Neural Substrates of Binge Drinking

暴饮暴食的神经基质

• 批准号: 10343789
• 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/10343789
• 关键词: Acute; Adult; Affective; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Animal Model; Animals; Behavior; Blood; Blood alcohol level measurement; Brain; Brain region; Cell Nucleus; Cessation of life; Chronic; Consumption; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Dangerousness; Data; Deep Brain Stimulation; Diagnosis; Economic Burden; Economics; Ethanol; Ethanol dependence; Exhibits; FOS gene; Female; Genetic Models; Health; Hippocampus (Brain); 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; base; behavioral pharmacology; binge drinking; brain circuitry; cost; craving; designer receptors exclusively activated by designer drugs; directed attention; drinking; drinking water; experience; high risk; immunoreactivity; male; military veteran; preference; preventable death; relating to nervous system; 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.

滥用酒精每年造成约88,000人死亡，每年的成本约为2500亿美元 美国。美国国家酒精研究所定义了暴饮暴食，约占这些费用的75％ 滥用和酒精中毒作为食用4-5种饮料和/或在2小时内达到80 mg/dl的血液酒精水平> 80 mg/dl 时期（Sacks等，2010）。在美国，暴饮暴食在增加，男性和女性都非常普遍 活跃的军事值班人员和退伍军人，是酒精使用障碍的有力预测指标（aud; Han et eT Al。，2017年； Stahre等，2009； Gowin等，2017）。超过40％的美国退伍军人一生 酒精使用障碍史（Fuerlein等，2016）。因此，酒精对健康，社会和 经济问题，尤其是在退伍军人事务部内。 个人如何应对他们对酒精的初次经历与他们发展的风险有关 AUD，包括频繁的早期成人狂欢饮酒（King等，2011； McCarty等，2004）。识别大脑 构成这种危险饮酒模式的电路是学习脆弱性的重要第一步 AUD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喝酒（在黑暗中喝酒；一种模型在小鼠中狂饮的范式）和 化学遗传学[即Dreadds（设计器受体专门由设计师药物激活）]。基于电路 在动物中的研究与具有AUD的人非常相关。耐药的男性与aud 诊断表现出降低的饮酒，渴望和复发率，并通过对NAC的深脑刺激（Pierce） 和Vassoler，2013年）。 NAC核心收到来自多个地区的预测，对许多地区很重要 行为。为了进一步了解暴饮暴食的电路，我们将确定对NAC的神经预测 在高饮用的C57BL/6J小鼠中参与的核心。我们将注入逆行标记， Raavretro-GFP进入NAC核心，将小鼠暴露于乙醇，糖精或水中，然后进行手术，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 在狂饮中使用的NAC核心电路都使用男性和女性。我们假设这一点 在乙醇中，将参与几个NAC投射大脑区域，包括中央和基底外侧 杏仁核，前皮层和岛座，腹侧侧距区域和腹侧海马。 我们的初步数据支持测试从中央核的研究的作用 杏仁核（CEA）在暴饮暴食中添加到NAC核心。众所周知，这两个区域都参与酒精 喝酒，但对这种投影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重病毒投影靶向）来确定该投影是否是否 调节暴饮暴食。 CEA神经元包含许多神经肽和调节剂；因此，我们会的 使用免疫组织化学确定这些预测的性质。根据文献和结果 我们的初步研究，我们专注于肽神经递质，皮质激素释放因子（CRF）。我们将 给管理皮质激素释放因子（CRF）内部内部释放因子，以确定它是否改变了暴饮暴食 喝。然后，我们将测试CRF受体的拮抗作用是否可以阻止刺激CEA-的影响 > NAC核心投影（通过化学遗传学）确实如此。我们假设CEA-化学发生刺激 > NAC预测将减少饮酒，NAC内核CRF会减少狂欢般的饮酒，而NAC内部CRF 拮抗剂将通过CEA-> NAC核心投射的化学遗传刺激来阻止饮酒的减少。 该建议将采用基于行为，药理和电路的方法来更好 了解暴饮暴食的神经底物。我们将确定对NAC核心重要的神经元预测 用于调节高饮用的C57BL/6J小鼠菌株中的暴饮暴食。我们假设CEA NAC核心的预测对于调节暴饮暴食至关重要，并且通过暴饮暴食而参与。