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The Epigenetics of Stress

The Epigenetics of Stress

Overly sensitive, aversive reactions to stress seem to run in families. The literature abounds with reports of relatives in these populations predisposed to depression, anxiety, and even suicide. Some family members present with glucocorticoid levels notched abnormally high, and in curiously deregulated concentrations. Behaviorally, they seem to exist at a permanent state of high alert.

Attempts to isolate the genetic underpinnings of this obvious hyperaroused stress sensitivity have met with mixed success. People carrying certain mutations in the serotonin transporter gene seem particularly vulnerable to the normal stresses and strains in life, although there have been difficulties in replicating all the findings. Plenty of people exist who are just as vulnerable to stress but who do not carry this mutation—or any other suspect genetic anomaly—that could explain the behavior.

It is now possible to characterize some of this seeming heritability—and accompanying statistical turbulence—without invoking heritability at all. This is the world of epigenetic transfer, the ability to pass on a trait without having to stop at a meiotic border. A recent study has demonstrated how a powerful environmental stressor can exert molecular effects that last over a long period. The mechanism is epigenetic. It is the first result to characterize a molecular mechanism, induced by early life stressors, that influences behaviors penetrating into adulthood.

To explain these findings, I will first talk about transplacental cortisol and its effects on the developing fetal brain. Then I will move to the data, which do not involve humans at all.

The starting observation

For years, we have known that stressed wombs tend to produce stressed babies. Most molecular explanations for this observation invoke the effects of transplacental glucocorticoids on fetal brain development. If mothers become too stressed (so the idea posits), too many stress hormones enter the womb, penetrate the fetal brain, and interfere with its proper development.

There is some empirical support for this notion. First, excess levels of maternal glucocorticoids have been shown to cross the placenta, targeting the fetal limbic system and causing it to develop much more slowly than in typical controls. This is thought to result in future behavioral dysfunction, particularly regarding reactions to external stressors. It specifically hampers the developing “braking system” of the hypothalamic-pituitary-adrenal (HPA) axis. (As you recall, the HPA axis is a series of biochemical reactions to threat that involve interactions between the hypothalamic, pituitary, and adrenal glands.)

This embryonic braking system is a coordinated series of responses that normally result in the inhibition of glucocorticoid production after some environmental stress has been successfully negotiated. Without this braking system, the fetal brain is wired to produce excess glucocorticoids in an increasingly unregulated fashion. The baby carries this deregulated system into adulthood. If the adult is female and becomes pregnant, her system, which is already flooded with cortisol, marinates her new baby with glucocorticoid. This once again creates a hyperaroused womb, complete with new fetal damage. The trait is thus passed along, not through the germ line but simply through womb exposure.

Although a great deal of work needs to be done to complete this admittedly depressing story, large parts have empirical support. This includes some intimate, biochemical details. Recently, a molecular mechanism has been uncovered that may explain this nongenetic inheritance. Although work has been done mostly in rats, there are broad implications for human behaviors. After a brief explanation of an epigenetic mechanism involving DNA methylation, it will be to these data that we turn next.

Social states experienced in early life can directly affect later behavior. Until now, exactly what molecular mechanisms undergird such effects have remained a complete mystery.

Early life stress

The work to be described involved inducing behavioral stress in a cohort of laboratory rodent pups, and then watching the effects of that stress on behavior as the rats matured. The standard protocol to induce developmental behavioral stress is to apply an infant-mother separation schedule early in postnatal life. Typically, the animal is separated from its mother 3 hours a day for the first 10 days of its life. The experience of early life stress (ELS) results in a lifelong elevation of glucocorticoid secretion and a disruption in normal stress responses (a permanent and heightened endocrine reaction to externally supplied stress). The animal becomes hyperaroused, presenting an abnormal regulation of the HPA axis. This arousal induces broad behaviors associated with mood and cognitive disorders.

A number of important hormones regulate the HPA axis, including 2 hypothalamic secretagogues—corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). When a stressful experience is encountered, signals arise that increase the synthesis and release of pituitary CRH and AVP. There is a rich history linking CRH and AVP to cognitive and affective disorders; their receptors are the targets of a number of psychopharmacological medications. AVP is also expressed in a specific subset of neurons within the hypothalamic paraventricular nucleus.


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