Role of microRNAs in Behavioral Sensitization to Cocaine

microRNA 在可卡因行为敏感性中的作用

• 批准号: 7712769
• 负责人: Vez REPUNTE-CANONIGO
• 金额: $ 28.49万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7712769
• 关键词: 3' Untranslated Regions; Acute; Address; Alcohols; Behavioral; Biochemical; Bioinformatics; Brain; Chronic; Cocaine; Cocaine Dependence; Drug usage; Elements; Functional RNA; Gene Expression; Gene Expression Alteration; Gene Expression Regulation; Genetic; Intake; Knowledge; Lasers; Light; Long-Term Effects; Messenger RNA; MicroRNAs; Modeling; Mus; Mutant Strains Mice; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Play; Process; Regulation; Reporting; Role; Testing; Transcript; Untranslated Regions; behavioral sensitization; drug of abuse; multidisciplinary; neurotropic; osmotic minipump; public health relevance; therapeutic target

DESCRIPTION (provided by applicant): We have profiled miRNA levels after acute and chronic cocaine administration in the mouse nucleus accumbens, one of cocaine's key target regions and identified a specific miRNA as a potential regulator of the mRNA for mouse brain derived neurotropic factor (BDNF). In particular, the miRNA recognizing element (MRE) for this miRNA was located in the long 3' untranslated region (UTR) of the mRNA for BDNF, which has been recently shown to be involved in neural plasticity, and that was selectively reduced by chronic cocaine administration in the mouse nucleus accumbens. BDNF has been previously implicated in the long-term effects of cocaine, including behavioral sensitization to the locomotor effects of cocaine, which is a classic paradigm of functional changes induced by repeated drug use. These findings suggest the overarching hypothesis of the present application that miRNAs play key regulatory roles in the neural plasticity induced by drugs of abuse and the specific hypothesis that the miRNA under study is a regulator of cocaine-induced behavioral plasticity. To test this hypothesis, in Specific Aim 1 we will investigate the role of this miRNA in cocaine-induced behavioral sensitization by use of chronic delivery by osmotic minipump of this miRNA or a specific antagonist or antimiR. We will also investigate whether cocaine-induced behavioral sensitization is impaired in mutant mice that lack the long BDNF 3'UTR. miRNA have the potential to regulate a large number of mRNAs and can therefore act as master regulator of specific genetic-modules. Therefore, Specific Aim 2 will address the sub-hypothesis that this specific miRNA is a master switch of a specific set of transcripts controlling aspects of cocaine-induced plasticity. To this aim, we will use a multidisciplinary strategy to investigate its regulation and targets in laser microdissected nucleus accumbens sub-regions. PUBLIC HEALTH RELEVANCE: The proposed studies will explore the role of microRNAs, a class of non-coding RNA, in the gene expression alterations in a model of cocaine-induced long-lasting functional changes. These studies will extend our understanding of the neurobiology of compulsive cocaine intake and may have implications for the identification of therapeutic targets for the treatment of cocaine addiction.

描述(申请人提供)：我们已经分析了急性和长期注射可卡因后小鼠伏隔核中的miRNA水平，这是可卡因的关键靶区之一，并确定了一种特定的miRNA作为小鼠脑源性神经营养因子(BDNF)mRNA的潜在调节因子。特别是，该miRNA的miRNA识别元件(MRE)位于BDNF的mRNA的长3‘非翻译区(UTR)，最近被证明参与神经可塑性，并被长期给予可卡因选择性地减少在小鼠伏隔核。BDNF以前被认为与可卡因的长期效应有关，包括对可卡因的运动效应的行为敏感化，这是反复使用药物引起的功能变化的经典范例。这些发现提出了目前应用的首要假设，即miRNAs在滥用药物诱导的神经可塑性中发挥关键调节作用，以及特定的假设，即正在研究的miRNA是可卡因诱导的行为可塑性的调节因子。为了验证这一假说，在特定的目标1中，我们将利用这种miRNA的渗透微泵或特定的拮抗剂或抗iR来研究这种miRNA在可卡因诱导的行为敏化中的作用。我们还将研究在缺乏长BDNF3‘UTR的突变小鼠中，可卡因诱导的行为敏感化是否受到损害。MiRNA具有调节大量mRNAs的潜力，因此可以作为特定遗传模块的主调节器。因此，特定的目标2将解决这个特定的miRNA是控制可卡因诱导的可塑性方面的一组特定转录本的主开关的子假说。为此，我们将使用多学科策略来研究其在激光显微切割伏隔核亚区的调控和靶点。公共卫生相关性：拟议的研究将探索microRNAs，一类非编码RNA，在可卡因诱导的长期功能变化模型中基因表达变化中的作用。这些研究将扩大我们对强迫性可卡因摄入的神经生物学的理解，并可能对确定治疗可卡因成瘾的治疗靶点有意义。