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（由申请方提供）：重复给予中枢兴奋剂（例如，甲基苯丙胺（MA）;可卡因）使神经回路敏感，这些神经回路将生物学意义分配给药物和与药物相关的线索，导致在缓解期间增加药物导向的动机和渴望。运动敏感性提供了这些神经变化的行为记录。然而，有基因型依赖性的变化，由重复，间歇性刺激治疗诱导的致敏的程度。此外，尽管已经在一些细节上确定了与鲁棒致敏相关的分子机制（例如，Robison & Nestler，2011），致敏程度和自愿药物摄入量之间的特定遗传关系尚不清楚。目前研究的目标是将知识扩展到意识之外，即核壳是重复MA治疗引起的变化的关键神经基质，以识别神经节点和相关的致敏和MA摄入的分子机制。转录组分析也将在杏仁核的中央核中进行，已知杏仁核对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。该应用程序有四个具体目标。在第一个目标中，将从具有甲基苯丙胺（MA）致敏倾向（MASP）和耐药（MASR）的异质种群协作杂交（HS-CC）建立者中创建2组重复的短期选定林斯。将建立两个数据集，以便仔细筛选数据，确保其可复制性。这些线路将进行MA测试 摄入在第二个目标中，将从两个重复的短期选择系中创建两个重复的短期选择系。 HS-CC是高（MAH）和低（MAL）MA消费者。还将检测这些品系的MA诱导致敏性。第三个目标将使用RNA-Seq和加权基因共表达网络分析（WGCNA）来研究选择如何影响每个选择性状的杏仁核和中央核中的基因转录连接。所使用的共识网络方法将允许我们确定哪些共表达模块与与“风险”相关的功能变化最密切相关（即，在无药物状态下所选择的线之间的差异）。此外，来自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，第四个目标将是使用RNA干扰载体操纵关键枢纽基因，然后检查对所选性状的影响。这将直接考验我们的 转录连接发现。实现这一目标将提供关键的分子水平的数据有关的遗传风险MA诱导的神经可塑性和摄入量之间的关系。HS-CC的使用特别重要，因为这种小鼠种群捕获了小家鼠中约90%的遗传多样性，并且更好地代表了在人类种群中发现的遗传多样性。