Identification of candidate genes for nicotine withdrawal in C57BL/6J × DBA/2J recombinant inbred mice

IF 2.4 4区 心理学 Q2 BEHAVIORAL SCIENCES
Maren L. Smith, Kristin M. Mignogna, Jo L. Rokita, Lorna MacLeod, M. Imad Damaj, Michael F. Miles
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引用次数: 0

Abstract

Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute to dependence. The molecular mechanisms underlying nicotine withdrawal behaviors, however, are poorly understood. Using recombinant inbred mice, chronic nicotine was delivered by minipump and withdrawal induced using mecamylamine. Somatic signs of withdrawal, and anxiety-like behavior using elevated plus maze, were then assessed. Interval mapping was used to identify associations between genetic variation and withdrawal behaviors, and with basal gene expression. Differential gene expression following nicotine exposure and withdrawal was also assessed in progenitor mice using microarrays. Quantitative trait loci mapping identified chromosome intervals with significant genetic associations to somatic signs of withdrawal or withdrawal-induced anxiety-like behavior. Using bioinformatics, and association with basal gene expression in nucleus accumbens, we implicated Rb1, Bnip3l, Pnma2, Itm2b, and Kif13b as candidate genes for somatic signs of withdrawal, and Galr1, which showed trans-regulation from a region of chromosome 14 that was associated with somatic signs of withdrawal. Candidate genes within the chromosome 9 region associated with anxiety-like withdrawal behavior included Dixdc1, Ncam1, and Sorl1. Bioinformatics identified six genes that were also significantly associated with nicotine or alcohol traits in recent human genome-wide association studies. Withdrawal-associated somatic signs and anxiety-like behavior had strong non-overlapping genetic associations, respectively, with regions of chromosome 14 and chromosome 9. Genetic, behavioral and gene expression correlations, and bioinformatics analysis identified several candidate genes that may represent novel molecular targets for modulating nicotine withdrawal symptoms.

Abstract Image

C57BL/6J × DBA/2J重组近交系小鼠尼古丁戒断候选基因的鉴定
尼古丁是烟草中的补强成分。在长期接触尼古丁后,突然停止使用尼古丁会产生负面的戒断症状,从而导致依赖。然而,尼古丁戒断行为背后的分子机制尚不清楚。以重组自交系小鼠为实验对象,采用小泵给药和甲胺诱导戒断。然后对戒断症状和焦虑样行为进行评估。区间定位用于确定遗传变异与戒断行为之间的关系,以及与基础基因表达之间的关系。使用微阵列技术还评估了尼古丁暴露和戒断后祖小鼠的差异基因表达。定量性状位点定位鉴定出染色体间隔与戒断或戒断诱导的焦虑样行为的躯体体征有显著的遗传关联。利用生物信息学和与伏隔核基础基因表达的关联,我们认为Rb1、Bnip3l、Pnma2、Itm2b和Kif13b是戒断体信号的候选基因,Galr1是14号染色体上一个与戒断体信号相关的区域的反式调控基因。9号染色体区域内与焦虑样戒断行为相关的候选基因包括Dixdc1、Ncam1和Sorl1。在最近的人类全基因组关联研究中,生物信息学鉴定出6个与尼古丁或酒精性状显著相关的基因。戒断相关的躯体体征和焦虑样行为分别与14号染色体和9号染色体区域具有较强的非重叠遗传关联。遗传、行为和基因表达相关性以及生物信息学分析确定了几个候选基因,这些基因可能代表了调节尼古丁戒断症状的新分子靶点。
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来源期刊
Genes Brain and Behavior
Genes Brain and Behavior 医学-行为科学
CiteScore
6.80
自引率
4.00%
发文量
62
审稿时长
4-8 weeks
期刊介绍: Genes, Brain and Behavior was launched in 2002 with the aim of publishing top quality research in behavioral and neural genetics in their broadest sense. The emphasis is on the analysis of the behavioral and neural phenotypes under consideration, the unifying theme being the genetic approach as a tool to increase our understanding of these phenotypes. Genes Brain and Behavior is pleased to offer the following features: 8 issues per year online submissions with first editorial decisions within 3-4 weeks and fast publication at Wiley-Blackwells High visibility through its coverage by PubMed/Medline, Current Contents and other major abstracting and indexing services Inclusion in the Wiley-Blackwell consortial license, extending readership to thousands of international libraries and institutions A large and varied editorial board comprising of international specialists.
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