CRF NEURAL CIRCUITS OF BINGE DRINKING

CRF 酗酒的神经回路

• 批准号: 9913430
• 负责人: DENNIS R. SPARTA
• 金额: $ 34.76万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-12 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913430
• 关键词: Accounting; Acute; Address; Alcohol consumption; Alcoholism; Amygdaloid structure; Area; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Corticotropin-Releasing Hormone; Coupled; Data; Detection; Disease; Dopamine; Electrophysiology (science); Etiology; Gene Targeting; Health; Heavy Drinking; Humpback Dolphins; Individual; Light; Maintenance; Mediating; Mus; Nature; Neuronal Plasticity; Neurons; Neuropeptides; Nucleus Accumbens; Output; Pathway interactions; Peripheral; Pharmacogenetics; Pharmacological Treatment; Pharmacology; Physiological; Public Health; Recording of previous events; Research; Rewards; Role; Signal Transduction; Site; Slice; Societies; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Synapses; Testing; Treatment Efficacy; United States; Ventral Tegmental Area; alcohol behavior; alcohol exposure; alcohol misuse; alcoholism therapy; binge drinking; biological adaptation to stress; brain reward regions; cost; dopaminergic neuron; experimental study; gamma-Aminobutyric Acid; in vivo; neural circuit; neurobiological mechanism; novel; optogenetics; patch clamp; preventable death; recruit; therapeutic target

Project Summary/Abstract Binge alcohol consumption is a severe public health problem and is the third leading cause of preventable death in the USA (Hingson et al., 2005; 2007). Defining the neural circuitry that modulates excessive binge alcohol intake is essential for developing effective therapeutics to treat this disease. Corticotropin releasing factor (CRF) is an important neuropeptide, in regards to binge alcohol consumption as peripheral and site- specific administrations of CRF antagonists can reduce excessive ethanol intake (Sparta et al., 2008; 2009; 2013). While CRF is found throughout the brain, the extended amygdala consisting of the central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST) CRF projections the to ventral tegmental area (VTA) remain a particularly interesting candidate targets for CRF’s modulation of binge drinking, since these structures provide direct connections from stress to reward brain regions I hypothesize that binge alcohol exposure leads to an increase of extended amygdalar CRF neuronal drive onto VTA GABA neurons. Specifically, I hypothesize that the CRF CeA to VTA projection is recruited during repeated binge drinking sessions, whereas the CRF BNST to VTA pathway is involved with the initiation of binge drinking. To test these hypotheses, I will utilize optogenetics, in vivo electrophysiology, ex vivo patch clamp, and behavior. Taken together, this proposal will provide a thorough characterization of both the CeA-and BNST-VTA CRF neural circuits after binge alcohol intake and may identify possible pharmacological targets for the treatment of alcoholism.

项目总结/摘要 酗酒是一个严重的公共卫生问题，也是可预防的第三大原因。 在美国死亡（Hingson等人，2005; 2007）。定义调节过度狂欢的神经回路 酒精摄入对于开发治疗这种疾病的有效疗法是必不可少的。皮质激素释放 因子（CRF）是一种重要的神经肽，在狂饮方面作为外周和部位， CRF拮抗剂的特定给药可以减少过量的乙醇摄入（斯巴达等人，2008年; 2009年; 2013年）。虽然CRF在整个大脑中被发现，但由中央核组成的扩展杏仁核 杏仁核（CeA）和终纹床核（BNST）的CRF投射到腹侧被盖 VTA仍然是CRF调节酗酒的一个特别有趣的候选靶点，因为 这些结构提供了从压力到奖励的直接联系，我假设， 酒精暴露导致向腹侧被盖区GABA神经元的扩展杏仁核CRF神经元驱动增加。 具体地说，我假设CRF的CeA到VTA的投射是在反复酗酒期间招募的 而CRF BNST至VTA通路与酗酒的开始有关。测试 这些假设，我将利用光遗传学，在体内电生理学，离体膜片钳，和行为。 总之，本提案将提供CeA和BNST-VTA CRF的全面表征 神经回路后，酗酒摄入，并可能确定可能的药理学目标，用于治疗 酒精中毒