Study First to Show That Substance Acting in the Brain, and not Adrenal Gland Stress Hormones, Triggers Brain Cell Death and Memory Losses

Memory loss and impaired cognitive abilities brought about by such stresses as neglect and abuse during infancy may be triggered by a hormone produced in the brain, a UC Irvine College of Medicine study has found.

The study, conducted in rats, is believed to be the first to show that the brain hormone--and not high levels of steroid stress hormones produced by the body's adrenal glands--is responsible for the impairment, and may lead to new types of treatments for stress-related injury to the central nervous system. The research study appears in the July 10 issue of the Proceedings of the National Academy of Sciences.

UCI post-graduate researcher Kristen Brunson, Dr. Tallie Z. Baram, the Danette D. Shepard Chair in Neurological Sciences, and colleagues found that injections of a nervous system hormone called CRH (corticotropin-releasing hormone) mimicked early life stress in infant rats. The CRH, which regulates nervous system responses to stress, resulted in the death of cells in an area of the brain that controls memory.

The researchers found that increases in cell death required only the CRH, and not increases in levels of so-called steroid "stress hormones" that are produced in the adrenal glands.

"While it's been known that early life stresses can lead to later cognitive impairment, the mechanism for how this occurs hasn't been well-known," Baram said. "Steroid hormones, produced by the adrenal glands at high levels in response to stress, were assumed to be responsible for this impairment. But we show that CRH actually triggers cell death that leads to impaired memory. If further research can find a way to block the actions of CRH on the brain, then it's possible to develop new, more effective ways to prevent cognitive impairment later in life."

The researchers found that rats injected with CRH during infancy (at about 2 weeks of age) were later less able to perform memory tests than rats that did not receive CRH. In addition, those rats with CRH-induced stress showed a significant loss of cells in an area of the brain called the hippocampus, which is responsible for handling memory.

Nerve cells called pyramidal cells in the hippocampus also contain a large number of CRH receptors, which were activated by the CRH injections; the prolonged activation of these receptors promoted nerve-cell injury and therefore memory impairment. Although the CRH stress inducement was given only once early in life, cell death in the hippocampus and memory problems continued to progress and worsened with age.

At the same time, the researchers noted that the rats that were experimentally prevented from producing adrenal steroid hormones--which often reach high levels during stressful events--still showed the memory loss and cell death produced by CRH given in infancy. In addition, the receptors for many of the steroid hormones were not in high numbers in the hippocampus where cells were killed, so it was less likely that they were responsible for the memory impairment seen by the researchers.

"The hippocampus cell loss and memory dysfunction seen here was brought about by the CRH, and not by steroid stress hormones," Baram said. "Since CRH is a crucial regulator of brain function and integrity during stressful events in early life, then it could be a target for developing treatments for infants who have experienced neglect and abuse. In addition, because cell death and memory loss progress with age and seem to be related to increases of CRH in the hippocampus, this opens the possibility of treatment even for adults who are showing signs of impairment resulting from early life stress."

The researchers are now looking at how CRH may be triggered by stressful events in early life, and hope to map out how it regulates cell function in the hippocampus.

Brunson and Baram's colleagues in the study included Mariam Eghbal-Ahmadi, Roland Bender and Yuncai Chen, all of UCI. The research was supported by grants from the National Institute of Neurological Disorders and Stroke.

Contact:
Andrew Porterfield
(949) 824.3969
amporter@uci.edu

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