Genetic Risk for Methamphetamine Abuse

甲基苯丙胺滥用的遗传风险

• 批准号: 9097077
• 负责人: TAMARA J. RICHARDS
• 金额: $ 44.05万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9097077
• 关键词: Accounting; Affect; Alternative Splicing; Amygdaloid structure; Animals; Awareness; Behavior; Behavioral; Biological; Brain; Breeding; Cell Nucleus; Central Nervous System Stimulants; Chronic; Cocaine; Consensus; Consumption; Coupled; Cues; Data; Detection; Disease remission; Drug Addiction; Drug Exposure; Event; Future; Genes; Genetic; Genetic Drift; Genetic Risk; Genetic Techniques; Genetic Variation; Genetic study; Genotype; Goals; Haloperidol; Hand; House mice; Human; Inbred Strain; Individual; Individual Differences; Intake; Knowledge; Laboratories; Link; Location; Measures; Methamphetamine; Methods; Modeling; Molecular; Motivation; Motor Activity; Mus; Nature; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Oral; Outcome; Pathway Analysis; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Quantitative Trait Loci; RNA Interference; Research; Resistance; Risk; Rodent; Role; Self Administration; System; Systems Biology; Testing; Time; Untranslated RNA; Variant; Weight; Work; addiction; alcohol response; base; behavioral sensitization; craving; drinking; gene environment interaction; genetic variant; high risk; methamphetamine abuse; neural circuit; public health relevance; relating to nervous system; response; trait; transcriptome; transcriptome sequencing; vector

 DESCRIPTION (provided by applicant): Repeated administration of central stimulants (e.g., methamphetamine (MA); cocaine) sensitizes neural circuits that assign biological significance to drugs and drug-related cues, leading to increased drug-directed motivation and craving during periods of remission. Locomotor sensitization provides a behavioral record of these neural changes. However, there is genotype-dependent variation in the magnitude of sensitization that is induced by repeated, intermittent stimulant treatment. Furthermore, although the molecular mechanisms related to robust sensitization have been determined in some detail (e.g., Robison & Nestler, 2011), the specific genetic relationships between magnitude of sensitization and amount of voluntary drug intake are not known. The goal of the current research is to extend knowledge beyond awareness that the nucleus accumbens shell is a critical neural substrate of changes induced by repeated MA treatment, to identification of neural nodes and associated molecular mechanisms for both sensitization and MA intake. Transcriptome analysis will also be performed in the central nucleus of the amygdala, known to be critical for MA craving (e.g., Li et al., 2015), to determine regulatory events relevant to risk for MA sensitization and consumption. This application has 4 specific aims. In the first aim, 2 replicate sets of short-term selected lins will be created from heterogeneous stock-collaborative cross (HS-CC) founders that are methamphetamine (MA) sensitization prone (MASP) and resistant (MASR). Two sets will be created so that data can be carefully screened for replicability. These lines will be tested for MA intake. In the second aim, two replicate sets of short-term selected lines will be created from the HS-CC that is high (MAH) and low (MAL) MA consumers. These lines will also be tested for MA-induced sensitization. The third aim will use RNA-Seq and Weighted Gene Co- expression Network Analysis (WGCNA) to examine how selection affects gene transcriptional connectivity in the nucleus accumbens and central nucleus of the amygdala for each selection trait. The consensus network approach to be used will allow us to determine which co expression modules are most closely linked to functional change associated with "risk" (i.e., differences between the selected lines in a drug-free state). In addition, genotype data from RNA-Seq will be used to perform quantitative trait locus (QTL) analysis and identify the locations of trait-relevant genes. Finally, the fourth aim will be to manipulate key hub genes using RNA interference vectors and then examine the effect on the selected trait. This will directly test our transcriptional connectivity findings. Accomplishing this set of aims would provide critical molecular level data pertaining to the relationship between genetic risk for MA-induced neuroplasticity and intake. Use of the HS- CC is particularly important because this mouse stock captures ~90% of the genetic diversity in Mus musculus and better represents the kind of genetic diversity found in human populations.

 描述（由申请人提供）：重复施用中枢兴奋剂（例如甲基苯丙胺（MA）；可卡因）会使神经回路变得敏感，这些神经回路对药物和药物相关线索赋予生物学意义，从而导致缓解期间药物导向的动机和渴望增加运动敏化提供了这些神经变化的行为记录，然而，由重复引起的敏化程度存在基因型依赖性变化。此外，尽管与强烈致敏相关的分子机制已得到一定程度的确定（例如，Robison & Nestler，2011），但致敏程度与自愿药物摄入量之间的具体遗传关系尚不清楚。当前研究的目的是将伏隔核壳是重复 MA 治疗引起的变化的关键神经基质的认识扩展到认知神经节点和相关分子机制的识别还将在杏仁核中央核中进行转录组分析，杏仁核对于 MA 渴望至关重要（例如，Li 等人，2015），以确定与 MA 致敏和消费风险相关的监管事件。该应用程序有 4 个具体目标，第一个目标是，将从异构股票协作交叉 (HS-CC) 创始人中创建 2 个短期选定林的复制集。将创建两组甲基苯丙胺 (MA) 致敏性 (MASP) 和耐药性 (MASR)，以便仔细筛选数据的可复制性。 在第二个目标中，将从短期选定的线中创建两组复制品。 高 (MAH) 和低 (MAL) MA 消费者的 HS-CC 还将测试 MA 诱导的致敏作用。第三个目标将使用 RNA 测序和加权基因共表达网络分析 (WGCNA) 进行检查。选择如何影响伏隔核和杏仁核中央核中每个选择性状的基因转录连接性所使用的共识网络方法将使我们能够确定哪些共表达模块与与功能变化相关的最密切相关。 “风险”（即在无药物状态下所选品系之间的差异）此外，RNA-Seq 的基因型数据将用于进行数量性状基因座 (QTL) 分析并确定性状相关基因的位置。最后，第四个目标是使用 RNA 干扰载体操纵关键的枢纽基因，然后检查对所选性状的影响，这将直接测试我们的结果。 实现这组目标将提供有关 MA 诱导的神经可塑性遗传风险和摄入量之间关系的关键分子水平数据，因为该小鼠种群捕获了约 90% 的遗传风险。小家鼠的多样性，更好地代表了人类群体中发现的遗传多样性。