Late-Life Environmental Enrichment Induces Acetylation Events and Nuclear Factor κB-Dependent Regulations in the Hippocampus of Aged Rats Showing Improved Plasticity and Learning

Abstract

Aging weakens memory functions. Exposing healthy rodents or pathological rodent models to environmental enrichment (EE) housing improves their cognitive functions by changing neuronal levels of excitation, cellular signaling, and plasticity, notably in the hippocampus. At the molecular level, brain derived-neurotrophic factor (BDNF) represents an important player that supports EE-associated changes. EE facilitation of learning was also shown to correlate with chromatin acetylation in the hippocampus. It is not known, however, whether such mechanisms are still into play during aging. In this study, we exposed a cohort of aged rats (18-month-old) to either a 6 month period of EE or standard housing conditions and investigated chromatin acetylation-associated events [histone acetyltranferase activity, gene expression, and histone 3 (H3) acetylation] and epigenetic modulation of the Bdnf gene under rest conditions and during learning. We show that EE leads to upregulation of acetylation-dependent mechanisms in aged rats, whether at rest or following a learning challenge. We found an increased expression of Bdnf through Exon-I-dependent transcription, associated with an enrichment of acetylated H3 at several sites of Bdnf promoter I, more particularly on a proximal nuclear factor κB (NF-κB) site under learning conditions. We further evidenced p65/NF-κB binding to chromatin at promoters of genes important for plasticity and hippocampus-dependent learning (e.g., Bdnf, CamK2D). Altogether, our findings demonstrate that aged rats respond to a belated period of EE by increasing hippocampal plasticity, together with activating sustained acetylation-associated mechanisms recruiting NF-κB and promoting related gene transcription. These responses are likely to trigger beneficial effects associated with EE during aging.

Significance statement: Aging weakens memory functions. Optimizing the neuronal circuitry required for normal brain function can be achieved by increasing sensory, motor, and cognitive stimuli resulting from interactions with the environment (behavioral therapy). This can be experimentally modeled by exposing rodents to environmental enrichment (EE), as with large cages, numerous and varied toys, and interaction with other rodents. However, EE effects in aged rodents has been poorly studied, and it is not known whether beneficial mechanisms evidenced in the young adults can still be recruited during aging. Our study shows that aged rats respond to a belated period of EE by activating specific epigenetic and transcriptional signaling that promotes gene expression likely to facilitate plasticity and learning behaviors.

Keywords: NF-κB; acetylation; aging; chromatin immunoprecipitation; environmental enrichment; spatial memory.