Chronic stress during pregnancy prevents brain benefits of motherhood

A new study in animals shows that chronic stress during pregnancy prevents brain benefits of motherhood, a finding that researchers suggest could increase understanding of postpartum depression.

Rat mothers showed an increase in brain cell connections in regions associated with learning, memory and mood.

In contrast, the brains of mother rats that were stressed twice a day throughout pregnancy did not show this increase.

The researchers were specifically interested in dendritic spines – hair-like growths on brain cells that are used to exchange information with other neurons.

Previous animal studies conducted by lead author Benedetta Leuner of Ohio State University showed that an increase of dendritic spines in new mothers’ brains was associated with improved cognitive function on a task that requires behavioral flexibility – in essence, enabling more effective multitasking.

The dendritic spines increased by about 20 percent in these brain regions in new mothers, according to her findings.

The stress in this new study negated those brain benefits of motherhood, causing the stressed rats’ brains to match brain characteristics of animals that had no reproductive or maternal experience.

The stressed rats also had less physical interaction with their babies than did unstressed rats, a behaviour observed in human mothers who experience postpartum depression.

“Animal mothers in our research that are unstressed show an increase in the number of connections between neurons. Stressed mothers don’t,” said Leuner, assistant professor of psychology and neuroscience at Ohio State.

“We think that makes the stressed mothers more vulnerable. They don’t have the capacity for brain plasticity that the unstressed mothers do, and somehow that’s contributing to their susceptibility to depression.”


Previous research has suggested that there are a number of risk factors for postpartum depression, including hormone fluctuations, prior history of mental illness and environmental factors such as smoking or low socioeconomic status.

One of the strongest predictors, however, is chronic stress during pregnancy, so Leuner sought to create an animal model that could help explain brain changes linked to postpartum depression.

“It’s devastating not only for the mother, because it affects her well-being, but previous research also has shown that children of depressed mothers have impaired cognitive and social development, may have impaired physical development, and are more likely as adults to have depression or anxiety,” she said.

“A better understanding of postpartum depression is important to help the mother but also to prevent some of the damaging effects that this disorder can have on the child.”

The researchers exposed pregnant rats to stress twice a day by limiting their mobility on some days and on other days placing them in water. For three weeks after the rats gave birth, Leuner and colleagues monitored the rats.

The animals showed classic signs of the effects of stress, including lower than normal weight gain and enlarged adrenal glands, a sign of high stress-hormone production. The mothers stressed during pregnancy also gave birth to smaller pups.

“And they were not very good mothers,” Leuner said. After separation from pups for 30 minutes, unstressed mothers would gather up their babies, put them in the nest and nurse them. Stressed mother rats left the pups scattered around, wandered around the cage and fed the babies less frequently.

The stressed mother rats also exhibited more floating than unstressed rats in a water test; animals that float rather than swim are showing depressive-like symptoms.

“These findings in rats mimic some of the symptoms that are seen in women with postpartum depression,” Leuner said.

An examination of the animals’ brains showed that the rats exposed to chronic stress did not grow the additional dendritic spines in the hippocampus and prefrontal cortex that the unstressed mother rats did.

The stressed rats’ brains more closely resembled the brains of control rats that had never been mothers.

“We don’t yet know what the exact trigger is for the increase in spines in motherhood, but we know that the increase goes away with stress,” Leuner said.

She is continuing the work by investigating whether the beneficial effects of motherhood on cognitive functions are also blocked in mothers who are exposed to pregnancy stress as well as whether hormonal factors play a role.

Why a mother's immune system doesn’t reject the fetus

Researchers at NYU School of Medicine have made an important discovery that partially answers the long-standing question of why a mother’s immune system does not reject a developing fetus as foreign tissue.

“Our manuscript addresses a fundamental question in the fields of transplantation immunology and reproductive biology, namely, how do the fetus and placenta, which express antigens that are disparate from the mother, avoid being rejected by the maternal immune system during pregnancy?” explained lead investigator Adrian Erlebacher, MD, PhD, associate professor of pathology and a member of the NYU Cancer Institute at NYU Langone Medical Center. “What we found was completely unexpected at every level.”

The researchers discovered that embryo implantation sets off a process that ultimately turns off a key pathway required for the immune system to attack foreign bodies. As a result, immune cells are never recruited to the site of implantation and therefore cannot harm the developing fetus.

The study, funded by grants from the National Institutes of Health and the American Cancer Society, appears in the June 8 issue of Science.

A central feature of the body’s natural immune defense against transplanted foreign tissues and pathogens is the production of chemokines as a result of the local inflammatory response.

The chemokines recruit various kinds of immune cells, including activated T cells, which accumulate and attack the tissue or pathogen. The chemokine-mediated recruitment of activated T cells to sites of inflammation is an integral part of the immune response.

During pregnancy however, the foreign antigens of the developing fetus and the placenta come into direct contact with cells of the maternal immune system, but fail to evoke the typical tissue rejection response seen with organ transplants.

Several years ago, Erlebacher and his research team found that T cells, poised to attack the fetus as a foreign body, were somehow unable to perform their intended role.

The finding prompted the researchers to wonder if perhaps there was some sort of barrier preventing the T cells from reaching the fetus.

They turned their attention to studying the properties of the decidua, the specialized structure that encases the fetus and placenta, and there, in a mouse model, they found new answers.

The research team has discovered that the onset of pregnancy causes the genes that are responsible for recruiting immune cells to sites of inflammation to be turned off within the decidua. As a result of these changes, T cells are not able to accumulate inside the decidua and therefore do not attack the fetus and placenta.

Specifically, they revealed that the implantation of an embryo changes the packaging of certain chemokine genes in the nuclei of the developing decidua’s stromal cells.

The change in the DNA packaging permanently deactivates, or “silences,” the chemokine genes.

Consequently, the chemokines are not expressed and T cells are not recruited to the site of embryo implantation.

Also of note, the observed change in the DNA packaging was a so-called ‘epigenetic’ modification, meaning a modification that changes gene expression without the presence of a hereditable gene mutation.

“These findings give insight into mechanisms of fetal-maternal immune tolerance, as well as reveal the epigenetic modification of chemokine genes within tissue stromal cells as a modality for limiting the trafficking of activated T cells,” Dr. Erlebacher said.

“It turns out that the cells that typically secrete the chemoattractants to bring the T cells to sites of inflammation are inhibited from doing so in the context of the pregnant uterus. The decidua appears instead as a zone of relative immunological inactivity.”

Inappropriate regulation of this process, Dr. Erlebacher explained, could cause inflammation and the accumulation of immune cells at the maternal-fetal interface, which could lead to complications of human pregnancy, including preterm labor, spontaneous abortion and preeclampsia.

Erlebacher and his team will next look to see if these epigenetic modifications are also present within the human decidua, and whether the failure to generate them appropriately is associated with complications of human pregnancy.

He explained that the study’s findings also raise the possibility that the same kind of mechanism could enhance a tumor’s ability to survive inside its host. The findings could have implications for autoimmune diseases, organ transplantation and cancer, as well as pregnancy.

“This is a very exciting finding for us because it gives a satisfying explanation for why the fetus isn’t rejected during pregnancy, which is a fundamental question for the medical community with clear implications for human pregnancy,” Dr. Erlebacher said.

“It also reveals a new modality for controlling T cell trafficking in peripheral tissues that could provide insight into a myriad of other conditions and diseases.”