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

基本信息

批准号：
9309618
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
项目类别：
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/9309618
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 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 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

项目摘要

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.

抽象的这是申请导师研究科学家发展奖（K01）以支持职业生涯 Jennifer Rinker 博士的发展和强化培训，以促进她向独立学者的过渡酒精研究领域的研究员。候选人是从早期研究者过渡到博士后研究员至助理教授。 Rinker 博士在体内药理学和化学遗传学操作来研究与酒精使用障碍有关的神经回路，但效果有限具有切片电生理学和先进分子技术来检查可塑性相关事件的经验。已经制定了密集而全面的培训、指导和研究计划，将提供评估 Kv7 通道参与酒精依赖引起的变化的先进技术培训功能可塑性。 Rinker 博士的培训将得到机构对她职业生涯的坚定承诺的支持酒精研究领域的开发和强大的领导者指导团队，每个人都提供战略为该提案的制定提供指导，并在她的职业发展过程中提供指导。拟议的研究计划是 Rinker 博士最近在导师的实验室中进行的研究的自然延伸。实验室，但其特点是对离散皮质纹状体回路中的 Kv7 通道进行调节的检查依赖引起的乙醇消费的影响。内侧前额叶皮层 (mPFC) 是一个关键的涉及对奖励驱动行为和对核心的投射进行抑制控制的结构伏隔核 (NAc)，中脑边缘奖赏通路的重要组成部分。乙醇依赖性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。具体来说，乙醇戒断会导致 NAc 投射的 mPFC 过度兴奋神经元，其潜在机制仍不清楚。 Kv7 通道产生关键的 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回路仍未被探索。因此，该提案的总体假设是皮质纹状体回路 Kv7 通道中依赖性诱导的神经适应（即 mPFC 到 NAc）导致乙醇消费的依赖不断升级且不受控制。本提案将对此进行测试使用多方面方法的假设，结合蛋白质表达和分析的亚细胞分析分别使用双元标记和切片电生理学来研究结构和功能可塑性。我们的成果证明 Kv7 通道参与重度饮酒和依赖性小鼠表明，继续这些研究将显着增进我们对乙醇细胞机制的理解依赖性。这个机会将为候选人提供全面的培训和坚实的基础在酒精神经科学领域建立一个成功且独立的研究项目。