Research confirms how early-life events shape later physiology

Underscoring the value of good prenatal care, new research suggests that early infection may create a cognitive vulnerability that appears later during stress on the immune system.

Researchers at the University of Colorado at Boulder have reported that rats who experienced a one-time infection as newborns didn’t learn as well as adult rats who were not infected as pups, after their immunity was challenged. The research is in February’s Behavioral Neuroscience, published by the American Psychological Association (APA).

The findings fit into a growing body of evidence that even a one-time infection can potentially permanently change physiological systems, a phenomenon called “perinatal programming.”

Understanding how infection in newborns can disrupt memory in immune-challenged adults may help scientists to understand how exposure to germs or environmental stressors before or just after birth may foster susceptibility to neuropsychiatric and neurodegenerative diseases. For example, prenatal viral infection has been implicated in schizophrenia, autism and cerebral palsy; bacterial infection is a risk factor for Parkinson’s disease. Up to 20 percent of pregnancies have complications involving infections of the uterus and its contents, a number that will rise as more children are born premature.

In the study, a team led by Staci Bilbo, PhD, injected a group of 49 rat pups on postnatal Day 4 either with the common intestinal bacteria E. coli, with salt water, or with nothing. In rats, Day 4 is like the third trimester in human pregnancies, a time when the brain grows significantly.

Once the pups grew up, Bilbo and her colleagues tested the adults’ memory about 60 days after birth. To test memory, each rat was allowed to explore a novel experimental chamber for several minutes on the first day. On the second day, each rat was placed back into the chamber and was shocked for two seconds and then put back in its home cage. After 24 hours, the researchers again put each rat in the experimental chamber and recorded whether the rats froze -- was immobilized by fear -- or stayed active.

All groups of rats froze the same amount, indicating they had learned. However, immediately after they explored the experimental chamber on the first day, a second group of these rats was injected with a low dose of lipopolysaccharide (LPS), a bacterial component that causes flu-like symptoms,. This time, the rats infected with E. coli as newborns froze 70 percent less often than the rats who’d been injected with salt water as newborns. In other words, under immune stress, the early-infected rats learned to fear the place where they’d been shocked significantly less often than rats who had not been infected as pups. They simply didn’t remember it was dangerous.

In a second experiment, the researchers injected 32 different neonatally infected and control adult rats with salt water or with bacterial LPS. Two hours later, they euthenized the rats and checked brain markers of the immune response. Because it spurs an immune response without live bacteria, LPS helps to reveal how the immune system works on its own, without the complication of side effects.

The team found that E. coli-infected pups later injected with LPS had significantly lower concentrations of cytokines called interleukins than control pups (they tested 32 PUPS in all). Immune cells release these cytokines, or certain protein molecules, in response to germs. Prior research had suggested that higher IL-1BETA in the brain’s hippocampus, a key memory area, disrupts the consolidation of memories following a learning experience. Thus it appears that there may be an optimal range for IL-1BETA, with either too much or too little inhibiting memory storage. Bilbo says, “The take-home message is that immune responses in a healthy brain are tightly regulated and controlled; any alteration in these responses is likely to cause problems.”

She adds that, “Memory impairment in wild animals would undoubtedly have severe implications for survival, for example remembering nest sites, food sites and predator vicinities, as well as for fitness, for example remembering territories and potential mate locations.”

Bilbo stresses that adults rats who were not infected as pups do not suffer memory impairment as the result of adult infection, and those who were infected are completely normal until they get that second immune system challenge. The relatively uncommon one-two punch seems to cause the problem, although researchers don’t know how long it lasts. Still, says Bilbo, “This may go far to explain some of the individual variability in disease susceptibility, other than genetic variation, in animals in the wild and perhaps humans.”

The authors conclude that neonatal infection can create later problems by changing how well the body can respond to future immune challenges. Those changes affect how well memories are stored. The early alterationS may be to the basic architecture of glial cells called astrocytes within the hippocampus, which in turn help the central nervous system respond to injury or infection. Because astrocytes also help to determine the number and connectivity of nervous system synapses early in life, especially the first week after birth in rats, they may be involved in the ability to learn and remember, possibly via some link (says Bilbo) to cytokine IL-1BETA production.

Article: “Neonatal Infection Induces Memory Impairments Following an Immune Challenge in Adulthood,” Staci D. Bilbo, PhD, Lindsay H. Levkoff, BA, John H. Mahoney, MA, Linda R. Watkins, PhD, Jerry W. Rudy, PhD, and Steven F. Maier, PhD, University of Colorado at Boulder; Behavioral Neuroscience, Vol. 119, No. 1.

Full text of the article is available from the APA Public Affairs Office and at http://www.apa.org/releases/earlylife_article.pdf

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