Summary: Recent studies have reported on a link between maternal infection and subsequent higher risk of autism in offspring. A new study from ACES reports similar findings in pigs. Mother pigs who develop infection during pregnancy have a higher risk of their piglets developing antisocial problems.
Source: ACES/University of Illinois.
When a pregnant woman gets a bad case of the flu, her immune system may react in a way that affects her baby’s developing brain, which could lead to behavioral disorders like autism in the child or schizophrenia in the young adult. The link is well established in humans, which is one reason it’s standard practice to get a flu shot during pregnancy. But until now, the majority of studies testing the underlying causes have been done with rodents, including two that were released just last week.
Some scientists think that immune cells called microglia are affected in the fetal brain when the mother’s body starts fighting an infection. Microglia play an important role in normal fetal brain development, but if their activity is altered, they could attack healthy synapses or prevent new neurons from forming. And that could increase the risk of learning or behavioral disorders after birth.
“This hypothesis has been supported by research in rodents, but brain development and morphology in rodents are quite different than in humans. The goal in our study was to test this hypothesis in domestic pigs because their brains develop similarly to humans,” says Rodney Johnson, professor of integrative immunology and behavior in the Department of Animal Sciences at the University of Illinois.
Adrienne Antonson, a doctoral student working with Johnson, and lead author of the new study, gave pregnant pigs a virus that causes flu-like symptoms and then compared piglets from those mothers with piglets from mothers that were not infected during pregnancy. “We wanted to understand how the mother’s immune response impacted the piglets’ behavior and their own immune responses to later infections,” she says.
The researchers looked at the piglets’ immune response to E. coli lipopolysaccharide (LPS) – a molecule given to mimic a bacterial infection. They expected piglets from infected mothers to have an exaggerated immune response to LPS, but that’s not what happened. Their immune systems functioned normally. But that was only the first surprise.
Because people with autism and schizophrenia often struggle with learning difficulties and social scenarios, the researchers wanted to assess those abilities in the piglets as well. In a spatial learning task, piglets had to find their way to a chocolate milk reward using visual cues – in this case, SpongeBob SquarePants and Mario Kart posters placed in different spots around a simple maze.
“They learn to locate their reward whether it’s next to the SpongeBob poster or Mario Kart. Instead of learning to come out of their start box and just turn left, we alternate what side the reward is on. So they have to learn instead of going left every time, they have to turn according to SpongeBob and Mario,” Antonson says.
Again, the researchers were surprised to find that the piglets completed the task just fine whether or not their mothers had been infected during pregnancy. The result suggested that the hippocampus, the brain region responsible for spatial learning, was largely unaffected in piglets from infected mothers. But Johnson says more research is needed to confirm their suspicion.
Like humans, pigs are highly social animals that usually prefer the company of others to isolation. Individuals with autism and schizophrenia, on the other hand, tend to isolate in social situations. So, in the last test, researchers gave piglets the choice of meeting a stranger or spending time alone.
Piglets were placed in an arena with two crates separated by an empty space. When a stranger piglet was placed in one of the crates, the researchers watched to see if the study piglets chose to visit the stranger or not. After about 10 minutes, another stranger was added to the second crate. If the piglet spent significantly more time with the new stranger, it would have been showing a preference for “social novelty,” a common behavior in social species.
In this test, an important effect of maternal immune activation was revealed. Unlike piglets from healthy mothers, piglets whose mothers had infections during pregnancy stayed away from the strangers.
Following the behavioral tests, the researchers examined microglial cells to see if there were differences between piglets whose mothers had an infection during pregnancy and those that came from healthy mothers.
“I think the most important finding is that the antisocial behavior caused by maternal immune activation was not accompanied by a change in microglial cell activity after birth,” Johnson says. “If microglial cells are contributing to antisocial behavior, those changes are likely happening in utero. It’s possible microglia become activated during maternal immune activation, alter fetal brain development, and then return to normal before birth.”
Antonson’s next project is to look at what’s happening in the brains of fetal pigs during the maternal infection, to try to pinpoint changes in real time.
The researchers are quick to point out that getting an infection during pregnancy does not guarantee the occurrence of neurodevelopmental problems in children. Instead, it’s all about levels of risk.
“We all know we’re supposed to wear seat belts,” Johnson says. “If I don’t put on my seat belt when I go home tonight, does that guarantee I’m going to die in a crash? Of course not. It just increases the likelihood, should an entire sequence of unfortunate events occur. It’s not a guarantee. It just adds risk.”
Antonson adds, “You have to mount a pretty significant immune response to see something like this. If it’s a less severe infection, it’s likely not going to trigger the same responses.”
Additional authors of the study include Emily Radlowski, Marcus Lawson, and Jennifer Rytych, all from U of I.
Funding: The project was supported by a “Dual Purpose with Dual Benefit” grant program administered through the National Institutes of Health and the U.S. Department of Agriculture.
Source: Rodney Johnson – ACES/University of Illinois
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Full open access research for “Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation” by Antonson AM, Radlowski EC, Lawson MA, Rytych JL, and Johnson RW in Brain, Behavior, and Immunity. Published online September 17 2017 doi:10.1016/j.bbi.2016.09.019
Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation
Maternal infection during pregnancy increases risk for neurodevelopmental disorders and reduced stress resilience in offspring, but the mechanisms are not fully understood. We hypothesized that piglets born from gilts infected with a respiratory virus during late gestation would exhibit aberrant microglia activity, cognitive deficits and reduced sociability. Pregnant gilts were inoculated with porcine reproductive and respiratory syndrome virus (PRRSV; 5 × 105 TCID50 of live PRRSV) or saline at gestational day 76. Gilts infected with PRRSV exhibited fever (p < 0.01) and reduced appetite (p < 0.001) for 2 weeks post-inoculation and were PRRSV-positive at parturition. Piglets born from infected and control gilts were weaned at postnatal day (PD) 1 and assigned to two groups. Group 1 was challenged with lipopolysaccharide (LPS, 5 μg/kg body weight i.p.) or saline on PD 14 and tissues were collected. Group 2 was tested in a T-maze task to assess spatial learning and in a 3-chamber arena with unfamiliar conspecifics to assess social behavior from PD 14–27. Microglia (CD11b+ CD45low) isolated from Group 2 piglets at PD 28 were challenged ex vivo with LPS; a subset of cells was analyzed for MHCII expression. Maternal infection did not affect offspring circulating TNFα, IL-10, or cortisol levels basally or 4 h post-LPS challenge. While performance in the T-maze task was not affected by maternal infection, both sociability and preference for social novelty were decreased in piglets from infected gilts. There was no effect of maternal infection on microglial MHCII expression or LPS-induced cytokine production. Taken together, these results suggest the reduced social behavior elicited by maternal infection is not due to aberrant microglia activity postnatally.
“Maternal viral infection during pregnancy elicits anti-social behavior in neonatal piglet offspring independent of postnatal microglial cell activation” by Antonson AM, Radlowski EC, Lawson MA, Rytych JL, and Johnson RW in Brain, Behavior, and Immunity. Published online September 17 2017 doi:10.1016/j.bbi.2016.09.019