Fear, memory and brain exploration

Deep in the base of your brain is an area of grey matter we know barely anything about. We don’t know what it does, or what it is for, and science has simply named it the zona incerta – the unknown zone.

But we do know that it is important because a lot of our neuron (nerve cell) circuitry runs through it, extending all over the brain and down the spinal cord.

We also know that this region of the brain appears to be involved with cognition, learning and memory. And it may be crucial in how we learn to control one of our strongest of emotions – fear.

Learning and memory are fundamental aspects of who we are, allowing us to shape our behaviour to suit the changing environment around us. We have evidence that the zona incerta plays an important role in this by helping to update our memories.

For example, traumatic events imprinted in our memories can trigger responses like fear and anxiety when these memories resurface. Eventually we can learn that the memory is simply that – a memory – and there is no reason to be fearful or anxious. It appears that the zona incerta is involved in the process in which we learn to put these stressful memories aside.

Better understanding the zona incerta could potentially help in the development of future treatments for mental health disorders like as anxiety and post-traumatic stress disorder (PTSD).

Understanding how we learn to express and control fear and anxiety in response to changes in the environment will not only help us understand normal behaviour, but also help us understand how such disorders develop and persist.

The zona incerta is a narrow structure below the thalamus in the middle of the brain, above the brain stem. One of the reasons why it has been so under-explored is that the zona incerta is small, and hard to distinguish from the brain regions around it – there are no obvious landmarks that delineate it.

It is also host to many different groups of neurons, including a group of dopamine-producing cells that are a promising therapeutic target for Parkinsons disease – dopamine is a hormone that controls movement and motivation.

But these highly diverse groups of cells are difficult to monitor when they are all clustered in the zona incerta, making it difficult to isolate which neurons are performing which function.

However, modern genetic tools are allowing researchers to control selected neurons and isolate small groups to see what they are doing. These tools include chemogenetics that use chemicals to take control of the receptors on neurons that receive signals, and cre-lox recombination that uses enzymes to control neuron genes.

There is now emerging research looking at the role of different cell-types in the zona incerta in cognition and motivated behaviour. We know that the zona incerta receives inputs from different regions of the brain, including the amygdala where emotional memories (like fear) are formed

It also projects to other regions that are important for expressing fear, including the periacqueductal grey region in the midbrain – at the top of the brain stem.

This led us to think that the zona incerta might modulate whether a fear memory is expressed – causing physical response like stress – or is inhibited (controlled).

In an unpublished pilot study we tested this by observing how mice eventually learn to suppress a fear that is no longer real.

To understand the drivers of this learning we used chemogenetics to control neurons inside the zona incerta. We found that when we activated specific neurons it was easier for the animal to suppress a learned fear response, helping it to instead relearn and remember that the previous threat was now safe.

By using these different genetic techniques we can now start to isolate the characteristics of distinct populations of neurons in the zona incerta, and build up a picture of all the different functions that might be carried out by this region.

We can then trace these different nerve pathways of the zona incerta to see the other regions of the brain and spinal cord that zona incerta is communicating with. We will use calcium imaging – allowing us to visualise the activity of specific groups of neurons at specific time points – to work out exactly when and where these cells are activated during the learning process.

Finally, we will manipulate activity in these pathways to identify which ones are important for switching on the fear response, and which ones are important for inhibiting it.

Our automatic fear responses can be crucial in keeping us safe in dangerous situations, allowing us to act without thinking. But dangerous situations can also demand that we stay calm and think through a course of action rather than panic.

And when we’ve had a traumatic experience, we don’t want to be re-living it, feeling stress and jumping at shadows. As the hero in Frank Herbert’s science fiction classic Dune says, ‘fear is the mind killer.’

The zona incerta may eventually tell us the mechanisms by which our minds can kill fear instead.

Professor Lawrence, Dr Perry and their team have been awarded a Discovery Project grant from the Australian Research Council to further explore the zona incerta.

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