A043 Huntington’s disease and the benefits of an enriched environment on cognition: investigating the role of epigenetic regulations

<h3></h3> Huntington’s disease (HD) is a rare genetic neurodegenerative disorder which generally manifests in mid-adulthood and primary affects the striatum, leading to the development of cognitive, motor and neuropsychiatric symptoms. It is due to a CAG expansion in exon 1 of the HTT gene, and leads to various dysfunctions. We recently showed that HD striatal neurons undergo accelerated epigenetic aging characterized by a loss of epigenetic information, i.e. a decrease in the expression of striatal identity genes (e.g. Pde10a) and a re-expression of developmental genes (e.g. Onecut1). Although there is currently no cure available, various studies have demonstrated the beneficial effect of environmental enrichment (EE) in patients and animal models of HD. Using enrichment cages, we demonstrate a beneficial effect on cognition and other behavioral components, such as anxiety or apathy-like behaviour, in HD R6/1 transgenic mice. In order to characterize the underlying molecular mechanism, using OMICS techniques, we focus on the impact of EE housing on epigenetic and transcriptional regulations. Interestingly, our striatal RNAseq data generated from R6/1 mice show that EE housing induces an upregulation of genes linked to the adiponectin pathway (e.g. AdipoR2, adiponectin receptor 2), and partially normalizes the expression of developmental genes. This analysis is paralleled by CUT&amp;Tag data, where we focus on neuronal H3K9 and H3K27 acetylation levels known to be deregulated in the disease, in order to specify the role of epigenetic regulations in this effect. Further analysis will enable us to identify which pathways respond positively to EE housing, potentially uncovering new therapeutic targets.