FREUD was famously preoccupied with the influence of early childhood experiences on development. His theory of psychoanalysis, which provided a new approach to the analysis and treatment of abnormal adult behaviour, has attracted both ardent followers and fierce critics. According to this theory, the unconscious mind carries imprints of the past that mercilessly haunt the present. Unearthing those imprints is the key to understanding what is going on and then treating it.

In Freudian theory, the imprints are memories, albeit unconscious ones. In other words, they are encoded in the way that the nerve cells which make up the brain are connected to one another. This theory of unconscious early memory is controversial. On the other hand, it seems clear that early experience is important to later behaviour. So what is going on?

There is a growing school of thought that Freud was right, but for the wrong reasons. According to the members of this school, early experience does profoundly mould the brain. However, it is not memory that it moulds—at least, not memory as conventionally understood. What it actually moulds is the way genes work.

A gene is a piece of DNA that encodes a protein molecule. In other words, it is a set of instructions. But instructions are no use unless they can be executed, and executed in an appropriate way. So cells contain a system to read genes, regulate their reading and convert the results into proteins, which then carry out various functions in the body. Part of this system is called epigenetic imprinting. This is a way of modifying how easily a gene can be read.

Moshe Szyf, of McGill University in Montreal, studies the effect of maternal care on epigenetic imprinting. As he explained at this week's meeting on Epigenetics and Neural Developmental Disorders, held in Beltsville, Maryland, imprinting might be a general mechanism whereby experiences are translated into behaviour. If that turns out to be so, it will affect the understanding and treatment of mental illness.

Imprints of care

The first inkling of this came when Michael Meaney, one of Dr Szyf's long-term collaborators, noticed that rat pups whose mothers spent a lot of time licking and grooming them grew up to be less fearful and better-adjusted adults than the offspring of neglectful mothers. Crucially, these well-adjusted rats then gave their own babies the same type of care—in effect, transmitting the behaviour from mother to daughter by inducing similar epigenetic changes.

When Dr Szyf looked at the brains of the two sorts of rats, he found differences in their hippocampuses. Among other jobs, the hippocampus is involved in responding to stress. Dr Szyf discovered that better-adjusted rats had, in their hippocampuses, more active versions of the gene that encodes a molecule called glucocorticoid-receptor protein. Glucocorticoid is a hormone produced in response to stress and its job is to make the animal behave appropriately. But too much glucocorticoid is a bad thing, so there is also a way to switch off its production. When glucocorticoid binds to its receptor in the hippocampus, that activates the expression of genes which dampen further synthesis of the hormone. This feedback system is weaker in rats that have had little maternal care. As a result, they are more anxious and fearful, and show a heightened response to stress.

The researchers went on to study what is responsible for the difference in expression of the glucocorticoid-receptor gene. They found that two types of imprinting are involved. One adds molecules called methyl groups to the DNA of the gene. This suppresses gene expression. The other adds acetyl groups, which are slightly larger, to the proteins around which the DNA is coiled. This has the opposite effect, making gene expression easier. Rats that had experienced little maternal care showed high levels of methylation and low levels of acetylation of the glucocorticoid-receptor gene and its neighbouring proteins. The opposite was true for those that had had a more attentive upbringing.

This explains why levels of glucocorticoid-receptor protein are different in the two groups of rats. But Dr Szyf still wanted to know what triggers epigenetic tagging in response to maternal care. He suspected a protein called NGFI-A, which is produced in response to stimulations such as licking and grooming. The more stimulation a rat pup receives, the more NGFI-A it produces.

This suspicion was confirmed when he found it is also the case that the more maternal care a pup receives, the more NGFI-A it has bound to its glucocorticoid-receptor genes. Then, in a series of experiments on cell cultures, he showed that when bound to this gene NGFI-A attracts two enzymes involved in epigenetic tagging. The enzymes in question are histone acetyltransferase (which adds acetyl groups to proteins) and methylated DNA-binding protein-2 (which removes methyl groups from DNA).

According to Dr Szyf, epigenetic modifications in response to maternal care occur during the first week of life after birth—the so-called critical period. The effects are stable, and persist into adulthood. Because this type of programming involves adding and removing chemical groups to and from the DNA and its nearby protein molecules, the researchers wondered whether reversing those reactions during adulthood would affect an animal's behaviour. To test this, they used two chemicals. One, called TSA, inhibits the enzyme that removes acetyl groups. The other, called L-methionine, is a donor of methyl groups.

When injected into the brain cavity near the hippocampus, TSA increased both the amount of acetylation and the level of expression of the glucocorticoid receptor in adult rats that had had little maternal care early in life. As a result, those rats became less anxious and fearful. By contrast, L-methionine increased the level of methylation and thus reduced the expression of the gene in animals with loving mothers, and led to fear, anxiety and a heightened response to stress.

Marked for life

Dr Szyf and Dr Meaney have made a strong case that different epigenetic profiles resulting from early experience correlate with behavioural differences in adults—in rats at least. They are now looking at people. Their first human study is into whether those who commit suicide have different imprints in their hippocampuses from those who die in accidents. They are also studying blood samples from people with depression or with violent tendencies, to look for epigenetic markers that may exist for either of these two behaviours. If successful, that might lead to new methods of diagnosing psychiatric conditions.

Meanwhile, Dr Szyf suspects that response to stress is just one behaviour that might be regulated this way. Whether epigenetics is important for other, more complex, behaviour remains to be seen. If it is, however, the implication could be huge. For decades, attempts to draw a direct line between genes and mental illnesses have disappointed their authors. But environmental explanations have failed, too. Psychiatrists now realise that there is something else in between. That something may be epigenetic imprinting.