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

Fyn 激酶在海洛因使用障碍中背侧纹状体中的作用

基本信息

批准号：
10679555
负责人：
Jeremy Sherman
金额：
$ 5.04万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679555
关键词：
Abstinence Accounting Affect Animal Model Autopsy Behavior Behavioral Behavioral Assay Behavioral Model Bioinformatics Biological Assay Calcium Cannulas Cells Characteristics Chromatin Compulsive Behavior Corpus striatum structure Cues Cyclic AMP Disease Dorsal Drug usage Epigenetic Process Female Fiber Fiber Optics Future Gene Expression Genes Genetic Transcription Glutamates Goals Heroin Heroin Users Human Image Implant Individual Infusion procedures Intoxication Laboratory Study Lateral Learning Long-Evans Rats Measures Medial Mediating Molecular Motivation Neurons Occupations Ontology Operative Surgical Procedures Opiate Addiction Overdose Pathology Pathway interactions Pharmaceutical Preparations Phase Phosphotransferases Photometry Physicians Population Promoter Regions Proto-Oncogene Proteins c-fyn Public Health Rattus Relapse Rewards Role Sampling Scientist Self Administration Signal Transduction Small Interfering RNA Substance Use Disorder Synapses Synaptic plasticity Testing Training United States Viral Withdrawal addiction career cell type craving density design differential expression drug craving drug seeking behavior epigenome experience experimental study heroin use in vivo inhibitor interest knock-down large datasets mRNA Expression male motivated behavior multidisciplinary negative affect neural opioid use disorder optical fiber overdose death postsynaptic prevent response screening small molecule synaptic function transcription factor transcriptome sequencing translational model

项目摘要

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.

项目摘要/摘要：阿片类药物使用障碍是美国的一场公共卫生危机，大约有 80,000 人服用过量 2021. 成瘾可以分为三个阶段：暴饮暴食/中毒、戒断/负面影响和目前对阿片类药物使用障碍的治疗替代奖励并防止戒断，但与成瘾第三阶段相关的习惯性/强迫性使用存在治疗差距，需要更好地了解这种行为的分子和细胞基础。对人类海洛因使用者的背侧纹状体死后样本的表观基因组进行公正的筛查， Hurd 实验室发现编码 Fyn 激酶的基因的启动子区域是变异最大的基因座解释是，在这些人类样本和神经元中使用海洛因时，Fyn mRNA 表达均升高。接受海洛因自我给药的大鼠的背侧纹状体或用小剂量的 Fyn 抑制。分子药物或 siRNA 输注到背侧纹状体，在转化过程中降低了对海洛因的反应复发模型。背侧纹状体的不同亚区域介导药物寻求的不同方面。我发现强迫性寻找海洛因的老鼠在两种行为中都表现出 Fyn 表达增加。背外侧纹状体，而非强迫性服用海洛因的老鼠表现出 Fyn 增加我的项目将研究其分子和细胞机制。海洛因自我给药行为中的 Fyn 我会击倒背外侧纹状体中的 Fyn。子区域并测试动机性和强迫性海洛因寻求行为，假设 Fyn 背外侧纹状体的击倒将减少目标导向的反应，而背外侧的 Fyn 击倒将减少目标导向的反应我将在这些次区域进行 RNA 测序来评估。 Fyn 调节的分子网络为了确定 Fyn 在寻找海洛因期间如何调节神经活动，我将使用体内光纤光度测定法记录背侧纹状体的神经活动。我要揭示 Fyn 在海洛因使用障碍中的作用及其背后的分子和细胞机制对动机性吸毒与习惯性吸毒行为模型的影响我将学习一个行为模型。强迫症、钙成像和 RNA 测序，这将使我能够回答相关问题在我未来作为一名医生科学家的职业生涯中，神经活动和行为的分子变化。