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 酗酒是酒精使用障碍（AUD）的危险因素，而酒精使用和AUD 虽然男性的诊断率高于女性，但这一差距已大幅缩小。有希望的治疗 已经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）。增加我们对SABV在神经回路中的理解 酗酒的潜在原因可能会导致更有针对性的干预措施。黑核的核心 （NAcc）具有多种传入连接，这些连接是其参与AUD所有阶段的关键基础。治疗 接受AUD、NAcc脑深部刺激的耐药男性患者减少了酒精渴望， 较低的酒精摄入量或完全戒酒，强调了该大脑区域在翻译AUD中的相关性 research.在啮齿动物中，乙醇（EtOH）饮用增加了NAc中的c-Fos（神经元活动的生物标志物）， 和NAc的操纵（通过损伤、DBS或化学遗传学）改变EtOH饮用。损害NAcc 在雄性DBA/2 J小鼠中， 对乙醇的奖励效应的敏感性。由于啮齿动物NAcc中存在一些已知的性别差异， 无论是基本的还是对EtOH的反应，在测试SABV的重要性的研究中， EtOH奖励和AUD中的NAcc。无水乙醇黑暗饮用（DID）摄入量存在明显的性别差异 在NAcc的化学遗传学操作之后，其中抑制减少了C57 BL/6 J（B6）雄性的摄入，但 增加女性的摄入量。相反，NAcc的刺激减少了女性的DID EtOH摄入量， 在男性中观察到的效果。这些发现表明，操纵NAcc可能会改变对奖励的敏感性。 EtOH以性别依赖的方式影响，如果是这样，这可能是化学发生诱导的变化的基础 喝酒总的来说，该提议解决了在2个月期间NAcc和SABV在B6小鼠中的重要性。 狂欢/中毒的方面- 1）改变NAcc活动如何影响 一个中毒剂量的乙醇和2）确定的NAcc电路从事在狂饮。 目的1测试是否化学遗传操作的NAcc改变条件奖励效应的乙醇 使用EtOH条件位置偏好（CPP）任务。Aim 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 在NAcc中施用。这将允许定量共标记的c-Fos和表达GFP的NAcc 输入，以确定在此行为期间哪些NAcc电路被占用。两性的包容使我们能够 确定c-fos诱导是否存在差异，以及NAcc的投射是否 在DID期间差分接合。拟议的研究将大大提高我们对以下问题的理解：1）如何 NAcc活性可能会影响EtOH的奖励效应，并且2）全脑和NAcc特异性 在男性和女性中，由狂欢式的乙醇饮酒所参与的回路。