Anterior Cingulate Cortex to Dorsal Striatal Circuits in Compulsive-like Binge Alcohol Drinking

强迫性酗酒中的前扣带皮层到背侧纹状体回路

• 批准号: 10387506
• 负责人: Meredith Rose Bauer
• 金额: $ 4.49万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10387506
• 关键词: Ablation; Alcohol Phenotype; Alcohol consumption; Alcohols; Anterior; Attenuated; Automobile Driving; Behavior; Behavioral; Biological Assay; C57BL/6 Mouse; Chemosensitization; Chronic; Chronic Disease; Collaborations; Corpus striatum structure; Decision Making; Development; Dorsal; Electrophysiology (science); Environment; Exhibits; Female; Glutamates; Goals; Home; Indiana; Investigation; Knowledge; Laboratories; Long-Term Potentiation; Maintenance; Mediating; Modeling; Molecular; Mus; Neurons; Neurosciences; Output; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Phenotype; Positioning Attribute; Prefrontal Cortex; Preparation; Prevention; Quinine; Recording of previous events; Research; Research Ethics; Research Personnel; Research Technics; Response to stimulus physiology; Rewards; Rodent; Role; Scientist; Symptoms; Synapses; Synaptic plasticity; Taste Perception; Techniques; Time; Training; Universities; Water; Work; addiction; alcohol abuse therapy; alcohol research; alcohol seeking behavior; alcohol use disorder; awake; base; binge drinking; career; cingulate cortex; drinking; drinking water; drug action; experience; flexibility; improved; male; neural circuit; neuromechanism; neuronal patterning; prevent; relating to nervous system; research and development; response; reward processing; skills

Project Summary/Abstract This project proposes to investigate the underlying neural mechanisms within the dorsal striatum driving the development and maintenance of compulsive-like binge-drinking, or consumption of alcohol despite known negative consequences, using chemogenetics and awake-and-behaving electrophysiology in male and female C57BL/6J mice. Despite the established functional relationship of the prefrontal cortex inputs into the dorsomedial striatum (DMS) for goal directed behaviorally flexible alcohol drinking and the dorsolateral striatum (DLS) in compulsive behaviorally inflexible alcohol drinking, the circuit level shift in control of modulating the development of compulsive-like alcohol drinking has not been defined, which limits prevention and treatment of alcohol use disorder (AUD). The major hypotheses of this project are 1) the development and maintenance of compulsive-like alcohol drinking relies on DLS mechanisms of potentiation from anterior cingulate cortex (ACC) excitatory inputs which are facilitated by reduced ACC-DMS input and 2) that neuronal activity in the DMS and DLS will differ based on alcohol drinking history, bull all mice will increase activity in the DLS and compulsive- like mice will have greater DLS activity than DMS activity. The proposed project will assess the neural mechanisms underlying home cage compulsive-like binge-drinking using drinking-in-the-dark during chemogenetic inhibition from the ACC-DMS and ACC-DLS and through awake-and-behaving electrophysiology recordings in the DS during compulsive-like alcohol drinking. The training plan for this project is curated in an ideal research environment, engaging collaboration between both Indiana University – Purdue University Indianapolis and the Indiana Alcohol Research Center to provide training in cutting edge neuroscience techniques, professional development, and research ethics that will facilitate my career as an independent scientist. The specific research hypotheses are 1) ablation of the excitatory projections from the ACC to the DMS will cause alcohol naïve mice to develop and alcohol history mice to increase compulsive-like alcohol drinking across drinking sessions. 2) Ablation of the excitatory projections from the ACC to the DLS will cause alcohol naïve mice to prevent development and alcohol history mice to attenuate compulsive-like alcohol drinking across drinking sessions. 3) Alcohol naïve and alcohol history mice will differ in their pattern of neuronal activity, with relatively increased activity in the DLS and relatively decreased activity in the DMS across drinking sessions in association with a compulsive-like alcohol drinking phenotype. Completion of the proposed work will elucidate understanding of the mechanisms and neural circuits underlying the development and maintenance of compulsive-like alcohol drinking and will serve to inform researchers in the field of addiction neuroscience, leading to increased understanding and ultimately improved prevention and treatment of AUD.

项目摘要/摘要 该项目建议研究背侧纹状体内潜在的神经机制， 发展和维持强迫性狂饮，或饮酒，尽管已知 使用化学遗传学和觉醒和行为电生理学对男性和女性的负面影响 C57BL/6J小鼠。尽管前额叶皮质传入大脑的功能关系已经建立 目标导向行为灵活饮酒的背内侧纹状体和背外侧纹状体 (DLS)在强迫性行为僵化饮酒中，电路水平的变化控制着 强迫性饮酒的发展还没有定义，这限制了预防和治疗 酒精使用障碍(AUD)。该项目的主要假设是1)开发和维护 强迫性饮酒依赖前扣带回(ACC)的DLS增强机制 通过减少ACC-DMS输入而促进的兴奋性输入和2)DMS中的神经元活动和 根据饮酒史的不同，DLS会有所不同，所有小鼠都会增加DLS的活动，并有强迫症- 例如，小鼠的DLS活性会比DMS活性更高。拟议的项目将评估神经 家庭笼子强迫症的机制类似狂饮在黑暗中饮酒 ACC-DMS和ACC-DLS以及觉醒和行为对化学发生的抑制 强迫性饮酒时DS的电生理记录。该项目的培训计划 是在理想的研究环境中策划的，在印第安纳大学和普渡大学之间进行合作 印第安纳波利斯大学和印第安纳酒精研究中心提供尖端技术培训 神经科学技术、专业发展和研究道德，这些都将促进我的职业生涯 独立科学家。具体的研究假设是1)消融来自大脑的兴奋性投射。 对DMS的ACC将导致酒精幼稚小鼠发育和酒精史小鼠增加强迫症样 在饮酒过程中饮酒。2)消融从ACC到DLS的兴奋性投射 使酒精天真小鼠阻止发育，使酒精史小鼠减弱强迫性酒精样 在饮酒过程中饮酒。3)单纯饮酒和有饮酒史的小鼠的行为模式不同。 神经元活动，DLS的活动相对增加，DMS的活动相对减少 与强迫性饮酒表型相关的跨饮酒阶段。已完成的 拟议的工作将阐明对发育的机制和神经回路的理解 和维持强迫性饮酒，并将有助于告知该领域的研究人员 成瘾神经科学，使人们加深了解，并最终改善预防和治疗 澳元。