Neural Substrates of Binge Drinking

暴饮暴食的神经基质

• 批准号: 10553598
• 负责人: Angela Renee Ozburn
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553598
• 关键词: Acute; Adult; Affective; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Animal Model; Animals; Behavior; Behavioral; Blood; Blood alcohol level measurement; Brain; Brain region; Cell Nucleus; Cessation of life; Chronic; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dangerousness; Darkness; Data; Deep Brain Stimulation; Diagnosis; Economic Burden; Economics; Ethanol; Ethanol dependence; Exhibits; FOS gene; Female; Genetic; Genetic Models; Health; Hippocampus; Human; Human Resources; Immunohistochemistry; Individual; Insula of Reil; Intoxication; Learning; Literature; Maintenance; Medial; Mediating; Military Personnel; Modeling; Mouse Strains; Mus; National Institute on Alcohol Abuse and Alcoholism; Nature; Neurons; Neuropeptides; Neurotransmitters; Nucleus Accumbens; Pattern; Peptides; Pharmacology; Play; Procedures; Recording of previous events; Relapse; Resistance; Risk; Role; Saccharin; Signaling Molecule; Testing; Tracer; United States Department of Veterans Affairs; Ventral Tegmental Area; Veterans; Virus; Work; alcohol misuse; alcohol risk; alcohol use disorder; antagonist; binge drinking; brain circuitry; cost; craving; designer receptors exclusively activated by designer drugs; directed attention; drinking; drinking water; experience; genetic manipulation; high risk; immunoreactivity; male; military veteran; neural; pharmacologic; preference; preventable death; sex; social; vapor

Alcohol misuse is responsible for ~88,000 deaths annually and exerts an annual cost of ~$250 billion in the US. Binge drinking, which accounts for ~75% of these costs, is defined by the National Institute on Alcohol Abuse and Alcoholism as consuming 4-5 drinks and/or achieving a blood alcohol level >80 mg/dL within a 2 hr period (Sacks et al., 2010). Binge drinking is increasing in the US, is highly prevalent in both male and female active military duty personnel and veterans, and is a strong predictor of an alcohol use disorder (AUD; Han et al., 2017; Stahre et al., 2009; Gowin et al., 2017). More than 40% of US military veterans have a lifetime history of alcohol use disorder (Fuerlein et al., 2016). Thus, alcohol exerts a large burden on health, social, and economic problems, especially within the Department of Veterans Affairs. How individuals respond to their first experiences with alcohol are related to their risk for developing an AUD, including frequent early adult binge drinking (King et al., 2011; McCarty et al., 2004). Identifying the brain circuitry that underlies this dangerous pattern of drinking is an important first step in learning about vulnerability factors for AUD. Our recent studies identified a key role for the nucleus accumbens (NAc) core in binge-like drinking using DID (Drinking in the Dark; a paradigm which models binge-like drinking in mice) and chemogenetics [i.e. DREADDs (designer receptors exclusively activated by designer drugs)]. Circuitry-based studies in animals are powerfully relevant for humans with AUD. Treatment-resistant males with an AUD diagnosis exhibit reduced drinking, craving, and rates of relapse with deep brain stimulation of the NAc (Pierce and Vassoler, 2013). The NAc core receives projections from several regions and is important for many behaviors. To further understand the circuitry of binge drinking, we will identify neural projections to the NAc core that are engaged during DID in high drinking C57BL/6J mice. We will inject the retrograde marker, rAAVretro-GFP, into the NAc core, expose mice to ethanol, saccharin, or water DID procedures, and then quantify c-Fos immunoreactivity in GFP positive neurons. The proposed work will be the first to identify the NAc core circuitry engaged during binge drinking using both in males and females. We hypothesize that several NAc projecting brain regions will be engaged during ethanol DID, including the central and basolateral amygdala, prelimbic cortex, and insula, ventral tegmental area, and ventral hippocampus. Our preliminary data support testing the role of an understudied projection from the central nucleus of the amygdala (CeA) to the NAc core in binge drinking. Both regions are well known to be involved in alcohol drinking, yet very little is known about the nature and role of this projection in drinking. We will manipulate CeA inputs to the NAc (via chemogenetics and dual virus projection targeting) to determine whether this projection modulates binge-like drinking. CeA neurons contain many neuropeptides and modulators; therefore, we will identify the nature of these projections using immunohistochemistry. Based on the literature and the results of our preliminary studies, we focus on the peptide neurotransmitter, corticotropin releasing factor (CRF). We will administer corticotropin releasing factor (CRF) intra-accumbens to determine whether it alters binge-like drinking. We will then test whether antagonism of CRF receptors can block the effects of stimulating CeA- >NAc core projections (via chemogenetics) on DID. We hypothesize that chemogenetic stimulation of CeA- >NAc projections will reduce drinking, intra-NAc core CRF will reduce binge-like drinking, and intra-NAc CRF antagonists will block reductions in drinking seen with chemogenetic stimulation of CeA->NAc core projections. This proposal will use behavioral, pharmacological, and circuitry based approaches to better understand the neural substrates of binge drinking. We will identify neuronal projections to NAc core important for regulating binge-like drinking in the high drinking C57BL/6J mouse strain. We hypothesize that CeA projections to the NAc core are important for regulating binge drinking and are engaged by binge drinking.

