Dependence-Induced Excessive Ethanol Consumption: Role of Corticostriatal Kv7 Channels

依赖性引起的过量乙醇消耗：皮质纹状体 Kv7 通道的作用

• 批准号: 9902262
• 负责人: Jennifer Anne Rinker
• 金额: $ 18.61万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9902262
• 关键词: Acute; Adult; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Anticonvulsants; Bioinformatics; Cessation of life; Chronic; Coupled; Data; Dendritic Spines; Dependence; Development; Diagnosis; Economic Burden; Electrophysiology (science); Ethanol; Ethanol dependence; Event; FDA approved; Foundations; Genes; Glutamates; Goals; Health; Heavy Drinking; Label; Laboratories; Maintenance; Medial; Mediating; Membrane Potentials; Mentored Research Scientist Development Award; Mentors; Messenger RNA; Modeling; Molecular; Mus; Neurobiology; Neuronal Plasticity; Neurons; Neurosciences; Nucleus Accumbens; Pathway interactions; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiology; Post-Translational Protein Processing; Postdoctoral Fellow; Potassium; Prefrontal Cortex; Protein Analysis; Public Health; Quantitative Trait Loci; Recurrent disease; Regulation; Research; Research Personnel; Rewards; Rodent; Role; Series; Signal Transduction; Site; Slice; Social Impacts; Solid; Structure; Surface; Synaptic plasticity; Techniques; Testing; Time; Training; Transgenic Mice; Ventral Tegmental Area; addiction; alcohol exposure; alcohol research; alcohol response; alcohol seeking behavior; alcohol use disorder; career; career development; channel blockers; chronic alcohol ingestion; density; design; designer receptors exclusively activated by designer drugs; dopaminergic neuron; drinking; economic impact; experience; experimental study; functional plasticity; hippocampal pyramidal neuron; in vivo; motivated behavior; neural circuit; neuroadaptation; neuromechanism; neuronal excitability; novel; overexpression; professor; programs; protein expression; protein transport; restoration; skills; synaptic function; trafficking; voltage

ABSTRACT This is an application for a Mentored Research Scientist Development Award (K01) to support the career development and intensive training of Dr. Jennifer Rinker to facilitate her transition to an independent academic investigator in the alcohol research field. The candidate is an early-stage investigator transitioning from Postdoctoral Fellow to Assistant Professor. Dr. Rinker has extensive experience with in vivo pharmacology and chemogenetic manipulations to study the neural circuitry involved in alcohol use disorder, but has limited experience with slice electrophysiology and advanced molecular techniques to examine plasticity-related events. An intense and comprehensive training, mentoring and research plan has been developed that will provide training in advanced techniques to assess Kv7 channel involvement in alcohol dependence-induced changes in functional plasticity. Dr. Rinker's training will be supported by a firm institutional commitment to her career development and a strong mentoring team of leaders in the alcohol research field, each providing strategic guidance in both the development of this proposal and mentoring as her career progresses. The proposed research plan is a natural extension of the recent studies Dr. Rinker has been conducting in the mentor's laboratory, but is distinguished by its examination of Kv7 channels in discrete corticostriatal circuits in modulating the effects of dependence-induced ethanol consumption. The medial prefrontal cortex (mPFC) is a critical structure involved in imposing inhibitory control over reward-motivated behaviors and projects to the nucleus accumbens (NAc), an essential component of the mesolimbic reward pathway. Ethanol dependence is associated with elevated and uncontrolled drinking and is known to alter the plasticity and physiology of mPFC pyramidal neurons. Specifically, ethanol withdrawal results in the hyperexcitability of NAc-projecting mPFC neurons, the underlying mechanism of which remains unknown. Kv7 channels generate the M-current that critical regulates neuronal excitability by maintaining the membrane potential and dampening neuronal firing. These channels have been implicated in regulating ethanol consumption in the NAc, but their role in the corticostriatal circuits in dependent rodents remains unexplored. Thus, the overarching hypothesis of this proposal is that dependence-induced neuroadaptations in Kv7 channels in the corticostriatal circuitry (i.e., mPFC to NAc) drive the escalated and uncontrolled ethanol consumption in dependence. This proposal will test this hypothesis using a multifaceted approach incorporating subcellular analysis of protein expression and analysis of structural and functional plasticity using diolistic labeling and slice electrophysiology, respectively. Our results demonstrating involvement of Kv7 channels in heavy drinking and dependent mice suggests that continuing these studies will significantly advance our understanding of the cellular mechanisms underlying ethanol dependence. This opportunity will provide the candidate with comprehensive training and a solid foundation on which to build a successful and independent research program in the alcohol neuroscience field.

摘要 这是一个指导研究科学家发展奖（K01）的应用程序，以支持职业生涯 Jennifer Rinker博士的发展和强化培训，以促进她过渡到独立的学术 酒精研究领域的专家。候选人是一名早期研究者， 博士后研究员到助理教授。Rinker博士在体内药理学方面具有丰富的经验， 化学遗传学操作来研究酒精使用障碍中涉及的神经回路，但有限 具有切片电生理学和先进分子技术检查可塑性相关事件的经验。 已经制定了一项密集和全面的培训、指导和研究计划， 培训先进的技术，以评估Kv7通道参与酒精依赖引起的变化， 功能可塑性Rinker博士的培训将得到对她职业生涯的坚定机构承诺的支持 发展和强大的指导团队的领导者在酒精研究领域，每个提供战略 在此建议书的制定过程中提供指导，并在她的职业发展过程中提供指导。拟议 研究计划是Rinker博士最近在导师的指导下进行的研究的自然延伸 实验室，但其区别在于它的检查Kv7通道在离散皮质纹状体电路的调制 依赖性导致的乙醇消耗的影响。内侧前额叶皮层（mPFC）是一个关键的 参与对奖励动机行为和项目施加抑制控制的结构 中脑边缘奖赏通路的重要组成部分。乙醇依赖是 与过量和不受控制的饮酒有关，并且已知会改变mPFC的可塑性和生理学 锥体神经元具体地说，乙醇戒断导致投射NAC的mPFC过度兴奋 神经元，其潜在机制仍然未知。Kv7通道产生M电流， 通过维持膜电位和抑制神经元放电来调节神经元兴奋性。这些 通道与调节NAc中的乙醇消耗有关，但它们在皮质纹状体中的作用 依赖性啮齿类动物的神经回路还未被探索。因此，这一提议的首要假设是， 皮质纹状体回路中Kv7通道的依赖性诱导的神经适应（即，mPFC至NAc） 推动乙醇消费的升级和失控。这项提案将检验这一点 假设使用多方面的方法，包括蛋白质表达和分析的亚细胞分析 的结构和功能的可塑性，分别使用diolistic标签和切片电生理学。我们的结果 在大量饮酒和依赖性小鼠中显示Kv7通道的参与表明， 这些研究将极大地促进我们对乙醇的细胞机制的理解 依赖这个机会将为候选人提供全面的培训和坚实的基础， 该项目旨在建立一个成功的、独立的酒精神经科学研究项目。