Beneficial intergenerational effects of exercise on brain and cognition: a multilevel meta-analysis of mean and variance

Physical exercise not only helps to improve physical health but can also enhance brain development and cognition. Recent reports on parental (both maternal and paternal) effects raise the possibility that parental exercise may provide benefits to offspring through intergenerational inheritance. However, the general magnitude and consistency of parental exercise effects on offspring is still controversial. Additionally, empirical research has long overlooked an important aspect of exercise: its effects on variability in neurodevelopmental and cognitive traits. Here, we compiled data from 52 studies involving 4786 rodents (412 effect sizes) to quantify the intergenerational transmission of exercise effects on brain and cognition. Using a multilevel meta-analytic approach, we found that, overall, parental exercise showed a tendency for increasing their offspring's brain structure by 12.7% (albeit statistically non-significant) probably via significantly facilitating neurogenesis (16.5%). Such changes in neural anatomy go in hand with a significant 20.8% improvement in neurobehaviour (improved learning and memory, and reduced anxiety). Moreover, we found parental exercise significantly reduces inter-individual differences (i.e. reduced variance in the treatment group) in progeny's neurobehaviour by 10.2% (coefficient of variation ratio, lnCVR), suggesting the existence of an individual by intervention interaction. The positive effects of exercise are modulated by several covariates (i.e. moderators), such as the exercised parent's sex, offspring's sex, and age, mode of exercise, and exercise timing. In particular, parental forced exercise is more efficient than voluntary exercise at significantly improving offspring neurobehaviour (26.0%) and reducing its variability (14.2%). We observed larger effects when parental exercise started before pregnancy. However, exercising only during pregnancy also had positive effects. Mechanistically, exercise significantly upregulated brain-derived neurotrophic factor (BDNF) by 28.9%, vascular endothelial growth factor (VEGF) by 35.8%, and significantly decreased hippocampal DNA methylation by 3.5%, suggesting that brain growth factor cascades and epigenetic modifications can moderate the transmission of parental exercise effects. Collectively, by coupling mean with variance effects, our analyses draw a more integrated picture of the benefits that parental exercise has on offspring: not only does it improve offspring brain development and cognitive performance, but it also reduces inter-individual differences in cognition-related traits. We advocate that meta-analysis of variation together with the mean of a trait provides novel insights for old controversies as well as emerging new questions, opening up a new era for generating variance-based hypotheses.