Stressed mice transmit depressive behaviors to their offspring via sperm

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In a discovery that could reshape our understanding of how mental health disorders arise, Chinese researchers reported that male mice exhibiting depression-like behaviors were able to pass these traits on to their offspring, apparently through material genetics encoded in their semen. The study was published in Scientists progress.

The team, led by researchers at Nanjing Medical University, had noted previous studies showing that mice were able to transmit characteristics such as food-induced metabolic disorders and symptoms of trauma through epigenetic alterations. These are genetic changes that do not alter the base sequence of DNA, but rather affect the way cells express that DNA by chemical conversion to RNA and then to proteins.

Importantly, however, no previous study had examined whether symptoms of depression could be transmitted epigenetically.

Study leader Xi Chen, research director at Nanjing University School of Life Sciences, explained the main results of the study to Technological networks: “We show that the offspring of depressed fathers develop an increased susceptibility to depression when exposed to mild stress, and that sperm RNAs (especially microRNAs) play a causal role in the inheritance of depression. . Such a mechanism of germline epigenetic inheritance opens a new way to fill the void 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 emotional intent of squeaks, it is not possible to diagnose a depressed mouse. In order to create the depressed rodents necessary for their study, the researchers instead subjected mice to a battery of stressful experiments over a period of several weeks. This produced a number of behaviors and physiological changes that mouse researchers generally understand to be an expression of depression in rodents. These mice swim less well when submerged in water, show less interest in food, and have high levels of stress hormones.

Chen’s team then mated their pseudo-depressed male mice with unstressed female mice. The puppies produced were not born slaughtered. In fact, they showed no biological difference compared to puppies from healthy fathers. However, when the researchers subjected the offspring of the mice to mild stress protocols, they adopted the same behavioral changes in response as their fathers.

Further analysis of depressed offspring showed changes in the brain systems that control responses to stressful situations; the same changes had been observed a generation earlier in their fathers. The mice also appeared to have inherited abnormal cellular activation and communication in areas of the brain that are believed to cause depression in humans, including the prefrontal cortex and the hippocampus.

Interestingly, analysis of the next generation of mice, the grandchildren of the originally stressed subjects, showed that the changes lasted only for one generation – the big toddlers behaved like mice. healthy in response to mild stress.

Transmit depression through semen

To study how their depressed mice apparently passed on their behaviors to their puppies, the team looked at semen from the original generation to see if there had been any changes in genetic content. Semen primarily transmits paternal DNA, but this is associated with a multitude of RNA molecules, which the researchers noted were altered in the semen of stressed and depressed mouse 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 about ten sperm, the injected zygotes grew to show the stressful behaviors shown by mice naturally born to depressed fathers. The team showed that when the stress-induced changes seen in RNA were blocked, the offspring of mice no longer inherited depression-like behaviors.

Chen’s team was notably able to reduce an important causal role for microRNAs (miRNAs) that are transported by sperm during fertilization. MiRNAs are short strands of RNA that do not code for any protein. Instead, they play a role in modulating how proteins are produced by encoding RNA molecules.

Chen explained that his team’s findings suggested an important new role for sperm miRNAs: “
Although previously thought to be negligible vestiges of spermatogenesis, it is shown here that sperm RNAs (especially miRNAs) transmit paternal depression to offspring. Mechanically, sperm RNAs can receive signals from the paternal environment and then reshape the genetic profiles of zygotes, thereby inducing a cascading change during early embryonic development. Thus, life experiences and environmental signals (eg, stress) can be stored in sperm RNAs as epigenetic information for intergenerational communication.

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

“Of course, more research needs to be done to replicate this before it can come close to human medicine. Our next step is to explore the potential roles of human sperm miRNAs in depression. We have already contacted several hospitals. and began to assess the scope of ethical clearance to measure sperm miRNA profiles in patients with depression, ”Chen concluded.

Reference:

Wang Y, Chen ZP, Hu H et al. MicroRNAs in sperm confer susceptibility to depression in offspring. Scientists progress. 2021; 7 (7): eabd7605. doi: 10.1126 / sciadv.abd7605


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