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Environmental Factor, April 2012

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Early-life infection may lead to adult memory loss

By Robin Arnette

A scan of a brain
Staci Bilbo, Ph.D.

Bilbo is an assistant professor in the department of psychology and neuroscience at Duke University. She presented a talk titled “Programming Innate Immunity: Implications for Brain Behavior Throughout the Lifespan.”. (Photo courtesy of Steve McCaw)

Lance, a 30-year-old law student, is studying for the bar exam. As he sifts through volumes of cases in a secluded corner of the law library, he’s a little anxious. It will be his third attempt to pass the test. Lance works as hard as his classmates, but he just can’t seem to hold all of the pertinent legal details in his head.

According to research performed in rodents, Lance’s memory problems may be the result of an infection he had early in life. NIEHS grantee Staci Bilbo, Ph.D., studies the influence of the neonatal environment on the immune system and its impact on the adult brain. During her talk March 8 at NIEHS, Bilbo said rat pups that suffered bacterial infections in utero, and experienced a second immune challenge later in life, displayed severe memory impairments as mature rats.

Bilbo explained that this early-life infection doesn’t just impact memory. She argued that it is a vulnerability factor that primes animals, particularly humans, to exhibit any number of disorders, such as multiple sclerosis, depression, and even addiction.

Learning and the immune response

Bilbo said microglia, one type of immune cell in the brain, is a major player in later-life brain function and behavior. Microglia cells produce interleukin-1beta (IL-1beta), a signaling molecule that is critical for normal brain development. To understand the role of microglia in later-life effects, Bilbo and her team exposed postnatal day four rats — equivalent to a preterm human infant in the second or third trimester — to E. coli, a common infection in developing fetuses. When the rats reached adulthood, Bilbo examined their learning ability using a standard conditioning program.

On the first day, the rats were placed into a new environment and allowed to explore. They were then separated into two groups. The control group received an injection of saline, while the other received bacterial lipopolysaccharide (LPS), a substance meant to stimulate the immune system. On day two, both sets of rats were placed in the same surroundings as the previous day and were given a mild foot shock. When placed in the same terrain on day three, the saline-treated rats had learned that a shock was imminent and froze in their tracks. Members of the LPS group, however, didn’t remember the shock and explored their environment as if nothing had ever happened.

“The neonatal exposure to E. coli allowed the brain to upregulate all of the genes it needed to respond to the infection,” Bilbo said. “But, if it had LPS on top of that, the microglia in the brain produced too much IL-1beta, allowing the rat to over respond when it encountered a second immune challenge.”

A mother’s love

Other scientists have shown that mother rats impact the brains of their offspring through licking, grooming, and nursing. The researchers mimicked this behavior, by separating the moms from their pups for 15 minutes a day and then placing them back with their babies. As a result, the moms increased their amount of care, and the pups grew up to have enhanced learning capabilities and decreased microglial activities in response to LPS.

Bilbo wondered if she could prevent the effect of early infection by augmenting rodent maternal care. She used the same separation protocol on early-infected pups, and found she could prevent microglial sensitization.

“The extra licking blocked an over response by the microglia, so we believe the entire process is epigenetically induced,” Bilbo remarked.

Huiming Gao, M.D., Ph.D., a postdoctoral fellow in the NIEHS Laboratory of Toxicology and Pharmacology, took copious notes during the seminar and said, "Bilbo's results not only help us better understand brain and immune system development, but also neurodegenerative diseases and mental illnesses."

It’s unclear whether attorney-to-be Lance suffered an infection as a developing fetus or if he had a nurturing mother. Nonetheless, Bilbo’s research offers an intriguing explanation for his poor memory and a new direction in understanding the influence of the immune system.

Michael Resnick, Ph.D. and Staci Bilbo, Ph.D.

After the lecture, NIEHS Laboratory of Molecular Genetics researcher Michael Resnick, Ph.D., left, asked Bilbo how her work relates to studies being done on post-traumatic stress disorder (PTSD) in troops returning from Iraq and Afghanistan. (Photo courtesy of Steve McCaw)

Staci Bilbo, Ph.D. and Jau-Shyong Hong, Ph.D.

NIEHS Laboratory of Toxicology and Pharmacology scientist Jau-Shyong Hong, Ph.D., right, who examines microglial response to brain injury, invited Bilbo to the Institute to talk about her work. (Photo courtesy of Steve McCaw)

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