Abstract
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.
Highlights
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches
Considering the high cellular heterogeneity of the human striatum, we carried out ATAC-seq on Fluorescence-assisted nuclear sorting (FANS)-sorted neuronal and nonneuronal cells based on the presence or absence of nuclear marker NeuN, a nuclear protein specific to neurons in vertebrates[12]
We examined the proportion of variance in open chromatin regions explained by cell type, heroin-use status, gender and post-mortem interval (PMI)
Summary
The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. We previously showed that chronic heroin use leads to hyperacetylation of specific lysine residues of histone H3 (H3K27ac) at specific genomic loci[2] These alterations contribute to transcriptional changes related to glutamatergic neurotransmission and have a significant role in mediating addiction-like behaviors[2]. We identify a region near the gene encoding for tyrosine kinase FYN as most significantly affected by heroin in neurons We show that this locus is a putative regulatory element that enhances transcriptional activity in vitro. Our findings suggest that opioid exposure induces neurodegenerative cellular processes associated with epigenetic disturbances and that the use of FYN inhibitors could be promising for heroin medication development
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