Environmental Enrichment Increased Bdnf Transcripts in the Prefrontal Cortex: Implications for an Epigenetically Controlled Mechanism.

Environmental enrichment (EE) is a condition characterized by its complexity regarding social contact, exposure to novelty, tactile stimuli and voluntary exercise, also is considered as a eustress model. The impact of EE on brain physiology and behavioral outcomes may be at least partly underpinned by mechanisms involving the modulation of the brain-derived neurotrophic factor (BDNF), but the connection between specific Bdnf exon expression and their epigenetic regulation remain poorly understood. This study aimed to dissect the transcriptional and epigenetic regulatory effect of 54-day exposure to EE on BDNF by analysing individual BDNF exons mRNA expression and the DNA methylation profile of a key transcriptional regulator of the Bdnf gene, exon IV, in the prefrontal cortex (PFC) of C57BL/6 male mice (sample size = 33). Bdnf exons II, IV, VI and IX mRNA expression were upregulated and methylation levels at two CpG sites of exon IV were reduced in the PFC of EE mice. As deficit in exon IV expression has also been causally implicated in stress-related psychopathologies, we also assessed anxiety-like behavior and plasma corticosterone levels in these mice to determine any potential correlation. However, no changes were observed in EE mice. The findings may suggest an EE-induced epigenetic control of BDNF exon expression via a mechanism involving exon IV methylation. The findings of this study contribute to the current literature by dissecting the Bdnf gene topology in the PFC where transcriptional and epigenetic regulatory effect of EE takes place.

Environmental enrichment enhances conditioned place preference to ethanol via an oxytocinergic-dependent mechanism in male mice.

Environmental conditions, such as stress and environmental enrichment (EE), influence predisposition to alcohol use/abuse; however, the underlying mechanisms remain unknown. To assess the effect of environmental conditions on the initial rewarding effects of alcohol, we examined conditioned place-preference (CPP) to alcohol following exposure to EE in mice. Since social context is a major factor contributing to initial alcohol-drinking, we also assessed the impact of EE on the levels of the "social neuropeptide" oxytocin (OT) and its receptor, OTR. Finally, we assessed the effect of pharmacological manipulations of the oxytocinergic system on EE-induced alcohol CPP. While EE increased sociability and reduced anxiety-like behaviors, it caused a ∼3.5-fold increase in alcohol reward compared to controls. EE triggered profound neuroadaptations of the oxytocinergic system; it increased hypothalamic OT levels and decreased OTR binding in the prefrontal cortex and olfactory nuclei of the brain. Repeated administration of the OT analogue carbetocin (6.4 mg/kg/day) mimicked the behavioral effects of EE on ethanol CPP and induced similar brain region-specific alterations of OTR binding as those observed following EE. Conversely, repeated administration of the OTR antagonist L,369-899 (5 mg/kg/day) during EE exposure, but not during the acquisition of alcohol CPP, reversed the pronounced EE-induced ethanol rewarding effect. These results demonstrate for the first time, a stimulatory effect of environmental enrichment exposure on alcohol reward via an oxytocinergic-dependent mechanism, which may predispose to alcohol abuse. This study offers a unique prospective on the neurobiological understanding of the initial stages of alcohol use/misuse driven by complex environmental-social interplay.