The role of the gut microbiota in alcohol seeking and decision-making

肠道微生物群在饮酒和决策中的作用

• 批准号: 10284474
• 负责人: Summer Loretta Thompson
• 金额: $ 13.65万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284474
• 关键词: Accounting; Age-Years; Alcohol consumption; Alcohol withdrawal syndrome; Alcohol-Induced Disorders; Alcohols; Antibiotics; Bacteria; Behavior; Behavior Therapy; Behavioral; Behavioral Mechanisms; Bioinformatics; Biological Models; Cessation of life; Chronic; Clinical; Cognition; Cognitive; Communication; Computer Models; Data; Decision Making; Development; Diet; Donor person; Ensure; Fiber; Gastrointestinal tract structure; Goals; Heavy Drinking; Human; Impairment; Individual; Inflammation; Inflammatory; Instruction; Intestinal permeability; Intestines; Knowledge; Learning; Measures; Mediating; Memory; Mental disorders; Mentors; Mentorship; Microbiology; Modeling; Molecular Biology; Mus; Nervous system structure; Neurosciences; Operant Conditioning; Play; Positioning Attribute; Public Health; Recording of previous events; Regimen; Relapse; Research; Research Training; Rewards; Risk Factors; Rodent; Rodent Model; Role; Sampling; Self Administration; Shotguns; Techniques; Testing; Therapeutic; Training; Withdrawal Symptom; addiction; alcohol consequences; alcohol effect; alcohol exposure; alcohol research; alcohol reward; alcohol seeking behavior; alcohol testing; alcohol use disorder; alternative treatment; behavior measurement; behavioral impairment; career; chronic alcohol ingestion; disability; experience; experimental study; feasibility testing; fecal transplantation; gastrointestinal; gut microbes; gut microbiome; gut microbiota; gut-brain axis; host-microbe interactions; metagenomic sequencing; microbiota; mouse model; neuromechanism; new therapeutic target; novel; prebiotics; premature; programs; reward processing; skills; systemic inflammatory response; tool; treatment strategy

ABSTRACT The goal of this proposal is to investigate the role of the gut microbiota in alcohol seeking and reward-related decision-making. Alcohol is the leading risk factor for premature death and disability for individuals between 15 and 49 years old, accounting for 3 million deaths worldwide yearly. Chronic alcohol consumption results in escalated alcohol seeking and impaired reward-related decision-making, which are core factors in perpetuating alcohol consumption. Mounting evidence supports a role for the gut microbiota in alcohol consumption. However, the role of the gut microbiota in alcohol seeking and in reward-related decision-making have not been systematically evaluated. Prebiotics, indigestible fibers that feed beneficial gut microbes, ameliorate alcohol- induced damage to the intestinal lining, enhance cognition, and may reduce alcohol withdrawal symptoms, suggesting that prebiotics may comprise a treatment target for the behavioral impact of alcohol. Here, we will use operant conditioning approaches in mouse models to dissect the role of the gut microbiota in alcohol seeking and alcohol-induced changes in reward-related decision-making. Aim 1 is to determine the role of the gut microbiota in alcohol seeking using prebiotics to alter the microbiota (Aim 1a) and fecal microbial transplant from prebiotic-receiving donor mice to determine a causal role for the microbiota (Aim 1b). Aim 2 is to determine the role of the gut microbiota in alcohol-induced changes in reward-related decision-making. To test this, mice will perform a novel, multi-stage decision-making task that we adapted directly from a human task to assess reward- related decision-making using computational modeling. Mice will receive prebiotics (Aim 2a) or fecal transplant from prebiotic receiving donors (Aim 2b) to determine whether prebiotics ameliorate alcohol-induced changes in decision-making, and whether these effects are mediated by the gut microbiota. The profile of the gut microbiome will be assessed using metagenomic sequencing and bioinformatics to determine what aspects of behavior, intestinal permeability, and inflammation correlate with the gut microbiota. Completion of these aims will test the feasibility of mitigating alcohol seeking and decision-making impairments by manipulating the gut microbiota using a putative alternative treatment target and determine whether the gut microbiota play a causal role. Dr. Thompson’s main career goal is to investigate the potential of the gut microbiota to provide alternative treatment options for psychiatric disorders. The proposed aims will provide Dr. Thompson with crucial training, research experience, and data that will advance this career goal. Dr. Thompson’s integrated mentorship team is comprised of experts in addiction models, clinical and translational alcohol research, host-microbe interactions, and computational modeling of decision-making, ensuring successful completion of the research and training aims. Dr. Thompson will expand this mentored training through didactic and technical coursework and professional development activities. Together, the proposed experiments and training will prepare Dr. Thompson for an independent career investigating the role of the gut microbiota in psychiatric disorders.

摘要 这项提案的目标是调查肠道微生物区系在寻求酒精和与奖励相关的过程中的作用。 决策。酒精是15岁以下人群过早死亡和致残的主要风险因素 49岁，每年全球死亡人数为300万人。长期饮酒导致 不断升级的酗酒和损害与奖励相关的决策，这些都是永久化的核心因素 饮酒。越来越多的证据支持肠道微生物区系在酒精消费中的作用。然而， 肠道微生物区系在酒精寻求和与奖励相关的决策中的作用尚未得到 系统评估。益生元，喂养有益肠道微生物的不可消化纤维，改善酒精- 对肠壁造成损伤，提高认知能力，并可能减少酒精戒断症状， 这表明益生元可能包括酒精对行为影响的治疗靶点。在这里，我们将 在小鼠模型中使用操作性条件反射方法分析肠道微生物区系在酒精寻求中的作用 以及酒精引起的与奖励相关的决策的变化。目标1是确定肠道的作用 酒精中的微生物区系使用益生元改变微生物区系(目标1a)和粪便微生物移植 接受益生素供体小鼠以确定微生物区系的因果作用(目标1b)。目标2是确定 肠道微生物区系在酒精诱导的奖赏相关决策改变中的作用。为了测试这一点，老鼠将 执行一项新颖的多阶段决策任务，我们直接从人工任务改编来评估奖励- 使用计算建模进行相关决策。小鼠将接受益生素(AIM 2a)或粪便移植 来自益生素接受者(目标2b)，以确定益生元是否改善酒精诱导的 决策，以及这些影响是否由肠道微生物区系介导。肠道微生物群的研究概况 将使用元基因组测序和生物信息学进行评估，以确定行为的哪些方面， 肠道通透性和炎症与肠道微生物区系相关。这些目标的实现将考验 通过控制肠道微生物区系减轻酒精寻求和决策障碍的可行性 使用假定的替代治疗目标，并确定肠道微生物区系是否起到因果作用。 汤普森博士的主要职业目标是研究肠道微生物区系提供替代选择的潜力 精神疾病的治疗选择。拟议的AIMS将为汤普森博士提供关键的培训， 研究经验，以及将推动这一职业目标的数据。汤普森博士的综合导师团队是 由成瘾模型、临床和转化性酒精研究、宿主-微生物相互作用、 和决策的计算建模，确保顺利完成研究和培训 目标。汤普森博士将通过授课和技术课程来扩大这种有指导的培训，并 职业发展活动。总之，拟议的实验和培训将为汤普森博士做好准备 从事研究肠道微生物区系在精神疾病中的作用的独立职业。