Sex Differences in Risk for Alcohol Use Disorder: Neural and Hormonal Influences

项目摘要/摘要 由于酒精消费惊人的增长，酒精消费的性别差距正在迅速缩小 在年轻女性中。因此，迫切需要确定导致性别差异的因素。 澳元的风险。目前的成瘾模型提出了驱动问题酒精的三个神经功能区 使用，因此可作为候选性别特有的风险因素：执行功能，消极情绪，和 激励突显。来自我们实验室和其他实验室的数据表明，糟糕的抑制控制是 对女性来说，执行功能是一个比男性更强的风险因素。此外，我们有初步证据表明 女性饮酒者表现出较少参与抑制控制的神经回路，而且这种性行为 差值受循环中雌二醇水平的影响。然而，激素调节的程度 执行功能的性别差异延伸到消极情绪性和激励性显著领域， 这些性别差异如何影响目前和未来的饮酒尚不得而知。在这里，我们将确定：1) 在这三个成瘾领域中的每一个领域，神经生物学因素都会导致AUD的性别特异性风险，2) 每个领域的性别差异对当前和未来饮酒的影响程度。女性 饮酒者将接受功能性核磁共振检查，以评估抑制控制(即执行功能)的神经相关性，阴性 情绪性和酒精在月经周期的三个阶段提示反应性(即激励性突显)：早期 卵泡期(低雌二醇，低孕酮)，卵泡晚期(高雌二醇，低孕酮)，以及 黄体中期(适中雌二醇、高孕酮)。男性饮酒者将接受三次fMRI扫描 匹配的间隔。每次扫描后，参与者将立即完成一次免费访问 静脉注射酒精自我给药。然后我们将对参与者进行为期18个月的纵向评估 饮酒模式的改变。我们假设荷尔蒙调节的神经功能是抑制的基础 控制和消极情绪将是当前和未来酒精消费的更强预测因素 女性与男性相比，神经酒精提示反应性将是男性更强的预测因素。这个 该项目利用了PI(早期职业调查员)的独特技能和强大的、协作的 调查小组。创新的设计将提供有关影响神经因素的基本信息 AUD的发展和维持，以及，关键的是，这种风险如何受到性别和性别波动的影响 荷尔蒙。归根结底，这项建议是一系列研究中的关键一步，这将导致 针对不同性别的澳门氏症的预防和治疗努力。

PROJECT SUMMARY/ABSTRACT The sex gap in alcohol consumption is closing rapidly, due to alarming increases in alcohol consumption among young women. As such, there is an urgent need to determine the factors underlying sex differences in risk for AUD. Current addiction models propose three neurofunctional domains that drive problematic alcohol use and therefore serve as candidate sex-specific risk factors: executive function, negative emotionality, and incentive salience. Data from our lab and others suggest that poor inhibitory control, a key component of executive function, is a stronger risk factor for women than for men. Moreover, we have preliminary evidence that female drinkers show less engagement of neural circuitry underlying inhibitory control, and that this sex difference is influenced by circulating levels of estradiol. However, the degree to which hormonally-moderated sex differences in executive function extend to the negative emotionality and incentive salience domains, and how these sex differences influence current and future drinking is unknown. Here we will determine: 1) the neurobiological factors contributing to sex-specific risk for AUD in each of these three addiction domains and 2) the degree to which sex differences in each domain influence current and prospective drinking. Female drinkers will undergo fMRI to assess neural correlates of inhibitory control (i.e., executive function), negative emotionality, and alcohol cue reactivity (i.e., incentive salience) at three phases of their menstrual cycle: early follicular phase (low estradiol, low progesterone), late follicular phase (high estradiol, low progesterone), and mid-luteal phase (moderate estradiol, high progesterone). Male drinkers will undergo three fMRI scans at matched intervals. Immediately following each scan, participants will complete a session of free-access intravenous alcohol self-administration. We will then follow participants for 18 months to longitudinally assess changes in drinking patterns. We hypothesize that hormonally-moderated neural function underlying inhibitory control and negative emotionality will be stronger predictors of current and future alcohol consumption in women compared to men, whereas neural alcohol cue reactivity will be a stronger predictor for men. The project capitalizes on the unique skill sets of the PI (an Early Career Investigator) and a strong, collaborative investigative team. The innovative design will provide essential information regarding neural factors influencing development and maintenance of AUD, and, critically, how this risk is influenced by sex and fluctuations in sex hormones. Ultimately, this proposal is a crucial step in a line of research that will lead to the development of sex-specific prevention and treatment efforts for AUD.