Prenatal Stress Linked to Worse MS Outcomes in Adulthood in Mouse Study

Exposure to stress before birth can worsen the clinical symptoms of multiple sclerosis (MS) during adulthood, a study in a mouse model of MS suggested.

Investigators also found that prenatal stress can change the levels of a protein critical for neurological development, called brain-derived neurotrophic factor (BDNF), which plays a key role in the maturation of cells that generate myelin — the fatty coating surrounding nerve fibers that is damaged in people with MS. 

The study, “Prenatal Stress Impairs Spinal Cord Oligodendrocyte Maturation via BDNF Signaling in the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis,” was published in the journal Cellular and Molecular Neurobiology.

Stress is one of the major environmental factors that have been linked to an increased risk of disease worsening in multiple neurological and psychiatric diseases, such as MS.

Stress before birth is also known to affect brain development in newborns, potentially enhancing susceptibility to certain diseases and physical impairments during adulthood via several altered biological mechanisms. 

Particularly, in animal models and humans, prenatal stress has been associated with changes in BDNF levels, a protein that is critical for neurological development and has been linked to several neurodegenerative and psychiatric disorders. 

Mice with experimental autoimmune encephalomyelitis (EAE), a disease that mimics MS in humans, are a well-established animal model of MS often used to study the long-term effects of the condition and to test the efficacy and safety of investigational therapies. 

How prenatal stress influences this EAE model, and its impact on the development of MS-like symptoms into adulthood, may provide insight into the effects of exposure to stress before birth in humans to later on disease onset. 

Now, researchers at the University of Milan, in Italy, designed a study that aimed to investigate the impact of prenatal stress on EAE-induced mice.

In the experiments, a group of pregnant female mice (dams) were exposed to daily stress sessions during the last three days of gestation. The investigators then followed the newborn mice into adulthood after triggering the onset of EAE. 

Specifically, a group of dams was placed in plastic cylinders under bright light with white noise, in which vision and hearing were blocked. This stress protocol did not cause any physical harm or suffering to the animals, as demonstrated by the fact that these mice delivered the same number of pups as control female mice that were left undisturbed. The dams exposed to stress also demonstrated a similar aptitude for maternal care compared with the control female mice.

After weaning, a group of control and stressed female pups were induced to develop EAE. The clinical symptoms of the stressed pups were scored and compared with the unstressed pups. Of note, the team induced only female pups, since MS affects up to three times more women than men. 

Analyses showed that pups born from stressed dams weighed less than their non-stressed counterparts during the early phase of EAE progression. Lower body weight also was observed in pups born from stressed dams that were not subjected to EAE induction.

Compared with the control EAE mice not subjected to prenatal stress, the clinical manifestations of EAE in the prenatally stressed mice were enhanced. This was demonstrated by the increase in EAE scores over time, especially during the early and middle phases of the disease. 

The cumulative disease score (CDS), which is the sum of the daily clinical scores of each animal, also was greater in the prenatally stressed EAE animals than in unstressed mice. However, the difference was not statistically significant.

Moreover, no stress-related discrepancies were found between the two groups of animals in the day of symptom onset and the maximum CDS score. 

“Taken together, these behavioral results provide clear evidences that [prenatal stress] enhances the susceptibility to EAE progression in the female offspring,” the researchers wrote. 

To further understand the molecular changes underlying the worse outcomes experienced by EAE mice exposed to prenatal stress, the investigators examined a portion of the cervical (neck region) spinal cord of the animals. 

After doing so, they found that, compared with non-stressed animals, prenatally stressed pups had a higher number of oligodendrocyte precursor cells (OPCs) that contained the protein receptor GPR17. That receptor protein modulates the maturation of OPCs into oligodendrocytes, or myelin-producing cells.

In agreement with these results, they also found a significant reduction in the levels of myelin-associated glycoprotein (MAG) — a protein produced only by mature myelin-generating oligodendrocytes — in stressed EAE animals.

These findings suggested that stressed animals may have “a defect in oligodendrocyte maturation that potentially leads to impaired remyelination,” the scientists said. 

After conducting a more detailed analysis, the researchers also found prenatally stressed mice had defects in the Akt/mTOR pathway, which is known to promote OPC maturation and myelination. 

These defects in the Akt/mTOR pathway were found to be caused by low BDNF levels, which were seen in both EAE and non-induced control mice subjected to prenatal stress. Drops in BDNF levels were worsened by EAE exposure. 

“In conclusion, our study demonstrates for the first time that stressful events occurring during the intrauterine life may exacerbate EAE clinical manifestations in the female population,” the researchers wrote. 

“Since several already marketed drugs are able to modulate BDNF levels, the possibility of drug repositioning for multiple sclerosis should be addressed in future studies,” they wrote.