Scientists have figured out how stress experienced early in life can cause long-lasting changes in physiology and behavior -- via epigenetics.

Image: Max-Planck Institute of Psychiatry, Munich

Specifically, early stress appears to induce epigenetic changes in a specific regulatory region of the genome, affecting the expression of a hormone important in controlling mood and cognition into adulthood, according to a study published online today (November 8) in Nature Neuroscience.

This is the first study to depict a molecular mechanism by which "stress early in life can cause effects that remain later in life," said epigeneticist Moshe Szyf of McGill University in Montreal. "This can explain a lot of things that happen to us as humans and our behavior later in life."

Stress endured early in life can influence the quality of physical and mental health in adulthood, such as by causing hormonal alterations associated with mood and cognitive disorders. But until now, scientists did not understand the mechanism by which early life experiences can produce such long-lasting effects.

According to a common hypothesis, the environment affects mental heath by causing alterations to the physical properties of the genome that influence gene expression -- the epigenome. Indeed, research suggests that DNA methylation, one of the most intensely studied forms of epigenetics, may explain why maternal care has a long-term influence on behavior and hormones in rats.

To explore whether DNA methylation is behind the changes associated with stress experienced early in life, molecular biologists Chris Murgatroyd and Dietmar Spengler of the Max Planck Institute of Psychiatry in Germany and colleagues examined the methylation patterns of mice that were separated from their mothers for three hours a day for the first ten days of their lives. Specifically, the researchers looked for differences in the gene that encodes arginine vasopressin (AVP), a hormone associated with mood and cognitive behaviors. The AVP receptor is also a promising therapeutic target for stress-related disorders.

From 6 weeks of age all the way up to 1 year, mice that experienced early stress -- and showed the predicted behavioral and hormonal differences -- also displayed significantly lower levels of methylation in the regulatory region of the Avp gene in the brain. This hypomethylation was specific to a subset of neurons in the hypothalamic paraventricular nucleus -- a brain area involved in regulating hormones linked to stress. These mice also had higher levels of Avp mRNA, suggesting that lower methylation levels do indeed affect hormone levels.

"Essentially the genome memorizes that [early life] stress," said Szyf, who was not involved in the study. "Stress changes methylation, and that stays the whole life."

The researchers further determined that the decreases in methylation in stressed mice result from the inactivation of a protein known as MeCP2, which is involved in the initial recruitment of proteins that methylate the DNA.

The concept that social states in early life can affect health in later life is "a completely revolutionary idea," Szyf said. This paper provides a "detailed" molecular mechanism by which this can occur, and "gives substance" to this theory.

Understanding the molecular details underlying this phenomenon is essential to developing potential therapies for mental disorders that stem from early adverse experiences, Murgatroyd added. "This has given us new insight in how to possibly develop drugs for [these illnesses]."

Treatments for reversing the effects of early life stress should begin as early as possible, Spengler said. Reversing the inactivation of MeCP2 might be possible, but "once [methylation] is laid down, you cannot erase [it]," he said. "This is a mark that is very stable." Treatments given later in life, then, must find ways to ameliorate the phenotype, such as by blocking AVP receptors in animals with higher AVP levels, he added.


Related stories:

Epigenetic suicide note
[August 2009]

An epigenetic inheritance
[19th January 2009]

Epigenetics: Genome, Meet Your Environment
[5th July 2004]