Susceptibility to depression may link back to sperm — study

Depression is often chalked up to a chemical imbalance in the brain, a disturbance in the carefully choreographed dance of dopamine, serotonin, and norepinephrine that keep the brain functioning normally.

But scientists know this disturbance is not the only factor. Some are working to pull apart the genetic factors which predispose a person to depression in an effort to one day better treat the condition.

A study in mice, published Wednesday in the journal Science Advances, shines a light on the importance of studying how epigenetic changes — traits that are acquired during a lifetime, influenced by behavior and environment — may factor into mental health. The study also adds to the growing body of evidence suggesting one can predispose their offspring to poor mental health, depending on how their own genes are influenced by stress.

In the study, a group of male mice were exposed to stress for five weeks and subsequently displayed depressive symptoms, like increased immobility and decreased weight. Their offspring, in turn, were compared to a control group. The mice born to stressed fathers didn't show depressive symptoms until they were exposed to mild stress, the factor which triggered depression in their fathers.

Depressive symptoms followed stress exposure in these mice, but not those born to fathers in the control group. The mice born to stressed fathers also had different gene expressions in certain areas of the brain — overexpression of some and underexpression in others. These genetic expressions appeared to be passed down over generations.

Co-author Xi Chen, head of the Department of Biochemistry and Molecular Biology at Nanjing University in China, tells Inverse his team was surprised to find these changes in offspring behavior appeared to be linked to a small number of small RNAs in sperm. Small RNAs are molecules that regulate other genes and influence health.

Why it matters — The new study builds on a growing body of evidence suggesting increased corticosterone levels in father mice can cause changes in some small RNAs in their sperm. These changes appear to be passed down to their offspring and then their grandchildren, and have been connected to the brain and behavioral changes relevant to depression and anxiety disorders.

"The paternal effects of epigenetics on offspring appear to be almost Lamarckian," Anthony Hannan, head of the Epigenetics and Neural Plasticity Laboratory at the Florey Institute of Neuroscience and Mental Health in Victoria, Australia, tells Inverse. Hannan is referring to the evolutionary theory suggesting parents can pass physical characteristics they acquired through their lifetime onto their offspring. Hannan was not involved in the new study.

Although the new study was peer-reviewed before being published, Hannan is skeptical about whether or not the new study could be replicated by another team of researchers. But he says that the larger body of research, which reliably connects depression and anxiety disorders to epigenetics, does help shape our understanding of — and highlight the importance of thinking about — the complex genetic and environmental factors that contribute to these and other brain disorders.

What’s new — Previously, research has focused on stressed mothers passing altered traits to their young, but preclinical research, including Hannan's, increasingly suggests stressed fathers can also epigenetically predispose their offspring to the brain and behavioral changes relevant to anxiety and depression.

"This has not been proven in humans, so a lot more research needs to be done before we can confidently say whether or not this occurs in humans and if so, how humans are impacted," Hannan says.

"However, evidence from the past decade or so indicates that we are also dealt an epigenetic deck of cards at conception... "

Because studies on how a mother's environmental exposures can affect her offspring are much older, scientists have a better understanding of how exposures and lifestyle can affect a woman's uterine environment, fetus, and breast milk, which ultimately impact her young. The study of paternal epigenetic inheritance, however, is a much newer field and most research on the subject has been published in the last decade.

“It is clear that we are all dealt a genetic deck of cards at conception, which we can do nothing about. However, evidence from the past decade or so indicates that we are also dealt an epigenetic deck of cards at conception, which, unlike traits such as eye color, our parents acquired during their lifetimes," Hannan says. Because epigenetic modifications are more malleable and responsive to our environments, we may be able to change them, he explains.

What’s next — Scientists anticipate we may one day be able to use this understanding of gene-environment interactions, epigenetics, and the brain to help prevent and treat a wide range of human disorders, including depression and anxiety disorders.

According to Chen, his research team was also able to correct the abnormal generic imbalances associated with depression in the mice born to depressed fathers, which shows promise for the possibility of more pointed future therapies for treating depression — though this potential is still a long way off. “This strategy is not fully established and deserves further investigation,” says Chen, who is currently working with hospitals to evaluate the ethics of studying sperm sRNA in men with depression.

If you or someone you know is affected by depression, please find help now. The International Association for Suicide Prevention provides a list of crisis centers across the world that can offer support in your region.

National Suicide Prevention Lifeline: 1-800-273-8255

Abstract: Evidence that offspring traits can be shaped by parental life experiences in an epigenetically inherited manner paves a way for understanding the etiology of depression. Here, we show that F1 offspring born to F0 males of depression-like model are susceptible to depression-like symptoms at the molecular, neuronal, and behavioral levels. Sperm small RNAs, and microRNAs (miRNAs) in particular, exhibit distinct expression profiles in F0 males of depression-like model and recapitulate paternal depressive-like phenotypes in F1 offspring. Neutralization of the abnormal miRNAs in zygotes by antisense strands rescues the acquired depressive-like phenotypes in F1 offspring born to F0 males of depression-like model. Mechanistically, sperm miRNAs reshape early embryonic transcriptional profiles in the core neuronal circuits toward depression-like phenotypes. Overall, the findings reveal a causal role of sperm miRNAs in the inheritance of depression and provide insight into the mechanism underlying susceptibility to depression.