Role of microRNAs in Behavioral Sensitization to Cocaine

描述（由申请人提供）：我们分析了小鼠伏隔核（可卡因的关键靶区之一）急性和慢性可卡因给药后的miRNA水平，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的潜在调节剂。特别是，该miRNA的识别元件（MRE）位于BDNF mRNA的长3'未翻译区（UTR），该区域最近被证明与神经可塑性有关，并且在小鼠伏隔核中被慢性可卡因选择性地减少。BDNF先前与可卡因的长期影响有关，包括对可卡因运动效应的行为敏感，这是反复吸毒引起的功能变化的经典范例。这些发现提出了miRNA在药物滥用诱导的神经可塑性中发挥关键调节作用的总体假设，以及研究中的miRNA是可卡因诱导的行为可塑性调节因子的具体假设。为了验证这一假设，在Specific Aim 1中，我们将研究该miRNA在可卡因诱导的行为致敏中的作用，方法是通过渗透小泵慢性递送该miRNA或特定拮抗剂或抗ir。我们还将研究缺乏长BDNF 3'UTR的突变小鼠是否会损害可卡因诱导的行为致敏。miRNA具有调节大量mrna的潜力，因此可以作为特定遗传模块的主要调节剂。因此，Specific Aim 2将解决这个子假设，即这个特定的miRNA是控制可卡因诱导可塑性方面的一组特定转录本的主开关。为此，我们将采用多学科策略来研究其在激光微解剖伏隔核亚区中的调控和靶点。公共卫生相关性：拟议的研究将探索microrna（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改变中的作用。这些研究将扩展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产生影响。

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.