The Epigenetics Revolution

But we know that adults who suffered traumatic childhoods are actually over-stressed. They produce too much cortisol, all the time. Something must be going wrong in this feedback loop. There are a few studies in humans that show that this is the case. These studies examined the levels of corticotrophin-releasing hormone in the fluid bathing the brain and spinal cord. As predicted, the levels of corticotrophin-releasing hormone were higher in individuals who had suffered childhood abuse than in individuals who hadn’t. This was true even when the individuals were healthy at the time of the experiments[207][208]. Because it’s so hard to investigate this fully in humans, a lot of the breakthroughs in this field have come from using animal models of certain conditions and then correlating them where possible with what we know from human cases.

Relaxed rats and mellow mice

A useful model has been based around the mothering skills of rats. In the first week of their lives, rat babies love being licked and groomed by their mothers. Some mothers are naturally very good at this, others not so much so. If a mother is good at it, she’s good at it in all her pregnancies. Similarly, if she’s a bit lackadaisical at the licking and grooming, this is true for every litter she has.

If we test the offspring of these different mothers when the pups are older and independent, an interesting effect emerges. When we challenge these now adult rats with a mildly stressful situation, the ones that were licked and groomed the most stay fairly calm. The ones that were relatively deprived of ‘mother love’ react very strongly to even mild stress. Essentially, the rats that had been licked and groomed the most as babies were the most chilled out as adults.

The researchers carried out experiments where newborn rats were transferred from ‘good’ mothers to ‘bad’ and vice versa. These experiments showed that the final responses of the adults were completely due to the love and affection they received in the first week of life. Babies born to mothers who were lacklustre lickers and groomers grew up nicely chilled out if they were fostered by mothers who were good at this.

The low stress levels of the adult rats that had been thoroughly nurtured as babies were shown by measuring their behaviour when they were challenged by mild stimuli. They were also monitored hormonally, and the effects were as we would expect. The chilled-out rats had lower levels of corticotrophin-releasing hormone in their hypothalamus and lower levels of adrenocorticotrophin hormone in their blood. Their levels of cortisol were also low, compared with the less nurtured animals.

The key molecular factor in dampening down the stress responses in the well-nurtured rats was the expression of the cortisol receptor in the hippocampus. In these rats, the receptor was highly expressed. As a result, the cells of the hippocampus were very efficient at catching even low amounts of cortisol, and using this as the trigger to subdue the downstream hormonal pathway, through the negative feedback loop.

This showed that levels of the cortisol receptor stayed high in the hippocampus, many months after the all-important licking and grooming of the baby rats. Essentially, events that only happened for seven days immediately after birth had an effect that lasted for pretty much all of a rat’s life.

The reason the effect was so long-lasting is that the initial stimulus – being licked and groomed by the mother – set off a chain of events that led to epigenetic changes to the cortisol receptor gene. These changes occurred very early in development when the brain was at its most ‘plastic’. By plastic, we mean that this is the time when it’s easiest to modify the gene expression patterns and cellular activities. As the animals get older, these patterns stay set in place. That’s why the first week in rats is so critical.

The changes that take place are shown in Figure 12.2. When a baby rat is licked and groomed a lot, it produces serotonin, one of the feel-good chemicals in mammalian brains. This stimulates expression of epigenetic enzymes in the hippocampus, which ultimately results in decreased DNA methylation of the cortisol receptor gene. Low levels of DNA methylation are associated with high levels of gene expression. Consequently, the cortisol receptor is expressed at high levels in the hippocampus, and can keep the rats relatively relaxed[209].

This is a very interesting model to explain how early life events can influence long-term behaviour. But it seems unlikely that just one epigenetic alteration – even one as significant as DNA methylation levels at a very important gene in a critical brain region – could be the only answer. Five years after the work described above, another paper was published by a different group. This also showed the importance of epigenetic changes but in a different gene.