A new study has helped to uncover some key mechanisms of brain development in mice fetuses, with possible implications for human fetus development.

Researchers at the Yale School of Medicine found changes in fetal brain cells of mice born to mothers with features of diabetes, indicating possible defects in their neural development. The findings, published in the journal PNAS on Sept. 17, help explain why babies of pregnant mothers who are obese or exhibit other metabolic disorders have higher risks of developing brain disorders.

“We confirmed, in rodents, that metabolic disorders can delay brain development and that the effect seems to involve cortical stem cells,” said Brian Rash, a neuroscientist at Yale and the lead author of the study.

Specifically, the researchers identified that a particular relationship between calcium and mitochondria is needed to promote normal stem cell development. Stem cells in the brain develop into different neurons for proper brain formation. Changes caused by obesity and other diabetic symptoms in their mothers may ultimately alter the brain development of the fetus.

The study found that by raising glucose levels in the mice models — mimicking the concentrations found in a diabetic person — the interrelationship between calcium activity and mitochondrial function in the brain was impaired.

After breeding mice with obesity and high blood sugar, the researchers found that the mice’s offspring’s brains were developmentally delayed. They then used fluorescent labeling to observe the calcium activity and mitochondrial function in the offsprings’ brains.

Since the study was conducted in mice models, Rash advised readers of the study to take the findings with a grain of salt before applying them to humans. Mice have different metabolic levels, and their brain structures vary in size and function. However, certain aspects of human and mouse brains, including stem cell functioning, are similar, he added.

Rash noted that more work needs to be done to establish the extent to which the results could be applicable to humans.

“In terms of the greater public, metabolic disorders have been reported previously to be associated with higher risks. It would make sense to urge [pregnant mothers] to control gestational diabetes with insulin and other available methods,” Rash said.

In brain formation, cells need to migrate properly at the correct time, and factors such as glucose levels affect the proper functioning of these processes. Even small changes due to changes in metabolism can be significant in neural development, according to Pasko Rakic, a professor of neuroscience and neurology and the senior author of the study.

“Environment can change genetics,”  Rakic said. “What this paper shows is that metabolic changes due to changes of molecules in the bloodstream of women [an environmental factor] could affect development of the brain in early stages.”

Rash said that future studies will continue to focus on the fetal brain and the effect of maternal obesity on cortical development. For example, researchers do not yet know how hormones and other molecules involved in metabolic disorders affect cortical stem cells. In addition, he said, their research team may study synonymous processes in other animal systems.

Casper Scott, an obstetrician-gynecologist affiliated with Yale New Haven Hospital who was not involved in the study, said that pregnant mothers who have diabetes do suffer from increased risks in deliveries, since their babies are generally larger at birth. Gestational diabetes has not yet been clearly linked to changes in cortical development, he said, and a higher risk of neural development disorders in obese mothers has not been commonly observed.

About 40 percent of women in the U.S. are obese or extremely obese, according to the National Institutes of Health.

Katherine Du | katherine.du@yale.edu