Childhood experiences play a crucial role in shaping the mental and physical health of a person. It has been observed that exposure to traumatic and stressful events in childhood increase the likelihood of developing depression, bipolar disorders, PTSD and anxiety later on in life.
These phenotypes show high variability in their heritability. Thus, it is suspected that epigenetic modifications may contribute to these symptoms.
Epigenetics is the study of the effect of our environment and behaviour on the function of our genes. It is not associated with changes in DNA sequence or mutation. Unlike mutations, epigenetic modifications are reversible. The commonly occurring epigenetic modifications include DNA methylation, histone acetylation or deacetylation. These change the expression of genes in the body. Since a gene contains information for protein synthesis, changes in the DNA sequence of a gene can change the type of protein synthesized. On the other hand, epigenetic modifications only influence when and how often your gene will be expressed as the corresponding protein.
Childhood trauma affects the physical and mental health of a person. It can lead to increased chances of cardiovascular diseases, obesity, diabetes, etc. The effect of trauma differs from one person to another. Some people are more vulnerable to traumatic events. Others show more “resilience” to adverse events and find it easy to bounce back from such situations
The way these traumatic events affect us in our childhood can influence our behaviour as adults. Studies indicate that exposure to traumatic events in childhood can lead to long-lasting effects because of epigenetic modifications. Previous studies had reported changes in gene expression in various brain regions, including the nucleus accumbens. This region is linked to depression. But, how the expression of genes was regulated in these brain regions remained unexplored. In a recently published study in Nature Neuroscience, researchers established that when mice are exposed to stress early on in their lives, they become more prone to stress as adults. This happens because of epigenetic modifications in a particular neuron. The researchers speculated that Early life stress(ELS) was responsible for epigenetic modifications in nucleus accumbens that influenced gene expression in this region.
In a series of experiments, researchers separated mice pups into two groups. The first group of mice were separated from their mothers for around 4 hours every day. They were given limited bedding. Such living conditions gave them early life stress. In another group, the mice were given proper bedding and they lived with their mothers. When both groups were confronted by an aggressive mouse in their adulthood, the ELS mice showed more depression-like symptoms as opposed to the control mice that had proper living conditions in their childhood. These symptoms included decreased exploration and lowered social interaction. The researchers then investigated an epigenetic mark, H3K79me2. This methylation is done at the 79th lysine residue of a histone H3 protein. Dot1l is the enzyme that methylates this site. Another enzyme called, Kdm2b removes the methyl group. The methylation at this site leads to upregulation of gene expression.
The D2 neurons of the nucleus accumbens contain D2 dopamine receptors. The activation of these receptors leads to enhanced susceptibility to stress. Knockdown of Kdm2b or overexpression of Dot1l in the neurons was done in control mice. These mice then showed depression-like symptoms similar to that of ELS mice after a confrontation with the aggressive mice. On the contrary, if kdm2b was overexpressed or Dot1l was knocked down, depression-like symptoms were reversed in the control mice. However, this effect was specific to the D2 neurons of the nucleus accumbens and not D2 neurons in the other regions of the brain. This study is significant as the team could identify the cell subtype in which the specific epigenetic modifications were occurring. This helps in understanding the effect of early stress on the behaviour of a person. RNA sequencing analysis of D2 neurons revealed gene expression patterns in ELS mice that were significantly similar to the mice group that had overexpressed Dot1l. This implicated the role of Dot1l and H3K79me2 in conferring epigenetic signatures that carry the effect of early life stress later on in life. The team also sought to use pinometostat, a known molecular inhibitor of the Dot1l enzyme as a potential therapeutic.
The mice administered with pinometostat had lower levels of H3K79me2 in the nucleus accumbens. They also had better social interaction scores after their interaction with the aggressive mice.
Even though this mechanism looks promising, scientists believe that there are still more questions that need to be answered. The brain is complex and more often than not, a large number of mechanisms are at play. Thus, more research is required to understand the other mechanisms that may be contributing to the life-long effects of childhood trauma and stress. Childhood is a unique period in a person’s life as it is characterised by fast development and high plasticity. Thus, it is necessary to provide a nurturing environment to children as a poor environment can affect the development of their brains.
- H. Kronman et al., “Long-term behavioural and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons,” Nat Neurosci, doi:10.1038/s41593-021-00814-8, 2021.
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Urvi is a biotechnology graduate. Her love for biology and writing motivated her to share interesting science stories. Currently, she is pursuing her interest in writing as a freelancer. In the future, she would like to make a career in scientific research and also continue to communicate science.
He has completed his Masters in Medical Biotechnology from The Maharaja Sayajirao University of Baroda and is currently an active researcher in Molecular Epidemiology at The Centre for Cancer Epidemiology, Navi Mumbai. His journey in Science and Creativity began together during his childhood days. He believes that Art and Science indeed have a beautiful world altogether in them and sailing across its spectrum inspires him to sow his thoughts deep into Science and carve out the pillars of Art through them! Being a Science enthusiast and an Artist, he wishes to devote a good share of his life to wildlife and marine conservation as he feels that the creativity of nature needs to be taken care of in the current era.