September 20, 2017
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. Until now, however, 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 (domesticated) pigs because their brains develop similarly to humans,” said 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 sows 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 said.
The researchers looked at the piglets’ immune response to Escherichia 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; instead, their immune systems functioned normally. However, 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 that instead of going left every time, they have to turn according to SpongeBob and Mario,” Antonson said.
Again, the researchers were surprised to find that the piglets completed the task just fine, regardless of whether 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. Johnson said more research is needed to confirm their suspicion.
Like humans, pigs are highly social animals that usually prefer the company of others versus 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 strange 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 said. “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 were quick to note 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 said. “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 added, “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.”
The article, “Maternal Viral Infection during Pregnancy Elicits Antisocial Behavior in Neonatal Piglet Pffspring Independent of Postnatal Microglial Cell Activation,” wass published in Brain, Behavior & Immunity.
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