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

> **NIH NIH F30** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $53,974

## Abstract

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.

## Key facts

- **NIH application ID:** 10808905
- **Project number:** 5F30DA057092-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Jeremy Sherman
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,974
- **Award type:** 5
- **Project period:** 2023-04-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10808905

## Citation

> US National Institutes of Health, RePORTER application 10808905, The Role of Fyn Kinase in the Dorsal Striatum in Heroin Use Disorder (5F30DA057092-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10808905. Licensed CC0.

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