Communicating between generations: sperm microRNA as an intergenerational signal for offspring risk of depression
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Sperm microRNAs reshape transcriptional profiles of core neuronal circuits, leading to expression of depression-like phenotypes in fertilized offspring that are exposed to stress.
Depression is the invisible enemy. Common symptoms associated with the disorder include persistent feelings of sadness, hopelessness, and worthlessness. Depression can also lead to a loss of interest in hobbies, failure to take care of one’s physical health, and even suicide. There are several types of depression, and there is no singular “cause” that leads to the development of the disorder. There are countless triggers and manners in which the disorder can arise, which makes it a difficult subject of study when considering biological and genetic factors. Despite being one of the most common mental disorders in the country, depression is frequently undiagnosed and untreated because individuals often mask the illness due to fear of judgment or being a burden on those around them. Over 264 million people in the world suffer from the disorder, and the CDC reported in 2018 that suicide was the second leading cause of death in individuals aged 10-34 (James et al. 2019 and CDC 2019). Depression is caused by a mixture of environmental, biological, genetic, and physiological factors. Research is still needed to discover and distinguish genuine depression genes, which could be used to generate disease models in rodents for preemptive treatment. When considering the wide range in causes of depression, Wang et. al sought to investigate how genetics play a role in the formation of depression. They researched using murine models by injecting sperm microRNA, which is known to be crucial in early embryo development, into zygotes and observed that sperm from individuals exposed to depression-like stress can pass these phenotypic traits on to their offspring when faced with a similar environment.
The germ line acts as a vector to induce phenotypes that are related to parental environment by transmission of histone modifications, noncoding RNAs, and DNA methylation, but the mechanism in which this occurs remains at large (Wang et al. 2021). This research is particularly sparse for father-to-offspring transmission due to prior notions that DNA was the only source of parental hereditary information. However, studies have found that sperm RNA has distinct species that can be passed into the egg cell upon fertilization (Rassoulzadegan et al. 2006). Wang et. al utilized this information to better investigate the mechanism underlying risk of depression. They found that sperm microRNAs reshape early embryonic transcriptional profiles in core neuronal circuits toward depression-like phenotypes, therefore uncovering one crucial mechanistic step of this inheritance (Wang et al. 2021).
Stress is one of the main causes of depression. The researchers began their study by creating a chronic mild stress-induced depression mouse model by exposing male mice to erratic mild stresses and found that the mice presented with lower weight, despair, and lower sucrose intake as compared to the control treatment. Upon further analysis of gene expression structures, they found significant changes and abnormalities in neuronal factors that reduce the plasticity of the nervous system in mice exposed to the depression-stress treatment.
Next they mated the mice of these two treatments with healthy female mice and found that under baseline conditions, the first-generation offspring shared similar levels of weight gain and sucrose level between treatments. However, when exposed to chronic variable stress for 2 weeks, the F1-Depression mice repeated the paternal depressive-like phenotypes whereas the F1-Control did not. The results were observed equally in male and female offspring. These findings suggest that the offspring of the depression-induced treatment had a lower resilience to combat stress and depression.
The researchers then performed molecular profiling in different regions of the brain that are related to depression, such as the hippocampus. The hippocampus is one of three parts of the brain that forms an evolutionarily conserved core neuronal circuit that is responsible for adaptations to environmental conditions (Wang et al. 2021). They found a decrease in neuronal activation was observed in the hippocampus for the depression-treatment offspring. Hierarchical clustering was used to compartmentalize similar genes and found shared hippocampal gene profiles for both generations of depression treatments and a different set of shared genes for the control treatments. The altered genes were found to be related to nervous system development, regulation signaling, behavior, and locomotion, which all pertain to neuronal function and are involved in the development of depression. So, if these depression-treatment offspring were born with impaired neural function due to signaling changes, this suggests an increased susceptibility to the disorder.
They then assessed whether susceptibility to depression is transgenerational or intergenerational by mating another generation. They found the F2-Depression mice did not respond to the chronic variable stress, meaning that risk of depression is intergenerational. I found these results to be of particular interest because I always thought that, similar to addiction, disorders such as depression are inherited from older familial generations. More research is needed to observe the association between ancestral genetics and depression.
Finally, to observe if sperm RNA is associated with the increase in depression-like phenotypes in offspring, the researchers were able to purify total RNAs from the sperm of both original parent generations and injected them into normal zygotes (Wang et al. 2021). Results observed were the same as prior offspring results. They then narrowed the scope of their research to investigating microRNAs following analysis that identified 19 miRNAs that were altered in the F0-Depression sperm, demonstrated repeated depression signature abnormalities in marker genes, and had a greater level of expression as compared to the control offspring (Wang et al. 2021).
These findings further highlight how miRNAs have the ability to be key cross-talk communicators between cells and tissues (Chen et al. 2012). In fact, this study shows how miRNA transcends even further than this definition, as this subset of sperm RNA has the ability to formulate cross-talk between generations, and the similarity in depression-like phenotypes between parent and offspring demonstrate this mechanism in action.
Advances in our understanding of depression are crucial, as mental illness has largely been stigmatized and viewed negatively in the eyes of our society. Any and all information that can be shed on this illness will further normalize and validate depression as an illness that impacts millions each day. Misconceptions are common for mental health issues especially and the findings discussed in this article shine a promising light on a better collective understanding of how these disorders are inherited and developed at the molecular level.
Through various injections of small-RNA and microRNA into zygotes, the researchers saw a common trend for each phase of the experiment: that under baseline conditions, neuronal activity and behavior did not differ in treatment groups, but when stress conditions were induced, the F1-Depression mice did respond with altered behavior, lowered sucrose levels, and have abnormal neuronal gene expression profiles. These findings support the idea that depression phenotypes are caused by an interplay between genetic and environmental factors. More research is needed to find appropriate methods to preemptively treat those who are susceptible to inheriting depression to minimize the likelihood that they will suffer from this invisible illness that takes the lives of so many.
Svenja Nanfelt is a senior biology major at Davidson College. Contact her at svnanfelt@davidson.edu.
References
Wang, Y., Zhang-Peng, C., Huanhuan, H., Jieqiong, L., Zhen, Z. et al. Sperm microRNAs confer depression susceptibility to offspring. Sci Adv7, eabd7605 (2021).
M. Rassoulzadegan, V. Grandjean, P. Gounon, S. Vincent, I. Gillot, F. Cuzin, RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006).
X. Chen, H. Liang, J. Zhang, K. Zen, C.-Y. Zhang, Secreted microRNAs: A new form of intercellular communication. Trends Cell Biol. 22, 125–132 (2012).
2021, FastStats – Leading Causes of Death. Centers for Disease Control and Prevention.
James, S. L., Abate, D., Hassen Abate, K., Abay, S. M. & Abbafti, C. et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet (2019). Available at: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32279-7/fulltext. (Accessed: 27th March 2021)
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