The role of GIRK3 in ethanol withdrawal-induced changes in learning and memory

GIRK3 在乙醇戒断引起的学习和记忆变化中的作用

• 批准号: 8454171
• 负责人: Megan E. Tipps
• 金额: $ 4.92万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454171
• 关键词: Abstinence; Acute; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcohols; Animals; Area; Attenuated; Behavior; Behavioral; Brain region; Chronic; Code; Complex; Conditioned Stimulus; Control Animal; Convulsions; Cues; Data; Development; Dorsal; Environmental Risk Factor; Ethanol; Ethanol dependence; Exhibits; Family; Freezing; Fright; G protein-coupled inwardly-rectifying potassium channel; GIRK3 subunit, G protein-coupled inwardly-rectifying potassium channel; Genes; Genetic; Genetic Models; Genotype; Goals; Heterozygote; Hippocampus (Brain); Homosynaptic Depression; Individual; Knock-out; Knockout Mice; Lead; Learning; Link; Long-Term Potentiation; Measures; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Mus; Neural Pathways; Play; Process; RNA Interference; Relapse; Reporting; Research; Role; Severities; Structure; System; Testing; Training; Translating; Wild Type Mouse; Withdrawal; Work; addiction; base; conditioned fear; knock-down; knockout animal; memory process; mouse model; novel; problem drinker; relating to nervous system; research study; response; trait

DESCRIPTION (provided by applicant): Alcohol addiction is one of the most common addictive disorders with a high rate of relapse among recovering alcoholics. The development of addiction and subsequent relapse following abstinence have been linked to several of the processes and neural structures that contribute to learning and memory, and multiple lines of research suggest that alcohol addiction may be a form of maladaptive learning. Ethanol withdrawal severity is an indicator of addiction development and a major factor in relapse. Our lab recently identified Kcnj9 as a quantitative trait gene (QTG) for ethanol withdrawal in mice. Kcnj9 codes for the GIRK3/Kir3.3 subunit of the G- protein coupled inwardly rectifying potassium (GIRK) channel family, and GIRK3 knockout (KO) and heterozygote (HET) mice show less severe ethanol withdrawal. In addition, GIRK channels modulate long-term potentiation, a cellular mechanism of learning and memory. The goal of the current proposal is to assess the role of GIRK3 in fear-conditioned learning and memory and determine if changes in GIRK3 expression alter the withdrawal-induced changes in fear conditioning responses. The long-term goals of this project also include investigating the role of GIRK3 in individual learning related brain regions. In Aim 1, GIRK3 KO, HET, and wildtype (WT) littermates will be trained using two fear conditioning paradigms (delay fear conditioning and trace fear conditioning) in acute ethanol withdrawn and control animals. These two forms of conditioned learning are thought to utilize distinct but overlapping neural substrates, allowing us to assess the effect of reduced GIRK3 expression in different learning-related brain regions. After training, animals will be assessed for freezing in response to the training context and the conditioned stimulus. In Aim 2, animals will be trained following chronic ethanol withdrawal using these two fear conditioning types, allowing us to compare the effects of GIRK3 expression on learning and memory across multiple forms of ethanol withdrawal. These aims will not only determine the role of GIRK3-containing channels in fear conditioned learning and memory, but also characterize the effect of alcohol withdrawal on learning and memory and the extent of overlap between the learning effects and the withdrawal-reducing effects of GIRK3. The third aim will use the results from Aims 1 and 2 to identify specific brain regions that contribute to the altered withdrawal severity and the learning/memory changes observed in these GIRK3 genotypes. We will use RNAi to knock-down GIRK3 expression in individual brain regions of WT mice and assess the ability of the knock-down to attenuate ethanol withdrawal and related changes in learning and memory. Overall, this work will contribute to our understanding of how ethanol alters learning and memory systems, a key aspect of addiction development and relapse. PUBLIC HEALTH RELEVANCE: The development of alcohol addiction and the high rate of relapse in recovering alcoholics have been linked to alcohol-induced changes in learning and memory systems. While both learning/memory and alcohol addiction are complex processes that result from multiple genetic and environmental factors, several groups have reported overlapping contributing chromosomal regions for these two groups of behaviors. This project uses a novel genetic model of alcohol withdrawal to investigate withdrawal-induced changes in fear-based learning and memory.

描述（由申请人提供）：酒精成瘾是最常见的成瘾性疾病之一，在恢复酗酒者中的复发率很高。戒酒后成瘾和随后的复发的发展与有助于学习和记忆的几个过程和神经结构有关，多种研究表明，酒精成瘾可能是适应不良的学习形式。乙醇戒断严重程度是成瘾发展和复发的主要因素的指标。我们的实验室最近将KCNJ9鉴定为小鼠乙醇提取的定量性状基因（QTG）。 KCNJ9编码GIRK3/KIR3.3 G蛋白的亚基，与内部整流（Girk）通道家族耦合，GIRK3敲除（KO）和杂合子（HET）小鼠显示出较少的严重乙醇。此外，Girk信道调节长期增强，一种学习和记忆的细胞机制。当前建议的目的是评估GIRK3在恐惧条件的学习和记忆中的作用，并确定GIRK3表达的变化是否改变了戒断诱导的恐惧条件反应的变化。该项目的长期目标还包括研究GIRK3在个别学习中的作用 相关的大脑区域。在AIM 1中，将使用两个恐惧调节范式（延迟恐惧调节和跟踪恐惧条件）在急性拔出和对照动物中使用两个恐惧调节范式（延迟恐惧调节和跟踪恐惧调节）对GIRK3 KO，HET和WILDTYPE（WT）同窝仔进行训练。人们认为这两种形式的条件学习使用了不同但重叠的神经底物，从而使我们能够评估不同学习相关的大脑区域中GIRK3表达降低的效果。训练后，将根据训练环境和条件刺激来评估动物的冻结。在AIM 2中，将使用这两种恐惧调节类型在慢性乙醇撤离后进行训练，从而使我们能够比较GIRK3表达对乙醇抽出多种形式的学习和记忆的影响。这些目标不仅将确定含GIRK3渠道在恐惧条件学习和记忆中的作用，而且还表征了戒酒对学习和记忆的影响以及学习效果与GIRK3的撤回效果之间的重叠程度。第三个目标将利用目标1和2的结果来确定有助于改变戒断严重程度以及在这些GIRK3基因型中观察到的学习/记忆变化的特定大脑区域。我们将使用RNAi在WT小鼠的单个大脑区域中敲除GIRK3的表达，并评估敲低减轻乙醇提取的能力以及学习和记忆中相关的变化。总体而言，这项工作将有助于我们对乙醇如何改变学习和记忆系统的理解，这是成瘾发展和复发的关键方面。 公共卫生相关性：酒精成瘾的发展和恢复酗酒者的高复发率与酒精引起的学习和记忆系统的变化有关。尽管学习/记忆和酒精成瘾都是由多个遗传和环境因素引起的复杂过程，但几个组报告了这两组行为的重叠造成染色体区域。该项目使用一种新型的酒精提取遗传模型来研究戒断诱导的基于恐惧的学习和记忆的变化。