Brain-Behavior Reactivity to Threat and Alcohol Abuse Risk in Young Adults

有问题的饮酒很早就出现了，并造成了巨大的负担。有迫切的需要 了解哪些人易受攻击及其原因，以便于准确检测、预防和治疗。至 要解决这一关键问题，就需要对行为-大脑风险有更精确的机械性理解。 我研究生研究的数据表明，有问题的饮酒的一个风险来源可能是 提高对不确定威胁(U-威胁)的反应性，这意味着暂时具有模糊性的威胁 在其强度上不可预测或不确定的。然而，到目前为止，还没有研究直接测试反应性 对U-Threat的作用是一个风险因素。调节这种潜在风险来源的神经过程也是 未知；尽管，有证据表明，协调的额缘回路，称为 预期焦虑网络(AAN)，调节U-威胁反应。鉴于建立一个经过验证的 生物行为风险模型，以及解释过度饮酒的机制，有可能 为了显著改善临床工作，拟议的研究结合了行为和神经测量，与 一项前瞻性设计，以测试对U-威胁的反应性是否是问题酒精的表型风险因素 使用。这项研究将招募150名健康的新兴成年人，年龄在17-19岁之间，在开始饮酒之前 并评估他们的行为(即惊吓眨眼)和神经(即功能磁共振) 成像[功能磁共振成像])对U威胁的反应性作为潜在风险的指标。所有个人随后将被跟踪 每隔3个月。为期1-2年，以确定有问题的饮酒和饮酒升级的开始 行为。来自该项目的数据将允许对行为的创新和良好控制的测试 对U威胁的反应性与AAN功能障碍(目标1)相关，以及它是否是 由AAN功能调节的有问题的酒精使用(目标2)。此外，目前的研究将测试 对U-威胁的反应性作为危险因素的区分效度也通过检验行为和 神经对不确定奖赏(U奖赏)的反应性，同样会引起预期，也是一种风险表型 对于有问题的酒精使用(目标3)。这项研究同时提供了一个极好的机会 在导师的指导下，在几个关键领域进行实践培训，以完善我的知识和技能。 具体地说，我提出了一个专注于三个新领域的培训计划：1)高级认知 行为神经科学和任务发展；2)行为和主观实验室评估 对年轻人的纵向研究设计的背景；以及3)生物统计学。这项研究结合了 完成培训目标将有效地推动我朝着独立的长期目标前进 在酒精中毒的翻译神经科学方面的职业生涯，并将为未来的几个高- Impact R01研究侧重于酒精使用障碍的预防和干预。

Problematic alcohol use emerges early and poses tremendous burden. There is an urgent need to understand who is vulnerable, and why, to facilitate accurate detection, prevention, and treatment. To address this critical issue, a more precise mechanistic understanding of behavioral-brain risk is needed. Data from my graduate research suggests that one source of risk for problematic alcohol use may be heightened reactivity to uncertain threat (U-threat), meaning threat that is ambiguous, temporally unpredictable or uncertain in its intensity. To date, however, no study has directly tested whether reactivity to U-threat functions as a risk factor. The neural processes that mediate this potential source of risk are also unknown; although, there is evidence to suggest that a coordinated frontolimbic circuit, referred to as the Anticipatory Anxiety Network (AAN), modulates U-threat responding. Given that establishing a validated biobehavioral risk model, and elucidating mechanisms underlying excessive alcohol use, has the potential to significantly improve clinical efforts, the proposed study combines behavioral and neural measures, with a prospective design, to test whether reactivity to U-threat is a phenotypic risk factor for problematic alcohol use. This study will enroll 150 healthy, emerging adults, ages 17-19, prior to the onset of alcohol use problems and assess their behavioral (i.e., startle eyeblink) and neural (i.e., functional magnetic resonance imaging [fMRI]) reactivity to U-threat as indices of potential risk. All individuals will subsequently be tracked every 3 mos. for 1-2 years to ascertain onset of problematic alcohol use and escalation in drinking behaviors. Data from this project will allow for an innovative and well-controlled test of whether behavioral reactivity to U-threat is associated with AAN dysfunction (Aim 1), and whether it is a risk factor for problematic alcohol use that is mediated by AAN functioning (Aim 2). In addition, the current study will test the discriminative validity of reactivity to U-threat as a risk factor by also examining whether behavioral and neural reactivity to uncertain rewards (U-reward), which similarly elicit anticipation, is also a risk phenotype for problematic alcohol use (Aim 3). This study concurrently provides an excellent opportunity to receive mentor-directed, hands-on training in several key areas necessary to refine my knowledge and skill-sets. Specifically, I propose a training plan that will focus on three new domains: 1) advanced cognitive behavioral neuroscience and task development; 2) behavioral and subjective laboratory assessments in the context of a longitudinal study design with young adults; and 3) biostatistics. This study coupled with completion of the training goals will effectively propel me towards my long-term goal of an independent career in the translational neuroscience of alcoholism, and will lay the foundation for several future, high- impact R01 studies focused on the prevention and intervention of alcohol use disorder.