Genetic Risk for Methamphetamine Abuse

甲基苯丙胺滥用的遗传风险

• 批准号: 9923047
• 负责人: TAMARA J. RICHARDS
• 金额: $ 41.8万
• 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/9923047
• 关键词: 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 Transcription; Genetic Variation; Genetic study; Genotype; Goals; Haloperidol; Hand; Heritability; House mice; Human; Inbred Strain; 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; Work; addiction; alcohol response; base; behavioral sensitization; craving; drinking; gene environment interaction; genetic variant; high risk; individual response; 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（由应用提供）：重复给中央兴奋剂（例如甲基苯丙胺（MA）；可卡因）敏感的神经回路，这些神经回路为药物和药物相关提示分配生物学意义，从而导致药物导向的动机增加和渴望在缓解期间。运动灵敏度提供了这些神经元变化的行为记录。然而，通过重复的间歇性刺激治疗引起的灵敏度大小存在基因型依赖性变化。此外，尽管已经确定了与鲁棒敏感性有关的分子机制（例如Robison＆Nestler，2011年），但尚不清楚灵敏度和自愿药物摄入量之间的特定遗传关系。当前研究的目的是将知识扩展到意识到伏隔核是由重复MA治疗引起的变化的关键神经底物，以鉴定神经节点和相关的分子机制，以实现敏感性和MA摄入量。转录组分析还将在杏仁核的中央核心中进行，已知对于MA渴望至关重要（例如Li等人，2015年），以确定与MA感觉和消费风险相关的调节事件。该应用程序具有4个特定目标。在第一个目的中，将创建2组短期选择的lins集，该lins由异质的股票合并杂交（HS-CC）创始人创建，这些创始人是甲基苯丙胺（MA）敏感性（MASP）和耐药性（MASR）。将创建两组，以便可以仔细筛选数据以获得可复制性。这些线将用于MA 进气。在第二个目标中，将创建两个复制的短期选择行 HS-CC高（MAH）和低（MAL）MA消费者。这些线也将测试MA诱导的灵敏度。第三个目标将使用RNA-seq和加权基因共表达网络分析（WGCNA）来检查选择如何影响每个选择性状的杏仁核的伏隔核和杏仁核的中央核的基因转录连通性。要使用的共识网络方法将使我们能够确定哪些CO表达模块与与“风险”相关的功能变化最紧密相关（即，在无药物状态下所选线之间的差异）。此外，来自RNA-SEQ的基因型数据将用于执行定量性状基因座（QTL）分析并识别与性状相关基因的位置。最后，第四个目标是使用RNA干扰向量操纵关键集线器基因，然后检查对所选性状的影响。这将直接测试我们的 转录连接性发现。实现这一目标将提供与MA诱导的神经可塑性和摄入量之间的关系有关的关键分子水平数据。 HS-CC的使用尤其重要，因为该小鼠库存捕获了Mus Musculus遗传多样性的90％，并且更好地代表了人类种群中发现的遗传多样性。