Oprk1-regulated neurocircuitry and phenotypes of alcohol use disorder

Oprk1 调节的神经回路和酒精使用障碍的表型

• 批准号: 10753867
• 负责人: Brendan M Walker
• 金额: $ 56.44万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-02 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753867
• 关键词: Abstinence; Acute; Affect; Affective; Alcohol Phenotype; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Model; Anxiety; Behavior; Behavioral; CRISPR/Cas technology; Cell Nucleus; Characteristics; Chronic; Cognitive; Complement; Cre lox recombination system; Data; Dependence; Development; Disease; Dissection; Dopamine; Dynorphins; Excision; Foundations; Gene Expression; Genes; Genetic; Goals; Health; Heavy Drinking; Human; Impaired cognition; Infusion procedures; Knowledge; Literature; Medial; Mediating; Memory impairment; Mental Depression; Midbrain structure; Motivation; National Institute on Alcohol Abuse and Alcoholism; Neurons; Nucleus Accumbens; Outcome; Pathogenicity; Pattern; Phenotype; Prefrontal Cortex; Principal Investigator; Public Health; Publishing; Rat Transgene; Rattus; Receptor Gene; Recovery; Regulation; Relapse; Research; Role; Self Administration; Self Medication; Short-Term Memory; Strategic Planning; System; Testing; Therapeutic; Ventral Tegmental Area; Viral; Withdrawal; Work; alcohol abuse therapy; alcohol comorbidity; alcohol exposure; alcohol measurement; alcohol relapse; alcohol use disorder; behavioral phenotyping; chronic alcohol ingestion; cognitive control; compliance behavior; design; dopaminergic neuron; effective therapy; executive function; genetic approach; genetic manipulation; interdisciplinary approach; kappa opioid receptors; knock-down; mRNA Expression; maladaptive behavior; negative affect; neural circuit; neuroadaptation; novel strategies; novel therapeutic intervention; overexpression; personalized medicine; personalized therapeutic; reduce symptoms; response; success; therapeutic target; therapeutically effective; therapy design; therapy development; treatment adherence; treatment strategy; virus genetics; welfare

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.

项目摘要。酒精使用障碍的一个基本特征是失去对酒精的控制。 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合并症 例如抑郁症的发病率非常高，因此人们认为， 导致持续过量饮酒和复发。此外，消极的情感状态 慢性酒精暴露所产生的神经递质会影响认知控制系统的神经回路， 继续过量饮酒。一旦达到这种程度的失调， 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。主要研究者的长期目标是确定有效的 治疗酒精使用障碍（AUD）的治疗目标和策略。的目的 应用，这是追求这一目标的下一步，是了解Oprk 1中的神经适应 （κ-阿片受体基因）调节系统，发生在响应慢性酒精暴露和 导致行为调节失调核心假设是Oprk 1调节的 神经回路以一种促进持续过度的 饮酒并使酒精依赖的循环永久化。建议的理由 了解Oprk 1表达失调在AUD中的作用将为研究提供基础。 旨在缓解适应不良行为的有效疗法开发基金会 由酒精依赖产生的调节。这一假设将通过利用诱导和 有条件的CRISPR/CAS9基因编辑和化学遗传学方法来重现或改善 酒精依赖的症状在非选择和转基因大鼠。操作性酒精的动物模型 自我管理、负性类情感行为和包括工作记忆在内的执行功能 将作为功能性终点，系统研究Oprk 1表达在 与酒精依赖相关的适应不良行为调节。此外，Oprk 1基因表达将 作为行为方法的补充进行评估。拟议的研究将有助于确定 神经适应在Oprk 1调节系统中的功能重要性， 酒精暴露，并将提供有关Oprk 1对 AUD相关表型的神经回路。这种贡献是重要的，因为它将有助于确定 并开发治疗AUD的治疗靶点，重点是消除适应不良的表型; 这将大大提高治疗依从性并降低复发率。