Negative emotion regulation in alcohol use disorder - (Epi)Genetic modulation of fear extinction, negative emotion, reward and stress processing

本研究的主要目的是评估（epi）遗传因素、早期生活应激（ELS）暴露和酒精使用障碍（AUD）在恐惧调节和消退的神经元机制中的作用和相互作用。由于与AUD发展最相关的环境因素之一是暴露于ELS，因此中心假设是AUD和ELS的参与者表现出中断的恐惧消退，这反过来又被认为与严重的AUD表型有关。因此，将使用休克调节（结合利用皮肤电反应的功能磁共振成像）来评估有或没有AUD、有或没有ELS的个体的恐惧调节和消退。此外，所有参与者都将进行全基因组甲基化分析，以评估全基因组甲基化模式。将进行与恐惧调节/灭绝生物学有关的候选基因变异的基因分型。识别和表征AUD/ELS中可靠的可测量的恐惧消退的内表型有助于阐明AUD的基本机制，从而为AUD的治疗提供新的途径；即开发干预措施，使不正常的恐惧灭绝“正常化”。例如，这些干预措施可以是基于心理治疗的，也可以是针对潜在的遗传/表观遗传途径的分子干预。

The primary goal of this study is to evaluate the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction. Since one of the environmental factors most associated with the development of AUD is exposure to ELS, the central hypothesis is that participants with AUD and ELS show disrupted fear extinction, which in turn is assumed to be related with severe AUD phenotypes. Therefore, individuals with and without AUD and with or without ELS will be evaluated for fear conditioning and extinction using shock conditioning (combined with fMRI imaging that utilizes galvanic skin response). Additionally, all participants will undergo whole-genome methylome analyses to assess genome wide methylation patterns. Genotyping of variants in candidate genes implicated in the biology of fear conditioning/extinction will be carried out.Identification and characterization of reliable measureable endophenotypes of fear extinction in AUD/ELS helps to elucidate essential AUD mechanisms and thus could provide new avenues for treatment of AUD; namely developing interventions that “normalize” abnormal fear extinctions. These interventions could be for example, psychotherapeutically based or molecular by targeting genetic/epigenetic pathways potentially identified.