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Neuron Subtype Translatomics in Opiate Abuse

阿片类药物滥用中的神经元亚型翻译组学

基本信息

批准号：
10013157
负责人：
DAVID M DIETZ
金额：
$ 19.62万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10013157
关键词：
Abstinence Applications Grants Attention Behavior Behavioral Brain Data Dependence Disease Dopamine Receptor Epidemic Foundations Functional disorder Genetic Transcription Health Heroin Hour Immunohistochemistry Investigation Lead Link Mediating Messenger RNA Molecular Molecular Profiling Mus Neurobiology Neurons Nucleus Accumbens Opiate Addiction Opioid Overdose Pharmaceutical Preparations Pharmacology Process Proteins RNA Relapse Reporter Research Reverse Transcriptase Polymerase Chain Reaction RiboTag Ribosomes Rodent Role Self Administration Therapeutic Uses Time Transgenic Organisms Translations addiction behavioral plasticity behavioral response brain dysfunction brain reward regions cell type cohort craving drug of abuse improved insight neuroadaptation novel novel therapeutics opioid abuse opioid exposure opioid use relapse risk response therapeutic target transcriptome sequencing translatome

项目摘要

Project Summary: Opiate use, dependence, and addiction have dramatically increased to epidemic proportions in recent years, leading to substantial financial and societal health burdens, as well as an increasing number of overdoses. Thus, there is a crucial need for novel therapies to treat opiate dependence and cravings occurring with abstinence, which lead to relapse. Many studies indicate dysfunctional brain circuits in opiate use and abstinence, while other studies have identified distinct molecular adaptations underlying opiate-induced behaviors. Such studies emphasize a need to approach opiate use from a combined circuit and molecular perspective to link candidate opiate use and abstinence molecules to dysfunctional neuronal subtypes. This could uncover molecules in disease vulnerable neuron subtypes that can be pharmacologically targeted for opiate use therapeutics. The neuronal subtypes in the nucleus accumbens (NAc) deserve considerable attention in opiate abuse. The NAc is a critical brain hub for altered molecular processes that mediate behavioral responses to opiates and other drugs of abuse. Further, we previously demonstrated distinct roles of the two NAc projection medium spiny neuron (MSN) subtypes, those enriched in dopamine receptor 1 vs. 2 (D1-MSNs vs. D2-MSNs), in opiate induced behaviors. However, there is little information into the molecular adaptations, and corresponding neuronal adaptations occurring in specific NAc neuron subtypes in opiate use and abstinence. To provide insight into this we will perform translatome profiling, using RiboTag, in the two MSN subtypes after opiate use. Since cellular and behavioral plasticity associated with opiate exposure occurs along a continuum we will perform this translatome profiling in D1-MSNs vs. D2-MSNs following abstinence from heroin self-administration at early and prolonged time periods. The studies proposed in this grant application will, for the first time, identify the distinct translatome adaptations occurring temporally following discontinuance of heroin in a cell-type-specific manner. Such studies are essential for uncovering molecules underlying cellular and circuit dysfunction in opiate use and abstinence, thus providing multiple avenues of investigation into the subtype-specific neurobiological underpinnings of opiate abuse.

项目摘要：近年来，阿片类药物的使用、依赖和成瘾急剧增加，达到了流行病的程度，导致巨大的财政和社会健康负担，以及越来越多的药物过量。因此，迫切需要新的疗法来治疗阿片依赖性和伴随阿片依赖性发生的渴望。禁欲，导致复发。许多研究表明，使用阿片类药物时大脑回路功能失调，戒断，而其他研究已经确定了不同的分子适应性基础阿片诱导行为。这些研究强调需要从结合回路和分子水平来研究阿片类药物的使用。将候选阿片类药物使用和戒断分子与功能障碍的神经元亚型联系起来的观点。这可以发现疾病易感神经元亚型中的分子，阿片类药物使用治疗。丘脑核（NAc）中的神经元亚型值得重视。注意阿片类药物滥用。NAc是改变分子过程的关键大脑中枢，对阿片类药物和其他滥用药物的行为反应。此外，我们先前展示了不同的角色，在两种NAc投射中型多刺神经元（MSN）亚型中，多巴胺受体1和2富集的亚型（D1-MSN与D2-MSN），在阿片诱导的行为。然而，很少有信息进入分子适应，以及阿片类药物使用中特定NAc神经元亚型中发生的相应神经元适应和禁欲为了深入了解这一点，我们将使用RiboTag在两个使用鸦片后的MSN亚型。由于细胞和行为的可塑性与阿片类药物的暴露发生沿着一个连续体，我们将在禁欲后的D1-MSN与D2-MSN中进行这种翻译组分析早期和长期自我注射海洛因。本补助金中提出的研究应用程序将首次识别在时间上发生的不同的翻译组适应，以特定细胞类型的方式停止海洛因。这样的研究对于发现分子是必不可少的阿片类药物使用和戒断中潜在的细胞和回路功能障碍，从而提供了多种途径，调查阿片类药物滥用的亚型特异性神经生物学基础。