Stress May Keep Neurons Down

For days after a traumatic event, mice seem to exhibit decreased levels of a key neurotransmitter, according to a report in the current Nature. The finding may help explain how acute stress could lead to chronic depression, irritability, memory loss, and other symptoms reported by veterans of the Persian Gulf War.

The neurotransmitter acetylcholine is released by nerve cells in the brain when people or mice are under mild stress or concentrating on learning something new. To prevent the nerves from firing excessively, however, the neurotransmitter is quickly broken down by an enzyme called acetylcholinesterase (AChE).

To investigate the longer-term effects of higher-than-normal acetylcholine levels on the brain, Hermona Soreq of the Hebrew University of Jerusalem and her colleagues first induced high levels of acetylcholine by forcing 26 mice to swim, an activity stressful to mice. This initial increase in acetylcholine is known to trigger the production of more AChE. Indeed, AChE activity increased in the mice by two to three times in the 50 minutes following stress and was elevated for up to 80 hours, the researchers say. That lengthy inhibition would probably result in a net decline in acetylcholine levels over the long-term, the researchers suggest.

Soreq speculates that if similar long-term drops occur in humans, the lack of acetylcholine may cause cognitive impairment such as that seen in post-traumatic stress disorder and possibly Gulf War Syndrome. In the Gulf War, soldiers were both exposed to stress and given AChE inhibitors to prevent nerve gas damage, which might combine to create a brief burst of unusually high acetylcholine levels--and a long-term acetylcholine deficit, Soreq points out. AChE inhibitors have also been given to Alzheimer's patients in an attempt to boost acetylcholine levels and improve cognitive function, she says--but her research suggests that the long-term effect may be the opposite of that intended.

The research suggests a novel way that stress might have long-term effects on the brain, says Robert Sapolsky, a neuroscientist at Stanford University. However, the work was done only in mice. "I think it is a bit of a stretch to apply [the finding] to humans," cautions neuroendocrinologist Bruce McEwan of Rockefeller University in New York. The researchers haven't shown that the mechanism affects cognition years or even months after the initial stress, as it is purported to do in humans, he says.

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