Multimodal Neuroimaging of Alcohol Cues, Cortisol Response and Compulsive Motivation

项目摘要 申请人的长期职业目标是发展一个独立的研究计划， 酒精使用障碍（AUD）发展的神经生物学机制，特别是那些 与酗酒有关2014年全国药物使用和健康调查结果显示， 在过去的一个月里，美国的成年人参与了酗酒（SAMSA 2014）。为什么有些人“成熟了” 这种行为而其他人坚持可能是由于一个人的生理反应，以狂饮。还从未有一位 一项研究评估了皮质醇和神经网络对酒精暗示的反应是否会导致 强迫性饮酒见于尚未有AUD的酗酒者。来 在申请人的职业生涯中，她希望有助于我们对基因组，神经内分泌， 以及AUD发展的神经机制。 到目前为止，她已经接受了关于神经化学和神经解剖学的优秀培训， 底物（从遗传学到功能网络）参与急性酒精对大脑的影响， 严重AUD的慢性复发过程。在临床和行为神经科学的坚实基础上，她 现在的目标是在耶鲁大学的高效和支持性基础设施中获得进一步的培训（1） 先进的多模式神经影像技术，（2）发病前危险饮酒的临床过程 AUDs，和（3）多层次，混合效应纵向分析，以启动作为一个独立的职业生涯 研究人员在跨学科领域，转化神经科学研究酗酒。没有这个 K99/R 00独立之路奖，申请人将没有受保护的时间，培训，或 资源启动这一新的研究方向。这个严格的K99培训计划将帮助申请人 获得开发长期研究计划所需的一套新技能，该计划包括多个 跨学科的方法在AUDs的发展研究。该培训计划将通过以下方式实现：1） 结构化的指导计划2）监督的研究经验，3）正式的课程， 研讨会/讲习班，以及4）出席国家和国际会议。 为了进一步培训申请人的独立研究项目，在R 00阶段， 申请人将招募21-45岁（N=90，性别相同）的饮酒、不吸烟男性和女性， 中度饮酒者或狂饮/重度饮酒者进行单一神经影像学和神经内分泌评估， 确定他们在未来一个月的随访中的真实的饮酒行为是否可以基于 皮质醇和神经网络对酒精的反应。最后，遗传变异的影响， FK 506结合蛋白5（FKBP 5）基因，调节皮质醇活性，对皮质醇和神经网络的影响 将探讨对酒精线索的反应。这项研究将是建立职业生涯的基础， 神经生物学变化导致人类AUD风险。

PROJECT SUMMARY The long-term career goal of the applicant is to develop an independent program of research on the neurobiological mechanisms underlying the development of Alcohol Use Disorders (AUDs), specifically those related to binge drinking. Results from the 2014 National Survey on Drug Use and Health show that 26% of adults in the US engaged in binge drinking in the past month (SAMSA 2014). Why some people “mature out” of this behavior while others persist may be due to one’s physiological response to binge drinking. No previous study has assessed whether disrupted cortisol and neural network responses to alcohol cues may drive the compulsive alcohol consumption seen in binge drinking individuals who do not yet have an AUD. Over the course of the applicant’s career, she hopes to contribute to our understanding of the genomic, neuroendocrine, and neural mechanisms that underlie the development of AUDs. So far, she has received excellent training regarding the neurochemical and neuroanatomical substrates (from genetics to functional networks) involved in the effects of acute alcohol on the brain and in the chronic, relapsing course of severe AUDs. On this solid foundation of clinical and behavioral neuroscience, she now aims to obtain further training within the highly productive and supportive infrastructure at Yale in (1) advanced multimodal neuroimaging techniques, (2) the clinical course of hazardous drinking prior to the onset of AUDs, and (3) multilevel, mixed effects longitudinal analyses to launch a career as an independent researcher in the field of interdisciplinary, translational neuroscience research on alcoholism. Without this K99/R00 Pathway to Independence Award, the applicant will not have the protected time, training, or the resources to initiate this new direction of research. This rigorous K99 training program will help the applicant obtain a new skill set required to develop a long-term program of research which incorporates multiple interdisciplinary methods in the study of the development of AUDs. This training plan will be achieved via: 1) structured mentoring programs 2) supervised research experience, 3) formal coursework and seminars/workshops, and 4) attendance at national and international conference meetings. To further the applicant’s training with an independent research project, during the R00 phase, the applicant will recruit beer drinking, non-smoking men and women ages 21-45 (N=90, equal gender) who are either moderate drinkers or binge/heavy drinkers for a single neuroimaging and neuroendocrine assessment to determine if their real world drinking behavior in a prospective one month follow up can be predicted based upon the cortisol and neural network responses to alcohol cues. Finally, the influence of genetic variation in the FK506-binding protein 5 (FKBP5) gene, which regulates cortisol activity, on the cortisol and neural network responses to alcohol cues will be explored. This study will be the basis to build a career in understanding the neurobiological changes that drive risk of AUDs in humans.