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'Cuddle hormone' oxytocin may play role in fear

According to The Daily Telegraph, a new study may “help explain why intense feelings of love can also lead to painful heartache that can be hard to move on from if a relationship turns sour.”

Given the headlines, you might expect the study to match the emotional complexity and power of “Anna Karenina” or “Wuthering Heights”. But the study actually involved mice.

The rodent research explored how oxytocin, the so-called “cuddle hormone” – considered to have pro-social and anti-anxiety effects in the brain – may actually be involved in increasing fear in some scenarios.

Mice underwent a variety of behavioural and biological tests that ultimately suggested oxytocin may be involved in enabling them to remember bad social memories. One of these memories was being “bullied” by a more aggressive mouse.

While this result is interesting, it isn’t wise to generalise the findings from a handful of mice in very controlled situations to the general human population’s complex social experiences. This is especially so given that research from earlier in the year came to the entirely contrary conclusion that oxytocin could ease the pain of social rejection.

This research was exploratory and improves our knowledge about the role of oxytocin, leading to new ideas, but it does not provide definitive proof that we fully understand the function of oxytocin in humans.

Where did the story come from?

The study was carried out by researchers from universities in the US and Japan, and was funded by US National Institutes of Health grants.

It was published in the peer-reviewed science journal Nature Neuroscience.

The general UK media’s reporting of this study was poor. It failed to highlight the limitations of the research and in some cases even failed to acknowledge that the research was in mice. Many readers might assume the research was in humans and may be surprised to learn this is not the case.

What kind of research was this?

This was a laboratory-based study in mice. It aimed to investigate the role of a hormone called oxytocin in the fear response.

The researchers highlight how oxytocin is generally understood to have anti-anxiety, pro-social and anti-stress properties. This is partly why the media has dubbed it the “cuddle hormone”.

However, the researchers mention that the view that oxytocin reduces fear and anxiety has recently been challenged by recent research in humans. 

Some research suggests that oxytocin may not always have an exclusively positive effect on human mood. In a recent overview on the issue, the New Scientist highlighted a number of studies that showed that oxytocin may promote feelings of envy and hostility to strangers (PDF, 826kb)

The researchers sought to investigate the issue by studying how changes in oxytocin signalling in a specific part of the brain involved with stress and fear (the lateral septum) were related to fear-related behaviour in mice.

What did the research involve?

The researchers used genetic engineering methods to generate two different groups of mice with alterations to normal levels of the oxytocin receptor, a protein that allows cells to respond to the hormone. 

One group were engineered to produce high levels of the oxytocin receptor in the lateral septum part of the brain, while the other group produced low levels of the receptor in the same area.

The researchers studied both the biological and behavioural impact of this genetic engineering to understand the role oxytocin plays in fear. The mice with high levels of the receptor were expected to be more responsive to oxytocin, while those with low levels were expected to be less responsive.

The mice were then administered three different tests to see how oxytocin levels influenced fear response.

Context-dependent fear conditioning

In a so-called “context-dependent fear conditioning” experiment, the mice were observed to see if they “froze” in anticipation of an electric shock. This involved placing the mice in a chamber with a metal floor that delivered a short shock to their feet after three minutes. They were placed back in the chamber – the same “context” – and observed to see how scared they were in anticipation of the shock.

Stress-enhanced fear

The second behaviour assessment was called “stress-enhanced fear”. This was complex and involved “social defeat” followed by “fear conditioning”. It aimed to to see if being socially wounded affected future fear responses. The media latched on to this as analogous to a relationship break-up.

For the social defeat element, mice were placed in a cage with an aggressive resident mouse for 10 minutes. Social defeat was monitored and confirmed based on the number of attacks by the aggressor, and defensive and submissive postures of the defeated mouse. Six hours later the mice underwent the contextual fear conditioning described above to see if the social defeat had any effect.

Social memory

The third test (social memory) involved taking the socially defeated mouse and allowing it to mingle with the aggressive mouse again six hours after the initial encounter. The researchers observed how often the defeated mouse approached the aggressive one as a sign of whether it remembered the fear it experienced six hours before.

Analysis focused on differences in the biology and behaviour of the two mice groups, who were genetically engineered to have different levels of response to oxytocin. They also compared them with mice that had no genetic engineering, so had “normal” levels of response to the hormone.

What were the basic results?

The results from the “context-dependent fear conditioning” suggested fear regulation was not directly mediated by oxytocin levels. This was because the results in the two groups of mice engineered to have both higher and lower levels of oxytocin receptors were very similar to normal mice in their contextual fear responses.

The “stress-enhanced fear” experiment showed that mice with genetically engineered low levels of oxytocin responsiveness were less scared than normal mice. Those with higher oxytocin responsiveness were more scared under the same conditions. 

The fear was also reduced by chemically inhibiting the oxytocin molecule, which reinforced the suggestion that oxytocin might be having an effect in stress-related fear.

The social memory experiment showed that mice with high levels of oxytocin responsiveness approached the aggressive resident mouse less than normal mice. 

This was interpreted to mean they had a better lasting memory of their previous interaction and so were more scared of the aggressive mouse on the second encounter. 

The mice with lower levels of oxytocin responsiveness approached the aggressor more frequently, suggesting their social memory and fear may be less strong.

How did the researchers interpret the results?

The researchers concluded that their results showed that “social defeat” activated the oxytocin pathway and enhanced fear conditioning. This means they thought past social knockdowns caused greater fear for future interactions and that these were at least partly caused by oxytocin-related signals in the brain.

Conclusion

This research, using mice, showed that oxytocin may have a role in enhancing the memory of past socially stressful events, which may cause more fear of future events. 

The main limitation of this research is that it is in mice, rather than humans. There are many biological similarities between mice and humans, and studies in mice can be useful to better understand the biology of behaviour.

However, their findings cannot necessarily be directly translated across species to humans, particularly when dealing with complex issues such as social interaction.

The media headlines focused on the impact on humans, which assumes that the findings in mice are directly relevant to humans. This type of assumption needs to be tested and may not always be true. 

Human behaviour is complex, so there are likely to be many factors involved in fear and social rejection that will vary from person to person. It is not possible to generalise the findings of a few mice to the majority of human social experiences as some of the headlines have done.

The researchers report that some initial studies have suggested that oxytocin may be associated with memories of unpleasant events and fear and anxiety in humans, and undoubtedly research into its role in these emotions will continue.

Given that previously oxytocin was largely thought to reduce fear and anxiety shows how complex the biology of these emotions are, and that we still have a lot to learn.

Nonetheless, this was a useful piece of research that adds to a growing body of evidence exploring how different molecules play a role in fear.

If you are having problems coping with feelings of fear and anxiety, contact your GP.

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