Modulation of Nicotine Reward-Associated Behaviors by MicroRNAs

MicroRNA 对尼古丁奖励相关行为的调节

• 批准号: 9049469
• 负责人: Alison Patrice Casserly
• 金额: $ 3.83万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2017-04-09
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9049469
• 关键词: Acetylcholine; Affinity; Alkaloids; Behavior; Binding; Biological Neural Networks; Brain; Brain region; Caenorhabditis elegans; Cell Culture Techniques; Cell surface; Cells; Cessation of life; Chronic; Cocaine; Data; Dependovirus; Development; Dose; Drosophila acetylcholine receptor alpha-subunit; Endoplasmic Reticulum; Exposure to; Gated Ion Channel; Gene Expression; Health; Histocompatibility Testing; In Situ Hybridization; In Vitro; Length; Ligands; Mammals; Measures; Mediating; Messenger RNA; MicroRNAs; Midbrain structure; Molecular Conformation; Mus; Neurons; Neurotransmitters; Nicotine; Nicotinic Receptors; Nucleotides; Pathway interactions; Pharmaceutical Preparations; Play; Post-Transcriptional Regulation; Property; Proteins; RNA; Regulation; Regulator Genes; Regulatory Pathway; Reporting; Repression; Reverse Transcription; Rewards; Rodent; Role; Serotyping; Structure; Testing; Tobacco; Tobacco Use Cessation; Tobacco use; Transcript; Up-Regulation; Ventral Tegmental Area; Work; addiction; alpha-bungarotoxin receptor; behavior test; derepression; drug of abuse; environmental tobacco smoke exposure; in vivo; mRNA Expression; mortality; novel; overexpression; preference; receptor; research study; response; stoichiometry; vector

DESCRIPTION (provided by applicant): Adverse health consequences of tobacco use are the leading cause of preventable mortality worldwide, resulting in approximately 6 million deaths per year. The addictive component of tobacco is nicotine, a tertiary alkaloid that binds and activates nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels that are normally activated by the endogenous neurotransmitter acetylcholine (ACh). Neuronal nAChRs are pentamers assembled from various combinations of receptor subunits and different subunit combinations confer different affinities and functionalities to the receptor subtypes. Eleven subunits, ¿2- ¿7, ¿9, ¿10 and ¿2- ¿4, have been identified in mammalian neuronal nAChRs. Interestingly, chronic nicotine or cigarette smoke exposure results in the upregulation of nAChRs in the brain, including structures within the mesocorticolimbic dopaminergic (DAergic) pathway that is implicated in reward and addiction. While not completely understood, nicotine- induced upregulation of nAChRs is thought to contribute to addiction by altering the neural network, possibly resulting in increased tolerance or altered sensitivity to nicotine. While there are many proposed mechanisms for nAChR upregulation, it is largely believed that multiple forms of posttranscriptional regulation is responsible for this phenomenon. Currently, there is not much known about posttranscriptional regulation of mammalian nAChR subunit expression by microRNAs (miRNAs), small single stranded RNA molecules that function as negative regulators of gene expression. However, there is emerging evidence that miRNA expression is decreased in various rodent tissue types in response to nicotine exposure. In addition, recent studies have found that miRNA dysregulation in response to exposure to various drugs of abuse, including cocaine, can influence rewarding properties of the drug and alter addiction-associated behaviors. We have recently generated preliminary data suggesting that a novel regulatory mechanism involving miRNAs may be at work in the nicotine-mediated upregulation of nAChRs. Preliminary experiments from our lab have identified several miRNAs that are predicted to target nAChR subunit mRNA transcripts, in particular miR-494 and miR-542-3p that target ¿4 and ¿2 transcripts, respectively. In Aim 1, I will determine if ¿4 and/or ¿2 are modulated by miR- 494 and/or miR-542-3p in primary midbrain neuronal cultures. In Aim 2, I will determine if miR-494 and/or miR- 542-3p are modulators of nicotine reward-associated behavior in mice. Through these aims, I hope to achieve a better understanding of the role of miR-494 and miR-542-3p in nicotine reward-associated behaviors, possibly revealing new targets for the development of tobacco cessation aids.

描述（由适用提供）：烟草使用的不利健康后果是全球可预防死亡率的主要原因，每年大约有600万人死亡。烟草的附加成分是尼古丁，尼古丁是一种结合和激活烟碱乙酰胆碱受体（NACHRS）的三级生物碱，通常由内源性神经递质乙酰胆碱（ACH）激活的配体门控离子通道。神经元NACHR是从受体亚基的各种组合和不同亚基组合组合组合的五聚会，会议会议与受体亚型的不同亲和力和功能。 11个亚基，€2-€7，€9，€10和2-€4，已在哺乳动物Neuronal NACHR中鉴定出来。有趣的是，慢性尼古丁或香烟烟雾暴露会导致大脑中NACHR的上调，包括在奖励和成瘾中暗示的中皮质糖多巴胺能（Daergic）途径内的结构。虽然尚未完全理解，但尼古丁引起的NACHR的上调被认为是通过改变神经元网络来导致成瘾的，可能导致耐受性提高或对尼古丁的敏感性改变。尽管有许多提出的NACHR上调的机制，但在很大程度上认为，转录后调节的多种形式是该现象的原因。当前，关于microRNA（miRNA）对哺乳动物NACHR亚基表达的转录后调节（miRNA），这是鲜为人知的，这是小的单链RNA分子，可作为基因表达的负调节剂。然而，有新的证据表明，各种啮齿动物组织类型的miRNA表达因尼古丁暴露而改善。此外，最近的研究发现，响应于包括可卡因在内的各种滥用药物的miRNA失调会影响药物的奖励性质并改变与成瘾相关的行为。我们最近生成了初步数据，表明涉及miRNA的新型调节机制可能在NACHRS的尼古丁介导的上调中起作用。我们实验室的初步实验已经确定了几个miRNA，这些miRNA预测将靶向NACHR亚基mRNA转录本，尤其是miR-494和miR-542-3p，分别靶向4和2转录本。在AIM 1中，我将确定在原发性中脑神经元培养物中，MiR-494和/或miR-542-3p是否通过miR-494和/或miR-542-3p调节。在AIM 2中，我将确定miR-494和/或mir-542-3p是否是小鼠尼古丁奖励相关行为的调节剂。通过这些目标，我希望更好地了解miR-494和miR-542-3p在尼古丁奖励相关行为中的作用，这可能揭示了开发烟草戒烟辅助工具的新目标。

项目成果

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family.

• DOI: 10.1261/rna.034066.112
• 发表时间: 2014-12
• 期刊: RNA (New York, N.Y.)
• 作者: Hogan EM;Casserly AP;Scofield MD;Mou Z;Zhao-Shea R;Johnson CW;Tapper AR;Gardner PD
• 通讯作者: Gardner PD