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

摘要 药物相关行为的性别差异已被充分记录，并主要归因于差异 雌激素水平的差异这个程序超越了这个假设 检查另一个重要因素，性染色体补体，重点是X染色体基因 逃避X染色体失活的基因在女性大脑中的表达水平高于男性。四个核心 基因型（FCG）小鼠模型允许单独分析性腺激素和性染色体 互补（XX与XY）。在目标1中，这些小鼠将用于检查以下物质的组合和单独作用： 雌二醇和性染色体补体对可卡因成瘾易感性的影响 局将对获得药物的获得率和动机水平进行评估。在目标2中， 将确定两个X染色体基因的作用，逃避失活在小鼠和人类大脑，Utx和 Smcx。这些基因编码的酶使组蛋白修饰去甲基化， 可访问性和广泛的基础上转录。这项工作将用两种诱导性组织进行- 特异性敲除小鼠前脑中CaMK 2 α基因（Utx或Smcx）表达缺失，包括 神经元的数量。将如目标1中测试小鼠的可卡因易感性， 动机在目标3中，来自在目标1和2中测试的小鼠的脑桥核的脑组织将用于 表观遗传分析ATAC（转座酶可降解染色质测定）、Pro（精密度） 核Run-On）和ChIP（染色质免疫沉淀）测序将用于鉴定 转录活性和抑制基因与染色质重组和重要 转录因子这项工作的长期目标是揭示性的新机制 成瘾脆弱性的差异，帮助临床医生设计针对性别的预防/干预措施。

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.