DFG - Deutsche Forschungsgemeinschaft : Deciphering alcohol addiction-associated gene regulation changes on a single cell level. 01/2020-12/2022.
Changes in brain structure and function that results from chronic exposure to alcohol suggest that neuroadaptive alterations in gene regulation substantially contribute to addictive behavior. Transcriptional and epigenetic profiling of brain tissue from animal models and post-mortem human samples has identified multiple candidate genes to be dysregulated upon chronic alcohol exposure. However, a detailed assignment of those changes to specific cell types has not been performed due to technical limitations and lack of appropriate tissue. In this planned consortium, we will apply paralleled single cell sequencing to decipher transcriptional and epigenetic changes underlying alcohol addiction. We will perform single nuclei RNAsequencing (snRNA-seq) and snATAC-seq epigenetic profiling using postmortem tissue from a well-defined, high-quality brain bank of deceased alcohol addicts. We have previously established a novel snRNA-seq platform that allows isolating and sequencing of individual nuclei from snap-frozen brain samples obtained from patients with other neuropsychiatric diseases. In parallel we will use standardized human iPSC-derived forebrain organoids from controls and alcohol addicts to monitor alcohol-induced changes in gene regulation and gene expression in an isogenic (non-exposed vs. exposed; acute, chronic intermitting, acute withdrawal) forward approach. We expect that the proposed project will deliver the largest available database on alcohol addiction-associated gene regulation changes on a single cell level and help define critical contributors in the pathogenesis of alcohol addiction eventually eading to new therapeutic paradigms.