RNA-Dependent Intergenerational Inheritance of Enhanced Synaptic Plasticity after Environmental Enrichment

Abstract

SummaryPhysical exercise in combination with cognitive training is known to enhance synaptic plasticity, learning, and memory and lower the risk for various complex diseases including Alzheimer’s disease. Here, we show that exposure of adult male mice to an environmental enrichment paradigm leads to enhancement of synaptic plasticity and cognition also in the next generation. We show that this effect is mediated through sperm RNA and especially miRs 212/132. In conclusion, our study reports intergenerational inheritance of an acquired cognitive benefit and points to specific miRs as candidates mechanistically involved in this type of transmission.

The contribution of epididymosomes to the sperm small RNA profile

“…Collectively, from the studies summarised in Table 1, it is now apparent that an array of paternal stressors, ranging from dietary perturbation (e.g. high fat, low protein), chronic psychological stress, ethanol consumption, environmental pollution and cigarette smoke exposure, can each differentially alter the sRNA profile of sperm of exposed males , Marczylo et al 2012, Rodgers et al 2013, Saavedra-Rodriguez & Feig 2013, Gapp et al 2014, Metzler-Guillemain et al 2015, Paris et al 2015, de Castro Barbosa et al 2016, Donkin et al 2016, Fullston et al 2016, Murashov et al 2016, Rompala et al 2016, Sharma et al 2016, Short et al 2016, Benito et al 2018, Dickson et al 2018, Ingerslev et al 2018, Rompala et al 2018. Further, some of these studies went on to demonstrate that an altered sperm sRNA profile contributed to altered phenotypic outcomes in the offspring post fertilisation.…”

“…Therefore, under stress conditions, the physiology of the epididymal epithelial cells is likely altered; a physiological change that could initiate a series of biochemical events which result in an altered sRNA population being produced and packaged into the epididymosomes generated by stressed cells. Currently, this is not an active area of research focus within this field, however, with each individual insult demonstrated to elicit a unique change to the sRNA profile of sperm (Table 1), it is likely that the production and packaging of sRNAs into epididymosomes within the stressed n/a n/a Improved cognition Benito et al (2018) Underlined sRNA species signifies altered accumulation of sRNA was validated by a second technique (commonly real time-quantitative PCR). Bold sRNA indicate species shown to be transferred from epididymosomes to sperm via in vitro co-incubation experiments.…”

Intergenerational Effects of Alcohol: A Review of Paternal Preconception Ethanol Exposure Studies and Epigenetic Mechanisms in the Male Germline

“…Using 1‐cell embryos, isolated sperm RNA can be directly injected into the fertilized oocyte to examine resultant progeny and determine whether sperm RNA is sufficient to recapitulate the cross‐generational phenotypes in question. To date, there have already been at least 6 studies using this method to draw a causal link between environmentally responsive sperm RNAs and heritable phenotypes (see Table ; Benito et al., ; Chen et al., ; Gapp et al., , ; Grandjean et al., ; Rodgers et al., ). Beginning in 2014, Isabella Mansuy and colleagues found that the intergenerational effects of maternal separation stress could be partially recapitulated in mice derived from one cell embryos from control, unstressed parents that were injected with total sperm RNA from stressed males (Gapp et al., ).…”

Nongenetic paternal effects via seminal fluid

“…; Bohacek and Mansuy ; Benito et al. ). Studies of rodents have shown that seminal fluid deficiency can affect the growth and health of adult offspring, either directly through the effect of seminal fluid on the integrity of sperm DNA (O et al.…”