Key Study: Childhood stress and its effects on serotonin (an animal experiment), (Gardner et al. 2009)

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This complex yet fascinating study is an excellent example of how the use of animal models can provide insight into possible explanations of human behaviour.

This animal experiment by Gardner et al. (2009) could explain links between stress early in life when we’re kids and our behaviour as adults. The use of rats in this study allows the researchers to manipulate and measure IVs and DVs in ways that would be impossible in human subjects. The study provides possible explanations for why early life stress may result in later-life aggression and disorders.

Background & Context

There is a wealth of research and studies that shows experiencing high levels of stress as a child can increase the chances of all sorts of problems later in life. Adverse childhood experiences (ACEs) have been linked to increased risks of antisocial behaviours like violence, aggression and criminality, as well as increasing chances of developing a psychological disorder like depression or an anxiety disorder. But why?

READ MORE

  • Key study: Serotonin, the PFC and aggression (Passamonti et al.) (LINK)
  • Serotonin and violence (LINK)

One aim of this experiment was to see how early-life stress affects the expression of an important gene – the TPH-2 gene. This could explain links between ACEs and negative adulthood outcomes (like increased risks of aggression) because the TPH-2 gene helps turn the amino acid tryptophan into serotonin. Serotonin is an important neurotransmitter that helps to regulate mood and it influences activity in the prefrontal cortex, which is a very important part of the brain. One function it has is to inhibit our impulsive behaviour. In other words, it allows us to think through our actions and make good decisions. If serotonin and PFC function is reduced, we may be prone to react aggressively when we’re provoked, which could explain links between serotonin, the PFC and violence.

Hand of scientist with cute rat in laboratory

Handling rat pups for 15 minutes per day every day is a model of experiencing chronic (long-term) stress as a child.

This study also looked at how childhood stress affects the expression of the TPH-2 gene* when we experience stress as an adult in a “social defeat” test.

*Gene expression: when the gene sends a signal from the cell. When the TPH-2 gene is expressed it means it’s sending signals to start the process of turning tryptophan into serotonin.

Methods

Models of ACEs: The researchers randomly allocated the rats into one of three different experimental conditions:

  • MS180: these rats were separated from their mothers (MS = Maternal Separation) for 180 mins per day from the day they were born
  • MS15: these rats were separated for just 15 minutes but were handled (kept in someone’s hands) by a researcher for the 15 minutes
  • Control AFR group (Animal Facility Rearing condition)

In previous studies, the MS180 has been shown to be a model of a risk factor for depression-like symptoms in the rat (they sit in the cage and don’t move much). The MS15 condition is designed to model chronic early life stress and how the brain adapts to this stress after a long period of time. A human equivalent would be a childhood experiences many ACEs for years and years, like having an abusive or negligent parent, coping with divorce, extreme poverty, addiction, violence, war, etc. (Read list of ACEs here).

Vector Illustration Of Rats Fighting Over Prey

The social defeat test is designed so the rat who is about to be euthanized (killed) will lose the battle. There are some obvious ethical concerns with this methodology.

Social Defeat: In order to see how the ACEs would affect gene expression in response to adult stress, after the pups were adults (10 weeks old) half of them were put in a “social defeat” test. This is where they are taken and put in a cage with a larger rat that the researchers know will be aggressive towards and dominate the smaller rat (hence, they are socially defeated). This is extremely stressful for the rat. The other half were put in a control cage by themselves for comparison.

Measuring Gene Expression: There is no way to measure gene expression in the brain in living animals, so after the rats were in the social defeat or control cage, they were returned to their regular cages for four hours before they were …”transferred to a procedure room, and rapidly decapitated…(and)…the brains were removed…” (Gardner et al. 2009). After this, the gene expression was measured (by measuring the amount of messenger RNA =, mRNA, in the brain).

Results

Effects of ACEs: The first interesting result to note is the effects of the different ACEs on the expression of the TPH-2 gene in the rats. MS15 rats had a 55% decrease in the expression of this gene when compared to the control group. However, the MS180 group’s increased and their TPH-2 expression was almost double the MS15 rats (91% higher).

Effects of ACEs after Social Defeat: Consistent with the above findings, social defeat decreased the TPH-2 gene expression in the MS15 rats (41%¹ lower than the control group), whereas it increased TPH-2 gene expression in the MS180 rats (39% higher).

Social Defeat Cage vs Control Cage: There were no observable differences in gene expression between the rats in the social defeat cage compared with the control cage “…if the differences in early life experiences were ignored…(and)…rats exposed to social defeat had comparable levels of tph2 mRNA expression in the DR relative to rats exposed to a novel cage.”

Conclusions

Firstly, the results above suggest that adult stress (in this case the social defeat) by itself doesn’t have an effect on gene expression – it is only when the stress is taken into consideration with what happened in childhood that gene expression is affected.

Insights into human behaviour: These results could explain why children who experience chronic long-term stress in childhood grow up to be antisocial adults and may react violently or impulsively if they’re threatened: their childhood stress means they have less TPH-2 expression in adulthood, especially when stressed, so they are producing less serotonin which is going to prevent their PFC from functioning fully, which may lead them to act impulsively without considering the consequences of their actions. This may explain findings like Moore et al.’s (2002) study that shows links between serotonin dysfunction and antisocial behaviour.

In exams, this study could be used in answers relating to neurotransmission, serotonin, genetics, experimental research, animal studies, ethics and even hormones.

Gang Of Youths Fighting

Kids and adults who are constantly getting into trouble for antisocial behaviour (e.g. violence, and criminal behaviour) often have experienced lifetimes of ACEs. This study could explain that connection.

Alternative Explanations: Another possible factor to consider in this relationship is the stress hormone, cortisol. Cortisol actually activates the TPH-2 gene and it is released when we’re stressed. However, prolonged childhood stress reduces cortisol release later in life (which could be why people with PTSD actually have low levels of cortisol). This could explain the above results – the chronic stress in the MS15 condition reduced cortisol so the TPH-2 gene’s expression was reduced.

 

 

The complexity of these potential explanations is why this study was left out of our revision guide in favour of more simplistic studies.

Critical Thinking Considerations

  • What are the ethical considerations with this study?
  • To what extent is a rat pup being handled 15 mins per day an accurate model of what it’s like to be a human child experiencing years of adverse childhood experiences, like abuse, neglect, violence or poverty?
  • Do the above results suggest that kids who are deprived from their mothers will grow up to have better function in their PFCs and so make better decisions and be less likely to develop antisocial behaviours?

References
Gardner, Katherine L. et al. “Adverse Experience during Early Life and Adulthood Interact to Elevate tph2 mRNA Expression in Serotonergic Neurons within the Dorsal Raphe Nucleus.” Neuroscience 163.4 (2009): 991–1001. Full Study
Puig, M. V., & Gulledge, A. T. (2011). Serotonin and prefrontal cortex function: neurons, networks, and circuits. Molecular neurobiology44(3), 449–464. doi:10.1007/s12035-011-8214-0 (Link)

Note: This study was conducted with the aim of understanding psychological disorders like depression. However, the results can still be applied to other behaviours like aggression and this is done to be consistent with how this study is used in our textbook, IB Psychology: A Student’s Guide.

¹ The textbook states 44% but 41% is the correct number.

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