system is activated, it works like an internal clock saying: "Now you should turn back." Many people have probably seen this behavior. I know it from our country house, for instance, where we have a bird feeder. The birds eat and then suddenly turn around, even though there are no birds of prey nearby. It’s a kind of survival mechanism. From an evolutionary perspective, more animals would survive if all prey animals exhibited this behavior.

A kind of built-in caution?

Yes, that’s a good way to describe it.

So is this part of the well-known "fight-or-flight response"?

No, because that is triggered by another area in the brain. If a bird or mouse sees a predator, it reacts to a visual stimulus and runs away due to the sudden threat. But we believe this is a reaction to an internal image of a potential risk in the current situation. The brain then converts this abstract image into a concrete action.

We are also studying the "fight-or-flight response" in another project, and in that case, we observe that the mice either freeze or flee. And they run very fast when they flee. In the reaction we’ve described here, the mouse runs more slowly.

What triggers this safety mechanism?

We don’t know yet. It might be something related to timing that makes the mice run back at certain intervals. That’s something we are currently investigating further.

How did you identify the neural networks?

We genetically modified the nerve cells we wanted to study and inserted light-sensitive channels into them. Through these, we could activate the cells by shining light on them with an optical probe—a small cable placed in the mouse’s brain above the cells we wanted to activate. We then sent the genetically modified, hungry mice with probes on their heads into an area where they could find food, and by "turning on" and "off" the nerve cells, we could observe how the neurons affected the mice’s behavior.

What caveats must be considered when transferring results from mouse brain experiments to humans?

Mouse brains are small compared to human brains, but the connections between different brain areas are the same. So they are a good model. However, we humans are better cognitively equipped to understand what is dangerous. And the question, of course, is whether the behavior we observe in mice is also important for animals and humans who are not being hunted. We don’t yet have a clear answer to that.

Even though this is basic research, can you envision how this new knowledge might be applied?

Yes, we are also working with Parkinson’s disease. It is a complex disease caused by a lack of dopamine in the brain. One consequence of that deficiency is problems with walking, and while dopamine-promoting medication can help, it doesn’t always. So one could imagine activating these circuits to improve gait function. Today, some Parkinson’s patients receive electrical stimulation of brain circuits through so-called Deep Brain Stimulation. The problem is that it stimulates everything around the electrode. But treatment of this specific circuit would require a very targeted, precise stimulation of nerve cells, and currently, we cannot do that in humans.

What is the most exciting part of this study for you?

The most exciting thing is that we have connected a very complex brain function to the motor system, allowing us to read the mouse’s brain function through its motor output. And it's incredibly exciting that we can now show how an abstract assessment of danger in the mouse’s brain is translated into a concrete action, where the mouse moves away to avoid the danger.

What’s the next step?

The next step is to investigate decisions to move—what you could call “from thought to action”—because one of the big questions in this field is how a decision is translated into action.

And I would like to place movement in a broader perspective. I usually say that the only thing that comes out of the brain is motor activity, and therefore, movements are a kind of key to understanding what is happening in the brain.