Genetic and hormonal contributions to sex differences in vulnerability to drug use

遗传和荷尔蒙对吸毒易感性性别差异的影响

• 批准号: 9886536
• 负责人: Wendy Jean Lynch
• 金额: $ 34.73万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886536
• 关键词: Adult; Alcohols; Behavior; Behavioral; Bioinformatics; Biological Assay; Brain; Candidate Disease Gene; ChIP-seq; Chromatin; Chronic stress; Cocaine; Cocaine Dependence; Code; Cognitive; Competence; Data; Development; Dopamine; Drug Addiction; Drug usage; Enzymes; Epigenetic Process; Estradiol; Estrogens; Female; Four Core Genotypes; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Gonadal Hormones; Gonadal structure; Grant; Histone Code; Hormonal; Human; Individual; Intravenous; Knockout Mice; Lead; Motivation; Mus; Mutation; Neurons; Nuclear; Nucleus Accumbens; Opioid Receptor; Ovarian; Ovary; Pain; Pharmaceutical Preparations; Phenotype; Ploidies; Prefrontal Cortex; Prevention strategy; Preventive Intervention; Prosencephalon; Regulation; Research; Research Personnel; Rewards; Risk; Rodent; Role; Running; Self Administration; Serotonin; Sex Chromosomes; Sex Differences; Testing; Testis; Tissues; Transposase; Woman; Work; X Chromosome; X Inactivation; XCL1 gene; addiction; brain tissue; design; drug of abuse; drug use vulnerability; gamma-Aminobutyric Acid; gene product; gene repression; genotypic sex; histone demethylase; histone modification; innovation; literate; male; men; mouse model; novel; overexpression; phenomenological models; programs; response; sex; transcription factor

Abstract Sex differences in drug-related behaviors have been well documented and attributed primarily to differences in levels of estrogens in adult men versus women. This program advances the field beyond this hypothesis to examine another important factor, sex chromosome complement, with a focus on X-chromosome genes that escape X-inactivation which are expressed in greater levels in female versus male brains. The four core genotype (FCG) mouse model allows separate analysis of gonadal hormones and sex chromosome complement (XX vs. XY). In Aim 1 these mice will be used to examine combined and separate actions of estradiol and sex chromosome complement on vulnerability to cocaine addiction using intravenous self- administration. Rates of acquisition and levels of motivation to obtain the drug will be evaluated. In Aim 2, we will define the role of two X-chromosome genes that escape inactivation in mouse and human brain, Utx and Smcx. These genes code for enzymes that demethylate histone modifications, regulating chromatin accessibility and transcription on a wide basis. This work will be conducted with two lines of inducible, tissue- specific knockout mice that lack the expression of either gene (Utx or Smcx) in CaMK2α in forebrain, including neurons in the nucleus accumbens. The mice will be tested as in Aim 1 for cocaine vulnerability and motivation. In Aim 3 brain tissue from the nucleus accumbens of mice tested in Aims 1 and 2 will be used for epigenetic analysis. A combination of ATAC (Assay for Transposase Accessible Chromatin-), Pro (Precision Nuclear Run-On-) and ChIP (Chromatin Immuno-Precipitation-) Sequencing will be used to identify transcriptionally active and repressed genes associated with chromatin restructuring and important transcription factors. The long term objective of this work is to reveal new mechanisms that underlie sex differences in vulnerability to addiction that help clinicians design sex-specific preventions/interventions.

摘要 与毒品相关的行为中的性别差异已经被很好地记录下来，并主要归因于差异 成年男性与女性的雌激素水平。这个计划使这个领域超越了这个假设。 检查另一个重要因素，性染色体互补，重点是X染色体基因 逃避X-失活的基因在女性大脑中的表达水平高于男性。四个核心 基因分型(FCG)小鼠模型可以单独分析性腺激素和性染色体 补语(XX对XY)。在目标1中，这些小鼠将被用来检查联合和单独的作用 自身静脉注射雌二醇和性染色体对可卡因成瘾易感性的影响 行政管理。将评估获得药物的速度和获得药物的动机水平。在目标2中，我们 将确定在小鼠和人脑中逃脱失活的两个X染色体基因的作用，UTX和 Smcx。这些基因编码的酶使组蛋白修饰去甲基化，从而调节染色质 广泛的可及性和转录能力。这项工作将用两条可诱导的组织- 前脑CaMK2α中缺乏任何一种基因(Utx或Smcx)表达的特定基因敲除小鼠，包括 伏隔核内的神经元。小鼠将接受与目标1相同的可卡因易感性测试，并 动力。在目标3中，目标1和目标2中测试的小鼠伏隔核脑组织将用于 表观遗传学分析。ATAC(转座酶可及染色质分析)、Pro(精确度)的组合 将使用核糖核酸(Run-on-On)和芯片(染色质免疫沉淀-)测序来鉴定 与染色质重组相关的转录活性和抑制基因 转录因子。这项工作的长期目标是揭示性行为背后的新机制 对成瘾易感性的差异有助于临床医生设计针对性别的预防/干预措施。