Beyond Biological Heritability in Mental Health

Every child has a DNA sequence made up of genes from both their mother and father. While we have learned much about how those genes can contribute to the development of mental health disorders, they do not—and cannot—fully explain why one child with a family risk of schizophrenia may develop the disorder and his sibling may not. The field of epigenetics, the study of the heritable changes in gene expression influenced by environmental factors, is shedding new light on how neuropsychiatric disorders can be passed down from generation to generation.

“What we’re looking at here is how cells and DNA can provide a kind of encyclopedia for the natural history of the human mind,” says Ian Weaver, an epigeneticist at Dalhousie University, in Nova Scotia. “These kinds of studies continue to enhance our understanding of how the environment can make changes to gene expression, and how these changes can arise in the brain and support variations both in our traits and our risk for disease pathologies.”

Several studies presented at Neuroscience 2016, the annual meeting of the Society for Neuroscience held in San Diego last month, help explain how a parent’s diet, drug use, and stress can alter the course of brain development—and, with that, increase the risk for mental health issues—in future generations.

Maternal diet, child health

The majority of pregnant women in the Western world are encouraged to maintain a healthy weight while pregnant. But the Centers for Disease Control and Prevention (CDC) says that the incidence of obesity in women of child-bearing age has increased by 80 percent over the past 20 years. That rise can profoundly affect the brain development and later behavior of more and more children, says Shelly Buffington, a researcher at Baylor College of Medicine.

“This isn’t just a health issue for the women who are overweight, it’s a mental health issue, because maternal obesity increases the risk for neurodevelopmental disorders in offspring by about 1.5 times,” she says. “We know that neurodevelopmental disorders like autism spectrum disorder are caused by a combination of genetics and environmental factors. So the goal of my work has been to understand how maternal obesity may affect the behavior of offspring.”

Buffington and colleagues placed female mice either on a regular or high-fat diet for eight weeks before allowing them to become impregnated. Once their offspring were born, all pups were put on a regular diet. When the researchers looked at the pups’ microbiome, or gut bacteria, they saw that the pups born to females on the high fat diet had significantly less diversity of gut bacteria, and showed social impairments including increased anxiety and decreased social interaction with other mice. The high-fat moms’ pups also showed decreased synaptic activity in areas of the brain involved with social interactions. The researchers found they could reverse some of the pups’ deficits by adding a particular bacterium, Lactobacillus reuteri, back to their gut.

“Taken together, our results show that maternal high-fat diet produces changes in the microbiome, which negatively impact social behaviors and leads to changes in synaptic plasticity in the offspring,” she says. “But our findings also suggest that adding back some of the missing microbiome diversity to the animals may hold therapeutic potential for eliminating some of the behavioral symptoms involved with neurodevelopmental disorders.”

Drug use and increased risk for addiction

Yasmin Hurd, an epigeneticist at the Mount Sinai Medical School, discussed the many epigenetic alterations that parental drug use can have on offspring during her lecture, “Translational Neuroepigenetic Insights of Addiction Vulnerability.” Her work has shown that heroin and other drug use can make epigenetic alterations to the brain derived neurotrophic factor (BDNF), a nerve growth tool, as well as glutaminergic signaling in the brain’s reward regions–changes that significantly increased the risk for addiction in offspring (in rats). What’s more, these effects were shown not just in the next generation but in following generations as well.

“We see that drug use results in greater sensitivity when offspring are exposed to an opiate. Think about how many people have been given an opiate prescription—and perhaps the fact that more and more people are becoming addicted could be because they were exposed to certain drugs in utero or during adolescence,” she says. “The results show us that the brain is adapting to this exposure—it is changing receptors and receptor signaling pathways that impact gene expression. And these changes last into adulthood, and beyond, into the next generation. It’s something we need to study deeper so we can better understand the implications—because while we are all different in our vulnerability to subsequent disease, addiction or otherwise, we know that there are some environmental exposures during development that will change your sensitivity and up your risk.”

Stress, Prozac, and the developing brain

Other drugs may actually have protective effects. It’s long been known that maternal stress, such as the kind that may be experienced during a depressive episode, can negatively impact the developing brain of the fetus and increase risk for the development of later neuropsychiatric disorders. But many obstetricians frown upon pregnant mothers taking common anti-depressant medications like Prozac (fluoxetine) because it’s not clear what the long-term effects might be.

Veronika Kiryanova, a researcher at the University of Calgary, compared and contrasted the use of Prozac in a mouse model. She and her colleagues studied the adult offspring of mothers who had been exposed only to chronic stress, given Prozac only, were both exposed to chronic stress and given Prozac, or exposed to neither. When measuring cognitive abilities, anxiety, exploratory behaviors, and the brain’s circadian “clock” functions, they found that male offspring of stressed mothers showed inappropriate circadian responses to environmental cues, as well as more timid and hyperactive behaviors, but the male animals of stressed mothers who were also given Prozac did not show the same level of deficits. Those treated solely with Prozac showed a decrease in anxiety and some changes to circadian rhythms.

“Maternal stress reduced the level of normal aggression we see in control mice. Prozac alone increased those levels,” says Kiryanova. “But the offspring of stressed mothers who were given the drug showed normal levels of aggression, suggesting that the drug reversed the effects of the stress. It seems to have a protective effect.”

While these results are compelling, Kiryanova says there is still a lot of work to be done to understand the long-term effects of anti-depressant use during pregnancy in humans.

“This remains a highly controversial issue, whether or not moms should be taking anti-depressants. It’s a complex decision for women and their doctors,” she says. “But maternal stress is bad for the baby without anything else. So our study suggests that Prozac could relieve some of those bad effects.”

Effects that last for generations

While there is still much to learn about how our lifestyle choices and environmental exposures shape brain development, it’s becoming clear that these changes can last for generations. Hurd, at the end of her lecture, said to the audience, mostly comprised of neuroscience students, “So be careful what you do tonight, because it may affect your grandchildren one day.”

While she says she made the comment in jest, she does hope that her message that DNA is not destiny, that one’s environment can greatly influence how the brain develops in your own children and beyond, is understood. She hopes that future work in epigenetics will provide even greater insights into why one individual develops a disorder and others do not.

“Your environment matters. It matters during your lifetime and affects your own vulnerability to disease and disorders. And it even matters to your offspring, and your offspring’s offspring,” she says. “We’ve long known there is genetic heritability for a variety of psychiatric disorders, but you just can’t find it on a genetic level. Epigenetics can help account for how that heritability occurs—and it can not only give us insight into how these different disorders develop but also how we might better treat them in the future.”