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.

项目概要 酗酒是酒精使用障碍 (AUD) 的一个危险因素，而饮酒和 AUD 男性的诊断率高于女性，这一差距已大大缩小。有前途的治疗 已使用啮齿动物模型确定了治疗 AUD 的候选药物；然而，很少有研究 将性别视为生物变量（SABV）。加深我们对神经回路中 SABV 的理解 酗酒的根源可能会导致更有针对性的干预措施。伏隔核核心 (NAcc) 具有多种传入连接，这是其在 AUD 各个阶段的重要参与的基础。治疗中 抵抗性男性患者接受 AUD、NAcc 深部脑刺激可减少对酒精的渴望并促进 较低的酒精摄入量或完全戒酒，强调了该大脑区域在转化 AUD 中的相关性 研究。在啮齿类动物中，饮用乙醇 (EtOH) 会增加 NAc 中的 c-Fos（神经元活动的生物标志物）， NAc 的操作（通过损伤、DBS 或化学遗传学）会改变 EtOH 的饮用情况。损害 NAcc 雄性 DBA/2J 小鼠可防止获得乙醇条件位置偏好 (CPP)，这是一种衡量 对乙醇奖励效应的敏感性。由于啮齿动物 NAcc 存在一些已知的性别差异， 无论是基础还是对 EtOH 的反应，在测试 SABV 重要性的研究中都必须解决 SABV 问题。 NAcc 的乙醇奖励和澳元。黑暗中饮酒 (DID) 摄入量存在明显的性别差异 对 NAcc 进行化学遗传学操作后，抑制作用会减少 C57BL/6J (B6) 雄性的摄入量，但 增加女性的摄入量。相反，刺激 NAcc 会减少女性的 DID EtOH 摄入量，但没有影响 效果见于男性。这些发现表明，NAcc 操纵可能会改变对奖励的敏感性 乙醇以性别依赖性方式产生影响，如果是这样，这可能是化学遗传学引起的变化的基础 在饮酒中。总体而言，该提案解决了 B6 小鼠在 2 个月期间 NAcc 和 SABV 的重要性。 暴饮暴食/中毒的各个方面 – 1) 改变 NAcc 活动如何影响以下行为的积极主观影响 致醉剂量的 EtOH 和 2) 确定在暴饮暴食期间参与的 NAcc 电路。 目标 1 测试 NAcc 的化学遗传学操作是否会改变 EtOH 的条件奖赏效应 使用 EtOH 条件位置偏好 (CPP) 任务。目标 2 使用全脑成像来识别区域 在 DID 期间参与（通过分析 c-Fos 表达），结合使用病毒逆行示踪剂 管理至 NAcc。这将允许对共同标记的 c-Fos 和表达 GFP 的 NAcc 进行定量 输入以确定在此行为期间使用哪些 NAcc 电路。包容两性使我们能够 确定 c-fos 诱导是否存在差异，以及对 NAcc 的预测是否存在差异 DID 期间差速接合。拟议的研究将极大地提高我们对 1）如何 NAcc 活动可能会因性别而异地影响 EtOH 的奖赏效果，并且 2) 全脑和 NAcc 特异性 男性和女性因酗酒而参与的循环。