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

描述（申请人提供）：酒精成瘾是最常见的成瘾障碍之一，在恢复期的酗酒者中复发率很高。成瘾的发展和戒酒后的复吸与促进学习和记忆的几个过程和神经结构有关，多项研究表明，酒精成瘾可能是一种适应不良的学习形式。乙醇戒断严重程度是成瘾发展的一个指标，也是复发的主要因素。我们的实验室最近发现Kcnj9是小鼠乙醇戒断的数量性状基因（QTG）。Kcnj9编码G-蛋白偶联内纠偏钾（GIRK）通道家族的GIRK3/Kir3.3亚基，GIRK3敲除（KO）和杂合子（HET）小鼠表现出较轻的乙醇戒断。此外，GIRK通道调节长时程增强，这是学习和记忆的细胞机制。本研究的目的是评估GIRK3在恐惧条件学习和记忆中的作用，并确定GIRK3表达的变化是否会改变退缩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在个体学习中的作用

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be trained using two fear conditioning paradigms (delay fear conditioning and trace fear conditioning) in acute ethanol withdrawn and control animals.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.