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，早期生活压力（ELS）暴露和酒精使用障碍（AUD）对恐惧条件反射和消退的神经元机制的作用和相互作用。由于与AUD发展最相关的环境因素之一是暴露于ELS，中心假设是AUD和ELS参与者表现出破坏性的恐惧消退，这反过来又被认为与严重的AUD表型有关。因此，将使用休克条件反射（结合利用皮肤电反应的功能性磁共振成像）评估有或无AUD和有或无ELS的个体的恐惧条件反射和消退。此外，所有参与者将接受全基因组甲基化组分析，以评估全基因组甲基化模式。候选基因中的变异体的基因分型涉及的生物学的恐惧条件反射/灭绝将carried.Identification和表征可靠的可测量的内源性恐惧灭绝的AUD/ELS有助于阐明AUD的基本机制，从而可以提供新的途径治疗AUD，即开发干预措施，“正常化”异常的恐惧防御。这些干预可以是例如基于心理治疗的或通过靶向潜在鉴定的遗传/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.