Epigenetic rejuvenation of the hippocampus by environmental enrichment

Abstract

10The decline of brain function during aging is associated with epigenetic changes, including DNA 11 methylation. Lifestyle interventions can improve brain function during aging, but their influence 12 on age-related epigenetic changes is unknown. Using genome-wide DNA methylation sequencing, 13 we here show that environmental enrichment counteracted age-related DNA methylation changes 14 in the hippocampal dentate gyrus of mice. Specifically, environmental enrichment prevented the 15 aging-induced CpG hypomethylation at target sites of the methyl-CpG-binding protein Mecp2, 16 which is known to control neuronal functions. The genes at which environmental enrichment 17 counteracted aging effects have described roles in neuronal plasticity, neuronal cell communication 18 and adult hippocampal neurogenesis and are dysregulated with age-related cognitive decline in the 19 human brain. Our results highlight the rejuvenating effects of environmental enrichment at the level 20 of DNA methylation and give molecular insights into the specific aspects of brain aging that can 21 be counteracted by lifestyle interventions. 22

DNA methylation as a mediator of genetic and environmental influences on Parkinson’s disease susceptibility: Impacts of alpha-Synuclein, physical activity, and pesticide exposure on the epigenome

“…CpH methylation changes have also been reported at 750 cytosines, primarily occurring in introns, in the hippocampi of mice housed in EE (Zocher et al, 2021). While DNAm at introns has the potential to influence transcription, differential CpH methylation was also shown to be depleted at promoters, CpG islands, and CpG shores in this study, making it difficult to draw any definitive conclusions about potential gene regulatory impacts (Zocher et al, 2021). Neuronal CpH methylation has been suggested to be more sensitive to environmental stimuli than neuronal CpG methylation due to its sparsity and replication independence (Fuso and Lucarelli, 2019).…”

“…These studies showed that environmental enrichment can alter hippocampal DNAm and DNAhm, and prevent some SNCA-induced alterations in gene expression (Irier et al, 2014;Wassouf et al, 2018;Zhang et al, 2018;Zocher et al, 2021). Intriguingly, EE was shown to reduce age-related epigenetic drift at the level of DNAm in the hippocampus, and to alter histone modifications, chromatin accessibility, DNAm, and gene expression in the cortex in mice (Espeso-Gil et al, 2021;Zocher et al, 2021). These studies support a potential role of DNAm as a mediator of the impacts of behavior and lifestyle-related factors on PD risk.…”

“…In rodents, the neuroprotective effects of exercise, increased cognitive stimulation, and increased social stimulation can be modeled with an "enriched environment" (EE) paradigm, consisting of housing more mice per cage with increased access to toys and exercise wheels (Wassouf and Schulze-Hentrich, 2019). Housing mice in an EE has been shown to reduce aging and inflammatory phenotypes, and to remodel gene expression, DNA modifications, and histone modifications (Irier et al, 2014;Wassouf et al, 2018;Zhang et al, 2018;Espeso-Gil et al, 2021;Zocher et al, 2021) (Supplementary Table S5). Exercise is also associated with reduced α-Syn levels in the mouse brain (Zhou et al, 2017).…”

“…Some allele-specific CpH methylation has been observed in the context of schizophrenia, with lower levels of CpH methylation surrounding SNPs that correspond to schizophrenia risk haplotypes (Alfimova et al, 2020). CpH methylation changes have also been reported at 750 cytosines, primarily occurring in introns, in the hippocampi of mice housed in EE (Zocher et al, 2021). While DNAm at introns has the potential to influence transcription, differential CpH methylation was also shown to be depleted at promoters, CpG islands, and CpG shores in this study, making it difficult to draw any definitive conclusions about potential gene regulatory impacts (Zocher et al, 2021).…”

LINE-1 retrotransposon activation intrinsic to interneuron development

“…That elevated PV + neuron L1 activity in adult DG was here moderately attenuated, rather than increased, by ENR housing, and not affected by voluntary exercise, was therefore unexpected. Environmental enrichment may counter physiological stress upon PV + neurons [67][68][69] , and could enhance L1 repression 70 . As shown in other biological contexts 1,3,10,21 , L1 activation in PV + neurons illustrates how retrotransposons may be incorporated into transcription factor programs guiding cell fate and mature function, potentially in an experience-dependent manner.…”