The Role of Fyn Kinase in the Dorsal Striatum in Heroin Use Disorder

Project Summary/Abstract: Opioid use disorder is a public health crisis in the United States with roughly 80,000 overdoses taking place in 2021. Addiction can be conceptualized in three phases: binge/intoxication, withdrawal/negative affect, and preoccupation/craving. Current treatments for opioid use disorder substitute reward and prevent withdrawal, but there exists a treatment gap for the habitual/compulsive use associated with the third phase of addiction, necessitating better understanding of the molecular and cellular underpinnings of this behavior. Using an unbiased screening of the epigenome of postmortem samples of dorsal striatum from human heroin users, the Hurd Lab identified a promoter region for the gene encoding Fyn kinase as the locus with the most variance explained by heroin use in neurons. Fyn mRNA expression was elevated both in these human samples and in the dorsal striatum of rats that underwent heroin self-administration. Inhibition of Fyn either with a small molecule drug or siRNA infusions into the dorsal striatum decreased response for heroin in a translational model of relapse. Different subregions of the dorsal striatum mediate different aspects of drug-seeking behavior. I found that rats that compulsively sought heroin showed increased Fyn expression in both dorsomedial and dorsolateral striatum, while rats that took heroin non-compulsively showed increased Fyn expression in the dorsomedial subregion. My project will investigate the molecular and cellular mechanisms of Fyn in heroin self-administration behavior. I will knock down Fyn in dorsomedial and dorsolateral striatal subregions and test motivated and compulsive heroin seeking behavior, with the hypothesis that Fyn knockdown in dorsomedial striatum will reduce goal-directed responding, while Fyn knockdown in dorsolateral striatum will reduce habitual responding. I will perform RNA-sequencing in these subregions to assess molecular networks modulated by Fyn. To determine how Fyn regulates neural activity during heroin seeking, I will record neuronal activity in the dorsal striatum using in-vivo fiber-photometry. These experiments will enable me to uncover the molecular and cellular mechanisms underlying Fyn’s role in heroin use disorder and its effects on behavioral models of motivated versus habitual drug taking. I will learn a behavioral model of compulsivity, calcium imaging, and RNA-sequencing which will equip me to answer questions relating molecular changes to neuronal activity to behavior in my future career as a physician-scientist.