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: 10314074
• 负责人: Wendy Jean Lynch
• 金额: $ 36.45万
• 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/10314074
• 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; Intervention; Intravenous; Knockout Mice; Lead; Motivation; Mus; Mutation; Neurons; Nuclear; Nucleus Accumbens; Opioid Receptor; Ovarian; Ovary; Pain; Pharmaceutical Preparations; Phenotype; Ploidies; Prefrontal Cortex; Prevention; Prevention strategy; 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; cocaine self-administration; 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