Chromatin accessibility mapping of the striatum identifies tyrosine kinase FYN as a therapeutic target for heroin use disorder

Gabor Egervari, Diana Akpoyibo, Tanni Rahman, John F. Fullard, James E. Callens, Joseph A. Landry, Annie Ly, Xianxiao Zhou, Noël Warren, Mads E. Hauberg, Gabriel Hoffman, Randy Ellis, Jacqueline Marie N. Ferland, Michael L. Miller, Eva Keller, Bin Zhang, Panos Roussos, Yasmin L. Hurd

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish
Article number4634
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

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