Role of nucleus accumbens core in ethanol reward and binge-like drinking: Focus on sex as a biological variable

伏隔核核心在乙醇奖励和酗酒中的作用：关注性别作为生物变量

• 批准号: 10749298
• 负责人: Amy Elizabeth Chan
• 金额: $ 4.77万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2026-05-08
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749298
• 关键词: Abstinence; Address; Alcohol consumption; Alcoholic Intoxication; Alcohols; Amygdaloid structure; Anatomy; Anesthesia procedures; Behavior; Bilateral; Biological; Biological Assay; Biological Markers; Blood; Blood specimen; Brain; Brain imaging; Brain region; Clozapine; Cues; Darkness; Deep Brain Stimulation; Dendritic Spines; Diagnosis; Dose; Ethanol; FOS gene; Female; Genetic; Genetic Transcription; Globus Pallidus; Hippocampus; Human; Hypothalamic structure; Image; Injections; Insula of Reil; Intake; Intervention; Intoxication; Label; Lesion; Life; Light; Liquid substance; Measures; Molecular; Mus; Neurons; Nucleus Accumbens; Oxides; Patients; Perfusion; Research; Resistance; Rewards; Risk Factors; Rodent; Rodent Model; Role; Saline; Sex Differences; Synapsins; Tactile; Technology; Testing; Time; Tracer; Ventral Striatum; Vertebral column; Viral; Virus; Visual; Water; Woman; Work; alcohol abstinence; alcohol abuse therapy; alcohol craving; alcohol effect; alcohol response; alcohol reward; alcohol use disorder; conditioned place preference; conditioning; density; designer receptors exclusively activated by designer drugs; drinking; drug of abuse; experimental group; genetic manipulation; human model; improved; male; men; microscopic imaging; mouse model; neural circuit; neural network; prevent; promoter; response; sex; therapeutic candidate

Project Summary Binge alcohol drinking is a risk factor for Alcohol Use Disorder (AUD), and while alcohol use and AUD diagnoses are more prevalent in men than women, this gap has drastically narrowed. Promising therapeutic candidates for the treatment of AUD have been identified using rodent models; however, few studies have addressed sex as a biological variable (SABV). Increasing our understanding of SABV in the neural circuitry that underlies binge-like drinking could lead to more tailored interventions. The nucleus accumbens core (NAcc) has diverse afferent connections that underlie its crucial involvement in all stages of AUD. In treatment resistant male patients with AUD, NAcc deep-brain stimulation reduced alcohol craving and promoted either lower alcohol intake or total abstinence, underscoring the relevance of this brain region in translational AUD research. In rodents, ethanol (EtOH) drinking increases c-Fos (a biomarker for neuronal activity) in the NAc, and manipulations of the NAc (via lesion, DBS, or chemogenetics) changes EtOH drinking. Lesioning the NAcc in male DBA/2J mice prevents acquisition of EtOH conditioned place preference (CPP), a measure of sensitivity to the rewarding effects of EtOH. Since there are some known sex-differences in the rodent NAcc, both basally and in response to EtOH, it is imperative to address SABV in studies testing the importance of the NAcc in EtOH reward and AUD. There are apparent sex differences in EtOH Drinking-in-the-Dark (DID) intake following chemogenetic manipulation of the NAcc, where inhibition reduces intake in C57BL/6J (B6) males but increases intake in females. Conversely, stimulation of the NAcc reduces DID EtOH intake in females, with no effect seen in males. These findings suggest that NAcc manipulation may alter sensitivity to the rewarding effects of EtOH in a sex-dependent manner, and if so, this could underlie chemogenetically-induced changes in drinking. Overall, this proposal addresses the importance of the NAcc and SABV in B6 mice during 2 facets of binge/intoxication – 1) how changing NAcc activity impacts the positive subjective effects of an intoxicating dose of EtOH and 2) determining the NAcc circuitry engaged during binge-like drinking. Aim 1 tests whether chemogenetic manipulation of the NAcc alters the conditioned rewarding effects of EtOH using an EtOH conditioned place preference (CPP) task. Aim 2 uses whole-brain imaging to identify regions engaged during DID (through analysis of c-Fos expression), in combination with use of a viral retrograde tracer administered into the NAcc. This will allow for quantification of co-labeled c-Fos and GFP-expressing NAcc inputs to determine which NAcc circuits are engaged during this behavior. Inclusion of both sexes allows us to determine whether there are differences in c-fos induction, and whether projections to the NAcc are differentially engaged during DID. The proposed studies will critically improve our understanding of 1) how NAcc activity may sex-specifically impact the rewarding effects of EtOH, and 2) whole brain and NAcc specific circuits engaged by binge-like EtOH drinking in males and females.

项目摘要 暴饮暴食是酒精使用障碍（AUD）的危险因素，而酒精使用和AUD 在男性中，诊断更为普遍，这一差距非常狭窄 使用啮齿动物模型对AUD进行处理的候选者； 将性别作为生物变量（SABV）。 这是暴饮暴食的基础，可能会导致量身定制的干预措施。 （NACC）具有多种传入的连接，是其在AUD各个阶段的关键参与 NACC深脑刺激的耐药性男性患者降低了酒精的渴望，并提升了 降低酒精摄入量或完全禁欲，强调转化AUD相关性的相关性 研究。 NAC（通过病变，DBS或化学植物）的操作会改变NACC的病变 在雄性DBA/2J小鼠中，可防止获得ETOH条件的位置偏好（CPP）的衡量标准 对eTOH的奖励效果的敏感性，因为啮齿动物NACC有性别差异 在基本和对ETOH的响应中，必须在测试您的重要性的研究中解决SABV NACC在ETOH奖励和AUD中。 NACC的化学发生操作后，居民减少了C57BL/6J（B6）男性屁股的直觉 女性的摄入量增加。 在男性中看到的效果。 ETOH的作用以性别依赖性的方式，如果是的，这可能是化学遗传和变化的基础 总体而 暴饮暴食/中毒的方面 - 1）改变NACC活动如何影响主观的积极影响 ETOH的陶醉剂量和2）确定在暴饮暴食期间参与的Naccuitry。 AIM 1测试NACC的化学发生操作是否会改变ETOH的条件奖励作用 使用ETOH条件的位置偏好（CPP）任务。 在DID期间（通过C-Fos Express分析）与使用病毒后示踪剂结合使用 在NACC中进行管理。 在此行为中确定哪些NACC电路的投入也可以 确定c-fos诱导存在差异，以及对NACC的预测是否是 在DID期间进行差异化。 NACC活动可能特异性地影响ETOH的奖励效应，2）整个大脑和NACC特异性 电路类似于男性和女性的英语饮酒。