Genetics of Chronic Mild Stress and Alcohol Consumption

慢性轻度压力​​和饮酒的遗传学

• 批准号: 8631812
• 负责人: BYRON C JONES
• 金额: $ 38.77万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-26 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631812
• 关键词: Acute; Address; Adrenal Glands; Alcohol Phenotype; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Animals; Behavior; Binding; Biochemistry; Biological; Chromosome Mapping; Chronic; Complex; Consumption; Control Groups; Corticosterone; Dependence; Disease; Environment; Environmental Risk Factor; Ethanol; Event; Exposure to; Gene Expression Microarray Analysis; Genes; Genetic; Genotype; Globulins; Glucocorticoids; Heritability; Hippocampus (Brain); Hormones; Human; Human Genome; Hypothalamic structure; Life; Marriage; Measures; Messenger RNA; Methods; Modeling; Molecular Genetics; Mouse Strains; Multivariate Analysis; Mus; Occupations; Pathway interactions; Pattern; Phase; Phenotype; Physiological; Pituitary-Adrenal System; Population; Production; Protocols documentation; Quantitative Trait Loci; Recombinants; Relapse; Research; Risk; Schedule; Serum; Stress; Stressful Event; System; Systems Biology; Testing; Thymus Gland; Typology; Variant; Water; Weight; Work; alcohol use disorder; anti social; base; consumption measures; drinking; endophenotype; genetic analysis; genetic variant; indexing; novel; public health relevance; research study; response; stress related disorder; stressor; transcriptome sequencing; water testing

Abstract Since the discovery of different typologies for alcohol-use disorders in the 1980s, two major patterns have emerged. One type is oftentimes called alcohol abuse, whereas the other is associated with alcohol dependence. The abuse typology is associated with antisocial behavior and has an estimated high heritability, whereas the dependence- based typology is associated with stressful life events, bad marriage, difficult job, etc. This latter type is also supposed to have some degree of heritability, but this is difficult to assess because not all susceptible genotypes are subjected to stressful events. Attempts to develop animal models of the stress-related disorder have yielded inconsistent results. This is because the stressors tend to be short in duration and not always similar to human life events; or, the measure of alcohol drinking may not capture the kind of consumption seen in humans prior, during or following the stressful events. The primary aim of this proposal is to develop a model of stress-related change (increase or decrease) in alcohol consumption in a genetic reference population of mice subjected to several weeks of unpredictable environmental perturbations, termed chronic mild stress (CMS). The approach is a systems biology/systems genetics analysis of alcohol consumption within the framework of other physiological changes caused by CMS. Alcohol consumption will be assessed by the drinking in the dark (DID) paradigm and will be measured prior to CMS, during CMS and following CMS. The physiological measures include hypothalamus-pituitary-adrenal axis function, i.e., fecal corticosterone determinations during all phases of the experiment, thymus and adrenal weights. All endpoints will be subjected to multivariate analysis and genetic analysis to identify polymorphic genes that influence alcohol drinking and the other indices. Gene expression by microarray analysis will be performed on hippocampus, hypothalamus and adrenal glands to identify genes whose expression is altered by CMS and which genes that change expression are related to the other parameters, especially DID. At the end of the work, we will identify genes and gene networks related to stress-related alcohol consumption and that are syntenic with the human genome.

摘要 自20世纪80年代发现酒精使用障碍的不同类型以来， 主要模式已经出现。一种类型通常被称为酒精滥用，而 另一种与酒精依赖有关。虐待类型学与 反社会行为，并具有估计的高遗传性，而依赖- 基础类型与压力性生活事件、糟糕的婚姻、困难的工作等有关。 后一种类型也应该有一定程度的遗传性，但这是很难的。 因为并不是所有的易感基因型都会受到压力事件的影响。 尝试开发与压力有关的疾病的动物模型已经取得了成果， 不一致的结果。这是因为压力源的持续时间往往很短，而不是 总是类似于人类生活事件;或者，饮酒的措施可能无法捕获 在人类经历压力事件之前，期间或之后的消耗。 这项建议的主要目的是建立一个与压力有关的变化模型 在遗传参考群体的小鼠中的酒精消耗（增加或减少） 遭受数周不可预测的环境扰动，称为慢性 轻度胁迫（CMS）。该方法是一种系统生物学/系统遗传学分析， 酒精消费的框架内的其他生理变化所造成的 CMS。将通过黑暗中饮酒（DID）范式评估酒精摄入量 并将在CMS之前、CMS期间和CMS之后进行测量。生理 测量包括下丘脑-垂体-肾上腺轴功能，即，粪皮质酮 在实验的所有阶段期间测定胸腺和肾上腺重量。所有 将对终点进行多变量分析和遗传分析，以确定 影响饮酒和其他指标的多态性基因。基因 通过微阵列分析的表达将在海马、下丘脑 和肾上腺来鉴定其表达被CMS改变并且 改变表达的基因与其他参数相关，特别是DID。在 工作的最后，我们将确定与压力相关的基因和基因网络 与人类基因组同线的基因。