Oprk1-regulated neurocircuitry and phenotypes of alcohol use disorder

项目摘要。酒精使用障碍的一个基本特征是失去对 酒精消费导致酒精使用水平逐步上升，并促进 发展成酒精依赖。考虑到酒精依赖和情感障碍的共病 如抑郁症极高，则一直被认为是自我用药的负面情绪状态 导致持续过量饮酒和复发。此外，消极的情感状态 慢性酒精暴露会影响认知控制系统的神经回路 使过度饮酒永久化。一旦达到这种程度的失调，就会有 依赖循环以一种对个人极其有害的方式相互促进， 家庭和社会福利。首席调查员的长期目标是确定有效的 酒精使用障碍(AUD)的治疗目标和策略。这样做的目的是 应用，这是追求这一目标的下一步，是理解OPRK1的神经适应 (Kappa-阿片受体基因)调节的系统，对慢性酒精暴露和 会导致不适应行为的调节。中心假说是OPRK1调控的 神经回路逐渐变得失调，导致持续过度 酒精的消耗，并使酒精依赖的循环永久化。建议的理由是 研究表明，了解异常表达的OPRK1在AUD中的作用将为 开发旨在减轻适应不良行为的有效疗法的基础 由酒精依赖产生的规则。这一假设将通过使用可诱导的和 条件性CRISPR/CAS9基因编辑和化学遗传学方法总结或改善 非转基因大鼠的酒精依赖症状。可操作酒精的动物模型 自我管理、负性情感样行为与包括工作记忆在内的执行功能 将作为功能终点，系统地研究OPRK1表达在 与酒精依赖相关的不适应行为调节。此外，OPRK1基因的表达将 被评估为行为方法的补充。拟议的研究将有助于确定 慢性疾病引起的OPRK1调节系统中神经适应的功能重要性 并将提供急需的信息，说明OPRK1对 AUD相关表型的神经回路。这样的贡献意义重大，因为它将有助于确定 并开发治疗AUD的治疗目标，重点是消除不适应表型；a 应大幅提高治疗依从性并降低复发率的战略。

Project Summary. A fundamental characteristic of alcohol use disorders is the loss of control over alcohol consumption that results in progressively escalating levels of alcohol use and facilitates the progression to alcohol-dependence. Given the comorbidity of alcohol dependence and disorders of affect such as depression is extremely high, it has been posited that self-medication of negative affective states contributes to continued excessive alcohol use and relapse. Furthermore, negative affective states produced by chronic alcohol exposure can influence the neurocircuitry of cognitive control systems to perpetuate further excessive alcohol use. Once that degree of dysregulation is reached, components of the dependence cycle serve to facilitate each other in a manner that is extremely deleterious to personal, familial and societal welfare. The principal investigator’s long-term goal is to identify effective therapeutic targets and strategies for the treatment of alcohol use disorder (AUD). The objective of this application, which is the next step in pursuit of that goal, is to understand the neuroadaptations in Oprk1 (kappa-opioid receptor gene)-regulated systems that occur in response to chronic alcohol exposure and contribute to maladaptive behavioral regulation. The central hypothesis is that the Oprk1-regulated neurocircuitry becomes progressively dysregulated in a manner that promotes the continued excessive consumption of alcohol and perpetuates the cycle of alcohol dependence. The rationale for the proposed studies is that understanding the contribution of dysregulated Oprk1 expression in AUD will lay the foundation for the development of effective therapies designed to alleviate maladaptive behavioral regulation produced by alcohol dependence. This hypothesis will be tested by utilizing inducible and conditional CRISPR/CAS9 gene editing and chemogenetic approaches to recapitulate or ameliorate symptoms of alcohol dependence in non-selected and transgenic rats. Animal models of operant alcohol self-administration, negative affective-like behavior and executive function including working memory will serve as functional end-points to systematically investigate the role of Oprk1 expression in maladaptive behavioral regulation related to alcohol dependence. In addition, Oprk1 gene expression will be assessed as a complement to the behavioral approaches. The proposed research will help to identify the functional importance of neuroadaptations in Oprk1-regulated systems that result from chronic alcohol exposure and will provide much needed information regarding the influence of Oprk1 on the neurocircuitry of AUD-related phenotypes. Such a contribution is significant because it will help identify and develop therapeutic targets to treat AUD that focus on the removal of maladaptive phenotypes; a strategy that should greatly increase treatment compliance and decrease rates of relapse.