Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (35 page)
This seems rather puzzling. If we don’t accept there is a molecular basis to a biological effect, what are we left with? A religious person may prefer to invoke the soul, just as a Freudian therapist may invoke the psyche. Both of these refer to a theoretical construct that has no defined physical basis. Moving into such a model system, where it is impossible to develop the testable hypotheses that are the cornerstone of all scientific enquiry, is deeply unattractive to most scientists. We prefer to probe for a mechanism that has a physical foundation, rather than defaulting to a scenario in which there is something which is assumed, somehow, to be a part of us, without having any physical existence.
This can generate a cultural clash, but it’s one that’s based on a misunderstanding. A scientist will expect that observable events have a physical basis. For the topic of this chapter, our proposed hypothesis is that terrible early childhood experiences change certain physical aspects of the brain during a key developmental period. This in turn affects the likelihood of mental health problems in adult life. This is a mechanistic explanation. It’s lacking in details, admittedly, but we’ll fill in some of these in this chapter. Mechanistic explanations often sit uncomfortably in our society, because they sound too deterministic. Mechanistic explanations are misinterpreted and taken to imply that humans are essentially robots, wired and programmed to respond in certain ways to certain stimuli.
But this doesn’t have to be the case. If a system has enough flexibility, then one stimulus doesn’t always have to result in the same outcome. Not every abused or neglected child develops into a vulnerable, unwell adult. A phenomenon can have a mechanistic basis, without being deterministic.
The human brain possesses sufficient flexibility to generate different adult outcomes in response to similar childhood experiences. Our brains contain one hundred billion nerve cells (neurons). Each neuron makes links with ten thousand other neurons to form an incredible three dimensional grid. This grid therefore contains a thousand trillion connections – that’s 1,000,000,000,000,000 (a quadrillion). It’s hard to imagine this, so let’s visualise each connection as a disc that’s 1mm thick. Stack up the quadrillion discs on top of each other and they will reach to the sun (which is ninety-three million miles from the earth) and back, three times over.
That’s a lot of connections, so it’s perfectly possible to imagine that our brains have a lot of flexibility. But the connections are not random. There are networks of cells within the giant grid which are more likely to link to each other than to anywhere else. It’s this combination of huge flexibility, but constrained within certain groupings, that is compatible with a system that is mechanistic but not entirely deterministic.
The child is (epigenetically) father to the man
The reason scientists have hypothesised that the adult sequelae of early childhood abuse may have an epigenetic component is that we’re dealing with scenarios where a triggering event continues to have consequences long after the trigger itself has disappeared. The long-term consequences of childhood trauma are very reminiscent of many of the effects that are mediated by epigenetic systems. We have seen some examples of this already. Differentiated cells remember what cell type they are, even after the signal that told them to become kidney cells or skin cells has long since vanished. Audrey Hepburn suffered from ill-health her whole life because of the malnutrition she suffered as a teenager during the Dutch Hunger Winter. Imprinted genes get switched off at certain stages in development, and stay off throughout the rest of life. Indeed, epigenetic modifications are the only known mechanism for maintaining cells in a particular state for exceptionally long periods of time.
The hypothesis that epigeneticists are testing is that early childhood trauma causes an alteration in gene expression in the brain, which is generated or maintained (or both) by epigenetic mechanisms. These epigenetically mediated abnormalities in gene expression predispose adults to increased risk of mental illnesses.
In recent years, scientists have begun to generate data suggesting that this is more than just an appealing hypothesis. Epigenetic proteins play an important role in programming the effects of early trauma. Not only that, they also are involved in adult depression, drug addiction and ‘normal’ memory.
The focus of a lot of research in this field has been a hormone called cortisol. This is produced from the adrenal glands which sit on top of the kidneys. Cortisol is produced in response to stress. The more stressed we are, the more cortisol we produce. The average level of cortisol production tends to be raised in adults who had traumatic childhoods, even if the individuals are healthy at the time of measurement
2
,
3
. What this shows is that adults who were abused or neglected as children have higher background stress levels than their contemporaries. Their systems are chronically stressed. The development of mental illness is, in many cases, probably a little like the development of cancer. A lot of things need to go wrong at the molecular level before a person becomes clinically ill. The chronic stress levels in the abuse survivors push them closer to that threshold. This increases their vulnerability to disease.
2
,
3
. What this shows is that adults who were abused or neglected as children have higher background stress levels than their contemporaries. Their systems are chronically stressed. The development of mental illness is, in many cases, probably a little like the development of cancer. A lot of things need to go wrong at the molecular level before a person becomes clinically ill. The chronic stress levels in the abuse survivors push them closer to that threshold. This increases their vulnerability to disease.
How does this over-expression of cortisol happen? It’s a consequence of events that happen far from the kidneys, in our brains. There is a whole signalling cascade involved here. Chemicals produced in one region of the brain act on other areas. These areas in turn produce other chemicals in response and the process continues. Eventually a chemical leaves the brain and signals to the adrenal glands and cortisol is produced. During an abusive childhood, this signalling cascade is very active. In many abuse survivors, this system keeps signalling as if the person is still trapped in the abusive situation. It’s as if the thermostat on a central heating system has malfunctioned, and the boiler and radiators continue to pump out heat in August, based on the weather from the previous February.
The process starts in a region of the brain called the hippocampus, which gets its name from the ancient Greek term for seahorse, it being shaped a little like this creature. The hippocampus acts as a master switch in controlling how much the cortisol system becomes activated. This is shown in
Figure 12.1
. In this figure, a plus symbol indicates that one event acts to stimulate the next link in the chain. A minus symbol shows the opposite effect, where one event decreases the level of activity of the next event in the chain.
Figure 12.1
. In this figure, a plus symbol indicates that one event acts to stimulate the next link in the chain. A minus symbol shows the opposite effect, where one event decreases the level of activity of the next event in the chain.
Because of changes in the activities of the hippocampus in response to stress, the hypothalamus produces and releases two hormones, called corticotrophin-releasing hormone and arginine vasopressin. These two hormones stimulate the pituitary, which responds by releasing a substance called adrenocorticotrophin hormone which gets into the bloodstream. When the cells of the adrenal gland take up this hormone, they release cortisol.
Figure 12.1
Signalling events in response to stress set up a cascade of events in selected regions of the brain that ultimately result in release of the stress hormone cortisol from the adrenal glands. Under normal circumstances, this system is controlled by a set of negative feedback loops that act to dampen down and limit the activation of the stress response pathways.
Signalling events in response to stress set up a cascade of events in selected regions of the brain that ultimately result in release of the stress hormone cortisol from the adrenal glands. Under normal circumstances, this system is controlled by a set of negative feedback loops that act to dampen down and limit the activation of the stress response pathways.
There’s a clever mechanism built in to this system. Cortisol circulates around the body in the bloodstream, and some of it goes back into the brain. The three brain structures shown in our diagram all carry receptors that recognise cortisol. When cortisol binds to these receptors, it creates a signal that tells these structures to calm down. It’s particularly important for this to happen at the hippocampus, as this structure can send out signals to dampen down all the others involved in this signalling. This is a classic negative feedback loop. Production of cortisol feeds back on various tissues, and the final effect is that the production of cortisol declines. This stops us from being constantly over-stressed.
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
4
,
5
. 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.
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
4
,
5
. 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
6
.
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
6
.
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.
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