Title: Epigenetic influences on the development of the serotonin system: A mechanism of risk for chronic aggressive behaviors in humans?
Name: Linda Booij
Year: 2010
Type: Research Grant

Many studies have shown that what happens early in development influences the way the brain develops and someone's risk to develop behavioral problems later on, including chronic aggression. Studies in animals have shown that adverse factors during a mother's pregnancy (e.g., malnutrition) or adverse experiences early in life (e.g. child abuse, bullying) can influence the way the child's genes are expressed through "DNA methylation", a process in which genes are marked with a chemical coating. This changes the development of certain brain regions and may have consequences for the way the child will develop emotionally, socially, and cognitively later in life.

In studies supported by the Guggenheim Foundation, we studied how early adversity affects the development of the brain, behaviour as well as the expression of genes that regulate serotonin; a brain chemical important for aggression. Two studies were supported: (1) one study in animals and (2) a study in boys and girls who were 15 years of age.

In the animal study, we investigated in rats how stress in the adolescent period affected the brain and neurochemical serotonin, as well as aggression and anxiety. We used the so-called social intruder paradigm, in which a rat is placed in the cage of another rat, thereby creating interpersonal conflict (which is considered an animal-analogue to bullying). We used a technique called immunohistochemistry to study the consequences of social defeat in adolescence for the density of the serotonin transporter in the brain in adulthood. We found that social defeat in adolescence increased serotonin transporter density in part of the prefrontal cortex when the rats were adults (Tao et al, 2017). Anxiety was also increased, with no effects of aggression. These results were somewhat different that what was previously observed when adverse experiences occurred earlier in life, and suggests that the effects of adverse experiences on brain, serotonin and behaviour may depend on the specific timing of the stressor.

In the human study, we studied the impact of early adversity on brain development, DNA methylation in genes that regulate serotonin and on behaviours. For this study, we tested teenagers that had been followed since birth, and thus we had good documentation on their home environment and childhood experiences. Individuals were genetically identical twins, which allowed us to look at specific environmental factors and control for genetic effects. All individuals underwent brain- imaging in combination with an emotion processing task to measure how their brain responded to various types of emotional information. A DNA sample was taken to study DNA methylation.

We found that, while controlling for genetics, prenatal factors (before birth) but not postnatal factors (after birth) predicted adolescent brain development. We also found that environmental- induced changes in epigenetic regulation in the serotonin transporter were predictive of neural activation in the Orbitofrontal Cortex and the way this brain region was connected to other regions (e.g. amygdala) of the so-called limbic-network. Associations were only observed when the brain was processing sad and/or fearful stimuli but not when processing angry stimuli.

Together, these studies suggest that early adversity associated with the development of the brain and with the regulation of the serotonin transporter. Serotonin transporter density (animals) and methylation (humans) was more linked to regulation of sadness / fear than of aggression. The specific effects on brain, expression of genes and behaviours may also depend on timing and/or type of the exposure to adverse events, genetics, and/or a combination of these.