Florey Department of Neuroscience and Mental Health - Theses
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ItemSperm noncoding RNAs as mediators of paternal epigenetic inheritance modulating offspring affective and social behaviours( 2023-06)Background: Studies have shown that paternal environmental conditions prior to conception can influence the innate behaviours of their offspring, and the evolutionary impacts of such intergenerational effects are therefore of considerable interest. Epigenetic mechanisms have been shown to underlie this inheritance, as the microinjection of sperm small noncoding RNAs into fertilised oocytes induces reprogramming of the early embryo, which is thought to be responsible for the differences observed in adult phenotype. Our group previously showed in a mouse model of daily stress that glucocorticoid treatment of adult male breeders prior to conception leads to increased anxiety-related behaviours in male offspring, and this accompanies changes in the paternal sperm small noncoding RNA profile. Additionally, in a model of paternal running wheel voluntary exercise preconception, our group observed lower anxiety levels and a more robust fear extinction memory in the male offspring, as well as changes in paternal sperm small noncoding RNA expression. Aims: In this study, we aimed to understand the transgenerational effects of paternal stress exposure on the social behaviour of the male progeny and its potential influence on reproductive success by analysing its effects on social reward, male attractiveness and social dominance. We also assessed the paternal sperm long noncoding RNA profile following glucocorticoid treatment or running wheel voluntary exercise. We used CaptureSeq, a sequencing technique that is more sensitive than the ones used in other studies in the field. We next sought to determine the role of sperm long noncoding RNAs by microinjecting them into fertilised oocytes. Results: We report that paternal corticosterone-treatment was associated with increased display of subordination towards other male mice. Those mice were unexpectedly more attractive to female mice while expressing reduced levels of the key rodent pheromone Darcin, contrary to its conventional role in driving female attraction. Furthermore, no overt differences of the prefrontal cortex transcriptome were found in the offspring, implying that peripheral mechanisms are likely contributing to the phenotypic differences. No transgenerational differences were observed. Paternal corticosterone exposure led to dysregulation of sperm long noncoding RNA expression, which encompassed lncRNAs, circular RNAs and transposable elements. Although they have poor functional annotation, bioinformatic approaches indicated their expression in the brain, as well as their potential in regulating brain function. Running wheel exercise led to hundreds of downregulated lncRNAs, as well as transposable elements, and bioinformatic strategies predicted their function in biological processes, such as cell adhesion. Lastly, we separated and isolated the sperm long noncoding RNA population after glucocorticoid exposure and performed microinjections into fertilised oocytes. We observed that the resulting adult offspring had lower body weight and altered behavioural responses in the light-dark box and Porsolt swim test. Conclusion: Our findings highlight the potential of paternal stress to affect intergenerational (mal)adaptive responses. They also provide insights into the potential biology of long noncoding RNAs and highlight that efforts to annotate their function are highly necessary for the understanding of the mechanisms underlying the epigenetic inheritance. We are also the first to show that voluntary exercise modulates sperm long noncoding RNAs expression.