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Early-Life Stress May Hurt Brain in Long Run

Rat study implicates new hormone in progressive damage

MONDAY, July 9, 2001 (HealthDayNews) -- Infant lab rats exposed to high levels of a stress-related hormone show signs of persistent and progressive brain damage, new research shows.

The finding offers a new explanation for the link between stress hormones and brain damage, which previously had focused on a different group of compounds. Experts say the finding could one day lead to new treatments for victims of child abuse, neglect and other early-life traumas, and possibly anxiety and depression as well. The study is reported in the July 17 issue of the Proceedings of the National Academy of Sciences.

The discovery centers on the hippocampus, a brain region important in learning and memory. Brain imaging studies of people suffering chronic depression and post-traumatic stress disorder have shown markedly smaller cell volume in the region. The shrinkage may be reversible by treatment.

The majority of neuroscientists have long held that hormones called glucocorticoids, secreted by the adrenal glands, caused the stress-related damage in the hippocampus. But the latest work implicates corticotropin-releasing hormone (CRH) as perhaps the more important player.

During acute stress, for instance, when an animal suddenly faces a menacing predator, CRH signals the brain's pituitary gland to release a flood of other hormones that trigger the "fight-or-flight" response, boosting the heart rate, upping blood pressure and otherwise preparing the body for action. Inside the brain, CRH facilitates communication between neurons in the hippocampus to better foster memories of stressful events.

In the new study, a team led by Dr. Tallie Z. Baram, a neuroscientist at the University of California at Irvine, gave a single dose of CRH to a dozen newborn male rats. After a year, the animals had between 10 percent and 18 percent fewer nerve cells in three areas of the hippocampus compared with a control group of untreated rodents.

The chemically-stressed rats also performed worse on tests of memory and learning -- like remembering the location of a hidden platform and recognizing objects -- than the untreated rats. Their deficits persisted, even worsened with age.

"The brain is designed very well to deal with acute stress, but we're not designed very well to deal with chronic stress," Baram says.

The researchers now are trying to determine if the same chemical process occurs during real-life trauma in rats, such as when a very young animal is separated from its mother.

Baram's group also is exploring how CRH kills brain cells. High doses of the hormone can kill individual neurons quickly, Baram says. "But we know that CRH alone does not kill brain cells. It does so working together with the normal mechanisms of brain communication. Excessive amounts of CRH may convert normal communication to abnormally excessive" communication.

Paul Plotsky, a psychiatrist at Emory University in Atlanta and an expert in CRH, says the "exceedingly interesting" findings should help recast the thinking about stress-related changes in the hippocampus.

"The hippocampus is known to be densely populated with glucocorticoid receptors, but the region with the most damage [from stress] doesn't have them, and that's been ignored," Plotsky says. "Things other than glucocorticoids may be mediating this, and CRH is a very good candidate."

Drug companies now are working on compounds to block CRH to counteract anxiety and depression, Plotsky says. "We've shown in preliminary studies that if you subject developing rats to adverse environments, but treat them with [CRH blockers], you can partly reverse or prevent the longer term effects" of the trauma, he says.

What To Do: For ways to fight the harmful effects of stress, visit the American Psychological Association. For more about neuroscience, check Neuroguide.

SOURCES: Interviews with Tallie Z. Baram, M.D., Ph.D., professor of anatomy-neurobiology and pediatrics, University of California, Irvine, and Paul Plotsky, Ph.D., professor of psychiatry, Emory University, Atlanta; July 17, 2001, Proceedings of the National Academy of Sciences
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