The Epigenetics Revolution

Researchers are gradually gathering data that suggest some of the changes seen in the rodent models of early stress may be relevant in humans. As mentioned earlier, there are logistical, but more importantly ethical, issues which make it impossible to perform the same kinds of studies in people. Even so, some intriguing correlations are emerging.

The original work in the rat model was carried out by Professor Michael Meaney at McGill University in Montreal. His group subsequently performed some interesting studies on human brain samples from individuals who had, sadly, committed suicide. The group analysed the levels of DNA methylation at the cortisol receptor gene in the hippocampus from these cases. Their data showed that the DNA methylation tended to be higher in the samples from people who had had a history of early childhood abuse or neglect. By contrast, the DNA methylation levels at this gene were relatively low in the suicide victims who had not had traumatic childhoods[212]. The high DNA methylation levels in the abuse victims would drive down expression of the cortisol receptor gene. This would make the negative feedback loop less efficient and raise the circulating levels of cortisol. This was consistent with the findings from the rat work, where the stressed-out animals from the less nurturing mothers had high levels of DNA methylation at the cortisol receptor gene in the hippocampus.

Of course, it isn’t just people who have had abusive childhoods who develop mental illnesses. The global figures for depression are startling. The World Health Organisation estimates that over 120 million people worldwide are affected by depression. Depression-related suicides have reached 850,000 per annum and depression is predicted to become the second greatest contributor to the global disease burden by 2020[213].

Effective treatment for depression took a big step forwards in the early 1990s with the licensing by the US Food and Drug Administration of a class of drugs called SSRIs – selective serotonin re-uptake inhibitors. Serotonin is a neurotransmitter molecule – it conveys signals between neurons. Serotonin is released in the brain in response to pleasurable stimuli; it’s the feel-good molecule that we met in our happy rat babies. The levels of serotonin are low in the brains of people suffering from depression. SSRI drugs raise the levels of serotonin in the brain.

It makes sense that drugs that cause an increase in serotonin levels would be useful in treating depression. But there’s something odd about their action. The serotonin levels in the brain rise quite quickly when patients are treated with the SSRI drugs. But it usually takes at least four to six weeks before the terrible symptoms of severe depression begin to lift.

This suggests that there is more to depression than simply a drop in the levels of a single chemical in the brain, which perhaps isn’t that surprising. It’s very unusual for depression to happen overnight – it’s not like coming down with the flu. There’s now a reasonable amount of data showing that there are much longer-term changes in the brain as depression develops. These include alterations in the numbers of contacts that neurons make with each other. This in turn is critically dependent on the levels of chemicals called neurotrophic factors[214]. These chemicals support healthy survival and function of brain cells.

Researchers in the depression field have moved away from a simple model based on levels of neurotransmitters and into a more complex network system. This involves sophisticated interactions between neuronal activity and a whole range of other factors. These include stress, production of neurotransmitters, effects on gene expression and longer-term consequences for neurons and how they interact with each other. While this system is in balance, the brain functions healthily. If the system moves out of balance, this complicated network begins to unravel. This moves the brain’s biochemistry and function further away from health and closer to dysfunction and disease.

Scientists are beginning to focus their attention in this field on epigenetics, because of its potential to create and sustain long-lasting patterns of gene expression. Rodents are the most common model system for these investigations. Because a mouse or a rat can’t tell you how it’s feeling, researchers have created certain behavioural tests that are used to model different aspects of human depression.