A new study, done with mice and published in the Federation of the American Societies of Experimental Biology Journal, suggests that miscommunication between the immune system and brain may be to blame for extended sickness symptoms and other cognitive disorders in elderly people and animals with an infection.

"In the course of our other studies on inflammation and aging, we repeatedly saw that old animals suffered an exaggerated inflammatory response in the brain compared to younger adults when their peripheral immune system was experimentally activated," said Rodney W. Johnson, a professor of integrative immunology and behavior in the department of animal sciences. "Knowing the role of brain inflammation in behavioral deficits and neurodegenerative diseases, we felt this could be important, especially because immunity is often suppressed in the elderly, making them more susceptible to infections."

Johnson and his colleagues compared behavior in young adult and aged mice that were made temporarily ill by exposure to lipopolysaccharide (LPS), a molecule present on E. coli and other gram-negative bacteria that strongly activates the immune system.

"When a person or pet develops an infection, their behavior changes: They stop eating; they become lethargic; they have reduced cognitive abilities," Johnson said.

How do you know a mouse feels sick? Like unhealthy humans, mice show decreased appetite, weight loss and less social interaction, said Johnson, who likened his own lack of interest in getting up off the couch to greet visitors when he is sick to a mouse's lack of curiosity about new cage mates when it is sick.

LPS injections caused older mice to stop eating for a longer amount of time, lose more weight and show less social behavior than younger mice.

"As expected, young adults showed signs of improvement eight hours after LPS treatment and fully recovered by the next day, but the aged animals still were 50 to 60 percent depressed," Johnson said. "We've completed follow-up studies that show aged animals are still depressed three to four days later."

Johnson and colleagues also studied how aging affects the response of microglial cells -- key immune cells in the brain -- during a peripheral infection.

It is important that the peripheral immune system inform the brain of an infection, Johnson said. "The peripheral immune system signals microglia to secrete inflammatory cytokines that cause behavioral changes."

In many ways microglia act as the Red Cross, he added. They can converge upon sites of injury in the brain to scour away neuronal debris and begin repairs, and during a peripheral infection the cytokines they produce cause behavioral changes that support convalescence and healing. However, if microglia overreact, the result can be pathological.

Johnson's study, which was published in August, revealed that older animals had an exaggerated inflammatory cytokine response in the brain compared with young animals when the peripheral immune system was stimulated with LPS.

"In the old animals, the message of a peripheral infection is conveyed to the brain, but the cells in the brain have an exaggerated response and produce more inflammatory cytokines than what is typical," Johnson said. "The exaggerated response can lead to a more intense and longer-lasting sickness behavior syndrome."

To study the phenomenon further, Johnson and colleagues examined the expression of more than 39,000 genes in the brain using microarray technology. The approach was helpful, because the gene expression pattern indicated brain inflammation emerged during aging. The emergence of a mild but chronic neuroinflammatory state appears to have a priming effect on microglial cells, Johnson said.

"Chronic neurodegenerative diseases prime microglia so that when an individual develops a peripheral infection, these cells overreact and exacerbate neurodegenerative disease," he said. "Peripheral infection is now recognized as a significant risk factor for relapse for multiple sclerosis, for example, and peripheral infection is a risk factor for delirium in Alzheimer's patients."

The research suggests that normal aging also may prime microglia, Johnson said.

The six co-authors with Johnson on the study were postdoctoral researcher Jonathan P. Godbout; research associate Jing Chen; graduate students Jayne Abraham, Amy F. Richwine and Brian M. Berg; and Keith W. Kelley, a professor of integrative immunology and behavior in the department of animal sciences.

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