NIH-funded study finds greater brain changes in male offspring
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Ms. Christine Guilfoy: Welcome to the National Institutes of Health. I’m Christine Guilfoy, and this is Research Developments, a podcast of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the NICHD.
When researchers triggered an immune response in the wombs of pregnant mice, their offspring showed signs of brain damage that lasted well into adulthood. The animal’s hippocampus—that’s the part of the brain responsible for memory and spatial orientation—was smaller, and they had poor motor skills and behavioral issues, like hyperactivity.
This study was designed to mimic an infection or other condition that might cause inflammation in the uterus of a pregnant woman. This kind of inflammation in human mothers has been linked to preterm births.
With us now is Dr. Irina Burd, who conducted the study with her colleagues at Johns Hopkins University School of Medicine. Dr. Burd, thank you for joining us.
Dr. Irina Burd: Thank you, Ms. Guilfoy.
Ms. Guilfoy: Could you describe the experiment you did and tell us why you did it?
Dr. Burd: Certainly. So we employ a lipopolysaccharide, also called a LPS. The components of Gram-negative bacteria, and it simulates a most-common clinical scenario associated with preterm birth, that of intrauterine inflammation.
So we injected intrauterine in mice during gestation and we mimic preterm birth andthen we also investigate what happens with pups or fetuses, and going long-term, how that affects fetal brain-development and neurobehavioral function long-term, before they wean from mom and well into adulthood.
Ms. Guilfoy: Okay. What is inflammation, and what could cause inflammation inside a woman’s uterus during pregnancy?
Dr. Burd: Well, in addition to infections that are associated with preterm birth, there are also other causes, immune causes, because of different exposures outside of infection. So, different immune reactions stimulate mom’s immune system, and that could also affect the fetus.
Ms. Guilfoy: Good. Is inflammation during pregnancy common?
Dr. Burd: Infection and inflammation do occur, and we connect it to preterm birth. Preterm birth now is about 11-plus percent in our population. And a fair amount of inflammation and infection happens with earlier gestations. The earlier gestation, the higher there is an association with infection. Others are associated specifically with inflammation within the mom’s uterus. That means that there are different immune cells that are activated within mom that produce specific mediators called cytokines. Those cytokines may impact placenta, which is a communication between mom and the baby, and then going further, affecting fetus, short-term and long-term.
Ms. Guilfoy: So you’ve done this experiment. What kinds of changes did you see in the mouse pups exposed to inflammation in the womb?
Dr. Burd: So, those pups that survived and were not born early, and continued to go with inflammation to term, and delivered and survived—those originally had problems with motor skills.
We found with imaging their brains with MRI [magnetic resonance imaging]—in, so to speak, adolescent period—we found a lot of edema, or water in the brain. However, those changes were then decreased, and actually the motor function somewhat normalized, and the edema decreased in the brain.
Long-term in the adulthood and later periods of life development, what we find is that a specific portion of the brain, hippocampus, became smaller. That was found also with MRI, with imaging.
What we found specifically what was happening with the hippocampus is that neurons—a major cell type in the brain—decreased in quantity. And that was affecting males more than females. Furthermore, we saw that immune cells were changed in the brain. We saw the infiltrating immune cells were increased, especially in males, in the brain.
That was being an effect of in-uterine inflammation exposure going far, far into adulthood. These results are concerning. We saw behavioral phenotype, also. These mice were hyperactive and having some spatial and memory issues going long-term. But no longer motor.
Ms. Guilfoy: Interesting. Can you just tell us a little bit about the hippocampus? How is it significant?
Dr. Burd: Hippocampus plays a very big part in memory and spatial learning. One would understand, if there is a decreased number of neurons that are firing, and if there are immune cells that are also secreting some mediators, inflammatory mediators, even impacting the small population of neurons, there might be some changes in synapse and some changes in neuronal communication not only between them, but with other cells. That may lead to the consequences in neurobehavioral development and in their behavior.
Ms. Guilfoy: Interesting. Do you know why these changes occur more in male mice than in females?
Dr. Burd: That is a great question. That’s something that we are currently investigating. We believe and speculate that it could be a difference in certain kinds of receptors, hormonal receptors, and may not be only attributable to hormonal levels—different hormonal levels such as estrogen in males and females and their protective role—but also a role of hormonal receptors in that.
Ms. Guilfoy: Great. For your research, what do you think the takeaway message is? Might your findings have implications for human infants whose mothers have an infection or inflammation during pregnancy?
Dr. Burd: That is a fantastic question. You know, these experiments are something we cannot conduct in humans, so we use mouse model in this case to simulate something that occurs in utero and then follow the offspring well into adulthood.
Understanding there might be some immune changes in brains of ex-preterm offspring gives us an opportunity to understand some biological processes that occur in ex-preterm children. So understanding those mechanisms, we then could go ahead and create some therapies that would be specifically targeted to decreasing these adverse perinatal outcomes and adverse adult outcomes going into adulthood while babies still in utero.
Ms. Guilfoy: Dr. Burd, thank you for speaking with us about your research.
Dr. Burd: Thank you very much. It was a pleasure being with you.
About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute's website at http://www.nichd.nih.gov/.