Stressed-Out Mice Pass on Depression-Like Behaviors to Their Offspring via Sperm

In a finding that could reshape our understanding of how mental health disorders arise, Chinese researchers have reported that male mice showing depression-like behaviors were able to pass on those traits to their offspring, apparently through genetic material encoded in their sperm. The study was published in Science Advances.

The team, led by researchers at Nanjing Medical University, had noted previous studies showing that mice were capable of passing on traits such as diet-induced disorders of metabolism and trauma symptoms through epigenetic alterations. These are genetic changes that don’t alter the base sequence of DNA, but instead affect how cells express that DNA through chemical conversion to RNA and then proteins.

Importantly, however, no prior studies had investigated whether symptoms of depression could be passed on in an epigenetic manner.

Study lead Xi Chen, a research director at Nanjing University’s School of Life Sciences, explained the study’s key findings to Technology Networks: “We show that the offspring of depressed fathers develop enhanced susceptibility to depression when exposed to a slight stress, and that sperm RNAs (particularly microRNAs) play a causal role in depression inheritance. Such a germline epigenetic inheritance mechanism paves a new way for filling the gap in our knowledge of the pathophysiology of depression.”

What makes a mouse depressed?

A major limitation to animal studies of depression is that, until psychiatry makes a bold foray into decoding the emotive intent of squeaks, it’s not possible to diagnose a depressed mouse. In order to create the depressed rodents needed for their study, the researchers instead subjected mice to a battery of stressful experiences over a period of weeks. This produced a number of behaviors and physiological changes that mouse researchers commonly understand as being a rodent expression of depression. These mice swim less hard when immersed in water, show less interest in food and have heightened levels of stress-related hormones.

Chen’s team then mated their pseudo-depressed male mice with unstressed female mice. The pups produced weren’t born downbeat. In fact, they didn’t show any biological differences from pups produced from healthy fathers. However, when the researchers subjected the offspring mice to mild stress protocols, they adopted the same behavioral changes in response as their fathers had.

A deeper analysis of the depressed offspring showed changes to brain systems that control responses to stressful situations; the same changes had been seen a generation before in their fathers. The mice also appeared to have inherited abnormal cell activation and communication in brain regions that are thought to underlie depression in humans, including the prefrontal cortex and hippocampus.

Interestingly, analysis of the next generation of mice, the grandpups of the originally stressed-out subjects, showed that the changes only lasted a single generation – the grandpups behaved as healthy mice did in response to mild stress.

Passing on depression through sperm

To investigate how their depressed mice had apparently passed on their behaviors to their pups, the team examined the original generation’s sperm to see if there were any changes to genetic content. Sperm primarily passes on paternal DNA, but this comes paired with a host of RNA molecules, which the researchers noted were altered in the sperm of stressed and depressed mice fathers. The team isolated the RNA content of these sperm and injected it into healthy mouse zygotes. Even though the RNA only totaled the genetic content of roughly ten sperm, injected zygotes grew up to show the stressed-out behaviors shown by mice naturally born to depressed dads. The team showed that when the stress-induced changes seen in the RNA were blocked, offspring mice no longer inherited depression-like behaviors.

Chen’s team were specifically able to narrow down a significant causal role to microRNAs (miRNAs) that are carried by sperm during fertilization. miRNAs are short strands of RNA that don’t code for any proteins. Instead, they play a role in modulating how proteins are produced by coding RNA molecules.

Chen explained that his team’s findings suggested a new, important role for sperm miRNAs: “Although previously thought to be negligible remnants of spermatogenesis, sperm RNAs (particularly miRNAs) are herein demonstrated to transmit a paternal depression to offspring. Mechanistically, sperm RNAs may experience signals from paternal environment and then reshape gene profiles in zygotes, thereby inducing a cascade change during early embryonic development. Thus, life experiences and environmental cues (e.g., stress) can be memorized in sperm RNAs as epigenetic information for cross-generation communication.”

Could the team’s findings have impacts for treatment of depression in humans? Chen is optimistic. “Our findings may offer a new dimension for the development of novel antidepressant treatments. For example, we showed that rescue of miRNA imbalance in zygotes can reverse the acquired depressive phenotypes in offspring born to depressed fathers. Since the sequences and biological functions of many miRNAs are conserved between humans and mice, it is intriguing to investigate if sperm miRNAs also play a role in the inheritance of human depression and can be employed as a therapeutic target.

“Of course, more research needs to be done to replicate this before it can get close to human medicine. Our next step is to explore the potential roles of human sperm miRNAs in depression. We have already reached out to several hospitals and started to evaluate the scope of ethical permission for measuring sperm miRNA profiles in depression patients,” concluded Chen.

Reference: 

Wang Y, Chen Z-P, Hu H, et al. Sperm microRNAs confer depression susceptibility to offspring. Science Advances. 2021;7(7):eabd7605. doi:10.1126/sciadv.abd7605