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.

项目总结/摘要 本项目旨在研究背侧纹状体内驱动神经元活动的潜在神经机制。 发展和维持强迫性的暴饮暴食，或饮酒，尽管已知 在男性和女性中使用化学遗传学和觉醒和行为电生理学的负面后果 C57 BL/6 J小鼠。尽管前额叶皮层输入到大脑的功能关系已经建立， 背内侧纹状体（DMS）的目标定向行为灵活饮酒和背外侧纹状体 (DLS)在强迫性行为不灵活的饮酒中，控制调节神经元的回路水平转移， 尚未定义强迫性饮酒的发展，这限制了预防和治疗 酒精使用障碍（AUD）本项目的主要假设是：1）开发和维护 强迫性饮酒依赖于前扣带皮层（ACC）的DLS增强机制 兴奋性输入，这是由减少ACC-DMS输入促进和2）在DMS中的神经元活动， DLS将基于饮酒史而不同，公牛所有小鼠将增加DLS中的活动和强迫性- 类似小鼠的DLS活性将大于DMS活性。拟议的项目将评估神经 在黑暗中饮酒的家庭笼强迫性酗酒的潜在机制 来自ACC-DMS和ACC-DLS的化学发生抑制以及通过唤醒和行为 在强迫性饮酒期间DS的电生理记录。本项目的培训计划 是在一个理想的研究环境策展，从事之间的合作印第安纳州大学-普渡大学 印第安纳波利斯大学和印第安纳州酒精研究中心提供尖端培训 神经科学技术，专业发展和研究道德，这将有助于我的职业生涯， 独立科学家具体的研究假设是：（1）消融来自大脑皮层的兴奋性投射， ACC对DMS的作用会导致酒精未处理小鼠的发展和酒精史小鼠的强迫样增加 在饮酒期间饮酒。2)消融从ACC到DLS的兴奋性投射， 使酒精未接触过的小鼠阻止发展，使酒精史小鼠减弱强迫性酒精样 在喝酒的时候喝酒3)未接触过酒精的小鼠和有酒精史的小鼠在它们的行为模式上是不同的。 神经元活动，DLS中的活动相对增加，DMS中的活动相对减少 与强迫性饮酒表型相关的饮酒过程。完成 拟议的工作将阐明发展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，导致更多的了解，并最终改善预防和治疗 的AUD。