Hippocampal epigenetic modification at the brain‐derived neurotrophic factor gene induced by an enriched environment

Abstract

Environmental enrichment is an experimental paradigm that increases brain-derived neurotrophic factor (BDNF) gene expression accompanied by neurogenesis in the hippocampus of rodents. In the present study, we investigated whether an enriched environment could cause epigenetic modification at the BDNF gene in the hippocampus of mice. Exposure to an enriched environment for 3-4 weeks caused a dramatic increase in the mRNA expression of BDNF, but not platelet-derived growth factor A (PDGF-A), PDGF-B, vascular endothelial growth factor (VEGF), nerve growth factor (NGF), epidermal growth factor (EGF), or glial fibrillary acidic protein (GFAP), in the hippocampus of mice. Under these conditions, exposure to an enriched environment induced a significant increase in histone H3 lysine 4 (H3K4) trimethylation at the BDNF P3 and P6 promoters, in contrast to significant decreases in histone H3 lysine 9 (H3K9) trimethylation at the BDNF P4 promoter and histone H3 lysine 27 (H3K27) trimethylation at the BDNF P3 and P4 promoters without any changes in the expression of their associated histone methylases and demethylases in the hippocampus. The expression levels of several microRNAs in the hippocampus were not changed by an enriched environment. These results suggest that an enriched environment increases BDNF mRNA expression via sustained epigenetic modification in the mouse hippocampus.

Reversible epigenetic histone modifications and Bdnf expression in neurons with aging and from a mouse model of Alzheimer’s disease

“…Rats exposed to fear conditioning show increases in H3K4 tri-methylation, a transcriptionally active mark, at the promoter of Bdnf I in the hippocampus (Gupta et al 2010). Mice that are exposed to environmental enrichment not only increase in H3K4 tri-methylation but also decrease in repressive transcriptional marks H3K9 and 27 trimethylation at the promoters of Bdnf variants causing an increase in total Bdnf mRNA levels (Kuzumaki et al 2011). The increase in H3K9 methylation explains the lower Bdnf expression that we and others observe in the hippocampus and cortex of AD-like mice but does not reveal how or why this mark is increased.…”

Epigenetic mechanisms underlying the role of brain-derived neurotrophic factor in depression and response to antidepressants

“…Prolonged housing in such conditions exerts antidepressant effects mainly through neuromorphological and neurogenic adaptations, which suggests the involvement of neurotrophins such as BDNF. Accordingly, several weeks of EE can rescue depression-like behaviors, and upregulate hippocampal BDNF expression through hypermethylation of the permissive H3K4 at Bdnf P3 and P6, associated with a coherent reduction in repressive methylation of H3K9 at Bdnf P4 and H3K27 at Bdnf P3 and P4 (Jha et al, 2011;Kuzumaki et al, 2011). Although these modifications have yet to be directly linked to the antidepressant properties of EE, these findings illustrate how epigenetic mechanisms translate environmental cues into long-lasting changes in gene expression.…”

Biological memories of past environments: Epigenetic pathways to health disparities

“…In mice, recent studies report environmental enrichment is associated with changes in methylation patterns. [125][126][127] Other studies suggest that increased exercise in mice modifies methylation at genes that regulate metabolism. 128 Thus studies in humans that evaluate the potential positive effects of behavioral interventions in early life or even adulthood would be useful for determining whether administering such interventions could modify epigenetic profiles and health risk.…”