滥用酒精每年导致约 88,000 人死亡，每年造成约 2500 亿美元的损失 美国。美国国家酒精研究所定义，酗酒约占这些成本的 75% 滥用和酗酒是指在 2 小时内饮用 4-5 杯饮料和/或达到血液酒精浓度 >80 mg/dL 时期（Sacks 等，2010）。在美国，酗酒现象日益增多，男性和女性都非常普遍 现役军人和退伍军人，并且是酒精使用障碍的强烈预测因子（AUD；Han 等 等，2017；斯塔尔等人，2009；高文等人，2017）。超过40%的美国退伍军人有一生 酒精使用障碍史（Fuerlein et al., 2016）。因此，酒精对健康、社会和社会造成巨大负担。 经济问题，特别是退伍军人事务部内部的问题。 个人对第一次饮酒经历的反应与他们患酒精中毒的风险有关。 AUD，包括成年早期频繁酗酒（King 等人，2011 年；McCarty 等人，2004 年）。识别大脑 这种危险饮酒模式背后的电路是了解脆弱性的重要第一步 澳元的因素。我们最近的研究确定了伏隔核 (NAc) 核心在暴饮暴食中的关键作用 使用 DID（黑暗中饮酒；模拟小鼠暴饮暴食的范例）饮酒 化学遗传学[即DREADD（仅由设计药物激活的设计受体）]。基于电路的 动物研究与患有 AUD 的人类密切相关。具有 AUD 的治疗抵抗性男性 诊断显示，通过 NAc 深部脑刺激，饮酒、渴望和复发率降低（Pierce 和瓦索勒，2013）。 NAc 核心收到来自多个地区的预测，对许多地区都很重要 行为。为了进一步了解酗酒的回路，我们将识别 NAc 的神经投射 在高饮酒 C57BL/6J 小鼠的 DID 过程中参与的核心。我们将注射逆行标记， rAAVretro-GFP，进入 NAc 核心，将小鼠暴露于乙醇、糖精或水 DID 程序中，然后 量化 GFP 阳性神经元中的 c-Fos 免疫反应性。拟议的工作将是第一个确定 NAc 核心电路在男性和女性的酗酒过程中都会起作用。我们假设 在乙醇 DID 过程中，多个 NAc 投射大脑区域将参与其中，包括中枢和基底外侧 杏仁核、前边缘皮质、岛叶、腹侧被盖区和腹侧海马。 我们的初步数据支持测试来自中心核的待研究投影的作用 酗酒时杏仁核 (CeA) 与 NAc 核心的关系。这两个地区都因酗酒而闻名 饮酒，但人们对这种投射在饮酒中的性质和作用知之甚少。我们将操纵 CeA NAc 的输入（通过化学遗传学和双病毒投影靶向）以确定该投影是否 调节暴饮暴食。 CeA神经元含有许多神经肽和调节剂；因此，我们将 使用免疫组织化学鉴定这些投影的性质。根据文献和结果 我们的初步研究，我们重点关注肽类神经递质，促肾上腺皮质激素释放因子（CRF）。我们将 在伏隔内注射促肾上腺皮质激素释放因子 (CRF) 以确定其是否会改变暴食样症状 喝。然后我们将测试CRF受体的拮抗作用是否可以阻断刺激CeA-的作用 > DID 上的 NAc 核心预测（通过化学遗传学）。我们假设 CeA 的化学遗传学刺激 >NAc 预测将减少饮酒，NAc 内核心 CRF 将减少暴饮暴食，NAc 内 CRF 将减少饮酒 拮抗剂将阻止通过 CeA->NAc 核心预测的化学遗传学刺激观察到的饮酒减少。 该提案将使用基于行为、药理学和电路的方法来更好地 了解酗酒的神经基础。我们将确定 NAc 核心的神经元投射很重要 用于调节高饮酒 C57BL/6J 小鼠品系的暴饮暴食。我们假设 CeA 对 NAc 核心的预测对于调节酗酒很重要，并且与酗酒有关。