How Stress Affects the Brain May Depend on Age

by Kayt Sukel

June 12, 2009

Researchers have long known that chronic stress can harm the brain. In particular, hormones called glucocorticoids, released by the adrenal gland in response to stress, have been linked to depression, reduced hippocampal volume and learning and memory deficits in some people. But new research suggests chronic stress alone does not cause the damage—instead, the stage of life in which one experiences that stress may be the key to understanding its potential lasting and detrimental effects.

The stress response

When human beings are stressed, their bodies unleash a cascade of molecular and hormonal events throughout the body and brain.

“When you have a stress, you produce hormones that turn on and off different pathways in the body to help you survive,” says Jonathan Seckl, a clinical scientist at the Queen's Medical Research Institute in Edinburgh, Scotland. Within a few seconds, the body releases adrenaline, the precursor to the so-called “fight or flight” response. And within a few minutes, glucocorticoids enter the bloodstream.

“Glucocorticoids get you poised and ready to make that fight or flight. It helps to produce extra fuel so you have more sugar and fat in the bloodstream. It raises your blood pressure. It makes you feel good about yourself,” says Seckl. “But it also turns off all the things you don’t need: the inflammatory response, since it’s painful and could slow you down. Reproductive processes and digestion are also turned off. It turns off fine learning in the hippocampus because it’s not necessary when you are being challenged. Really, it’s all about restoring, adapting and helping you survive a challenge.”

But this speedy system was not designed to handle chronic stress. In fact, scientists have noted that when large amounts of glucocorticoids are repeatedly and chronically released into the system, these hormones seem to damage neurons.

“If you look into the literature, there are a lot of indications that glucocorticoids are detrimental rather than protective in the brain,” says Freddy Jeanneteau, a researcher at the Skirball Institute of Biomolecular Medicine at New York University. But how and why they show this detrimental effect—in particular, why some people seem so susceptible to the negative effects of stress and others do not—have been difficult to determine.

In a review that appeared in the June 2009 issue of Nature Reviews Neuroscience, Sonia Lupien, director of the Centre for Studies on Human Stress at the University of Montreal, and her colleagues suggest that the timing of chronic stress in an individual’s life may be important.

“It was first postulated that chronic activation of these hormones does something bad to the cells,” says Lupien. “Not necessarily killing them, but injuring them and causing an atrophy of the structures that eventually led to problems with memory and emotional regulation—the same kind of problems you see in disorders like post-traumatic stress disorder  and depression. But that is not the whole story. The missing variable in the equation may just be time.”

Stress and the life cycle

People may be more vulnerable to damage during chronic stress during different stages in life, a model that Lupien calls “the life cycle model of stress.” She argues that the particular brain area that is developing at a time of chronic stress may determine what kind of damage is done, not necessarily neuron death but perhaps a slowdown or even a stoppage of normal development.

“If a child is exposed to adverse experiences between birth and 2 years of age, that’s when the hippocampus is developing and it may delay the development of that, giving someone a smaller hippocampal volume at adulthood,” says Lupien. “The frontal lobe starts developing at 8 years of age and terminates around 14 years of age, so again, any kind of adversity could have an impact on how the frontal lobe develops. This kind of vulnerability model may explain all the discrepancies we see on the effects of chronic stress.”

Seckl, who studies the effects of maternal stress on offspring, an emerging field called developmental programming, agrees that the idea has merit. He has found that early-life challenges in humans, both before and after birth, can lead to persistent negative effects in the brain.

“You can begin to see this pattern, these windows of vulnerability—around conception, during the last third of gestation, in the early years of life and then again at puberty and old age,” he says. “In these different ages of vulnerability, I suspect the mechanisms of how stress works on the brain are quite different.”

He, like Lupien, thinks that the life cycle model of stress could help direct future research about the negative consequences of chronic stress. But as a clinician, he cautions that we still have much to learn.

“For every great idea we see in a rat or in a Petri dish, very few end up making a squat of difference in how we treat human beings,” says Seckl. “But this, at least, is a hypothesis that fits very nicely, very attractively, with our observations in human biology.”


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