Alcohol Drinking Induced Alterations in Dynorphin Signaling in the Extended Amygdala

饮酒引起扩展杏仁核强啡肽信号的改变

• 批准号: 9396807
• 负责人: Daniel W Bloodgood
• 金额: $ 3.25万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396807
• 关键词: Accidents; Adult; Agonist; Alcohol consumption; Alcohols; Amygdaloid structure; Animals; Brain; Brain region; Cell Nucleus; Consumption; Dangerousness; Darkness; Data; Disinhibition; Dynorphins; Economics; Electrophysiology (science); Equilibrium; Ethanol; Future; Goals; Health Care Costs; Heavy Drinking; Individual; Knock-out; Knowledge; Ligands; Light; LoxP-flanked allele; Mediating; Modeling; Mus; Neurons; Outcome; Output; Pathway interactions; Pattern; Peptides; Play; Presynaptic Terminals; Procedures; Productivity; Property; Public Health; Receptor Signaling; Regulation; Reporting; Rodent; Role; Signal Transduction; Site; Slice; Stress; Structure of terminal stria nuclei of preoptic region; Synaptic Transmission; Techniques; Testing; Time; Tracer; United States; United States Substance Abuse and Mental Health Services Administration; Viral; Virus; Work; alcohol misuse; base; binge drinking; biological adaptation to stress; cost; drinking; drinking behavior; drug of abuse; experimental study; gamma-Aminobutyric Acid; in vivo; innovation; kappa opioid receptors; knock-down; negative affect; neural circuit; novel; optogenetics; prevent; small hairpin RNA; transmission process; virus genetics

PROJECT SUMMARY/ABSTRACT Binge drinking is a form of excessive alcohol consumption that is responsible for a number of negative economic and public health outcomes. Repeated episodes of binge drinking result in adaptation in the brain's natural stress/anti-stress circuitry that can promote future alcohol use. The extended amygdala, principally comprised of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST), is a key regulator of stress response is thought to mediate the negative reinforcing properties of drugs of abuse. Abundant within these brain regions is the kappa opioid receptor (KOR) and its endogenous ligand dynorphin (Dyn), which together have been shown to promote alcohol consumption and negative affective states. Binge-like drinking can be modeled in rodents using Drinking in the Dark (DID) and Intermittent Access (IA) to examine the specific neural circuits involved. Our preliminary results demonstrate that CeA neurons projecting to the BNST show increased excitability following repeated cycles of binge drinking and that chemogenetic inhibition of CeA dynorphin neurons can decrease binge drinking. The goal of the current proposal is thus to mechanistically dissect the effects of repeated binge drinking on dynorphin circuit function and assess how its perturbation may impact future alcohol use. The first set of experiments will use slice electrophysiology to examine how dynorphin transmission in the CeA is altered following three cycles of drinking in the IA paradigm. Next we will use optogenetics and slice electrophysiology to examine alcohol-induced alterations in evoked transmission onto BNST neurons, a major output of CeA dynorphin neurons and a nucleus that has recently been shown to be important for regulating binge alcohol intake. Finally, we will use a novel viral genetic knockdown approach to test the requirement of dynorphin signaling in vivo to mediate excessive drinking behavior. Through this innovative set of experiments, we will obtain a circuit-based model of how binge drinking alters dynorphin transmission in the extended amygdala. This knowledge will be critical for understanding how binge drinking may predispose individuals for future alcohol misuse.

项目总结/摘要 酗酒是一种过度饮酒的形式，它会导致许多负面的后果。 经济和公共卫生成果。反复的酗酒导致大脑的适应性变化， 天然的压力/抗压力回路，可以促进未来的酒精使用。延伸的杏仁核主要是 包括中央杏仁核（CeA）和终纹床核（BNST），是一个关键的调节因子， 人们认为，压力反应介导了滥用药物的负面强化特性。丰富的内部 这些脑区是κ阿片受体（KOR）及其内源性配体强啡肽（Dyn）， 一起被证明会促进酒精消费和消极的情感状态。狂饮 可以在啮齿动物中使用在黑暗中饮酒（DID）和间歇性访问（IA）进行建模，以检查 涉及特定的神经回路我们的初步结果表明，CeA神经元投射到BNST 显示在反复循环暴饮和CeA化学发生抑制后兴奋性增加 强啡肽神经元可以减少酗酒。因此，本提案的目标是机械地 剖析反复酗酒对强啡肽回路功能的影响，并评估其干扰可能如何 影响未来的酒精使用。第一组实验将使用切片电生理学来研究如何 在IA范例中，CeA中的强啡肽传递在三个饮酒周期后改变。接下来我们将 使用光遗传学和切片电生理学检查酒精诱导的诱发传递的改变 到BNST神经元，CeA强啡肽神经元的主要输出和最近已被证明， 对控制酗酒很重要最后，我们将使用一种新的病毒基因敲除方法， 以测试体内强啡肽信号传导介导过量饮酒行为的需要。通过这个 通过一系列创新的实验，我们将获得一个基于电路的模型，来研究酗酒如何改变强啡肽 在杏仁核中的传播。这些知识对于理解酗酒是如何 可能会使个体倾向于未来的酒精滥用。