Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety

Abstract

There is growing evidence that the preconceptual lifestyle and other environmental exposures of a father can significantly alter the physiological and behavioral phenotypes of their children. We and others have shown that paternal preconception stress, regardless of whether the stress was experienced during early-life or adulthood, results in offspring with altered anxiety and depression-related behaviors, attributed to hypothalamic–pituitary–adrenal axis dysregulation. The transgenerational response to paternal preconceptual stress is believed to be mediated by sperm-borne small noncoding RNAs, specifically microRNAs. As physical activity confers physical and mental health benefits for the individual, we used a model of voluntary wheel-running and investigated the transgenerational response to paternal exercise. We found that male offspring of runners had suppressed reinstatement of juvenile fear memory, and reduced anxiety in the light–dark apparatus during adulthood. No changes in these affective behaviors were observed in female offspring. We were surprised to find that running had a limited impact on sperm-borne microRNAs. The levels of three unique microRNAs (miR-19b, miR-455 and miR-133a) were found to be altered in the sperm of runners. In addition, we discovered that the levels of two species of tRNA-derived RNAs (tDRs)—tRNA-Gly and tRNA-Pro—were also altered by running. Taken together, we believe this is the first evidence that paternal exercise is associated with an anxiolytic behavioral phenotype of male offspring and altered levels of small noncoding RNAs in sperm. These small noncoding RNAs are known to have an impact on post-transcriptional gene regulation and can thus change the developmental trajectory of offspring brains and associated affective behaviors.

Adolescence and the next generation

“…The paternal preconception environment modulates the RNA content of the developing sperm, with possible effects on post-fertilization development and offspring phenotypes 53 . In animal studies, paternal exposures to high-fat and high-sugar diets produce metabolic disturbances in offspring 54 , and both stress and exercise affect stress responses of the offspring [55][56][57] . Animal and some human studies have found effects of preconceptional tobacco, alcohol and illicit drug use on gamete epigenomes, with diverse effects on offspring development 58,59 .…”

Physical exercise as an epigenetic modulator of brain plasticity and cognition

“…Importantly, the authors observed that exercise increased DNA methylation at promoters of several genes associated with brain pathologies such as schizophrenia and Parkinson disease (Denham et al, 2015). Recently, it has been reported that physical exercise alters the expression of miRNAs in paternal sperm, whereas suppresses the reinstatement of fear memory and reduces anxiety in male mice offspring (Short et al, 2017). …”

Inter- and transgenerational inheritance of behavioral phenotypes

“…Third, more direct causal proof still needs to be provided and 'reversal' studies showing a correction of epigenetic alterations like in Gapp et al [36 ] or in Benito et al [34 ] are needed. Reversal studies could employ parental and/or offspring environmental manipulations known to have transgenerational effects such as EE [9,34 ,36 ] or exercise [48], or molecular manipulations in germ cells such as ncRNA silencing [34 ] or epigenome editing through CRISPR-dCas [49]. Importantly, different mechanisms may be responsible for the transmission of phenotypes depending on the environmental stimuli, the time window and severity of exposure, and the time of analyses (whether shortly or long after exposure).…”