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

酒精使用问题出现得早，造成巨大负担。迫切需要 了解谁是脆弱的，为什么，以促进准确的检测，预防和治疗。到 为了解决这一关键问题，需要对行为大脑风险进行更精确的机械理解。 我的研究生研究数据表明，酗酒的一个风险来源可能是 对不确定威胁（U型威胁）的反应性增强，这意味着威胁在时间上是模糊的， 其强度不可预测或者不确定。然而，到目前为止，还没有研究直接测试反应性是否 U型威胁的功能作为一个风险因素。调节这种潜在风险源的神经过程也是 未知;虽然，有证据表明，一个协调的额叶边缘电路，被称为 预期焦虑网络（AAN），调节U-威胁反应。鉴于建立一个有效的 生物行为风险模型，并阐明过度饮酒的潜在机制，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， 一项前瞻性设计，旨在测试对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，新兴的成年人，年龄17-19岁，在开始饮酒之前， 问题并评估他们的行为（即，惊吓眨眼）和神经（即，功能磁共振 成像[fMRI]）对U-威胁的反应性作为潜在风险的指标。所有个人随后将被追踪 每3个月1-2年，以确定问题酒精使用的开始和饮酒的升级 行为。来自该项目的数据将允许一个创新的和良好的控制测试是否行为 对U-威胁的反应性与AAN功能障碍相关（目标1），以及它是否是 有问题的酒精使用是由AAN功能介导的（目标2）。此外，目前的研究将测试 对U威胁的反应性作为风险因素的区分有效性，也通过检查行为和 对不确定奖励（U-奖励）的神经反应，类似地引发预期，也是一种风险表型 有问题的酒精使用（目标3）。这项研究同时提供了一个绝佳的机会来接受 在几个关键领域进行导师指导的实践培训，以完善我的知识和技能。 具体来说，我提出了一个培训计划，将重点放在三个新的领域：1）先进的认知 行为神经科学和任务开发; 2）行为和主观实验室评估， 青年人纵向研究设计的背景;和3）生物统计学。这项研究与 培训目标的完成将有效地推动我走向我的独立的长期目标 在酒精中毒的转化神经科学的职业生涯，并将奠定基础，未来几个，高- 影响R 01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.