Epigenetic control of stress and environmental enrichment interplay on anxiety and prefrontal cortex BDNF expression

Despite widespread recognition of the detrimental effects of chronic stress in developing stress-related psychopathologies, the interplay between environmental enrichment (EE) and chronic stress, along with their underlying mechanisms, remains poorly understood. Chronic stress disrupts brain-derived neurotrophic factor (BDNF) signalling pathways in the prefrontal cortex (PFC) and promotes epigenetic modifications that contribute to the pathogenesis of depression and anxiety disorders. Environmental enrichment (EE) has also been investigated for its effects on BDNF expression and epigenetic regulation, with evidence suggesting a possible role in modulating vulnerability to stress-related psychopathologies. Here, we investigated the impact of subthreshold chronic unpredictable mild stress (CMS) on mice pre-housed in EE conditions, examining anxiety-like behaviour, corticosterone levels, PFC Bdnf expression, BDNF protein levels, and DNA methylation profiles. We also explored whether the effects of CMS on EE-housed mice are mediated by DNA methylation mechanisms. CMS precipitated anxiety-like behaviour in EE-housed mice, but not in non-enriched controls. This phenotype was attenuated by systemic administration of the DNA methylation inhibitor 5-aza-2'-deoxycytidine, suggesting an epigenetic mechanism. While prolonged EE alone elevated plasma corticosterone levels, this was suppressed when EE was combined with CMS. EE followed by CMS downregulated Bdnf exons I, II, IV, and IX mRNA expression in the PFC. No changes in DNA methylation profile were detected at exon IX. While no effect was detected on BDNF protein levels, 5-azaC reduced BDNF specifically in EE-housed mice. These findings shed light on the emotional behavioural consequences and the molecular and epigenetic mechanisms underlying the interplay between CMS and EE.