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

项目总结/摘要 由于饮酒量惊人的增长，饮酒量的性别差距正在迅速缩小。 在年轻女性中。因此，迫切需要确定造成性别差异的因素， 澳元风险目前的成瘾模型提出了三个神经功能领域，驱动问题酒精 使用，因此作为候选性别特异性风险因素：执行功能，负面情绪， 激励显著性来自我们实验室和其他实验室的数据表明，不良的抑制控制， 执行功能是女性比男性更强的风险因素。而且我们有初步证据 女性饮酒者表现出较少的神经回路参与抑制控制，这种性别 差异受雌二醇循环水平的影响。然而，在多大程度上， 执行功能的性别差异延伸到消极情绪和激励显著性领域， 这些性别差异如何影响当前和未来的饮酒是未知的。在这里，我们将确定：1） 在这三个成瘾领域中，神经生物学因素对AUD的性别特异性风险有贡献; 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磁共振成像以评估抑制控制的神经相关性（即，执行功能），阴性 情绪和酒精线索反应性（即，在月经周期的三个阶段： 卵泡期（低雌二醇，低孕酮），卵泡晚期（高雌二醇，低孕酮），和 黄体中期（中等雌二醇，高孕酮）。男性饮酒者将接受三次功能磁共振成像扫描， 匹配的间隔。每次扫描后，参与者将立即完成一次免费访问会议 静脉注射酒精自我管理。然后，我们将跟踪参与者18个月，纵向评估 饮酒模式的变化。我们假设，大脑调节的神经功能抑制 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， 女性相比，男性，而神经酒精线索反应将是一个更强的预测男性。的 项目利用PI（早期职业调查员）的独特技能和强大的协作能力， 调查小组。创新的设计将提供有关神经因素影响的基本信息 AUD的发展和维持，以及性别和性别波动如何影响这种风险 荷尔蒙最终，这一提议是一系列研究的关键一步，将导致 针对不同性别的AUD预防和治疗工作。

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.